APRN20 • Advanced Practice Nurses 2020 (Includes 23.5 Pharmacology Hours)

Table of Contents

APRN20 • Advanced Practice Nurses 2020 (Includes 23.5 Pharmacology Hours)

How to Receive Credit

NetCE 15 Hour Course #98782 • Healthcare-Associated Infections

98782 • Healthcare-Associated Infections

1. OVERVIEW

2. EPIDEMIOLOGY AND BACKGROUND

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

4. SOURCES OF HAIS

5. TYPES OF INFECTIONS

6. INFECTION CONTROL

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #35110 • Clinical Use of Neuromuscular Blocking Agents

35110 • Clinical Use of Neuromuscular Blocking Agents

1. INTRODUCTION

2. A BRIEF HISTORY OF NEUROMUSCULAR BLOCKERS

3. THE NEUROMUSCULAR JUNCTION

4. NEUROMUSCULAR BLOCKING AGENTS

5. MONITORING NEUROMUSCULAR BLOCKADE

6. REVERSAL OF NEUROMUSCULAR BLOCKADE

7. COMMON USES OF NEUROMUSCULAR BLOCKING AGENTS AND AREAS OF CONCERN FOR THE PRACTITIONER

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #95150 • Responsible and Effective Opioid Prescribing

95150 • Responsible and Effective Opioid Prescribing

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

8. MANAGEMENT OF OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #34160 • Iron: Impact on Health and Wellness

34160 • Iron: Impact on Health and Wellness

1. INTRODUCTION

2. FUNCTIONS OF IRON IN THE BODY

3. IRON HOMEOSTASIS

4. DIETARY IRON

5. IRON DEFICIENCY

6. TREATMENT OF IRON DEFICIENCY

7. IRON TOXICITY

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #94150 • The Coronavirus Disease (COVID-19) Pandemic

94150 • The Coronavirus Disease (COVID-19) Pandemic

1. BACKGROUND

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

4. COVID-19 IN CHILDREN

5. DIAGNOSTIC TESTING FOR SARS-COV-2

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

9. OTHER AVAILABLE RESOURCES

Works Cited

APRN20 • Advanced Practice Nurses 2020 (Includes 23.5 Pharmacology Hours)

Lori L. Alexander, MTPW, ELS, MWC

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired)

Mark Rose, BS, MA, LP

Evangeline Y. Samples, MS, RDN, LD, EdD

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

APRN20 • Advanced Practice Nurses 2020 (Includes 23.5 Pharmacology Hours)

Expiration Date: 04/30/2021

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

98782 • Healthcare-Associated Infections

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, ventilator-associated pneumonia, intravascular device-related infections, and Clostridium difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families.

Table of Contents

98782 • Healthcare-Associated Infections

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. OVERVIEW

2. EPIDEMIOLOGY AND BACKGROUND

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

DEVELOPMENT OF DRUG-RESISTANT MICRO-ORGANISMS

4. SOURCES OF HAIS

ENVIRONMENTAL FACTORS

PATIENT-RELATED FACTORS

IATROGENIC FACTORS

5. TYPES OF INFECTIONS

CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

SURGICAL SITE INFECTIONS

PNEUMONIA

INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

CLOSTRIDIUM DIFFICILE INFECTIONS

6. INFECTION CONTROL

SURVEILLANCE

HAND HYGIENE

INFLUENZA VACCINATION

PRECAUTIONS AND ISOLATION TECHNIQUES

PREVENTION OF ANTIBIOTIC-RESISTANT INFECTION

EDUCATION FOR HEALTHCARE PROFESSIONALS

EDUCATION FOR PATIENTS AND FAMILIES

PREPAREDNESS AND CONTROL OF OUTBREAKS

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98782 • Healthcare-Associated Infections

Education Category. Infection Control / Internal Medicine

Release Date. 02/01/2019

Expiration Date. 01/31/2022

Course Overview

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, ventilator-associated pneumonia, intravascular device-related infections, and Clostridium difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families.

Audience

This course is designed for healthcare professionals who would benefit from enhanced knowledge of healthcare-associated infections, including physicians, physician assistants, nurses, surgical technologists/assistants, and others involved with the care of patients in hospitals, long-term care facilities, or other healthcare institutions.

Course Objective

The purpose of this course is to provide physicians, nurses, pharmacists, microbiologists, and other healthcare professionals with an updated review of healthcare-associated infections, including evidence-based guidelines, strategies for prevention, and selection of appropriate treatment options.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the effect of healthcare-associated infections on morbidity, mortality, and cost of health care, including the importance of surveillance and prevention.

2. Discuss the pathogenesis of infection and modes of antimicrobial resistance.

3. Identify the environmental, patient-related, and iatrogenic risk factors for healthcare-associated infection.

4. Anticipate the impact of nonimplanted and implanted devices and procedures on healthcare-associated infection.

5. List the most common types of healthcare-associated infections.

6. Identify the most common pathogens and risk factors associated with catheter-related urinary tract infections, and outline the appropriate prevention measures, means of diagnosis, and treatment.

7. List the most common pathogens and causes of surgical site infections, and develop a strategy for prevention, diagnosis, and treatment.

8. Define the most common pathogens and risk factors associated with healthcare-associated pneumonia, and devise appropriate measures for prevention, diagnosis, and treatment.

9. Outline the most common pathogens and risk factors associated with intravascular device-related bloodstream infections, and discuss the appropriate prevention measures, diagnosis, and treatment.

10. Discuss the risk factors and prevention strategies for nosocomial Clostridium difficile infection.

11. Implement an effective hand hygiene program and strategies to increase compliance.

12. Outline interventions to control influenza transmission in the healthcare setting.

13. Describe the appropriate use of precautions and isolation techniques.

14. Define additional elements of an institution's infection control program, including the education of healthcare workers and patients with respect to healthcare-associated infections and the need to address challenges in educating non-English- proficient individuals.

15. Discuss the need for hospital preparedness for potential outbreaks.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. OVERVIEW

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, hospital-acquired pneumonia, intravascular device-related bloodstream infections, and Clostridium difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families. The course content is limited to infections in adults in acute care hospitals, although many measures for prevention are applicable in all settings for all patient populations.

2. EPIDEMIOLOGY AND BACKGROUND

HAI is one of the leading causes of death and increased morbidity for hospitalized patients. About 1 in 31 patients hospitalized has at least one healthcare-associated infection, a complication estimated to affect more than 1 million patients each year who reside in hospitals or other inpatient care facilities [1,2]. Historically, these infections have been known as nosocomial infections or hospital-acquired infections because they develop during hospitalization. As health care has increasingly expanded beyond hospitals into outpatient settings, nursing homes, long-term care facilities, and even home care settings, the more appropriate term has become healthcare-acquired or healthcare-associated infection. Many factors have contributed to an increase in HAIs. Advances in medical treatments have led to more patients with decreased immune function or chronic disease. The increase in the number of these patients, coupled with a shift in health care to the outpatient setting, yields a hospital population that is both more susceptible to infection and more vulnerable once infected. In addition, the increased use of invasive devices and procedures has contributed to higher rates of infection; more than 80% of HAIs are caused by four types of infection: catheter-related urinary tract infection, intravascular device-related bloodstream infection, surgical site infection, and ventilator-associated pneumonia [1]. These HAIs, along with infections caused by C. difficile and drug-resistant micro-organisms (especially methicillin-resistant Staphylococcus aureus [MRSA]), have garnered the most attention and research because of their impact in terms of morbidity, mortality, economic costs, and potential for prevention.

The prevalence of HAIs has come down somewhat in recent years, the result of an ongoing national collaborative effort, though much remains to be accomplished. Based on CDC-sponsored hospital surveillance data from 2018, about 3% to 4% of inpatients are infected and an estimated 633,000 hospitalized patients develop an HAI each year [3]. These infections lead to excess mortality and add billions of dollars in total direct medical costs annually [1,4]. The increased focus on healthcare quality over the past decade has highlighted the need to prevent HAIs as part of overall efforts to enhance patient safety as well as reduce costs, and national initiatives have been developed by healthcare quality agencies, advocacy organizations, healthcare regulating bodies, and policymakers (Table 1) [5,6,7,8,9,10,11,12,13].

Table 1: EXAMPLES OF NATIONAL INITIATIVES TO REDUCE FREQUENCY OF HEALTHCARE-ASSOCIATED INFECTIONS

Organization

Initiative(s)

Agency for Healthcare Research and Quality: Making Health Care Safer: A Critical Analysis of Patient Safety, 2001 (25 safety practices)

Prevent central line-related infections with use of maximum sterile barriers during insertion

Use antibiotic prophylaxis appropriately to prevent surgical site infections

Prevent ventilator-associated pneumonia with use of semirecumbent positioning

Institute of Medicine: Priority Areas for National Action: Transforming Health Care Quality, 2003 (20 priority areas)

Prevent nosocomial infections and implement surveillance programs

Institute for Healthcare Improvement: 5 Million Lives Campaign, 2006 (12 safety interventions)

Prevent central line-related infections

Prevent surgical site infections

Prevent ventilator-associated pneumonia

Reduce methicillin-resistant Staphylococcus aureus (MRSA) infection

Surgical Care Improvement Project (partnership of several organizations), 2006

Reduce postoperative complications, including surgical site infections

Centers for Medicaid and Medicare Services (effective October 1, 2008)

No reimbursement for hospital costs related to catheter-associated urinary tract infections, vascular catheter-associated infections, and mediastinitis after coronary artery bypass graft surgery

U.S. Department of Health and Human Services, 2009

National Action Plan to Prevent Healthcare-associated Infections (9 targets for elimination of HAIs)

U.S. Department of Health and Human Services, 2011

Partnership for Patients: Better Care, Lower Costs

National Quality Forum: Patient Safety, 2012 (3 broad goals)

Goal 2: Reduce the incidence of adverse healthcare-associated conditions

The Joint Commission, National Patient Safety Goals, 2013 (6 broad goals)

Prevent Infection: Follow the CDC guidelines for hand hygiene, and use proven guidelines to prevent bloodstream infections from central lines, to prevent infection after surgery, and to prevent catheter-related urinary tract infections

Source: [5,6,7,8,9,10,11,12,13]

In 2009, the U.S. Department of Health and Human Services developed the national Action Plan to Prevent Healthcare-Associated Infections, an initiative with a steering committee that represents a host of government health-related agencies. The plan includes 5-year goals for nine specific measures of improvement in HAI prevention [14]. Phase I of the plan called for reducing the rate of HAIs in acute care hospitals by the implementation of a collaborative 10-point strategy aimed at prevention [14]:

Frontline Clinicians

- Reduce inappropriate/unnecessary use of devices

- Improve adherence to hand hygiene and barrier precautions

- Implement and improve antimicrobial stewardship

Clinical Leaders, Executives, and Administrators

- Demonstrate leadership support at the highest levels of the facility

- Implement a culture of safety

Government, Advocates, Clinical Leaders, and Administrators

- Enhance financial incentives and regulatory oversight

- Implement system-based approaches/protocols/checklists

- Achieve better use of technology

- Improve public reporting of credible data

- Enhance traditional and nontraditional partnerships

Phase two of the HAI Action Plan focused on ambulatory surgical centers, renal dialysis facilities, and influenza vaccination of healthcare personnel. Phase three is focused on long-term care facilities, and phase four focused on antibiotic stewardship and prevention of antibiotic resistance [14].

Evidence-based guidelines are at the heart of strategies to prevent and control HAIs and drug-resistant infections and address a wide range of issues from architectural design of hospitals to hand hygiene (Table 2) [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Adherence to individual guidelines varies but, in general, is low. For example, hand hygiene is the most basic and single most important preventive measure, yet compliance rates among healthcare workers have averaged 30% to 50% [26,39,40,41,42]. Decreasing the number of HAIs will require research to better understand the reasons behind lack of compliance with guidelines and to develop education and interventions that target those reasons.

Table 2: SAMPLE OF GUIDELINES RELATED TO PREVENTING AND MANAGING HEALTHCARE-ASSOCIATED INFECTIONS

Organization

Guideline(s)

American College of Chest Physicians/American Association for Bronchology

Consensus statement: prevention of flexible bronchoscopy-associated infection (2005)

American Institute of Architects

Guidelines for Design and Construction of Health Care Facilities (2014)

American Thoracic Society/Infectious Diseases Society of America

Management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia (2005, updated 2016)

Canadian Critical Care Trials Group/Canadian Critical Care Society

Prevention of ventilator-associated pneumonia (2004)

Centers for Disease Control and Prevention (CDC)

Prevention of catheter-associated urinary tract infections (2009)

Disinfection and sterilization in healthcare facilities (2008)

Isolation precautions (2007)

Management of multidrug-resistant organisms in healthcare settings (2006)

Prevention of healthcare-associated pneumonia (2003)

Environmental infection control in healthcare facilities (2003)

Hand hygiene in healthcare settings (2002)

Prevention of intravascular device-related infections (2011)

Prevention of surgical site infections (1999, updated 2017)

Infectious Diseases Society of America

Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults (2010)

Strategies to prevent catheter-associated urinary tract infection in acute care hospitals (2014)

Society for Healthcare Epidemiology of America

Prevention of nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus (2003, 2014)

Multi-society guideline for reprocessing flexible gastrointestinal endoscopes (2003)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America

Clostridium difficile infection in adults (2010, updated 2017)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America/Joint Committee on the Prevention of Antimicrobial Resistance

Prevention of antimicrobial resistance in hospitals (1997)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (published as supplement to Infection Control and Hospital Epidemiology, 2008)

Strategies to prevent central line-associated bloodstream infections, ventilator-associated pneumonia, catheter-associated urinary tract infections, surgical site infections in acute care hospitals, and transmission of methicillin-resistant S. aureus and C. difficile infections

World Health Organization (WHO)

Prevention of Hospital-Acquired Infections: A Practical Guide, 2nd ed. (2002)

Source: [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]

"Zero tolerance" of HAIs became a common catch-phrase as a call to improve prevention strategies and eliminate HAIs. Zero tolerance for HAIs is a worthy goal, but the complete elimination of all HAIs is not feasible, primarily because interventions address only exogenous sources of infection and do not address many other important factors, such as host response, patient case mixes, pathogen virulence, and lack of specificity in definitions and diagnostic criteria [43,44]. Furthermore, the literature has not supported the complete elimination of HAIs with enhanced compliance to prevention protocols. The results of the CDC's Study of Efficacy of Nosocomial Infection Control (SENIC) suggested that 6% of all HAIs could be prevented by minimal infection control efforts and 32% by "well organized and highly effective infection control programs" [45,46]. A later review of 30 studies suggested that an estimated 20% of HAIs are preventable [47]. A 2011 study estimated that approximately 65% to 75% of central line-associated bloodstream infections and catheter-associated urinary tract infections were preventable using current evidence-based strategies; 55% of ventilator-associated pneumonia and surgical site infections were estimated to be preventable [48]. Furthermore, complete elimination is not needed to reap substantial benefit. The U.S. Department of Health and Human Services estimates that a 40% decrease in preventable HAIs (compared with the 2010 rate) would result in 1.8 million fewer injuries and more than 60,000 lives saved over 3 years [8]. A 70% decrease in the rate of HAIs would save an estimated $25 to $31.5 billion [1].

The results of studies evaluating strategies to prevent HAIs have shown a wide range in efficacy, particularly with respect to specific HAIs. For example, the effectiveness of strategies to prevent surgical site infections has not been consistent, with some studies showing significant improvement and other studies showing no substantial improvement [49,50,51]. Still, research has shown that strict adherence to prevention interventions has an effect; one study demonstrated a decrease of as much as 66% in the prevalence of intravascular device-related bloodstream infections with adherence to a combination of interventions [52,53,54,55,56]. Combinations of interventions, or "bundles," have been found to be the most effective for preventing HAIs, and the Institute of Healthcare Improvement (IHI) has developed how-to guides on implementing these bundles, which are available for download from the IHI website [57,58,59]. More research is needed to determine the direct impact of many guideline recommendations and the combinations of "best practices" that yield the lowest rates of individual HAIs.

Among the national initiatives to reduce the number of HAIs was a move by the Centers for Medicare and Medicaid Services (CMS) to suspend reimbursement of hospital costs related to HAIs it considers "reasonably preventable:" catheter-related urinary tract infection, central line-associated bloodstream infection, and some surgical site infections [9,10]. However, studies have shown that this policy has not been a contributor to any decrease in the rate of HAIs, and a survey indicated that adherence to only some prevention strategies has increased as a result of the policy [60,61]. The policy also has the potential to lead to increased unnecessary use of antimicrobials in an effort to prevent infections [62].

In contrast, educating healthcare personnel helps to reduce HAIs, with a systematic review showing a statistically significant decrease in infection rates after an educational intervention in 21 of 26 studies [63]. Education is one of the key elements found to be necessary for a successful HAI prevention program. When such programs at 33 diverse hospitals were evaluated, the following were found to be essential for success [64]:

- Educate and re-educate

- Foster change by first understanding resistance

- Engage frontline staff by involving them in the program and enlisting champions

- Commit to regular strategic communication and join a collaborative

- Start small and tailor implementation to local needs and cultures

- Convince administration to provide leadership, funds, and dedicated staff and assign accountability

- Provide timely, relevant feedback and celebrate successes

Accurate data collection is crucial for understanding trends and the burden of HAIs and for identifying emerging infectious threats. The Association for Professionals in Infection Control and Epidemiology (APIC), the Infectious Diseases Society of America (IDSA), and the Society for Healthcare Epidemiology of America (SHEA) have led efforts to establish uniform standards for surveillance of HAIs and standardized systems for collecting and reporting. The CDC's National Healthcare Safety Network (NHSN), the nation's most widely used HAI surveillance system, is a shared resource for HAI prevention. More than 23,000 hospitals and other healthcare facilities provide data to NHSN, which in turn is used for national- and state-level analyses, including for periodic HAI reports and for targeted prevention initiatives by healthcare facilities, states, regions, quality groups, and national public health agencies, including the CDC [65,66].

In response to a call for mandatory reporting of HAIs, several states passed legislation requiring the mandatory reporting of specific HAIs, and reporting requirements vary by state. The number of states with mandates for public reporting grew from 3 in 2004 to 31 (and the District of Columbia) in 2015 [67,68].

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

A comprehensive description of the pathogenesis of infection is beyond the scope of this course. However, a broad overview of pathogen-host interaction will aid in the understanding of how infection develops in the healthcare setting. In addition, a discussion of the development of antibiotic resistance is warranted because of the substantial impact of resistant pathogens on the management of HAIs.

A healthy human body has several defenses against infection: the skin and mucous membranes form natural barriers to infection, and immune responses (nonspecific and specific) are activated to resist micro-organisms that are able to invade. The skin can effectively protect the body from most micro-organisms unless there is physical disruption. For example, the human papillomavirus can invade the skin, and some parasites can penetrate intact skin, but bacteria and fungi cannot [69]. Other disruptors of the natural barrier are lesions, injury, or, in the healthcare setting, invasive procedures or devices.

In addition to breaks in the skin, other primary entry points for micro-organisms are mucosal surfaces, such as the respiratory, gastrointestinal, and genitourinary tracts. The membranes lining these tracts comprise a major internal barrier to micro-organisms due to the antimicrobial properties of their secretions. The respiratory tract filters inhaled micro-organisms, and mucociliary epithelium in the tracheobronchial tree moves them out of the lung. In the gastrointestinal tract, gastric acid, pancreatic enzymes, bile, and intestinal secretions destroy harmful micro-organisms. Nonpathogenic bacteria (commensal bacteria) make up the normal flora in the gastrointestinal tract and act as protectants against invading pathogenic bacteria. Commensal bacteria are a source of infection only if they are transmitted to another part of the body or if they are altered by the use of antibiotics [15].

The transmission of infection follows the cycle that has been described for all diseases, and humans are at the center of this cycle [15]. In brief, a micro-organism requires a reservoir (a human, soil, air, or water), or a host, in which to live. The micro-organism also needs an environment that supports its survival once it exits the host and a method of transmission. Inherent properties allow micro-organisms to remain viable during transmission from a reservoir to a susceptible host, another essential factor for transmission of infection. The primary routes of transmission for infections are through the air, blood (or body fluid), contact (direct or indirect), fecal-oral route, food, animals, or insects. Once inside a host, micro-organisms thrive because of adherent properties that allow them to survive against mechanisms in the body that act to flush them out. Bacteria adhere to cell surfaces through hair-like projections, such as fibrillae, fimbriae, or pili, as well as by proteins that serve as adhesions [70]. Fimbriae and pili are found on gram-negative bacteria, whereas other types of adhesions are found with both gram-negative and gram-positive bacteria. Receptor molecules in the body act as ligands to bind the adhesions, enabling bacteria to colonize within the body. The virulence of the micro-organism will determine whether only colonization occurs or if infection will develop. With colonization, there is no damage to local or distant tissues and no immune reaction; with infection, bacterial toxins that break down cells and intracellular matrices are released, causing damage to local and distant tissues and prompting an immune response in the host. Bacteria continue to thrive within a host through strategies that enable them to acquire iron for nutrition and to defend against the immune response. These virulence factors enhance a micro-organism's potential for infection by interrupting or avoiding phagocytosis or living inside phagocytes [70].

A healthcare environment increases the risk of infection for two primary reasons. First, it is likely that normally sterile body sites will become exposed, allowing pathogens to cause infection through contact with mucous membranes, nonintact skin, and internal body areas. Second, the likelihood of a susceptible host is high due to the vulnerable health status of patients. Especially in an era of decreased hospital stays and increased outpatient treatments, it is the sickest patients who are hospitalized, increasing the risk not only for infection to develop in these patients but also for their infection to be more severe and to be transmitted to others.

Infection is transmitted in a healthcare environment primarily through exogenous and endogenous modes. Exogenous transmission is through patient-to-patient or staff-to-patient contact. Patients who do not have infection but have bacterial colonization can act as vectors of transmission. Staff members can also act as vectors because of colonization or contamination. Endogenous infection occurs within an individual patient through displacement of commensal micro-organisms.

In general, the spread of infectious disease is prevented by eliminating the conditions necessary for the micro-organism to be transmitted from a reservoir to a susceptible host. This can be accomplished by:

- Destroying the micro-organism

- Blocking the transmission

- Protecting individuals from becoming vectors of transmission

- Decreasing the susceptibility of potential hosts

Antiseptic techniques and antibiotics will kill micro-organisms, and proper hand hygiene will block their transmission. Gloves, gowns, and masks remove healthcare workers from the transmission cycle by protecting them from contact with micro-organisms. Contact precautions and isolation techniques help patients avoid being vectors of transmission. Lastly, ensuring that patients and healthcare workers are immune or vaccinated can help decrease the availability of potential hosts.

DEVELOPMENT OF DRUG-RESISTANT MICRO-ORGANISMS

The prevalence of drug-resistant micro-organisms has reached a critical level, and the inappropriate use of antibiotics is often cited as a primary cause of drug-resistant infections. As much as 50% of antimicrobial use is inappropriate [71]. The prophylactic use of antibiotics preoperatively and the empiric use of antibiotics have helped bacteria to develop resistance in the healthcare setting. To meet the challenge of drug resistance, the management of antibiotic use has been a priority recommendation in guidelines developed for infection control programs in healthcare institutions, and review of the antibiotic formulary is required by institutions as part of compliance with Joint Commission standards [15,23,72,73]. (Guidelines for preventing drug-resistant infections in the healthcare setting are discussed in the Infection Control section.)

Although the inappropriate use of antibiotics is a major contributor to the development of drug resistance, other factors play an important role. These other factors include the natural ability of micro-organisms to adapt through genetic plasticity and rapid replication and the lack of antibiotic discovery and development over the past decades [74]. For example, when the efficacy of antibiotics was first demonstrated in the late 1920s, their development and manufacture increased rapidly, and they began to be widely used (too widely, perhaps). However, over the next 40 years, no new class of antibiotics was developed, and the number of new antibiotics decreased substantially between 1983 and 2014 [74]. In 2009, 16 antimicrobial compounds were in late-stage clinical development (phase II or later); however, these compounds represent only incremental advances compared with currently available options, and few address the most commonly resistant pathogens [75]. A 2013 IDSA report identified seven drugs in clinical development that were not included in the 2009 list, but indicated that these agents fell short of addressing the clinically relevant spectrum of resistance [76]. Only two new antibiotics were approved between 2009 and 2013, but five new antibiotics were approved in 2014–2015. Drug resistance typically emerges first in the healthcare setting, varies according to healthcare setting and geography, and subsequently extends to the community setting [23]. The transmission and persistence of resistant strains of pathogens in a healthcare setting depends on several factors: availability of vulnerable patients, selective pressure from use of antimicrobial agents, number of patients with colonization of infection, and presence and adherence to prevention efforts [23].

Several risk factors for HAI caused by multidrug-resistant organisms have been identified [77,78]:

- Older age

- Underlying disease and severity of illness

- Transfer of patients from another institution, especially from a nursing home

- Exposure to antimicrobial drugs, especially cephalosporins

- Prolonged hospitalization

- Gastrointestinal surgery or transplantation

- Exposure to invasive devices (urinary catheter, central venous catheter)

Antimicrobial-resistant pathogens have been reported to be the source of approximately 14% to 20% of HAIs, and these HAIs are associated with higher rates of morbidity and mortality and greater economic costs than antimicrobial-susceptible infections [39,79,80,81].

The most common drug-resistant HAI is MRSA, which emerged as a significant problem in the 1980s and increased steadily in prevalence, with a rate of approximately 59% of S. aureus infections in U.S. intensive care units (ICUs) in 2004 [78]. Since that time, however, the rate of MRSA associated with HAIs has decreased, most likely because of increased preventive strategies [78,81]. Overall, the rate of HAIs attributable to antimicrobial-resistant pathogens has not changed substantially since 2010 [81]. According to data on HAIs reported to the NHSN in 2009–2010, 20% of the infections were with antimicrobial-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (3%); extended-spectrum cephalosporin-resistant Klebsiella pneumoniae and K. oxytoca (2%); Escherichia coli (2%); Enterobacter spp. (2%); and carbapenem-resistant Pseudomonas aeruginosa (2%) [81]. The discovery of carbapenem-resistant Enterobacteriaceae as a new threat led the CDC to issue a guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in the healthcare setting [82,83]. Data from the 2015 HNSN network survey report showed that 45% of S. aureus isolates were methicillin-resistant, and among E. coli, Enterobacter, and Klebsiella isolates, 5% were carbapenem-resistant [3].

Antimicrobial-resistant HAIs are associated with substantial morbidity and mortality compared with antimicrobial-susceptible HAIs, with longer hospital stays (excess of approximately 7 to 13 days), greater attributable mortality (up to 15%), and higher costs (additional $7,000 to $15,000) [78]. Guidelines for the prevention and management of multidrug-resistant pathogens in the hospital setting have been developed by the CDC, SHEA, and IDSA, with the most recent guidelines focusing specifically on the treatment of MRSA [23,30,33,84]. More information on antimicrobial-resistant pathogens is given in the discussions of each type of HAI. In addition, prevention of MRSA infection is addressed in the Infection Control section, as prevention is an important aspect of a healthcare facility's infection control program.

4. SOURCES OF HAIS

In general, the sources of HAIs can be categorized as being related to environmental factors (air, water, architectural design), patient-related factors (age, degree of illness/immune status, length of hospital stay), and iatrogenic factors (invasive procedures, devices, and equipment).

ENVIRONMENTAL FACTORS

Factors specifically related to the healthcare environment are not common causes of HAIs [15,85,86]. However, consideration should be given to the prevention of infection with environmental pathogens, such as fungi (e.g., Aspergillus), bacteria (e.g., Legionella species), or viruses (e.g., varicella) (Table 3). CDC guidelines provide clear recommendations for infection control measures according to several environment-related categories, including air (normal ventilation and filtration, as well as handling during construction or repair), water (water supply systems, ice machines, hydrotherapy tanks and pools), and environmental services (laundry, housekeeping). The infection control program of a facility has oversight of these measures.

Table 3: ENVIRONMENTAL SOURCES OF PATHOGENS IN THE HEALTHCARE SETTING

Source

Bacteria

Viruses

Fungi

Air

Gram-positive cocci (originating from skin)

Tuberculosis

Varicella zoster (chickenpox)

Influenza

Aspergillus

Water (tap and bath)

Gram-negative bacteria (Pseudomonas aeruginosa, Aeromonas hydrophilia, Burkholderia cepacia, Stenotrophomonas maltophilia, Serratia marcescens, Flavobacterium meningosepticum, Acinetobacter calcoaceticus, and Legionella pneumophila)

Mycobacteria (Mycobacterium xenopi, Mycobacterium chelonae, or Mycobacterium avium-intracellularae)

Molluscum contagiosum

Human papillomavirus (bath water)

Noroviruses

Aspergillus

Exophiala jeanselmei

Source: [15,85,86]

Air

Droplets containing micro-organisms can be transmitted in the air, causing infection in patients either directly or indirectly (through contamination of devices or equipment). Cleaning activities, such as sweeping, dry mopping, dusting, or shaking linen, can contribute to the transmission of airborne micro-organisms. Bacteria in the air primarily consist of gram-positive cocci from the skin, and they can be eliminated with appropriate ventilation and circulation of air [87]. Many airborne viruses, such as influenza and other respiratory viruses and measles, do not carry far from the source; others, such as tuberculosis and varicella zoster, may be spread over long distances [15]. The most common fungal spore to be transmitted through air is Aspergillus, which is carried through dust particles, can survive for long periods, and is easily inhaled [88]. Under normal circumstances, the level of contamination with this airborne fungus' spores is not high enough to cause disease in otherwise healthy individuals. However, in the healthcare setting, the fungus causes respiratory infection, primarily pneumonia, in susceptible hosts.

The prevalence of infection with Aspergillus within a healthcare setting has been strongly associated with Aspergillus spore counts. Consequently, air conditioning systems with high-efficiency particulate air (HEPA) filters are needed to minimize contamination [89]. HEPA filters are especially needed to prevent infection with Aspergillus in patients at high risk for infection due to a suppressed immune system. In one study, the risk of transplant-related mortality and overall mortality in the first 100 days after transplantation were significantly lower among patients treated in rooms with HEPA and/or laminar flow units than among patients treated in conventional isolation units [90]. In these units, the air exchange rate should be high (more than 15 exchanges per hour), rooms should be tightly sealed, and the air pressure in the rooms should be positive in relation to the hallway [89,91,92]. HEPA filters are also used in the hoods in microbiology laboratories and pharmacies, laminar flow units in ICUs, and unidirectional flow units in operating room suites [15].

Air in the Operating Room

Maintaining a high quality of air in operating rooms is an essential factor in preventing postoperative infection. The number and movement of staff within the operating room create the primary sources of airborne bacteria. Other factors influencing airborne contamination include the type of surgery, the rate of air exchange, the initial quality of the air, the quality of the staff clothing and cleaning processes, and the level of compliance with infection control practices [15].

The CDC makes several suggestions about ventilation in the operating room in its guidelines for prevention of surgical site infections [28]. The Level I recommendations include:

- Maintain positive-pressure ventilation in the operating room with respect to the corridors and adjacent areas.

- Maintain a minimum of 15 air changes per hour, of which at least three should be fresh air.

- Filter all air, recirculated and fresh, through the appropriate filters per recommendations of the American Institute of Architects.

- Introduce all air at the ceiling and exhaust near the floor.

- Do not use ultraviolet radiation in the operating room to prevent surgical site infection.

- Keep operating room doors closed except as needed for passage of equipment, personnel, and the patient.

Air During Construction

Special care must be taken to protect patients during repair or renovation of a healthcare facility, as construction work can facilitate the spread of airborne organisms such as Aspergillus species [15]. Some construction issues that contribute to the spread of infection include water-damaged building materials, disruption of duct work, open windows, and improper setting of fans or installation of filters [93].

The Joint Commission requires an inspection process for construction on a facility, and a risk assessment is part of that process [93]. Risk factors to consider include the patient population, the extent and duration of the project, the impact of the project on mechanical systems, and whether space with construction will be occupied [93]. A representative from a facility's infection control program should review any plans for construction to ensure that barriers are used as appropriate and patients, especially those with compromised immune systems, are moved to an area away from construction [87].

Water

Water is a reservoir for several types of micro-organisms, including bacteria, fungi, and viruses, with viruses accounting for only a small percentage [85,94]. The quality of water within a healthcare setting must meet standards that vary according to use. Tap water must be safe to drink and use for baths (for hygiene and therapy) according to criteria dictated by local regulations and public health standards. The water supply to the healthcare facility can be disinfected by several methods, including chlorination, thermal eradication, ultraviolet light, and metal ionization [89].

The most common pathogen identified in tap water is P. aeruginosa [78]. In one study, researchers evaluated the association between tap water from faucets in a surgical ICU and patients with colonization or infection with P. aeruginosa [95]. The pathogen was found in 58% of water samples taken from individual faucets but was not identified in the main water supply. The genotypes of the micro-organism in 21 of the 45 patients were identical to those found in the tap water from the sink in the patient's room (15 patients) or in the adjacent room (6 patients). According to epidemiologic analysis, transmission of the pathogen had occurred from faucet to patient as well as from patient to faucet. P. aeruginosa is also the primary bacterial pathogen found in bath water [96]. The effect of infection with P. aeruginosa may be mild, as in folliculitis and external otitis, but wound infection may be more severe. Greater morbidity is associated with infection in individuals who have a compromised immune system or who have another health condition, such as diabetes [15].

Legionella, which causes infection of the respiratory tract, is another micro-organism commonly found in tap water and bath water. The highest concentrations of Legionella are found in areas of water distribution systems (hot water storage, cooling towers, condensers), where it colonizes [89]. Infection with Legionella is transmitted only through water, not through person-to-person contact. Inhalation of contaminated water droplets from shower heads or faucet aerators may cause disease [85]. In addition, high humidity levels in a room (through mists produced by respiratory equipment, for example) may promote the growth of Legionella and molds [90].

The WHO suggests that there is potential risk for HAIs if tap water is used for such purposes as ice machines or devices for washing eyes or ears, or for cleaning equipment [15]. Point-of-use filtration may help to reduce the risk of HAIs related to water [94]. Ducts, humidifiers, dehumidifiers, and other areas of a ventilation system should be kept clean and dry, as micro-organisms can colonize in water that accumulates in these areas [90]. Patients at high risk for infection should not be exposed to hospital water and sterile water should be used instead [86].

Architectural Design

Another factor in the transmission of infection in the healthcare setting is the architectural design of the facility, and the AHRQ lists "good hospital design principles" as one of its 10 patient safety tips for hospitals [97]. When the American Institute of Architects and the Facility Guidelines Institute updated its Guidelines for Design and Construction of Hospital and Health Care Facilities in 2006, they set single-bed private rooms as the minimum standard for new hospital construction [18]. This new standard was based on a literature review that showed, in part, that private rooms have been associated with lower rates of HAIs [98]. Among the benefits of single-patient rooms compared with multibed rooms are decreased risk of infection through contaminated surfaces (e.g., blood pressure cuffs, privacy curtains); availability of private bathrooms; greater ease of cleaning and decontamination; increased likelihood of appropriate hand hygiene between rooms (rather than between beds within a single room); and decreased risk of prolonged hospital stays and patient transfers, all of which are risk factors for HAIs [98].

The WHO guidelines on infection control refer to "architectural segregation" according to risk [15]. Four areas of a healthcare facility are defined, with administrative sections considered as low-risk areas; regular patient wards as moderate-risk areas; ICUs, burn units, or isolation units as high-risk areas; and operating rooms as very high-risk areas. The WHO and others have recommended that traffic flow should be limited in higher risk areas [15].

The type of sink and the placement of sinks throughout a healthcare facility have been of critical concern because of the substantial role of handwashing in reducing the transmission of infection. As a result, sinks have been placed within easy access in each patient room. However, it is unclear that such placement promotes better hand hygiene, with no long-term clinically significant improvement in handwashing found when sinks are placed near points of clinical activity [99].

With the advent of alcohol-based handrub solutions as more effective hand hygiene, the placement of handrub dispensers has become more important than the placement of sinks [26]. The CDC guidelines on hand hygiene recommend placing dispensers in convenient locations, such as at the entrance of each patient room or at the bedside.

PATIENT-RELATED FACTORS

Patient-related risk factors for HAIs include age, general health status, and the type of procedure to be carried out, and risk can be classified as minimal, medium, or high [15]. Patients are at minimal risk if they have no significant underlying disease, have an intact immune system, and will not undergo an invasive procedure. Medium risk is assigned to older patients who are susceptible to disease for a variety of reasons, including decreased immune function, comorbid conditions, and low nutritional status. Medium risk also refers to patients who are to have a nonsurgical invasive procedure, such as a peripheral venous catheter or a urinary catheter.

Advances in medical treatments have led to longer lives for individuals of all ages who have had organ transplantation, cancer, or infection with human immunodeficiency virus (HIV), and their compromised immune system puts them at high risk for HAI. High risk is also assigned to patients with multiple trauma or severe burns, or those who have surgery or an invasive procedure that is considered to be high risk, such as endotracheal intubation or insertion of a central venous catheter.

IATROGENIC FACTORS

The primary iatrogenic factors contributing to the development of HAIs are devices (nonimplanted and implanted) and invasive procedures. As noted, the four most common HAIs—catheter-associated urinary tract infection, intravascular device-related bloodstream infection, surgical site infection, and pneumonia (ventilator-associated and hospital-acquired)—are related to the use of invasive devices or invasive procedures.

Nonimplanted Devices

HAIs have been associated with several types of devices and equipment unique to healthcare facilities. The Spaulding classification, developed in 1968, is widely used to categorize devices according to their associated risk of infection [100]. The system includes three categories:

- Critical: A device that enters normally sterile tissue or the vascular system

- Semicritical: A device that comes into contact with intact mucous membranes and does not ordinarily penetrate sterile tissue

- Noncritical: A device that does not ordinarily touch a patient or touches only intact skin

Most HAIs can be attributed to devices in the critical and semicritical categories, including intravascular catheters, surgical drains, urinary catheters, and endoscopic instruments [87]. Discussion here is limited to endoscopic instruments, as infections related to the other devices are addressed in detail later. In general, the transmission of pathogens on endoscopic devices has been attributed to noncompliance with appropriate reprocessing (cleaning, disinfection, sterilization, and drying) [16,31,101,102]. In particular, appropriate drying has been overlooked as an integral component of reprocessing, and guidelines have been inconsistent in recommendations on drying [103].

Bronchoscopes and gastrointestinal endoscopes are the primary diagnostic scopes used in healthcare settings. Both types of devices are associated with a low risk of infection transmission. Approximately 500,000 flexible bronchoscopies are done in the United States each year [16,104]. Few studies, however, have been carried out to evaluate the risk of infection; nosocomial infection related to bronchoscopy is difficult to detect and is likely under-recognized and under-reported [105]. In 2003, there were two reports of multiple pseudoinfections and true infections, primarily with P. aeruginosa, associated with bronchoscopes that had been reprocessed according to current standards [106,107]. However, in both reports, loose fittings over the valve stem for the working channel of the bronchoscope were thought to have prevented effective mechanical cleaning and disinfection [105]. Overall, the pathogens associated with bronchoscopy-related infection have been P. aeruginosa, Serratia marcescens, nontuberculous mycobacteria, and environmental fungi [105]. In 2014, the U.S. Food and Drug Administration (FDA) received 50 medical device reports that mentioned infection or device contamination associated with reprocessed flexible bronchoscopes [104]. During the course of investigating these reports, the FDA identified two recurrent themes that contributed to device contamination or device-associated infection: failure to meticulously follow the manufacturer's instructions for reprocessing (e.g., failure to perform thorough manual cleaning before high-level disinfection), and continued use of devices, despite integrity, maintenance, and mechanical issues (e.g., persistent channel kinks or bends).

More studies have evaluated the risk of infection associated with gastrointestinal endoscopy, which is performed on approximately 10 to 20 million people each year [108]. The American Society for Gastrointestinal Endoscopy (ASGE) estimates that infectious organisms are transmitted in 1 of 1.8 million gastrointestinal endoscopies [101]. Furthermore, all instances of infection during endoscopy have been the result of noncompliance with established guidelines for reprocessing of endoscopy equipment, highlighting the importance of adhering to these recommendations [31,108,109,110].

As with bronchoscopy, the pathogen with the highest rate of transmission associated with gastrointestinal endoscopy is P. aeruginosa [108,110]. As is true for other pathogens associated with endoscopy, infection with P. aeruginosa has resulted from nonadherence to reprocessing guidelines; however, this pathogen differs from the others because of its predilection for a moist environment. Many cases of infection with P. aeruginosa have been linked to the water supply to the endoscope and to failure to completely dry the endoscope channels with a 70% alcohol solution and forced air [103,108,110]. Salmonella species have also been associated with endoscopy, but no cases have been reported since the publication of the 1988 guidelines for standardized cleaning and disinfection of the devices [108,110]. Infection with Helicobacter pylori has also been related to suboptimal cleaning and disinfection [108]. Low rates of hepatitis B and C virus transmission have been reported, and most cases of infection with hepatitis C were found to be related to the inappropriate use of multiple-dose vials and/or syringes rather than to the endoscope itself [31,108].

Noncritical devices are often overlooked by healthcare workers as vectors for infection. These devices include diagnostic equipment, stethoscopes, and other commonplace items. A systematic review of 23 studies found bacterial contamination of 87% of sampled healthcare equipment, primarily stethoscope membranes, as well as diagnostic ultrasound equipment, otoscopes, and auriscopes [111]. The organisms found on healthcare equipment have primarily been S. aureus, including MRSA; Pseudomonas spp.; Acinetobacter spp.; and Pasteurella spp. [112]. Washing stethoscopes with either an ethanol-based cleanser or isopropyl alcohol pads significantly reduces bacterial growth, even that of MRSA [113,114,115].

Contamination of therapeutic ultrasound transducer heads and ultrasound gels were evaluated in another study, and the rate of contamination was 27% for the heads and 28% for the gels [116]. The transducer heads had low levels of contamination, and most of the micro-organisms were normal flora; however, high levels of contamination were found in the gels, and the micro-organisms included such pathogens as Stenotrophomonas maltophilia, S. aureus, Acinetobacter baumannii, and Rhodotorula mucilaginosa. In two other studies, contamination of dermatoscopes was evaluated. One study indicated colonization of only nonpathogenic bacteria and the other showed that use of an alcohol-based antibacterial gel as immersion fluid yielded no bacterial growth [117,118].

Ward-based computer terminals have also been shown to have low levels of contamination. In a study of two hospitals, MRSA was found on one of 13 computer terminals in one hospital and on five of 12 in another hospital. The rate of MRSA transmission was significantly higher at the hospital with the greater number of contaminated computers [119].

In summary, a high rate of micro-organism colonization has been found on equipment within the hospital setting, but contamination is usually at low levels and the risk of direct infection is low. In general, the findings of studies have suggested that adequate cleaning of equipment can prevent as many as one-third of HAIs [111].

Implanted Devices

Surgically implanted devices are a major source of HAI, and the development and use of intracardiac devices, orthopedic implants (prostheses and fixation devices), neurosurgical devices, cochlear implants, and breast and penile implants have increased over the past several years. The most common complication with all of these devices is infection [120,121,122]. The prevalence of infection associated with these devices varies, with the prevalence highest for left ventricular assist devices (Table 4) [120]. Orthopedic implants, such as joint prostheses and fracture fixation devices, are associated with the lowest rate of infection, but reported mortality rates have been as high as 18% [120].

Table 4: DEVICE-RELATED INFECTIONS

Type of Device

Prevalence

Probable Cause

Typical Duration to Occurrence after Implantation

Most Common Micro-organisms

Signs and Symptoms

Diagnosis

Treatment

Left ventricular assist devices

25% to 50%

Biofilm formation

Within 2 to 6 weeks

Methicillin-resistant staphylococcal spp.,Pseudomonas spp., Klebsiella spp., E. coli, Enterobacter spp., Proteus spp., Serratia spp., Candida spp., Enterococcus spp.

Signs of poor healing, localized inflammation, pocket abscess, frank sepsis, new and persistent drainage

Blood cultures

Empiric therapy with vancomycin and an anti-pseudomonal agent (ceftazidime or ciprofloxacin) or empiric antifungal therapy

Cerebrospinal fluid (CSF) shunts

10%

Bacteria originating from patient's skin introduced at time of operation

Within 30 days

Staphylococcus epidermidis (40% to 45%), S. aureus (25%), Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Acinetobacter baumanii, Corynebacterium spp., Propionibacterium spp., and streptococci/enterococci

Fever, focal pain, ventriculitis with lethargy and malaise (proximal shunts), infected intraperitoneal fluid cysts, or frank peritonitis (distal shunts)

CSF analysis (cell count, glucose, protein), gram stain, culture; abdominal ultra-sonography (distal shunts)

Antimicrobial agent effective against noted micro-organisms, modified with results of culture; removal of shunt

Prosthetic cardiac valves

3% to 5.7%

Contamination of the valve at time of implantation or transient bacteremia

Within 60 days (early)

Coagulase-negative staphylococci, specifically methicillin-resistant S. epidermidis, S. aureus

Fever, new or changing regurgitant murmurs, CHF, shock, cardiac conduction disturbances on EKG

Blood cultures, transesophageal echocardiography

Delayed antibiotic therapy until results of culture available (if subacute course and hemodynamically stable); empiric antibiotic therapy with vancomycin, gentamicin, rifampin (evidence of significant valve dysfunction); valve replacement (new or increasing murmurs, severe CHF, persistent fever)

Penile implants

2% to 8%

Contamination at time of implantation

Not available

S. epidermidis

Erythema, induration, tenderness, fever, discharge, device extrusion, prosthesis-associated pain

Culture of specimen from the operative site

Empiric antibiotic therapy with ciprofloxacin or a cephalosporin for 10 to 12 weeks; removal of implant if pain persists or recurs after antibiotic treatment or if purulent discharge

Cochlear implants

1.7% to 3.3%

Contamination at time of implantation

Within 30 to 90 days

S. aureus, Streptococcus pneumoniae, Haemophilus influenzae

Skin flap necrosis, wound dehiscence, wound infection

Not available

Antibiotic therapy, incision and drainage, local wound care; removal of device if extrusion of device or implant-related sepsis

Transvenous permanent pacemakers/automatic implantable cardioverter defibrillators

1% to 7%

Intraoperative contamination of the device or the pocket (early); contamination of pocket as a result of erosion of generator/defibrillator through skin (late)

Within 30 days (early); within 60 days (late)

S. aureus, Propionibacterium acnes, Micrococcus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp. (early); coagulase-negative staphylococci (late)

Erythema, pain, warmth at site ("pocket cellulitis"), draining sinus tract or erosion of overlying skin, systemic symptoms (fever, chills, malaise, nausea)

Blood cultures, transesophageal echocardiography

Prolonged antibiotic therapy, removal of all hardware; empiric therapy with vancomycin, gentamicin, or rifampin

Breast implants

1.7% to 2.5%a

Not available

Within 2 to 4 weeks

S. aureus, peptostreptococci, Clostridium perfringens

Erythema, edema, poor healing, purulent discharge, inflammatory symptoms (breast or axillary pain, paresthesia of upper extremity)

Wound or fluid culture

Empiric antibiotic therapy, local debridement

Orthopedic implants

<1% to 2%

Intraoperative contamination (early and late)

<2 to 4 weeks (early); >30 days (late)

S. aureus, coagulase-negative staphylococci, Propionibacterium spp. (early and late)

Persistent pain, fever, evidence of wound infection (early); loosening of prosthesis, sinus tract formation with discharge

Joint aspiration, complete blood count, erythrocyte sedimentation rate, C-reactive protein, imaging

Surgical exploration and debridement followed by empiric antibiotic therapy

aAfter augmentation mammoplasty; rates may be higher after mastectomy.

Source: [120]

Many implanted device-related infections are caused by contamination during insertion, but these infections are not always the result of micro-organisms transmitted in the healthcare setting. Rather, bacteria (and sometimes fungi) colonize by adhering to the surface of the implant through the development of a biofilm [120]. Biofilms present another challenge in managing infection; biofilms provide bacteria with an extremely high level of resistance to antimicrobial agents. In fact, biofilms can tolerate antibiotic concentrations of 10 to 1,000 times of that needed to destroy free-floating (planktonic) bacteria [120]. Many bacteria, including P. aeruginosa, are capable of existing in a planktonic state [110].

The CDC defines implanted device-related HAIs as those occurring within one year after implantation of a device, and the typical interval between implantation and infection varies according to the type of implant [123]. For some implants, early and late infections differ with respect to etiology and the causative micro-organisms [120].

The treatment of infections related to these devices depends on the severity of the infection and the patient's underlying condition. A multidisciplinary approach involving antibiotic therapy and surgical intervention (either debridement or removal of the device) can have a substantial impact on morbidity and mortality. For example, prosthetic valve endocarditis is associated with mortality rates of 42% to 100%, but the rate can be decreased 20-fold through an approach that combines medical and surgical therapy rather than medical therapy alone [120]. Empiric antibiotic therapy is usually appropriate once specimens have been obtained for culture, with the antibiotic agent chosen on the basis of the most common micro-organisms.

5. TYPES OF INFECTIONS

HAI is clearly defined by the CDC in the NHSN as a "localized or system condition (1) that results from adverse reaction to the presence of an infectious agent(s) or its toxin(s); and (2) that was not present or incubating at the time of admission to the hospital" [2,123]. Thus, an infection is considered to be healthcare associated if it is unrelated to the admitting diagnosis and develops within 48 hours after admission. The CDC notes that an infection should be considered healthcare associated if it is thought that the infection was acquired in the hospital but did not become evident until after discharge [2,123]. The diagnosis of infection is made on the basis of a combination of clinical findings and the results of laboratory studies or other diagnostic testing [123]. The NHSN provides comprehensive details about the criteria for infection at 13 major anatomic sites and has developed clinical and biologic criteria for 48 specific sites or types of infection [123]. The WHO has simplified the criteria to facilitate infection control in healthcare institutions with limited resources [15].

The rates of the five most common HAIs and the percentage each infection accounts for among all HAIs vary according to several factors, including time, geography, healthcare setting (including specific units within a hospital), and the data source. In general, catheter-related urinary tract infections are the most common, representing nearly one-third of all HAIs, and are the least costly; intravascular device-related bloodstream infections tend to be the most costly (in dollars); and ventilator-associated pneumonia is associated with the highest number of deaths (Table 5) [1,2,29,78,81,124,125,126,127,128,129,130]. Other HAIs defined in the NHNS include infection of bones and joints; the central nervous system; the cardiovascular system; the eye, ear, nose, throat, or mouth; the lower respiratory tract (other than pneumonia); the reproductive tract; skin and soft tissue; and systemic infection. Many of these other HAIs develop as complications of surgically implanted devices [120].

Table 5: CHARACTERISTICS OF THE MOST COMMON HEALTHCARE-ASSOCIATED INFECTIONS

Infection

Proportion of All HAIs

Incidence

Costs

Excess Stay

Attributable Mortality

Mean Hospital Cost per Infection (U.S. Dollars)

Catheter-associated urinary tract infection

32%

20% to 40% of patients with an indwelling catheter

10 days

1%

$1,006

Surgical site infection

22%

1% to 3% of surgical patients

7 to 10 days

3% to 5%

$25,546

Central line-associated bloodstream infection

14%

1% of patients with a central line

10 to 20 days

35%

$36,441

Ventilator-associated pneumonia

15%

10% to 65% of intubated patients

4 days

10% to 50%

$9,966

Healthcare-associated pneumonia (other than ventilator associated)

<1%

NA

NA

NA

NA

Clostridium difficile-associated diarrhea

Not available

30% of hospitalized adults with diarrhea

3 to 6 days

6% to 7%

$9,000–$11,000

NA = Not available.

Source: [1,2,29,37,78,81,125,126,127,128,129,130]

The risk factors for each of these HAIs have been delineated in many studies (Table 6) [19,78,131,132,133,134,135,136,137,138]. Yet, predicting which patients are at risk can be difficult. In one study, physicians in a surgical ICU were asked to assess at admission the individual risk of major HAI during the patient's stay in the unit. The investigators found that the physicians could not accurately predict risk, with positive predictive values that ranged from 8.4% to 14.5% and negative predictive values that ranged from 92.1% to 100% [139].

Table 6: RISK FACTORS FOR HEALTHCARE-ASSOCIATED INFECTIONS

Infection

Patient-Related Factors

Iatrogenic Factors

Urinary tract infection

Older age

Female gender

Diabetes mellitus

Renal insufficiency

Other site of infection

Urethral stent

Use of catheter to measure output

Disconnection of catheter from drainage tube

Duration of catheterization

Retrograde flow of urine from drainage bag

Surgical site infection

Nutritional status

History of smoking

History of alcohol use disorder

Obesity

Diabetes

Hypovolemia

Poor tissue perfusion

Compromised immune system

Pre-existing infection (local or other site)

Anesthesia score

Nonviable tissue in wound

Hematoma

Dead space

Wound classification

Foreign material (including drains and sutures)

Skin antisepsis

Duration of operation

Length of time sterile tray left open

Intraoperative contamination

Duration of preoperative hospital stay

Hypothermia during operation

Duration of surgical scrub

Antimicrobial prophylaxis

Preoperative preparation (wash/shave)

Surgical technique

Central line-associated bloodstream infection

Severity of illness

Burns or surgical wounds

Compromised immune system

Nutritional status

Heavy colonization on skin at site of insertion

Location in internal jugular or femoral vein

Length of time in place

Contamination of catheter hub

Type of infusate

Total parenteral nutrition

Location of insertion

Ventilator-associated pneumonia

Older age

Severity of illness

Chronic pulmonary disease

Head trauma

Elevated gastric pH

Upper abdominal or thoracic surgery

Reintubation

Supine position

Aspiration of gastric contents

Nasogastric tube

Sedation

Duration of mechanical ventilation

Hospital-acquired pneumonia (not associated with a ventilator)

Older age

Chronic pulmonary disease

Surgery

ASA class 2 or higher

Functional dependence

Congestive heart failure

History of tobacco use

Duration of operation

Emergency surgery

Surgical site

Sedation

Enteral nutrition

Clostridium difficile-associated diarrhea

Age

Severity of illness

Compromised immune system

Gastrointestinal surgery or manipulation

Debilitation

Length of stay

Antibiotic use

Nasogastric intubation

ASA = American Society of Anesthesiologists.

Source: [19,78,131,132,133,134,135,136,137,138]

HAIs are predominantly caused by bacteria. Of the 81,139 pathogens (69,475 HAIs) reported to the NHSN between January 2009 and December 2010, 90% were bacteria and 10% were fungi [81]. Approximately 82% of the reported pathogens belonged to one of eight main pathogen groups [81]:

- S. aureus (16%)

- Enterococcus spp. (14%)

- E. coli (12%)

- Coagulase-negative staphylococci (11%)

- Candida spp. (10%)

- Klebsiella spp. (8%)

- P. aeruginosa (8%)

- Enterobacter spp. (5%)

The micro-organisms causing HAIs vary according to several factors, including the type of infection; in the overviews of the HAIs that follow, the most common micro-organisms specific to each infection are noted. Infectious agents also vary among healthcare facilities and even units within a single institution. Knowledge of trends in the pathogens responsible for HAIs is important in determining appropriate empiric therapy. This information changes frequently, and healthcare professionals should remain up-to-date with the pathogens identified in their own healthcare facilities and even on specific units within the facility. The IDSA/SHEA recommends computer-based surveillance (level II, B) as part of an overall antimicrobial stewardship program [71].

CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

The IDSA defines a catheter-associated urinary tract infection as an infection occurring in a patient with an indwelling urinary catheter either currently in place or in place within the previous 48 hours [29]. Approximately 15% to 25% of inpatients will have a urinary catheter inserted at some time during the hospital stay, and a urinary tract infection will develop in 20% to 40% of them [20,29]. The risk of infection varies from 3% to 8% per day when an indwelling catheter is in place [29].

The NHSN survey in 2011 found the rate of catheter-associated urinary tract infections to be 4.7 to 5.3 infections per 1,000 catheter-days [140]. Of the estimated 722,000 HAIs in U.S. acute care hospitals in 2011, approximately 93,300 were catheter-associated urinary tract infections. The most recent NHSN survey observed a significant reduction in catheter-associated urinary infection in 2015, compared with 2011, and the national status report the following year showed a 7% reduction over that reported in 2015 [3,66]. This improvement has been attributed in part to a reduction in urinary catheter use and to the implementation of a Comprehensive Unit Based Safety Program (focused on prevention of urinary infection) in 603 US hospitals between 2011 and 2013 [3].

Risk Factors

The duration of catheterization is the most important risk factor for infection [29]. Studies have shown that catheterization for more than 2 days is a significant risk factor for urinary tract infection as well as increased 30-day mortality [143]. Other risk factors for catheter-related urinary tract infection include no treatment with systemic antimicrobial agents, positive results on culture of the urethral meatus, microbial colonization of the urinary drainage bag, insertion of the catheter outside the operating room, and nonadherence to guidelines for appropriate catheter care. Patient-related risk factors include female gender, older age, diabetes, and an elevated level of serum creatinine at the time of catheterization [29].

Transmission and Common Pathogens

Urinary tract infections can be caused by both endogenous and exogenous transmission. Normal flora from the gastrointestinal tract can spread to the urinary tract, or pathogens can be transmitted by caregivers carrying out tasks related to the catheter or drainage bag. Occasionally, pathogens are transmitted through urologic equipment that has not been adequately disinfected. Extraluminal ascension of bacteria along the catheter-urethral mucosa interface is the most common pathway of infection, accounting for approximately two-thirds of infections [29].

According to NHSN data for 2015, the pathogens most commonly isolated from catheter-related urinary tract infections are E. coli (46%), followed by K. pneumonia/oxytoca (18%), Enterococcus faecalis (10%), P. aeruginosa (13%), and Enterobacter species (8%) [3]. Infections related to short-term catheterization is usually caused by a single agent, whereas infections related to long-term catheterization (30 days or more) is typically caused by multiple pathogens. P. mirabilis, Morganella morganii, and P. stuartii are additional common pathogens in infections related to long-term catheterization [29].

With regard to antimicrobial-resistant pathogens, the percentage of S. aureus infections resistant to oxacillins decreased in 2009–2010 (59% vs. 65% in 2007–2008) [81]. The percentage of Enterococcus faecium resistant to vancomycin increased, to 83% (from 80% in 2007–2008), as did the percentage of vancomycin-resistant E. faecalis (approximately 8% vs 6% in 2007–2008). The prevalence of multidrug-resistance among E. coli, Klebsiella, and Enterobacter spp., previously reported as having increased from 3% in 2007–2008 to nearly 5% in 2015 [3,81].

Prevention

The principles of care required for prevention of catheter-associated urinary tract infection are well established: appropriate use, sterile catheter placement, maintenance of a closed drainage system, avoidance of back-flow, and minimal duration of catheter insertion. In addition to these technical aspects, a systems approach that standardizes care, educates, and fosters an interprofessional culture of attentiveness is also necessary for optimal preventive care [20,150].

The evidence-based guidelines for prevention of catheter-associated urinary tract infections were published by the CDC in 2009 (Table 7). The IDSA has published evidence-based clinical practice guidelines on the prevention, diagnosis, and treatment of catheter-associated urinary tract infections in 2010 [20,29]. According to both guidelines, the most important principles for prevention are:

- Limit the use of indwelling urinary catheters.

- Use aseptic technique and sterile equipment when inserting a catheter.

- Secure the catheter properly.

- Use a closed sterile drainage system.

- Maintain unobstructed urine flow.

- Remove the catheter as soon as feasible.

Table 7: SUMMARY OF LEVEL I RECOMMENDATIONS FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) FOR THE PREVENTION OF CATHETER-ASSOCIATED URINARY TRACT INFECTIONa

Appropriate Urinary Catheter Use

Insert catheters only for appropriate indications, and leave in place only as long as needed.

Minimize urinary catheter use and duration of use in all patients, particularly those at higher risk for infection or mortality from catheterization, such as women, individuals older than 65 years of age, and patients with impaired immunity.

Avoid use of urinary catheters in patients and nursing home residents for management of incontinence.

Use urinary catheters in operative patients only as necessary, rather than routinely.

For operative patients who have an indication for an indwelling catheter, remove the catheter as soon as possible postoperatively, preferably within 24 hours, unless there are appropriate indications for continued use.

Proper Techniques for Urinary Catheter Insertion

Perform hand hygiene immediately before and after insertion or any manipulation of the catheter device or site.

Ensure that only properly trained persons (e.g., hospital personnel, family members, or patients themselves) who know the correct technique of aseptic catheter insertion and maintenance are given this responsibility.

In the acute care hospital setting, insert urinary catheters using aseptic technique and sterile equipment.

Use sterile gloves, drape, sponges, an appropriate antiseptic or sterile solution for periurethral cleaning, and a single-use packet of lubricant jelly for insertion.

Properly secure indwelling catheters after insertion to prevent movement and urethral traction.

If intermittent catheterization is used, perform it at regular intervals to prevent bladder overdistension.

Proper Techniques for Urinary Catheter Maintenance

Following aseptic insertion of the urinary catheter, maintain a closed drainage system.

If breaks in aseptic technique, disconnection, or leakage occur, replace the catheter and collecting system using aseptic technique and sterile equipment.

Maintain unobstructed urine flow.

Keep the catheter and collecting tube free from kinking.

Keep the collecting bag below the level of the bladder at all times. Do not rest the bag on the floor.

Empty the collecting bag regularly using a separate, clean collecting container for each patient; avoid splashing, and prevent contact of the drainage spigot with the nonsterile collecting container.

Use Standard Precautions, including the use of gloves and gown as appropriate, during any manipulation of the catheter or collecting system.

Unless clinical indications exist (e.g., presence of bacteriuria when catheter is removed after urologic surgery), do not use systemic antimicrobial agents routinely to prevent catheter-associated urinary tract infection for patients requiring either short-term or long-term catheterization.

Do not clean the periurethral area with antiseptics to prevent infection while the catheter is in place. Routine hygiene (e.g., cleansing of the meatal surface during daily bathing or showering) is appropriate.

Quality Improvement Programs

Implement quality improvement programs or strategies to enhance appropriate use of indwelling catheters and to reduce the risk of catheter-associated urinary tract infections based on a facility risk assessment. The purposes of quality improvement programs should be to: ensure appropriate utilization of catheters; identify and remove catheters that are no longer needed (e.g., daily review of their continued need); and ensure adherence to hand hygiene and proper care of catheters.

Administrative Infrastructure

Provide and implement evidence-based guidelines that address catheter use, insertion, and maintenance.

Ensure that healthcare personnel and others who take care of catheters are given periodic in-service training regarding techniques and procedures for urinary catheter insertion, maintenance, and removal. Provide education about catheter-associated urinary tract infections, other complications of urinary catheterization, and alternatives to indwelling catheters.

aLevel I recommendations are supported by high-to-moderate quality evidence suggesting net clinical benefits or harms, or by low-quality evidence suggesting net clinical benefits or harms, or an accepted practices supported by low-to-very low quality evidence.

Source: [20]

As with prevention of all HAIs, handwashing is an essential element of aseptic technique and care of patients with catheters. In addition, healthcare staff should be educated and trained in proper techniques of catheter insertion and care.

Alternatives to indwelling catheters have been evaluated as an approach to preventing catheter-related urinary tract infections. The IDSA guidelines note that a suprapubic catheter may be considered as an alternative to short-term catheterization (level III, C), but use of this type of catheter is limited because an invasive procedure is needed for insertion [29]. Intermittent catheterization may also be considered as an alternative to short-term (level I, C) or long-term (level III, A) catheterization, and, for men who have minimal postvoid residual urine, condom catheterization can be considered as an alternative to short-term (level II, A) or long-term (level II, B) catheterization in those who are not cognitively impaired [29].

The use of catheters coated with an antimicrobial surface has been evaluated, especially those coated with silver, a highly effective antibacterial substance. In one study, the addition of silver did not reduce the incidence of bacteriuria when compared with silicone-based, hydrogel-coated urinary catheters with and without silver impregnation [144]. One meta-analysis (12 trials; 13,392 patients or catheters) showed that antimicrobial-coated catheters prevented or delayed the onset of bacteriuria in select patients, but the magnitude of the effect varied substantially according to several variables, including catheter type and publication year [145]. A subsequent systematic review (eight studies) found a favorable trend toward a lower rate of infection with silver alloy (vs uncoated) catheters, but the quality of some studies was poor and there was significant heterogeneity among the studies [146]. The 2009 CDC guidelines state that antimicrobial/antiseptic-impregnated catheters can be considered if the rate of catheter-associated urinary tract infections does not decrease after a comprehensive prevention strategy has been implemented [20]. The guidelines add that further research is needed to determine the effect of these catheters in reducing the risk of symptomatic infection, their inclusion among the primary interventions, and the patient populations most likely to benefit from them [20].

Similarly, the IDSA states that catheters coated with an antimicrobial surface may be considered to reduce the risk of infection for patients who are to have short-term catheterization (level II, B), but notes that the data on the effectiveness of this strategy are insufficient [29].

The IDSA guidelines note several prevention strategies that should not be used routinely, primarily because of insufficient data [29]:

- Systemic antimicrobials in patients with short-term (level III, A) or long-term (level II, A) catheterization

- Antimicrobials or antiseptics added to the drainage bag (level I, A)

- Catheter irrigation with antimicrobials (level II, A) or normal saline (level II, B)

- Enhanced meatal care (level I, A)

- Cranberry products

- Methenamine salts (although prophylaxis with methenamine salts may be considered after gynecologic surgery for women who have a catheter for less than 1 week) (level 1, C)

Diagnosis

The CDC and the IDSA classify catheter-associated urinary tract infections as symptomatic urinary tract infection, asymptomatic bacteriuria, or other infection of the urinary tract. Urine samples for urinalysis and quantitative urine culture (using a clean catch technique or catheterization) are necessary for accurate diagnosis [29,123].

Evidence Based Practice Recommendation

According to the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), signs and symptoms compatible with catheter-associated urinary tract infection include new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause; flank pain; costovertebral angle tenderness; acute hematuria; pelvic discomfort; and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain or tenderness.

https://academic.oup.com/cid/article/50/5/625/324341

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: AIII (Good evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees)

The IDSA notes that catheter-associated urinary tract infection is defined by the presence of signs or symptoms compatible with a urinary tract infection with no other identified source, and at least one bacterial species at a count of ≥10^3 cfu/mL in one urine specimen (level III, A) [29]. This threshold differs from that defined by the CDC (≥10^5 cfu/mL), which is intended for infection control surveillance rather than detection of infection in an individual patient [123]. In addition, the 2009 CDC guidelines define the criteria for symptomatic catheter-associated urinary tract infection as symptoms plus a positive urine culture at the threshold of ≥10^5 cfu/mL; if the urine culture result is between ≥10^3 and ≤10^5 cfu/mL, a positive urinalysis is needed to meet the diagnostic criteria [20].

Urine specimens for culturehould not be obtained from the drainage bag; instead, a sample should be taken through the catheter port with use of aseptic technique [29]. If there is no port, a needle and syringe can be used to puncture the catheter tubing and collect the specimen [29]. For patients with a long-term indwelling catheter, the IDSA recommends replacing the catheter and collecting the specimen from the newly placed catheter [29].

Signs and symptoms suggestive of catheter-associated urinary tract infections include fever (new or worsening), flank pain, hematuria, pelvic discomfort, altered mental status, and malaise or lethargy not attributable to another cause; among patients without a current indwelling catheter, dysuria, urgency, and frequent urination are other symptoms [29]. However, studies have shown that the classic symptoms of urinary tract infection are uncommon among patients with a catheter-associated infection [29]. Pyuria is not diagnostic of catheter-associated urinary tract infection in patients with an indwelling catheter [29].

Asymptomatic bacteriuria is defined as the presence of significant bacteriuria with no signs or symptoms referable to the urinary tract [29].

Treatment

The presence of bacteriuria (as defined by a positive urine culture) in a patient with a chronic indwelling catheter should be interpreted with caution. Often, this represents poor culture technique or may reflect an asymptomatic infection that need not be treated until the catheter can be removed or unless there is fever, flank pain, or worsening renal function. The IDSA recommends that in the absence of such signs these infections not be treated, as treatment has not been found to be beneficial [29,147,148]. However, for symptomatic infection, the results of urine culture and antibiotic sensitivities are an essential guide to effective treatment [29]. For patients with a catheter in place, the catheter should be discontinued, if possible, and the urine specimen should be one that is voided midstream (level III, A) [29]. If the catheter has been in place for more than 2 weeks and continued catheterization is necessary, the catheter should be replaced (level I, A) and the urine specimen should be collected from the newly placed catheter (level II, A) [29].

The IDSA guidelines do not specify which antimicrobial to use for treatment but do recommend duration of treatment. Treatment for 7 days is recommended for patients in whom symptoms resolve promptly, and treatment for 10 to 14 days is recommended for patients in whom symptom response is delayed (level III, A) [29]. The guidelines note that a five-day regimen of levofloxacin may be considered for patients who are not severely ill (level III, B) [29].

Guideline Adherence and Quality Improvement

It has been suggested that catheter-associated urinary tract infection is the most preventable HAI [48]. Some studies have noted an increase in adherence to strategies to prevent catheter-associated urinary tract infection [52]. The greatest adherence has been to guidelines for wearing gloves (97%), using appropriate hand hygiene (89%), and maintaining a sterile barrier (81%) [149]. However, adherence to appropriate catheterization (in terms of both initial indication and duration) has been suboptimal, with studies demonstrating the following [29,143,150,151,152]:

- No justifiable indication or an inappropriate indication (such as incontinence) for more than 50% of catheterizations

- Lack of awareness of catheterization in 25% of physicians

- Catheterization for more than two days among 50% of postoperative patients

- No system for monitoring which patients had insertion of catheters in 56% of hospitals

- No system for monitoring duration of catheterization in 74%

- Policy for nurse-initiated discontinuation of catheterization in 10% of hospitals

Use of alternatives to catheterization is also low, ranging from 14% to 20% [151,152].

The use of provider reminder systems—alone or in combination with base strategies—has a moderate strength of evidence [1]. In one study, the combination of prompts in a computerized order-entry system and handheld bladder scanners led to an 81% decrease in the use of catheters and a 73% reduction in HAIs [153]. For hospitals without order-entry systems, a handwritten reminder that the patient has a catheter has been effective in reducing the rate of infection [154]. However, the use of reminder systems has been reported to be 9% to 12% [151,152].

Despite the lack of adherence to prevention guidelines, some progress has been made in reducing this HAI; the rate of symptomatic catheter-associated urinary tract infections decreased 19% to 67% between 2000 and 2007 in ICUs [155]. Compliance with a nurse-driven evidence-based checklist led to a decrease in infections from 2.88/1,000 catheter days to 1.46/1,000 catheter days [156].

The CDC guidelines note that the following are effective elements of a quality improvement program [20]:

- A system of alerts or reminders to identify all patients with urinary catheters and assess the need for continued catheterization

- Guidelines and protocols for nurse-directed removal of unnecessary urinary catheters

- Education and performance feedback regarding appropriate use, hand hygiene, and catheter care

- Guidelines and algorithms for appropriate perioperative catheter management (such as procedure-specific guidelines for catheter placement and postoperative catheter removal and protocols for management of postoperative urinary retention, such as nurse-directed use of intermittent catheterization and use of bladder ultrasound scanners)

SURGICAL SITE INFECTIONS

According to National Hospital Discharge Survey data, 51.4 million inpatient surgical procedures were performed in 2010, creating a large population at risk for surgical site infections [157]. The CDC healthcare-associated infection (HAI) prevalence survey found that there were an estimated 157,500 surgical site infections associated with inpatient surgeries in 2011 [142]. Infection will develop postoperatively in approximately 2.6% of all patients who have surgery [158]. The rate has decreased since the 1990s, but the lower rate is not thought to be an accurate representation because of the increased number of operations done on an outpatient basis; a decrease in the length of the postoperative hospital stay; and a wound infection incubation period of 5 to 7 days [39]. This potential for underestimation of the number of surgical site infections is reflected in the findings of a study in which one-third of healthcare-associated wound infections were detected after the patient had been discharged [159]. Surgical site infections are associated with extended lengths of stay, a high rate of readmissions, excess hospital costs, and a mortality rate of 3%, with a higher mortality rate reported for patients 70 years of age and older [2,160,161].

The NHSN program enables the CDC to monitor the distribution, etiology, and antimicrobial resistance pattern of infections in relation to the category of surgical procedure. The number of surgical site infections reported through NHSN increased from 10,778 in 2007–2008 to 16,019 in 2009–2010 [81]. However, this may in part be a measure of improved surveillance, as the CDC reported a 19% decrease in infection associated with 10 select procedures performed between 2008 and 2013 [162]. The 2016 NHSN progress report showed a further 6% decrease in surgical site infections for 10 procedures tracked during the previous year [66]. Table 8 shows the distribution of procedure-associated infections and common pathogens, by type of surgery, as reported to NHSN for 2009–2010 [81]. Please note that the distribution percentage is primarily a reflection of the frequency (commonality) with which the given category of surgery is performed and not an indication of the actual rate, or risk, of infection from the specific procedure itself. It may be seen that, with the exception of abdominal procedures and transplant surgery, S. aureus (of which 44% of isolates were MRSA) accounted for the majority of these infections [81].

Table 8: DISTRIBUTION OF SURGICAL SITE INFECTION AND MOST COMMON PATHOGENS ACCORDING TO TYPE OF SURGERY: DATA REPORTED TO THE NATIONAL HEALTHCARE SAFETY NETWORK, 2009–2010

Type of Surgery

Percentage of Reported Surgical Site Infections

Most Common Pathogens

Orthopedic

41%

Staphylococcus aureus (47%), coagulase-negative staphylococci (14%), Streptococcus spp. (6%)

Abdominal

23%

Escherichia coli (19%), S. aureus (12%), Enterococcus faecalis (9%)

Cardiac

22%

S. aureus (31%), coagulase-negative staphylococci (17%), Pseudomonas aeruginosa (8%)

Obstetric/gynecologic

10%

S. aureus (20%), E. coli (13%), coagulase-negative staphylococci (9%)

Neurologic

2%

S. aureus (37%), coagulase-negative staphylococci (23%), Enterobacter spp. (7%)

Vascular

2%

S. aureus (33%), coagulase-negative staphylococci (8%), P. aeruginosa (8%), E. coli (8%)

Transplant

1%

Coagulase-negative staphylococci (16%), Enterococcus faecium (15%), E. coli (10%)

Source: [81]

The category of surgery and the duration of the procedure are factors affecting the incidence of post-procedure surgical site infection. The rate of infection by type of surgery varies across facilities; for example, in a multicenter Veterans Administration study, the overall rate of surgical site infection was 6%, with the highest rate (11.3%) following colorectal procedures and the lowest (1.3%) following orthopedic procedures [163].

Risk Factors

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends that a basic nutritional assessment should be considered on all patients undergoing surgery, as malnutrition is a known risk factor for decreased wound healing and increased surgical site infections.

http://www.guideline.gov/content.aspx?id=48408

Last Accessed: January 28, 2016

Level of Evidence: Consensus Statement/Expert Opinion

Several patient-related and surgery-related factors increase the risk for surgical site infection. Patient-related factors include [28,132,136,164]:

- Older age (≥65 years)

- Obesity

- Poor nutritional status

- Low serum albumin concentration

- History of smoking

- History of alcohol use disorders

- Existing infection

- Diabetes mellitus

- Trauma

- Blood transfusion

- Hypothermia, hypoxia, or hyperglycemia

Among the most common surgery-related factors are anesthesia score, duration of the operation, the use of drains, and inadequate aseptic technique [87]. In a study to determine the influence of risk factors on complications after colorectal surgery, body mass index, duration of the operation, and the surgeon who performed the operation were the three most important factors influencing surgical site infections [165].

Transmission and Common Pathogens

Surgical site infections arise from both endogenous and exogenous transmission. The microbial sources of surgical site infections vary according to the type of surgery, and the micro-organism reported as being the most common in 2009–2010 was S. aureus, which accounted for nearly half of all reported orthopedic surgical site infections [81]. Other common causative pathogens were coagulase-negative staphylococci and E. coli [81].

Among the facilities reporting data on surgical site infections to the NHSN in 2009–2010, the percentage of resistant phenotypes was low for pathogens most often associated with surgical site infections [81]. The percentage resistance for most pathogens decreased compared with data for 2007–2008; for example, 44% of S. aureus infections were resistant to oxacillins, a significant decrease from 48% in 2007–2008. The percentage of vancomycin-resistant E. faecium remained relatively stable (62% in 2009–2010), but the percentage of vancomycin-resistant E. faecalis increased from 4.6% to 6.2% in 2009–2010 [81]. Also increasing were rates of resistance of E. coli to extended-spectrum cephalosporins (11%) and of P. aeruginosa to aminoglycosides (6%) [81].

Prevention

The CDC guideline for preventing surgical site infections, published in 1999, addresses a wide variety of issues, including preoperative preparation of the patient, antisepsis of the surgical team, management of surgical personnel with colonization or infection, antimicrobial prophylaxis, ventilation, cleaning and disinfection of environmental surfaces, microbiologic sampling, sterilization of surgical instruments, surgical attire and drapes, asepsis and surgical technique, postoperative incision care, and surveillance. The CDC's current guideline for prevention of surgical site infection was published in 2017 [28,166]. The guidelines recommend a combination of key components as a strategy to prevent surgical site infection (Table 9).

Table 9: LEVEL IA AND IB RECOMMENDATIONS FOR THE PREVENTION OF SURGICAL SITE INFECTIONSa

1999 Guideline

2017 Additions

Preoperative

Whenever possible, identify and treat all infections remote to the surgical site before elective operation, and postpone elective operations on patients with remote site infections until the infection has resolved. Do not remove hair preoperatively unless the hair at or around the incision site will interfere with the operation. If hair is removed, remove immediately before the operation, preferably with electric clippers. Adequately control serum blood glucose levels in all diabetic patients and particularly avoid hyperglycemia perioperatively. Encourage tobacco cessation. At minimum, instruct patients to abstain for at least 30 days before elective operation from smoking cigarettes, cigars, pipes, or any other form of tobacco consumption (e.g., chewing/dipping). Do not withhold necessary blood products from surgical patients as a means to prevent surgical site infection. Thoroughly wash and clean at and around the incision site to remove gross contamination before performing antiseptic skin preparation. Use an appropriate antiseptic agent for skin preparation.

Implement perioperative glycemic control; use serum blood glucose target (upper) level <200 mg/dL in diabetic and nondiabetic patients.

Maintain perioperative normothermia. Perform intraoperative skin preparation with an alcohol-based antiseptic agent, unless contraindicated.

Antimicrobial Prophylaxis

Administer a prophylactic antimicrobial agent only when indicated, and select it based on its efficacy against the most common pathogens causing surgical site infection for a specific operation and published recommendations. Administer by the intravenous route the initial dose of prophylactic antimicrobial agent, timed such that a bactericidal concentration of the drug is established in serum and tissues when the incision is made. Maintain therapeutic levels of the agent in serum and tissues throughout the operation and until, at most, a few hours after the incision is closed in the operating room. Before elective colorectal operations, in addition to above recommendation, mechanically prepare the colon by use of enemas and cathartic agents. Administer nonabsorbable oral antimicrobial agents in divided doses

In all cesarean sections, administer the appropriate parenteral prophylactic antimicrobial agent prior to skin incision.

In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain.

Do not apply antimicrobial agents (i.e., ointments, solutions, powders) to the surgical incision for the prevention of surgical site infection.

Oxygenation

__

For patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation, administer increased FiO_2 both intraoperatively and postextubation in the immediate postoperative period. To optimize tissue oxygen delivery, maintain perioperative normothermia and adequate volume replacement.

Postoperative Incision Care

Protect with a sterile dressing for 24 to 48 hours postoperatively an incision that has been closed primarily. Wash hands before and after dressing changes and any contact with the surgical site.

__

aLevel I recommendations are supported by high-to-moderate quality evidence suggesting net clinical benefits or harms, or by low-quality evidence suggesting net clinical benefits or harms, or are accepted practices supported by low-to-very low quality evidence.

Source: [28]

Before surgery, patients should be advised to shower or bathe (full body) with soap (antibacterial or non-antibacterial) or an antiseptic agent on at least the night before the operative day [28]. Antimicrobial prophylaxis should be administered only when indicated based on published clinical practice guidelines and timed such that a bactericidal concentration of the agents is established in the serum and tissues when the incision is made [28]. Antibiotic prophylaxis need not be maintained longer than a few hours after the incision has been closed. Additional guidance is provided in reference to specific surgical procedures and specialty operations (e.g., prosthetic joint arthroplasty) [28].

The CDC guidelines reference appropriate antibiotics on the basis of the type of surgery [28,166]. Meta-analyses have demonstrated lower rates of infection with a single-dose (long-acting) antibiotic and broader spectrum antibiotics, such as third-generation cephalosporins [168]. However, a complication of perioperative antibiotic prophylaxis is an increased frequency of adverse events, the most serious of which is infection with C. difficile, and this risk may be higher in association with a broad-spectrum antibiotic [168].

Systematic reviews reported in the mid-2000s showed that two previously recommended measures for preventing postoperative infection have no effect on the rate of surgical site infection. One review involved six trials in which preoperative washing was evaluated in a total of 10,007 patients. There was no significant difference in the rate of surgical site infections when 4% chlorhexidine gluconate was compared with placebo or no washing [169]. The other review involved 11 randomized controlled trials in which preoperative hair removal practices were evaluated. Comparison of razor, depilatory cream, or no hair removal showed no significant difference in the rate of surgical site infection [170,171]. However, when shaving was compared with clipping, there were significantly more surgical site infections after shaving. No difference was found in the rate of surgical site infections between clipping 1 day preoperatively or on the day of surgery. On the basis of these findings, preoperative antiseptic washing and shaving are no longer recommended.

Attention should also be directed at strategies to prevent surgical site infections with MRSA. The use of an MRSA prevention bundle—adherence to the guidelines for hand hygiene, decontamination of environment and equipment, active surveillance cultures, and contact precautions for patients with MRSA infection or colonization—led to significant decreases in the overall rate of surgical site infections in one study, with a 1% decrease in surgical site infections after cardiac surgery and a 65% decrease after orthopedic surgeries [172].

Diagnosis

IDSA guidelines on the diagnosis and management of skin and soft tissue infections include a section on surgical site infections [158,173]. The guidelines note that the most reliable diagnostic information is the physical appearance of the site; local signs of infection include pain, swelling, erythema, and purulent drainage [158,173]. Clinical manifestations of a surgical site infection do not occur for at least 5 days postoperatively, with many infections not becoming apparent for as long as 2 weeks [158,173]. The IDSA notes that most postoperative fevers are not associated with a surgical site infection [158,173].

Surgical site infections are classified as superficial incisional, deep incisional, and organ/space infections. Strict criteria and standardized definitions are used in reporting infections and in surveillance programs [28,168]. The CDC described the criteria for each type of infection in its guidelines for the prevention of surgical site infections and defined the infections in the NHSN system according to this classification [28,123,174].

Superficial Incisional Classification

Infection occurs within 30 days after the operative procedure and involves only skin and subcutaneous tissue of the incision and at least one of the following:

- Purulent draining from the superficial incision

- Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision

- At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon, unless incision is culture-negative

- Diagnosis of superficial incisional surgical site infection by the surgeon or attending physician

Deep Incisional Classification

Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and involves deep soft tissues (e.g., fascial and muscle layers) of the incision and at least one of the following:

- Purulent drainage from the deep incision but not from the organ/space component of the surgical site

- Deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (>38 degrees Centigrade) or localized pain or tenderness, unless incision is culture-negative

- Abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiographic examination

- Diagnosis of a deep incisional surgical site infection by a surgeon or attending physician

Organ/Space Classification

Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if the implant is in place and the infection appears to be related to the operative procedure and infection involves any part of the body, excluding the skin incision, fascia, or muscle layers, that is opened or manipulated during the operative procedure and at least one of the following:

- Purulent drainage from a drain that is placed through a stab wound into the organ/space

- Organisms isolated from an aseptically obtained culture or fluid or tissue in the organ/space

- Abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiographic examination

- Diagnosis of an organ/space surgical site infection by a surgeon or attending physician

Treatment

Based on expert opinion, the IDSA recommends opening an infected surgical site, removing the infected material, and continuing dressing changes until the wound heals by secondary intention [158]. Although treatment with antibiotics is commonly started when a surgical site infection is diagnosed, the IDSA notes that little evidence has supported this approach [158]. A short course (24 to 48 hours) of antibiotics may be indicated for patients with a temperature higher than 38.5 degrees Centigrade or a pulse rate of more than 100 beats/min [158]. The guidelines add that treatment is usually empirical but may be selected according to results of wound culture [158]. IDSA offers guidance on the selection of antibiotics according to the operative site [158].

Intestinal or Genital Tract

Single agents: ticarcillin/clavulanate, piperacillin/tazobactam, imipenem/cilastatin, meropenem, ertapenem

Combination agents: ceftriaxone/metronidazole, ciprofloxacin/metronidazole, levofloxacin/metronidazole, ampicillin-sulbactam/gentamicin ampicillin-sulbactam/tobramycin

Trunk and Extremities (away from axilla or perineum)

Oxacillin, nafcillin, cefazolin, cephalexin, SMX-TMP, vancomycin

Axilla or Perineum

Metronidazole/ciprofloxacin, levofloxacin, ceftriaxone

For surgical site infections after implantation of a joint prosthesis, the approach depends on the duration of infection, stability of the implant, antimicrobial susceptibility of the pathogen, and condition of the surrounding soft tissue [175]. In this setting, rifampin has shown excellent activity against adherent staphylococci and may be useful in combination with beta-lactams, glycopeptides, fluoroquinolones, minocycline, trimethoprim, or fusidic acid [176].

Guideline Adherence and Quality Improvement

The effect of prevention strategies—primarily the appropriate use of prophylactic antibiotics—on the rate of surgical site infection has been evaluated in several studies, and the results have been conflicting. For example, 56% adherence to this measure significantly reduced the incidence of surgical site infections in one study of patients who had colorectal surgery, with the rate decreasing from 22% to 3.5% [177]. There was no significant difference in the rate of surgical site infection between compliant and noncompliant prophylactic antibiotics [177]. In a retrospective review of 605 patients who had colorectal surgery with intestinal anastomosis showed that early administration of antibiotic prophylaxis and a nonstandard antibiotic were significantly associated with a greater risk of surgical site infection [178]. However, the timely administration of prophylactic antibiotics did not improve the rate of surgical site infections among nearly 9,200 elective major surgeries (all types); the rate was 5% for patients who received timely antibiotics compared with 6% for patients who received antibiotic prophylaxis outside of the recommended time [50].

More recent studies have analyzed adherence to the Surgical Care Improvement Project (SCIP) quality measures, with analysis of individual measures as well as groups of measures. Some studies have indicated that an increase in compliance with SCIP measures leads to a decrease in the rate of surgical site infection; the rate decreased from nearly 26% to 16% in one study and in another study, increasing compliance with SCIP measures from 38% to 92% led to a decrease in the rate of superficial surgical site infections from 13% to 8% [49,179]. Among patients who had laparotomy related to trauma (gunshot wound, stab wound, or blunt trauma), adherence to SCIP measures related to antibiotic prophylaxis resulted in a significantly lower rate of surgical site infection (17% vs 33%) as well as a shorter hospital stay (14 vs 19 days), even after controlling for several factors [180].

However, these data have not been consistent. In a study of nearly 500 patients who had colorectal surgery, compliance with all SCIP measures improved—from 40% to 68%—but the rate of surgical site infections remained essentially the same (approximately 19%) [51]. In addition, a retrospective review of 60,853 surgeries done over a five-year period at 112 Veterans Administration (VA) hospitals showed that improving adherence to five SCIP measures did not significantly lower the odds of surgical site infection [163].

Many have been critical of the SCIP strategy, noting that the evidence has not indicated that adherence to these quality measures alone has had an effect on reducing the overall risk of surgical site infection [181]. The quality measures do not factor in the skill of the surgeon, and other factors, such as state-of-the-art skin antisepsis and innovative antimicrobial technology, should be included in quality improvement programs [181,182].

Ways to help increase adherence to effective prevention strategies are the use of computerized standard orders for antibiotics, reminders and checklists, and auditing of the rates for individual physicians, with feedback [28]. A study demonstrated that point-of-care prompts increased compliance with timely antibiotic prophylaxis from 62% to 92%, with a corresponding decrease in the incidence of surgical site infections, from 1.1% to 0.7% [183]. In an extensive systematic review, there was moderate strength of evidence for the use of audit and feedback, with or without provider reminder systems, for improving adherence to appropriate timing of prophylactic antibiotics [1]. The IHI how-to guide for the prevention of surgical site infection outlines practical steps to help healthcare professionals ensure that prevention strategies are carried out (Table 10) [184].

Table 10: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT SURGICAL SITE INFECTIONS

Appropriate Use of Prophylactic Antibiotics

Use preprinted or computerized standing orders specifying antibiotic, timing, dose, and discontinuation. Develop pharmacist- and nurse-driven protocols that include preoperative antibiotic selection and dosing based on surgical type and patient-specific criteria (e.g., age, weight, allergies, renal clearance). Change operating room drug stocks to include only standard doses and standard drugs, reflecting national guidelines. Reassign dosing responsibilities to anesthesia or holding area nurses to improve timeliness. Involve pharmacy, infection control, and infectious disease staff to ensure appropriate timing, selection, and duration. Verify administration time during "time-out" or preprocedural briefing so action can be taken if not administered.

Appropriate Hair Removal

Ensure adequate supply of clippers and train staff in proper use. Remove all razors throughout the hospital. Work with the purchasing department to ensure that razors are no longer purchased by the hospital. Use signs or posters as reminders. Educate patients about not shaving preoperatively.

Maintaining Adequate Glycemic Control

Implement one standard glucose control protocol (sliding scale or insulin drip). Regularly check preoperative blood glucose levels on all patients. Assign responsibility and accountability for blood glucose monitoring and control.

Maintaining a Warm Body Temperature

Use hats and booties on patients preoperatively. Use warmed forced-air blankets preoperatively, during surgery, and in the recovery room. Use warmed intravenous fluids. Use warming blankets under patients on the operating table.

Maintaining a Warm Body Temperature

Prevent hypothermia at all phases of the surgical process. Use hats and booties on patients perioperatively. Use warmed forced-air blankets preoperatively, during surgery, and in the recovery room. Use warmed intravenous fluids. Use warming blankets under patients on the operating table. Adjust engineering controls so that operating rooms and patient areas are not permitted to become excessively cold overnight, when many rooms are closed. Measure temperature with a standard type of thermometer.

Source: [184]

PNEUMONIA

Pneumonia associated with healthcare facilities is classified in three categories: hospital-acquired, ventilator-associated, and healthcare-associated. Hospital-acquired pneumonia refers specifically to pneumonia that develops 48 hours after hospital admission (usually occurring postoperatively), and ventilator-associated pneumonia refers to pneumonia that develops 48 hours after tracheal intubation [185]. Healthcare-associated pneumonia develops in individuals in healthcare facilities outside hospitals, such as long-term care facilities and outpatient settings.

Hospital-acquired pneumonia, also referred to as post-procedure pneumonia, is not included in most discussions of HAIs because it represents less than 1% of all such infections; although this type of pneumonia is not reportable to NHSN, 23 cases were reported in 2009–2010 [81]. Still, hospital-acquired pneumonia can increase the length of stay by more than 1 week and is associated with increased mortality and financial cost [186].

The rate of ventilator-associated pneumonia is higher than that for hospital-acquired pneumonia, with a reported rate of 1 to 4 cases per 1,000 ventilator-days, and rates as high as 10 cases per 1,000 in some neonatal and surgical populations [17,187]. An estimated 10% of patients requiring mechanical ventilation will develop pneumonia as a complication, and the mortality rate directly attributable to ventilator-associated pneumonia is estimated at 13% [17]. Excess cost of care resulting from prolongation of hospital stay is estimated to be range from $30,000 to $40,000 per patient [17].

Risk Factors

Hospital-Acquired Pneumonia

In a systematic review, the American College of Physicians found several patient-related and surgery-related factors that increased the risk of postoperative pulmonary complications. The most common patient-related factors were the presence of COPD and an age older than 60 years [137]. Other significant factors were an American Society of Anesthesiologists (ASA) class 2 (defined as a patient with mild systemic disease) or higher, functional dependence, and congestive heart failure. Cigarette use was associated with a modest increase in risk, and obesity and mild or moderate asthma were not found to increase risk [137]. Use of a PPI or histamine-2 receptor antagonist is also thought to be a risk factor [138]. Surgery-related factors included prolonged duration of surgery (more than three to four hours), emergency surgery, and surgical site, with abdominal surgery, thoracic surgery, neurosurgery, head and neck surgery, vascular surgery, and aortic aneurysm repair being associated with the greatest risks [137].

Ventilator-Associated Pneumonia

The risk of ventilator-associated pneumonia correlates with the duration of intubation; the risk has been estimated to be 3% per day during the five-day period after intubation, decreasing to 2% per day for days 5 through 10 and to 1% per day for longer durations [190].

Nearly half of all cases of ventilator-associated pneumonia develop within the first four days of mechanical ventilation [185]. In addition to duration of ventilation, several other risk factors among adults have been identified, including a supine head position; use of a nasogastric tube, paralytic agents, or PPI or histamine-2 receptor antagonists; patient age; chronic lung disease; and head trauma [19,138]. In one study, ventilator-associated pneumonia was most frequently associated with ICU admission diagnoses of postoperative care, neurologic conditions, sepsis, and cardiac complications [191].

Transmission and Common Pathogens

Gram-negative enteric bacilli and Pseudomonas spp. rarely colonize the upper respiratory tract of healthy individuals, but often do so in persons with an underlying disease, such as alcohol use disorder, and in those who are hospitalized or reside in nursing homes. Most cases of pneumonia that develop in a healthcare facility are caused by aspiration of oropharyngeal or gastric secretions colonized with hospital bacterial flora. Consequently, the prevalent causation as well as the antibiotic sensitivity pattern of resident pathogens will vary from region to region in relation to the type of facility and burden of antimicrobial usage. The selection of initial antibiotic therapy in these cases is based on the patient's risk factors for infection with a multidrug-resistant organism, such as MRSA, P. aeruginosa, K. pneumoniae, or Acinetobacter. The infectious disease and pulmonary specialty societies (IDSA and American Thoracic Society [ATS]) list the following risk factors for multidrug-resistant pathogens in patients presenting with hospital-acquired or ventilator-associated pneumonia [17]:

- Prior intravenous antibiotic use within 90 days

- Septic shock at time of ventilator-associated pneumonia

- Acute respiratory distress syndrome prior to onset of ventilator-associated pneumonia

- High frequency of antibiotic resistance in the community of residence or the hospital unit of residence

- Five or more days of hospitalization prior to onset of pneumonia

- Home infusion therapy

- Chronic dialysis within 30 days

- Family member with multidrug-resistant infection

- Immunosuppression

Approximately 50% of all cases of healthcare-associated pneumonia develop following surgical procedures, of which cardiac, abdominal, and orthopedic surgery confer the greatest risk. Viral and fungal pathogens are rare causes of hospital-acquired and ventilator-associated pneumonia in immunocompetent adults. Outbreaks of viral pneumonia may occur during influenza season, and influenza, parainfluenza, adenovirus, and respiratory syncytial virus (RSV) are involved in about 70% of those cases [17]. Candida spp. and Aspergillus fumigatus may cause pneumonia in patients who have had organ transplantation or who have a compromised immune system and neutropenia.

Hospital-Acquired Pneumonia

Among adults with no previous antibiotic exposure, the most common bacterial causes of hospital-acquired pneumonia are S. aureus, S. pneumoniae, H. influenzae, E. coli, and K. pneumoniae [17,185,186,193]. Gram-negative bacilli resistant to first-generation cephalosporins also frequently develop in late-onset hospital-acquired pneumonia. When patients who have previously received antibiotics develop late-onset hospital-acquired pneumonia, the likelihood of causation by a multidrug-resistant pathogen, such as P. aeruginosa, A. baumannii, or MRSA, approaches 40% [186]. In a study of more than 3,600 patients admitted to an ICU, Pseudomonas spp. was the cause of pneumonia in 25% of patients; MRSA in 18%; and Acinetobacter spp. in 6% [193]. Other studies have shown that S. aureus is common among patients who are in a coma or have diabetes or renal failure; P. aeruginosa is common among patients who have had a prolonged stay in the ICU, have received prior antibiotics or corticosteroids, or who have structural lung disease; and Legionella is usually found in patients who have compromised immune systems [193].

Ventilator-Associated Pneumonia

In 2009–2010, the most common pathogens reported with ventilator-associated pneumonia in adults were S. aureus (24%) and P. aeruginosa (17%), followed by K. pneumonia/oxytoca (10%), Enterobacter spp. (9%), and A. baumannii (7%) [81]. Almost half of all cases of ventilator-associated pneumonia are caused by infection with more than one pathogen [185]. As with other forms of HAI, the percentage of S. aureus resistant to methicillin has decreased in recent years [3,142]. The percentage of vancomycin-resistant E. faecium has remained stable, but the percentage of vancomycin-resistant E. faecalis increased from 6% in 2007–2008 to nearly 10% in 2009–2010 [81]. In the past decade, rates of resistance among Klebsiella spp. have increased for extended-spectrum cephalosporins (24%), carbapenems (11%), and multidrug (13%), while the rate of multidrug-resistant E. coli is stable at about 3% [81].

Prevention

The CDC has published guidelines for the prevention of hospital-acquired and ventilator-associated pneumonia, with a focus on strategies to decrease or eliminate modifiable risk factors [24]. These strategies are related to preoperative and postoperative care and measures to reduce the risk of transmission of etiologic pathogens. In addition, steps to prevent the spread of influenza virus are essential, especially during influenza season.

Hospital-Acquired Pneumonia

For many years, preventing postoperative pneumonia has been a part of initiatives to decrease complications among patients who have surgery. The Respiratory Risk Index was developed to classify patients as being at low, medium, or high risk for postoperative respiratory failure [186]. The factors in the index include the complexity of the surgery, the ASA status, and comorbidities.

Smoking triples the risk for pulmonary complications after surgery, and smoking cessation for at least 8 weeks before surgery, when possible, is recommended for current smokers [186]. The risk for complications in patients with respiratory disease or congestive heart failure can be ameliorated by optimum treatment before surgery (e.g., treatment with steroids for patients with COPD or asthma) [186].

Effective pain management after surgery can also help decrease the risk of pulmonary complications. For postoperative patients who are not mechanically intubated, the ability to cough and clear secretions is important for preventing pulmonary complications [186]. The use of incentive spirometry and deep breathing exercises are recommended, especially for people at high risk for pulmonary complications, as are frequent coughing and early movement (in bed and/or walking) [24,137,186]. Fair evidence supports the selective (rather than routine) use of a nasogastric tube after abdominal surgery [137].

Ventilator-Associated Pneumonia

Two guidelines were developed to focus specifically on the prevention of ventilator-associated pneumonia; one was jointly developed by the SHEA and IDSA, and the other was jointly developed by the Canadian Critical Care Trials Group and the Canadian Critical Care Society [19,35]. In addition, prevention of ventilator-associated pneumonia is addressed in the CDC's guidelines for preventing healthcare-associated pneumonia and in the IDSA/ATS guidelines on the management of healthcare-associated pneumonias [17,24]. The following multicomponent prevention strategy is suggested by these guidelines:

- Assessment of readiness to extubate and daily interruptions of sedation

- Elevation of the head of the bed

- Daily oral care with chlorhexidine

- Prophylaxis of peptic ulcer disease

- Prophylaxis of deep vein thrombosis

Assessment of Readiness to Extubate

Because of the increasing risk of infection as the duration of ventilation increases, the primary goal is to extubate patients as early as possible. Thus, assessment of the readiness for extubation and weaning protocols are key aspects in the preventive approach [17,193]. Daily interruption of sedation until the patient is awake has been shown to significantly decrease the number of days on mechanical ventilation, from 7.3 days to 4.9 days in one study [194]. There are risks to this approach, such as the potential for increased pain, anxiety, and desaturation. However, the use of sedation interruption has been further demonstrated to reduce the complications of prolonged mechanical ventilation [195]. The SHEA/IDSA guidelines recommend daily assessment of the readiness to wean and the use of weaning protocols [35].

Elevation of the Head of the Bed

Reducing the risk of aspiration and contamination with gastric secretions also helps to prevent the development of ventilator-associated pneumonia. The risk of aspiration has been significantly reduced by positioning the patient with the head of the bed at an angle of 30 to 45 degrees [19,196,197]. In one randomized controlled trial, there were 18% fewer cases of ventilator-associated pneumonia among intubated patients in the group assigned to the recumbent position (45 degrees) compared with the group assigned to the supine position [197]. In another study, elevation of the head of the bed at 30 degrees was the most effective measure among a group of preventive interventions, resulting in a 52% variance in the rate of ventilator-associated pneumonia [198]. Both the ATS/IDSA and SHEA/IDSA guidelines recommend maintaining the head of the bed at a 30- to 45-degree angle [17,35].

Daily Oral Care with Chlorhexidine

Oral care interventions have been suggested by some, in part because of an association between a high level of dental plaque and a high rate of colonization with aerobic pathogens, including S. aureus, gram-negative bacilli, and P. aeruginosa [199]. Research has shown that oral decontamination with chlorhexidine leads to a significant reduction in the colonization of pathogens in the oropharynx; in most studies, the intervention has not had a significant effect on the rate of ventilator-associated pneumonia or associated mortality, but more recent studies showed significant decreases in the rate of ventilator-associated pneumonia [198,200,201,202]. Including tooth brushing with chlorhexidine does not seem to add benefit [202]. Regular oral care with an antiseptic solution or chlorhexidine is recommended in the ATS/IDSA and SHEA/IDSA guidelines [17,35].

Prophylaxis of Peptic Ulcer Disease

Prophylaxis of peptic ulcer disease has evolved with some conflicting views. Antacids, histamine-2 antagonists, and sucralfate have been traditionally given to patients receiving mechanical ventilation to prevent the formation of ulcers. However, reducing the amount of gastric acid can increase the risk of colonization of gram-negative bacilli in the stomach. As a result, WHO recommended avoiding the use of these agents [15]. The CDC noted that there was insufficient evidence on the use of peptic ulcer prophylaxis and included no recommendations in this regard in its guidelines [24]. The ATS/IDSA guidelines stated that the risks and benefits of prophylaxis should be weighed carefully [17]. The most recent guidelines, developed by SHEA/IDSA, notes that histamine-2 receptor antagonists and PPIs should be avoided in patients who are not at high risk for developing a stress ulcer or stress gastritis [35].

Prophylaxis of Deep-Vein Thrombosis

There is no clear relation between prophylaxis of deep-vein thrombosis and ventilator-associated pneumonia, but the American College of Chest Physicians reported a decrease in the rate of ventilator-associated pneumonia when such prophylaxis was implemented as part of a package of interventions and included this measure in its clinical practice guidelines [203].

Other Measures

In addition to these interventions, other measures have been recommended to help prevent ventilator-associated pneumonia. One such measure is selective decontamination of the digestive tract, which involves the use of either topical antiseptic, oral antibiotics, or a brief course of systemic antibiotics [186]. A meta-analysis (28 studies) showed that selective decontamination of the digestive or respiratory tract with use of topical antiseptic or antimicrobial agents helped reduce the frequency of ventilator-associated pneumonia in the ICU [204]. The estimate of efficacy in prevention was 27% for antiseptics and 36% for antibiotics. Neither had an effect on mortality. This intervention is recommended in the SHEA/IDSA guidelines [35].

Other preventive measures are targeted primarily to the care and use of ventilator equipment and practices in direct patient care. Meticulous attention to aseptic care of the equipment is necessary, and all reusable components, such as nebulizers, should be disinfected or sterilized. Tubing circuits should be replaced after more than 48 hours, or earlier if there are signs of malfunction or contamination [24]. Changes in the design of the endotracheal tube have also been evaluated; for example, a tube with a suction port above the cuff allows for continuous aspiration of subglottic secretions. Use of this specially designed endotracheal tube has led to significantly lower rates of ventilator-associated pneumonia, as well as shorter durations of ventilation and shorter stays in the ICU [205,206]. Among patients who had major cardiac surgery, the greatest benefit was found for patients who received ventilation for more than 48 hours [206]. The cost of the tube is higher than traditional tubes but is offset by overall cost savings in preventing ventilator-associated pneumonia [205]. In one meta-analysis, subglottic secretion drainage was significantly associated with a decreased incidence of ventilator-associated pneumonia, shorter time on mechanical ventilation, and longer time to the development of ventilator-associated pneumonia [207]. The CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend subglottic secretion drainage with this tube when possible [17,24,35].

The use of noninvasive ventilation is another measure that has reduced the incidence of ventilator-associated pneumonia [24,208,209]. In one study, the incidence decreased from 20% to 8% when noninvasive ventilation was used routinely for critically ill patients with acute exacerbation of chronic obstructive pulmonary disease or severe cardiogenic pulmonary edema [210]. Again, the CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend the use of noninvasive ventilation when possible [17,24,35].

Diagnosis

The difficulty in diagnosing hospital-acquired or ventilator-associated pneumonia has been well established [17,190,211]. The clinical signs can resemble those of other, noninfectious conditions, and the specificity of clinical criteria is low [185]. According to the CDC definition, the diagnosis in adults is made on the basis of clinical signs and symptoms and results of laboratory testing or imaging and must meet one of two criteria [212].

Criterion 1

For any patient, at least one of the following:

- Fever (>38°C or >100.4°F)

- Leukopenia (<4,000 WBC/mm^3) or leukocytosis (≥12,000 WBC/mm^3)

- For adults ≥70 years of age, altered mental status with no other recognized cause

AND at least two of the following:

- New onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements

- New onset or worsening cough, or dyspnea, or tachypnea

- Rales or bronchial breath sounds

- Worsening gas exchange (e.g., oxygen desaturations [e.g., PaO_2/FiO_2 ≤240 mm Hg], increased oxygen requirements, or increased ventilator demand)

Criterion 2

Two or more serial chest radiographs showing at least one of the following:

- New or progressive and persistent infiltrate

- Consolidation

- Cavitation

- Pneumatoceles, in infants 1 year of age or younger

In patients without underlying pulmonary or cardiac disease (e.g., respiratory distress syndrome, pulmonary edema, chronic obstructive pulmonary disease), one definitive chest radiograph is acceptable.

There are no compelling data to recommend a specific approach to diagnosing hospital-acquired or ventilator-associated pneumonia. For patients who are not receiving mechanical ventilation, collection of a sputum specimen should be attempted before antibiotic therapy is begun [193,213]. Specimens for culture can be obtained by bronchoscopy with a protected specimen brush to limit contamination or by bronchoalveolar lavage. The latter method has been found to lead to higher rates of treatment than that based on the CDC definition, and one study showed that preferential sampling of the right lung improved the diagnostic accuracy of bronchoalvolar lavage [193,214,215]. However, the invasive procedure has disadvantages, including high cost, need for technical expertise, and potential for false-negative results [193,214].

The 2016 IDSA/ATS guidelines recommend collecting specimens from the lower respiratory tract for culture, preferably by noninvasive techniques and reliance on semiquantitative culture technique [17]. Noninvasive methods to obtain respiratory samples in patients with hospital-acquired (but not ventilator-associated) include spontaneous expectoration, sputum induction, nasotracheal suctioning (in a patient unable to produce a sample), and endotracheal aspiration in a patient who subsequently requires mechanical ventilation [17]. A 2012 meta-analysis found no evidence that the use of quantitative cultures of respiratory secretions resulted in decreased mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change compared with qualitative cultures in patients with ventilator-associated pneumonia [216]. In addition, there was no difference in mortality, whether invasive or noninvasive methods were used to obtain specimens.

Treatment

Treatment is complicated by two divergent needs: the need for empiric therapy with a broad-spectrum antibiotic, to aid in reducing mortality rates, and the need to avoid the indiscriminate use of antibiotics, to avoid the development of resistance. To address this complex issue, the strategy of de-escalation therapy was developed. With this treatment approach, a broad-spectrum antibiotic targeted to likely pathogens is administered, and the antibiotic regimen is altered, if necessary, after the results of cultures are known [218,219]. This strategy has reduced the mortality rate while achieving an overall objective of a more judicious use of antibiotics [218,220,221]. In one study, de-escalation therapy led to a significantly lower mortality rate compared with either escalation therapy or therapy that was neither escalated nor de-escalated (17% compared with 43% and 24%, respectively) [191].

It has been emphasized that this approach, and empiric treatment of healthcare-acquired pneumonia in general, calls for knowledge of the infection history of the healthcare facility and of individual patient units [185,193,222]. Microbiology laboratory reports can provide such details, and physicians should prescribe initial antibiotics that are likely to be active against these pathogens.

Evidence Based Practice Recommendation

In patients with suspected ventilator-associated pneumonia, the IDSA and the American Thoracic Society recommend including coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens.

https://www.idsociety.org/practice-guideline/hap_vap

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: Strong recommendation, low-quality evidence

The IDSA/ATS guidelines provide several recommendations for the management of both hospital-acquired and ventilator-associated pneumonia [17]:

- Obtain sputum samples from the lower respiratory tract for culture before beginning antibiotic therapy. Do not delay initiation of therapy for critically ill patients in order to obtain specimens.

- Begin treatment promptly, selecting an empiric antibiotic regimen that coversS. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.

- In selecting coverage for S. aureus, choose an agent active against MRSA (vancomycin or linezolid) for patients with any of the following:

- Risk factor for antimicrobial resistance

- Treatment in hospital or units where >10% of isolates are methicillin-resistant

- Patients in settings where the prevalence of MRSA is unknown

- In selecting coverage for P. aeruginosa, one antibiotic active against this pathogen is satisfactory if the patient has no risk factors for antimicrobial resistance and <10% of gram-negative isolates from the patient's unit are resistant to the agent chosen; otherwise, prescribe two antipseudomonal antibiotics from different classes.

- Consider de-escalation of antibiotics after the results of cultures and sensitivities are known and the clinical response is satisfactory.

- When an optimal antibiotic regimen is confirmed, a seven-day course of therapy is recommended, provided the rate of improvement of clinical, radiographic, and laboratory parameter is satisfactory.

- It is suggested to use serum procalcitonin levels plus clinical criteria to guide discontinuation of antibiotic therapy, rather than clinical criteria alone.

Specific treatment depends on the timing of onset and the presence or absence of risk factors for infection with multidrug-resistant organisms. For early-onset pneumonia and/or patients with no such risk factors, limited-spectrum antibiotic therapy is recommended (Table 11) [17]. For late-onset pneumonia and/or patients at increased risk for multidrug-resistant bacteria, a broad-spectrum antibiotic therapy is recommended.

Table 11: RECOMMENDED ANTIBIOTIC THERAPY FOR HEALTHCARE-ASSOCIATED PNEUMONIA ACCORDING TO SITE OF CARE

Site of Care

Recommended Regimen

General ward

Antipseudomonal cephalosporin, antipseudomonal carbapenem, or extended-spectrum ß-lactam/ß-lactamase inhibitor and antipseudomonal fluoroquinolone or aminoglycoside and anti-MRSA agent (vancomycin or linezolid)

Intensive care unit

Empiric MRSA and double coverage of Pseudomonas pneumonia

Source: [17]

Evidence Based Practice Recommendation

For patients with ventilator-associated pneumonia, the IDSA and the American Thoracic Society recommend a seven-day course of antimicrobial therapy rather than a longer duration. There exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters.

https://www.idsociety.org/practice-guideline/hap_vap

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: Strong recommendation, moderate-quality evidence

Vancomycin has been considered the first choice for treatment of MRSA infections [218]. However, the ATS/IDSA guidelines note that linezolid may have advantages over vancomycin for ventilator-associated pneumonia caused by MRSA [17]. Linezolid has been compared with vancomycin for the treatment of pneumonia caused by MRSA in many studies and has been found to improve survival and to be more cost-effective [223,224,225,226]. In one study, the rate of early microbiologic cure was not significantly higher for linezolid than for vancomycin, although there were trends favoring linezolid in several secondary clinical outcomes, such as clinical cure; duration of ventilation, hospitalization, and stay in ICU; survival time not on a ventilator; and overall survival [227]. The findings led the authors to suggest that the benefit of linezolid may be related to factors other than bacterial clearance.

According to a meta-analysis, a short fixed-course (7 or 8 days) of antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days) for patients with ventilator-associated pneumonia not caused by non-fermenting gram-negative bacilli [228]. The short course reduced the recurrence rate of ventilator-associated pneumonia caused by multiresistant organisms without adversely affecting other outcomes. Among patients with non-fermenting gram-negative bacilli, recurrence was greater after the short course. The authors confirmed these findings in a follow-up study published in 2015 [229].

Role of Inhaled Antibiotic Therapy

For cases of ventilator-associated pneumonia caused by gram-negative bacilli that are susceptible only to aminoglycosides or polymyxins the suggestion is to use both inhaled and systemic antibiotics, rather than systemic antibiotics alone [17]. It is also reasonable to consider adjunctive inhaled antibiotic treatment as a last resort for patients who are not responding to intravenous antibiotics alone, whether the infecting organism is or is not multidrug resistant.

Guideline Adherence and Quality Improvement

Adherence to guidelines for the prevention of ventilator-associated pneumonia is low, with surveys of nurses demonstrating rates of adherence to specific preventive measures ranging from 15% to 50% [187,230]. Adherence to a bundle of prevention strategies (head-of-bed elevation, oral chlorhexidine gel, sedation holds, and a weaning protocol), with 70% compliance, led to a significant reduction in ventilator-associated pneumonia, from 32 cases per 1,000 ventilator-days to 12 cases per 1,000 ventilator-days [53]. The IHI how-to guide on preventing ventilator-associated pneumonia provides several practical recommendations, and posting compliance with the ventilator bundle in a prominent place in the ICU can encourage and motivate staff (Table 12) [231].

Table 12: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT VENTILATOR-ASSOCIATED PNEUMONIA

Elevation of the Head of the Bed

Include the intervention on nursing flow sheets and discuss at multidisciplinary rounds. Encourage respiratory therapy staff to notify nursing staff if the head of the bed is not elevated or empower respiratory therapy staff to place the bed in this position with help of nursing staff. Include the intervention on order sets for initiation and weaning of mechanical ventilation, delivery of tube feedings, and provision of oral care.

Sedative Interruptions and Assessment of Readiness to Extubate

Implement a protocol to lighten sedation daily at an appropriate time to assess for neurologic readiness to extubate. Include precautions to prevent self-extubation, such as monitoring and vigilance, during the trial. Include a sedative interruption strategy in the overall plan to wean the patient from the ventilator; add the strategy to the weaning protocol, if available. Assess compliance each day on multidisciplinary rounds. Consider implementation of a sedation scale, such as the Richmond Agitation Sedation Scale (RASS) scale, to avoid oversedation.

Prophylaxis of Peptic Ulcer Disease

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form. Include intervention as an item for discussion on daily multidisciplinary rounds. Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Prophylaxis of Deep Venous Thrombosis

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form. Include intervention as an item for discussion on daily multidisciplinary rounds. Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Source: [231]

The use of physician-led multidisciplinary rounds with team decision making, checklists, and a focus on the ventilator bundle has led to significant reductions in ventilator-associated pneumonia [232,233,234]. Moderate strength evidence has shown that the use of audit and feedback and reminder systems improve adherence to an overall ventilator-associated pneumonia bundle as well as reduce infection rates [1]. Education sessions have also led to enhanced knowledge and practice among healthcare professionals caring for intubated patients [235].

The lack of adherence to guideline-directed treatment of pneumonia cases associated with healthcare facilities is evidenced by wide variations in practice. For example, one study showed that more than 100 different antibiotic regimens had been prescribed as initial treatment and that de-escalation therapy was used for only 22% of patients [191]. Adherence rates for treatment of pneumonia associated with healthcare facilities have been reported to be lower than rates of adherence to guidelines for treatment of community-acquired pneumonia. In one survey, guideline-recommended antibiotics were used 9% of the time for healthcare-associated pneumonia compared with 78% of the time for community-associated pneumonia [236]. This lack of adherence was not due to unfamiliarity or disagreement with the guidelines; 71% of the survey respondents said they were aware of the guidelines, and 79% said they agreed with and practiced according to them. It is reasonable to expect that strategies used to enhance adherence to guidelines in the community-acquired pneumonia setting would also be effective in the setting of hospital-acquired and ventilator-associated pneumonia. Such strategies include feedback on performance, reminder systems, standardized order sets, and education emphasizing outcomes and cost-effectiveness.

INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

Bloodstream infections, such as septicemia and bacteremia, can develop from other types of HAIs or infections at other sites in the body, but about half are caused by intravascular devices, primarily central venous catheters [87]. It has been estimated that 5.3 infections occur per 1,000 catheter-days in the ICU [27,39,237]. The number of infections reported to NHSN has increased substantially, with 27,766 reported in 2009–2010, compared with 18,651 reported in 2007–2008, perhaps in part a consequence of improved surveillance [81]. These infections are also the most costly, with a mean cost of more than $50,000 per infection [238]. In recent years, following implementation of the CDC/NHSN national action plan, the incidence of hospital-acquired intravascular bloodstream infection has declined somewhat. The 2016 progress report showed an 11% decrease in central line-associated bloodstream infections between 2015 and 2016 [66].

Risk Factors

There are several types of intravascular catheters, and the risk of intravascular device-related bloodstream infections varies according to type. These catheters include:

- Peripheral venous catheters

- Peripheral arterial catheters

- Midline catheters

- Nontunneled central venous catheters

- Pulmonary artery catheters

- Pressure monitoring system catheters

- Peripherally inserted central venous catheters

- Tunneled central venous catheters

- Totally implantable devices

The nontunneled central venous catheter accounts for the majority of all intravascular device-related bloodstream infections [27]. Peripheral catheters (arterial and venous) are rarely associated with bloodstream infections, and totally implantable catheters are associated with the lowest risk [27]. A systematic review of 200 prospective studies of intravascular device-related bloodstream infections indicated that the level of risk associated with various types of devices can vary substantially depending on whether risk is expressed as the number of infections per 100 intravascular device-days or 1,000 intravascular device-days [239]. The risks associated with peripheral intravenous catheters were much higher when expressed over 1,000 intravascular device-days, pointing to the need for prevention strategies targeted to all types of devices [239].

Other risk factors are the length of time the catheter is in place and factors related to the patient's health status (severity of illness, presence of burns or surgical wounds, compromised immune system, nutritional status) [34].

Transmission and Common Pathogens

Intravascular device-related bloodstream infections are transmitted by both endogenous and exogenous routes. The most common cause of infection related to short-term catheters is migration of skin organisms at the site of insertion, with the organisms traveling along the surface of the catheter and colonization at the catheter tip [27]. Direct contamination of the catheter or catheter hub by contact with hands or contaminated fluids or devices is another cause [27]. Hematogenous seeding from another focus of infection is a less common cause, and contamination of infusion fluid is rare [27].

The most commonly reported pathogens for intravascular device-related bloodstream infections in 2015 were S. aureus (23%), Streptococcus spp. (12%), coagulase-negative staphylococci (12%), Enterococcus spp. (12%), Candida spp. (12%), E. coli (8%), and K. pneumonia/oxytoca (6%) [3].

The percentage of resistant S. aureus was stable compared with previous data, with a rate of 55% in 2009–2010 [81]. Among the drug-resistant pathogens with the greatest increases compared with data for 2007–2008 were multidrug-resistant E. coli (4% vs. 2%), extended spectrum cephalosporin-resistant E. coli (19% vs. 12%), aminoglycoside-resistant P. aeruginosa (10% vs 7%), and carbapenems-resistant A. baumannii (62% vs. 50%) [81].

Prevention

The CDC guidelines on the prevention of intravascular device-related bloodstream infections were published in 2002 and updated in 2011 [27]. The most recent guidelines emphasize the following points [27]:

- Using maximal sterile barrier precautions during central venous catheter insertion

- Using a >0.5% chlorhexidine skin preparation with alcohol for antisepsis

- Avoiding routine replacement of central venous catheters as a strategy to prevent infection

- Using antiseptic/antibiotic impregnated short-term central venous catheters and chlorhexidine-impregnated sponge dressings if the rate of infection is not decreasing despite adherence to other strategies

- Educating and training healthcare providers who insert and maintain catheters

The CDC guidelines define maximal sterile barrier precautions as the use of a cap, mask, sterile gloves, sterile gown, and a sterile full-body drape during insertion of an intravascular device (level IB) [27]. A sterile sleeve should also be used to protect pulmonary artery catheters during insertion (level IB) [27].

The CDC guidelines recommend use of an antiseptic of 70% alcohol, tincture of iodine, or chlorhexidine gluconate solution with alcohol before insertion of peripheral venous catheters (level IB) and a >0.5% chlorhexidine preparation with alcohol before insertion of central venous catheters or peripheral artery catheters and during dressing changes (category IA) [27]. The guidelines note that chlorhexidine preparations with alcohol have not been compared with povidone iodine in alcohol and thus no recommendation can be made in this regard [27]. In a meta-analysis of eight studies (4,143 catheters, primarily central line catheters), the chlorhexidine solution was found to reduce the risk for bloodstream infection by 49% [240]. In a subsequent study, use of this solution led to a 1.6% decrease in the rate of bloodstream infection, a 0.23% decrease in the incidence of death, and a cost savings of $113 per catheter used compared with povidone-iodine solutions [241].

Most intravascular device-related bloodstream infections develop at the site of insertion, due to the density of skin flora [27]. Rates of infection vary according to insertion site, with catheters in the internal jugular vein being associated with a greater risk of infection than catheters in the subclavian vein [27,242,243]. A 2005 study indicated that the site of insertion was not a risk factor for infection when experienced or trained healthcare workers inserted the catheters [244]. However, such experience will not always be the norm, and the subclavian vein has been recommended by the CDC as the preferred site when possible [27].

Another strategy to prevent infection has been the development of central venous catheters with antimicrobial coatings. These coatings have included a combination of chlorhexidine and silver sulfadiazine and a combination of minocycline and rifampin [245]. Both types of catheters are associated with a significantly lower rate of infection than that associated with standard catheters. When compared with each other, catheters impregnated with minocycline and rifampin were 12 times less likely to cause bloodstream infections than those coated with chlorhexidine and silver sulfadiazine [246]. The chlorhexidine-silver sulfadiazine coating has since been enhanced, and these second-generation catheters have significantly reduced bacterial colonization, with a trend toward fewer bloodstream infections [247]. Each coating adds to the cost of the catheter, and cost-effective analyses are necessary.

On the basis of studies of intravascular device-related bloodstream infections, a bundle consisting of five preventive measures has been recommended:

- Compliance with appropriate hand hygiene

- Use of maximal barrier precautions

- Use of 2% chlorhexidine solution for skin antisepsis

- Selection of optimal site for the catheter, with the subclavian vein as the preferred site for nontunneled catheters

- Daily review of the need for the line, with prompt removal if line is deemed unnecessary

Diagnosis

As defined by the CDC, bloodstream infections fall into two categories: laboratory-confirmed infection and clinical sepsis. Clinical sepsis is no longer used in reporting on adults and children and is restricted to use for neonates and infants [123]. For a diagnosis of laboratory-confirmed bloodstream infection, one of the two following criteria must be met [212].

Criterion 1

Recognized pathogen found on one or more blood cultures and organism cultured from blood is not related to an infection at another site

Criterion 2

At least one of the following signs or symptoms:

- Fever (>38 degrees Centigrade)

- Chills (with no other recognized cause)

- Hypotension (with no other recognized cause)

and signs and symptoms and positive laboratory results are not related to an infection at another site and common skin contaminant (e.g., diphtheroids, Bacillus spp., Propionibacterium spp., coagulase-negative staphylococci, viridans group streptococcus, Aerococcus spp., or Micrococcus spp.) is cultured from two or more blood cultures drawn on separate occasions. Criterion elements must occur within a timeframe that does not exceed a gap of one calendar day [212].

There are several approaches to diagnosing an intravascular device-related bloodstream infection. A meta-analysis of 51 studies published between 1966 and 2004 was designed to identify which method was the most accurate [248]. The studies had involved the eight most commonly used diagnostic methods: culture (qualitative, semiquantitative, or quantitative) of a catheter segment; culture (qualitative or quantitative) of blood obtained through the catheter; paired quantitative cultures (blood obtained through the catheter as well as from a peripheral site); differential time to positivity (monitoring of cultures of blood obtained through the catheter and from a peripheral site); and acridine orange leukocyte cytospin. The paired cultures method was the most accurate, with a pooled specificity of 99%, followed by qualitative culture of blood drawn through the catheter and acridine orange leukocyte cytospin [248].

Treatment

The management of an intravascular device-related bloodstream infection does not always include removal of the device. Authors of consensus-based treatment guidelines advise that the decision to remove a tunneled catheter or implanted device suspected to be the source of bacteremia or fungemia should be based on the following factors [249]:

- Underlying health status of the patient

- Type of catheter

- Strength of the evidence that the catheter is the source of the infection

- Responsible pathogens

- Presence of local or systemic complications

Evidence Based Practice Recommendation

The Centers for Disease Control and Prevention recommends using a chlorhexidine/silver sulfadiazine- or minocycline/rifampin-impregnated central venous catheter in patients whose catheter is expected to remain in place longer than five days if, after successful implementation of a comprehensive strategy to reduce rates, the central line-associated bloodstream infection rate is not decreasing.

https://www.cdc.gov/hai/pdfs/bsi-guidelines-2011.pdf

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: IA (Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies)

Nontunneled central venous catheters should be removed in most cases of bacteremia or fungemia [249]. Antibiotic therapy alone has resolved 80% of infections caused by coagulase-negative staphylococcal bacteria, but in cases of infection with S. aureus or Candida, infection has persisted when the catheter has been maintained [249,250].

One strategy was developed in an attempt to retain the catheter. With so-called antibiotic lock therapy, antibiotics are instilled through the catheter after injection of an anticoagulant, locking a high concentration of the antibiotic in the lumen [250]. This approach is used in combination with systemic antibiotic therapy, and the antibiotics used have included vancomycin, cefazolin, and clindamycin. Fluconazole and amphotericin B have been used occasionally for infection with Candida spp., and another flush solution (low concentrations of minocycline and EDTA) has demonstrated activity against staphylococci, gram-negative bacilli, and Candida spp. [250]. Early empiric antifungal therapy is important if infection with Candida is suspected, as delayed treatment has been associated with higher mortality [251].

The guidelines for treatment of intravascular device-related bloodstream infection suggest antimicrobial selection according to the known or suspected pathogen (Table 13) [249]. Empiric antibiotic therapy should be selected according to clinical features and context, with due consideration for the local prevalence of resistant pathogens. Vancomycin is recommended as initial treatment for coagulase-negative staphylococci and for S. aureus until the sensitivity to methicillin is determined, at which point treatment should be changed to semisynthetic penicillin if the identified pathogen is sensitive [249]. Vancomycin should not be used as a front-line treatment for infections with methicillin-sensitive S. aureus.

Table 13: TREATMENT OF INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS IN ADULTS

Pathogen

Preferred Antimicrobial Agent

Staphylococcus aureus

Sensitive to methicillin

Resistant to methicillin

Resistant to vancomycin

Penicillinase-resistant penicillin

Vancomycin

Daptomycin or linezolid

Coagulase-negative staphylococci

Sensitive to methicillin

Resistant to methicillin

Penicillinase-resistant penicillin

Vancomycin

Enterococcus spp.

Sensitive to ampicillin

Resistant to ampicillin/sensitive to vancomycin

Resistant to ampicillin/resistant to vancomycin

Ampicillin or (ampicillin or penicillin) + aminoglycoside

Vancomycin + aminoglycoside

Linezolid or daptomycin

Escherichia coli and Klebsiella spp.

ESBL negative

ESBL positive

Third-generation cephalosporin

Carbapenem

Enterobacter spp. and Serratia marcescens

Carbapenem

Acinetobacter baumannii

Ampicillin/sulbactam or carbapenem

Pseudomonas aeruginosa

Fourth-generation cephalosporin or carbapenem or antipseudomonal beta-lactam plus aminoglycoside

Burkholderia cepacia

SMZ-TMP or carbapenem

Candida albicans or Candida spp.

Echinocandin or fluconazole

Corynebacterium spp.

Vancomycin

Mycobacterium spp.

Susceptibility varies by species

SMZ-TMP: sulfamethoxazole/trimethoprim.

Source: [249]

If fever or other signs of infection persist after removal of the catheter, the patient should be evaluated for complications such as septic phlebitis, distant abscess, and endocarditis. Bacterial endocarditis has been found in 25% of patients with intravascular device-related bloodstream infection caused by S. aureus [250]. The findings of one study suggested that patients with MRSA bacteremia and underlying chronic liver disease were at higher risk for endocarditis [252].

Guideline Adherence and Quality Improvement

As is the case with guidelines for other HAIs, adherence to prevention guidelines is suboptimal. A survey of more than 500 hospitals showed that, while adherence to the two most strongly recommended prevention strategies—maximal sterile barrier precautions and antisepsis with chlorhexidine gluconate—was good at VA hospitals (84% and 91%, respectively), the rates were lower at non-VA hospitals (71% and 69%) [253]. Adherence to a combination of maximal sterile barrier precautions, chlorhexidine gluconate, and avoidance of central line changes was even lower: 62% and 44%, respectively [253]. In another study, central venous catheters were routinely changed to prevent infection in about 15% of hospitals [254].

Implementing a prevention bundle has significantly reduced intravascular device-related bloodstream infections: the decrease was from 5.9 per 1,000 catheter-days to 3.1 per 1,000 in one study and from 7.7 per 1,000 catheter-days to 1.4 per 1,000 in another [56,232]. A how-to guide developed by the IHI provides practical suggestions for implementing the bundle (Table 14) [255]. A checklist should be developed for use when inserting a catheter to ensure adherence to all prevention strategies [34].

Table 14: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

Hand Hygiene

Include hand hygiene as part of the checklist for placement of central lines. Keep soap/alcohol-based hand hygiene dispensers prominently placed, and make universal precautions equipment, such as gloves, available only near hand sanitation equipment. Post reminder signs at the entry and exits to patient rooms. Initiate a campaign using posters including photos of celebrated hospital physicians/employees recommending hand hygiene. Create an environment in which reminding each other about hand hygiene is encouraged.

Maximal Barrier Precautions

Include maximal barrier precautions as part of the checklist for placement of central lines. Keep equipment stocked in a cart for central line placement to avoid the difficulty of finding necessary equipment to institute maximal barrier precautions. If a full-size drape is not available, apply two drapes to cover the patient or consult with the operating room staff to determine how to obtain full-size sterile drapes, as they are used routinely in surgical settings.

Chlorhexidine Skin Antisepsis

Include chlorhexidine antisepsis as part of the checklist for placement of central lines. Include chlorhexidine antisepsis kits in carts or grab bags storing central line equipment. (Many prepared central line kits include povidone-iodine kits, and these must be avoided.) Ensure that the solution dries completely before attempting to insert the central line.

Selection of Optimal Insertion Site

Include optimal site selection as part of the checklist for placement of central lines, with room to note appropriate contraindications (e.g., bleeding risks).

Daily Review of Need for Central Line

Include daily review of the need for the central line as part of multidisciplinary rounds. Include assessment for removal of central lines as part of daily goal sheets. Record time and date of line placement for record-keeping purposes and evaluation by staff to aid in decision making.

Source: [255]

Adherence to appropriate postinsertion care has been the focus of some studies. In one study, there were breaches in postinsertion care in 45% of cases [256]. The primary breaches were non-intact dressing (158 breaches per 1,000 catheter-days) and incorrectly placed caps and taps (156 breaches per 1,000 catheter-days) [256]. The rate of intravascular device-related bloodstream infection during the study period was 5.5 per 1,000 catheter-days [256]. In another study, nursing staff used a postinsertion care bundle that consisted of the following: daily inspection of the insertion site; site care if the dressing was wet, soiled, or had not been changed for 7 days; documentation of ongoing need for the catheter; proper application of a chlorhexidine gluconate-impregnated sponge at the insertion site; appropriate hand hygiene before handling the intravenous system; and application of an alcohol scrub to the infusion hub for 15 seconds before each entry [257]. Adherence to this bundle led to a significant decrease in intravascular device-related bloodstream infections, from 5.7 per 1,000 catheter-days to 1.1 per 1,000 catheter-days [257].

The availability of policies regarding prevention strategies is also lacking. Although 80% of 25 ICUs (10 hospitals) had written policies for insertion of central venous catheters, only 28% had a policy requiring maximal sterile barrier precautions, and 36% and 60% of the units required hand hygiene before accessing a central venous catheter or treating the exit site, respectively [254]. A formal educational program on catheter insertion was in place at 52% of the units [254]. Education, in the form of self-study modules with pretest and post-test, along with didactic lectures and integration of evidence-based guidelines have been associated with increases in adherence to recommended practices and decreases in bloodstream infections [258].

A systematic review demonstrated moderate strength of evidence for audit and feedback and provider reminder systems, along with base strategies [1].

CLOSTRIDIUM DIFFICILE INFECTIONS

C. difficile is the most common cause of infectious diarrhea among adults in healthcare settings [32]. Colonization with the inactive spore is much more prevalent in the healthcare setting than in the community. Studies show that the rate of asymptomatic colonization is approximately 2% to 3% in the community, 3% to 26% among adult inpatients in acute care hospitals, and 5% to 7% among elderly patients in long-term care facilities [32]. In contrast, the prevalence of C. difficile in the stool of asymptomatic adults without recent healthcare facility exposure is <2% [32]. Although colonization with C. difficile is relatively common among patients in healthcare facilities, clinical illness emerges only when there is production of toxins (A and B) that cause inflammation, secretion of mucous and fluid, and damage to the mucosa, resulting in diarrhea or colitis [259]. Disease can further progress to toxic megacolon, sepsis with or without intestinal perforation, and death [260,261].

The incidence of C. difficile-associated diarrhea has increased dramatically in recent decades. The incidence more than tripled between the 1990s and 2005 (from 30 to 40 cases per 100,000 individuals to 131 per 100,000) [262]. During this same time, some bacterial strains have become more virulent and perhaps more resistant [263]. As with other HAIs, C. difficile infection in the healthcare setting has been associated with increased length of stays, increased mortality, and higher costs [129,264,265,266,267].

Beginning in 2009, the CDC has conducted ongoing surveillance of C. difficile infection in the community and healthcare environment through the Emerging Infections Program, a sentinel network of 10 reporting sites in 35 counties of 10 states. Data from 2015 showed a total of 17,340 C. difficile infections reported within this population group of 11,682,000 persons, for a total annual rate of 149 incident infections per 100,000 population [192]. The rate of C. difficile HAI was 83 cases per 100,000, compared with the community-based incidence of 66 per 100,000. The risk increases with age, and the elderly are especially vulnerable. Among persons older than 65 years of age the rate of HAI caused by this pathogen was 378 cases per 100,000 patients [192]. Serial surveys show that C. difficile accounts for 15% of all HAIs, and the incidence has remained stable during the period 2011 to 2015. When extrapolated to the nation at large, CDC data analysis shows that C. difficile causes more than 450,000 incident infections in the United States each year and is associated with approximately 29,000 deaths [192]. The 2016 HAI progress report showed a more positive trend, with about a 8% decrease in C. difficile infections reported from acute care hospitals between 2015 and 2016 [66].

Risk Factors

The primary risk factors for infection with C. difficile are antibiotic use, older age, and hospitalization [32]. Exposure to antibiotic agents is the most modifiable risk factor, an association reported in more than 96% of hospitalized patients in one study [268]. Antibiotics increase the risk by suppressing or altering normal bowel microflora, thereby facilitating overgrowth of relatively dormant C. difficile organisms. Many antibiotics have been implicated, but fluoroquinolones, cephalosporins, carbapenems, and clindamycin have been found to confer high risk [32]. The likelihood of infection increases with longer hospitalizations, with a 15% to 45% risk of colonization among patients hospitalized for one to three weeks [268].

Transmission

C. difficile is an exogenous infection that is transmitted person-to-person through the fecal-oral route and possibly via contact with contaminated environmental surfaces (e.g., bedding, commodes, bath tubs).

Prevention and Control

Guidelines developed by SHEA/IDSA in 2010, and updated in 2018, offer recommendations for prevention, diagnosis, and management of C. difficile [32]. Control measures include restriction of antibiotic use; isolation precautions for healthcare workers, patients, and visitors; and environmental cleaning and disinfection (Table 15) [32]. The guidelines note that the use of antibiotics should be minimized and that an antibiotic stewardship program should be developed and implemented by all hospitals [32]. Appropriate hand hygiene is essential, and soap and water should be used rather than alcohol-based handrubs, as alcohol is not effective at killing C. difficile spores [32]. Gowns, gloves, and contact precautions for the duration of diarrhea are also recommended. The guidelines suggest that removing environmental sources of C. difficile, such as replacing rectal thermometers with disposable ones, can help reduce the incidence of C. difficile infection. The guidelines also note that the following are not recommended: routine environmental screening for C. difficile (level III, C); routine identification of asymptomatic carriers for infection control purposes (level III, A); and use of probiotics to prevent infection (level I, B) [32].

Table 15: SHEA/IDSA GUIDELINES FOR INFECTION CONTROL MEASURES FOR CLOSTRIDIUM DIFFICILE

Restriction of Antibiotic Use

- Minimize the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed (level II, A).

- Implement an antimicrobial stewardship program (level II, A). Antimicrobials to be targeted should be based on the local epidemiology and the C. difficile strains present, but restricting the use of fluoroquinolones, cephalosporin and clindamycin (except for surgical antibiotic prophylaxis) may be particularly useful (level III, C).

Measures for Healthcare Workers, Patients, and Visitors

- Healthcare workers and visitors must use gloves (level I, A) and gowns (level III, B) on entering the room of a patient with C. difficile infection.

- Emphasize compliance with appropriate hand hygiene (level II, A).

- Instruct visitors and healthcare workers to wash hands with soap (or antimicrobial soap) and water after caring for or contacting patients with C. difficile infection (level III, B).

- Use a private room with contact precautions for patients with C. difficile infection (level III, B); cohort patients if single rooms are not available, and provide a dedicated commode for each patient (level III, C).

- Maintain contact precautions until 48 hours after diarrhea has resolved (level III, C).

Environmental Cleaning and Disinfection

- Identify and remove environmental sources of C. difficile, to reduce the incidence of infection (level II, B).

- Use chlorine-containing cleaning agents or other sporicidal agents to address environmental contamination in areas associated with increased rates of C. difficile infection (level II, B).

Source: [32]

Diagnosis

Infection with C. difficile is diagnosed on the basis of clinical findings and the results of laboratory testing [32]. C. difficile infection is defined as (1) the presence of diarrhea (passage of three or more unformed stools in up to 24 consecutive hours) and (2) positive results on stool testing for the presence of toxigenic C. difficile or its toxins or findings of pseudomembranous colitis on colonoscopy or histopathologic evaluation [32]. Diarrhea may be absent in up to 20% of patients with fulminant colitis or postoperative ileus [268]. Other symptoms include fever, nausea, vomiting, abdominal pain or tenderness, and loss of appetite, but these symptoms are found in about half of patients with the infection [32,259].

Evidence Based Practice Recommendation

The IDSA and the SHEA assert that patients with unexplained and new-onset of three or more unformed stools in 24 hours are the preferred target population for testing for C. difficile infection.

https://academic.oup.com/cid/article

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: Weak recommendation, very low quality of evidence

Diagnostic stool testing should be done only on unformed stool (level II, B), and testing for asymptomatic patients is not useful (level III, B) [32]. Repeat testing during the same episode of diarrhea is discouraged, as it does not provide clinically useful information (level II, B) [32].

Several diagnostic tests are available to detect C. difficile, and they vary in terms of sensitivity, specificity, and turnaround times. Stool culture is the most sensitive test, but it is not clinically practical because of the slow turnaround time [32]. The sensitivity of cell cytotoxicity assay has been reported to range from 67% to 100%, whereas enzyme immunoassay testing for toxins A and B has a sensitivity ranging from 63% to 94% and a specificity of 75% to 100% [32]. Enzyme immunoassay testing is rapid and less expensive than other tests but it is a suboptimal choice compared with cell cytotoxicity assay (level II, B) [32]. The SHEA/IDSA guidelines note that polymerase chain reaction testing appears to be rapid, sensitive, and specific, but more data on its usefulness are needed before it can be recommended for routine use (level II, B) [32].

Treatment

Evidence Based Practice Recommendation

According to the IDSA and the SHEA, either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of C. difficile infection. The dosage is vancomycin 125 mg orally four times per day or fidaxomicin 200 mg twice daily for 10 days.

https://academic.oup.com/cid/article/66/7/e1/4855916

Last Accessed: January 28, 2019

Strength of Recommendation/Level of Evidence: Strong recommendation, high quality of evidence

The most important step in treating C. difficile-associated diarrhea is to discontinue the inciting antibiotic as soon as possible [32]. This approach alone will lead to resolution of diarrhea in approximately 15% to 25% of patients with mild infection [259,268]. Antibiotic treatment of the diarrhea should not begin until the culture or toxin assay results are known, as approximately 30% of hospitalized patients with antibiotic-associated diarrhea will have C. difficile infection [32]. However, if severe or complicated C. difficile infection is suspected, empirical treatment should be started as soon as the diagnosis is suspected (level III, C) [32]. The SHEA/IDSA guidelines recommend either vancomycin or fidaxomicin over metronidazole for an initial episode of C. difficile gastrointestinal infection, whether mild or moderately severe. The dosage is vancomycin 125 mg orally four times per day or fidaxomicin 200 mg twice daily for 10 days [32]. Table 16 outlines the guideline recommendations for treatment according to severity of illness [32].

Table 16: SHEA/IDSA GUIDELINES FOR THE TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION ACCORDING TO SEVERITY OF DISEASE

Severity of Disease

Preferred Treatment

Mild to severe (WBC ≤15,000)

Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days (Strong/High)

Alternative: Metronidazole 500 mg three times daily orally

Severe (WBC >15,000, serum creatinine >1.5 mg/dL)

Vancomycin PO 125 mg, four times per day for 10 days OR fidaxomicin 200 mg twice daily for 10 days (Strong/High)

Fulminant (hypotension, ileus, or megacolon)

Vancomycin 500 mg, four times per day by mouth or nasogastric tube

If ileus, add rectal administration of vancomycin and intravenous metronidazole 500 mg every 8 hoursa (Strong/Moderate)

Recurrent

First recurrence

Second recurrence or more

Vancomycin PO 125 mg four times daily for 10 days if metronidazole was used for initial treatment; fidaxomicin 200 mg twice daily for 10 days if vancomycin was used initially

Vancomycin in a prolonged tapered and pulsed regimen OR vancomycin standard 10-day regimen followed by rifaximin 400 mg three times daily for 20 days

aIf ileus is present, vancomycin may be given per rectum as a retention enema, at a dose of 500 mg/100 mL normal saline, every 6 hours.

Source: [32]

Surgical management may be necessary for severe, fulminant cases of C. difficile colitis. In such cases, subtotal colectomy with preservation of the rectum is advisable; alternatively, a diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes may lead to improved outcomes [32].

In addition to infection-directed antibiotics, treatment of C. difficile infection also includes fluid replacement, and electrolyte normalization [269]. The use of antiperistaltic agents should be avoided, as they may obscure symptoms, lead to retained toxin, and precipitate toxic megacolon (level III, C) [32]. The use of probiotics has been suggested as an adjunct to antibiotic treatment, but a systematic review found insufficient data to support probiotics as adjunct therapy and no evidence to support its use alone [270].

6. INFECTION CONTROL

The development of formal infection control programs in hospitals and other healthcare facilities was spurred by the Joint Commission accreditation standards for infection control, published in 1976. According to the standards, accredited facilities must have a program for the surveillance, prevention, and control of HAIs [87]. In 1974, the CDC designed the Study on the Efficacy of Nosocomial Infection Control project to determine if infection surveillance and infection control programs could reduce the number of HAIs [271]. The nationwide study evaluated rates of HAIs in hospitals before and after the implementation of infection control programs; the researchers noted that programs with four components were associated with a one-third reduction in the rate of HAIs: an effective hospital epidemiologist, one infection control practitioner for every 250 beds, active surveillance mechanisms, and ongoing control efforts [272]. With the increased focus on prevention of HAIs, infection control professionals have come to be known as infection preventionists [273].

An infection control program is usually overseen by a committee chaired by an infectious disease physician and consisting of staff representing departments throughout the facility, such as nursing, pharmacy, surgery, clinical microbiology, central sterilization services, housekeeping, maintenance, food services, and laundry services. Among the responsibilities of an infection control program are to:

- Conduct surveillance of HAIs

- Develop policies regarding prevention and control, such as hand hygiene and precautions

- Ensure adherence to standards for environmental services

- Establish a program to monitor and evaluate antimicrobial therapy

- Provide education to healthcare workers about adherence to infection control policies

- Develop guidelines for outbreak preparedness

The policies and procedures in each of these areas, as well as guidelines for adherence, should be documented in an infection control manual.

All physicians and staff within a healthcare facility have responsibility for helping to advance infection control goals. Physicians should assume the following responsibilities [15]:

- Protect their patients from other infected patients or staff

- Comply with the practices approved by the infection control committee

- Obtain appropriate microbiologic specimens when infection is suspected or present

- Notify the infection control committee about confirmed cases of HAIs

- Comply with the institution's recommendations regarding the use of antibiotics

- Educate patients, visitors, and staff about techniques to prevent the transmission of infection.

As direct providers of care in a healthcare facility, the nursing staff plays a substantial role in carrying out infection control practices. Nursing administrators should promote the development and enhancement of nursing techniques, review nursing policies regarding aseptic techniques, and offer educational training programs on best practices [15]. Nurses on patient care units have the following responsibilities [15]:

- Comply with established infection control practices

- Monitor aseptic techniques, including handwashing and use of isolation precautions

- Report evidence of infection immediately to the attending physician

- Initiate patient isolation and order culture specimens when infection is suspected and a physician is not immediately available

- Limit patient exposure to infections from others (visitors, hospital staff, other patients, or equipment used for diagnosis or treatment)

Community hospitals have had success with participating in an infection control network. In 12 community hospitals in North Carolina and Virginia that joined such a network (the Duke Infection Control Outreach Network), there were significant decreases in the annual rates of healthcare-associated bloodstream infections, infection and colonization with MRSA, ventilator-associated pneumonia, and exposure of staff to bloodborne pathogens [274]. After network participation for five years, the average decrease in the number of device-related infections and HAIs due to MRSA decreased by an average of 50% [275]. The cost savings was approximately $100,000 per hospital, and in total, an estimated 52 to 105 deaths related to ventilator-associated pneumonia or intravascular device-related infection were prevented [275].

Most prevention and control policies focus on general measures, such as surveillance; adherence to guidelines for hand hygiene, influenza vaccination, precautions and isolation techniques, management of drug-resistant micro-organisms, and standards for environmental services; and education of healthcare workers as well as patients and families.

SURVEILLANCE

Surveillance is an essential component of an infection control program. The infection control team has traditionally conducted surveillance through open communication with the nursing staff and physicians and meticulous review of patient records and microbiology results. The infections most commonly targeted for surveillance are those associated with substantial costs in terms of morbidity, mortality, or economics, and those difficult to treat. In addition, infections with a predilection for epidemics are a focus. The data gathered should be evaluated in relation to regional and national norms, and temporal trends should also be noted. Continuing analysis of the data allows the infection control team to evaluate the efficacy of programs designed to enhance compliance with hospital-wide strategies to prevent HAIs.

HAND HYGIENE

Hand hygiene is the most important preventive measure in hospitals, and the Joint Commission mandates that hospitals and other healthcare facilities comply with the Level I recommendations in the CDC guidelines for hand hygiene [26]. The CDC guidelines state the specific indications for washing hands, the recommended hand hygiene techniques, and recommendations about fingernails and the use of gloves (Table 17) [26]. The guidelines also provide recommendations for surgical hand antisepsis, selection of hand-hygiene agents, skin care, educational and motivational programs for healthcare workers, and administrative measures.

Table 17: SUMMARY OF CDC RECOMMENDATIONS FOR HAND HYGIENE

Indications for Hand Hygiene

Wash hands with nonantimicrobial or antimicrobial soap and water when they are visibly dirty, contaminated, or soiled. If hands are not visibly soiled, use an alcohol-based handrub for routinely decontaminating hands.

Specific Indications

Wash hands before patient contact and before putting on gloves for insertion of invasive devices that do not require surgery (e.g., urinary catheters or intravascular devices). Wash hands after:

- Contact with a patient's skin

- Contact with body fluids or excretions, nonintact skin, or wound dressings

- Removing gloves

Recommended Handrub Technique

Apply to palm of one hand, rub hands together, covering all surfaces until dry.

Recommended Handwashing Techniques

- Wet hands with water, apply soap, and rub hands together for at least 15 seconds.

- Rinse and dry with disposable towel.

- Use towel to turn off faucet.

Fingernails and Artificial Nails

Keep tips of natural nails to a length of ¼ inch. Do not wear artificial nails during direct contact with high-risk patients (e.g., patients in intensive care unit or operating room).

Use of Gloves

Use gloves when there is potential for contact with blood or other potentially infectious materials, mucous membranes, or nonintact skin. Change gloves after use for each patient.

Source: [26]

Despite the simplicity of the intervention, its substantial impact, and wide dissemination of the guidelines, compliance with recommended hand hygiene has ranged from 16% to 81%, with an average of 30% to 50% [26,39,40,41,42] A 2010 systematic review of studies on compliance with hand-hygiene guidelines in hospital care found an overall median compliance rate of 40%, with lower rates in intensive care units (30% to 40%) than in other settings (50% to 60%), lower rates among physicians than among nurses (32% and 49%, respectively), and lower rates before (21%) rather than after (47%) patient contact [276]. Among the reasons given for the lack of compliance are inconvenience, understaffing, and damage to skin [26,40,87]. The development of effective alcohol-based handrub solutions addresses these concerns, and studies have demonstrated that these solutions, as well as performance feedback and accessibility of materials, have increased compliance [41,276,277,278]. The CDC guidelines recommend the use of handrub solutions on the basis of several advantages, including [26]:

- Better efficacy against both gram-negative and gram-positive bacteria, mycobacteria, fungi, and viruses than either soap and water or antimicrobial soaps (such as chlorhexidine)

- More rapid disinfection than other hand-hygiene techniques

- Less damaging to skin

- Time savings (18 minutes compared with 56 minutes per 8-hour shift)

The guidelines suggest that healthcare facilities promote compliance by making the handrub solution available in dispensers in convenient locations (such as the entrance to patients' room or at the bedside) and provide individual pocket-sized containers [26]. The handrub solution may be used in all clinical situations except for when hands are visibly dirty or are contaminated with blood or body fluids. In such instances, soap (either antimicrobial or nonantimicrobial) and water must be used.

However, there are many other reasons for lack of adherence to appropriate hand hygiene, including denial about risks, forgetfulness, and belief that gloves provide sufficient protection [26,40]. These reasons demand education for healthcare professionals to emphasize the importance of hand hygiene. Also necessary is research to determine which interventions are most likely to improve hand-hygiene practices, as no studies have demonstrated the superiority of any intervention [279]. Single interventions are unlikely to be effective [279].

Several single-institution studies have demonstrated that appropriate hand hygiene reduces overall rates of HAIs, including those caused by MRSA and VRE [42,277,278]. However, rigorous evidence linking hand hygiene alone with the prevention of HAIs is lacking, making it difficult to evaluate the true impact of hand hygiene alone in reducing HAIs [56]. One challenge in evaluating the impact of hand hygiene is that a variety of methodologies have been used to assess compliance (surveys, direct observation, measurement of product use), each with its own advantages and disadvantages [280]. Measuring the effect of appropriate hand hygiene alone is also difficult because the intervention is often one aspect of a multicomponent strategy to reduce infection [42]. Lastly, as noted previously, the development of HAIs is complex, with many contributing factors. Although more research is needed to assess the individual impact of appropriate hand hygiene, this basic prevention measure is the essential foundation of an effective infection control strategy and an element of every infection control guideline.

INFLUENZA VACCINATION

The vaccination status of healthcare workers has been found to have a direct effect on transmission of the influenza virus to patients. Outbreaks of influenza in healthcare settings have been associated with low rates of vaccination among healthcare workers, and lower rates of nosocomial influenza have been related to higher vaccination rates among healthcare workers [281,282]. Because of these findings, several organizations have addressed the need for vaccination. The CDC and the Advisory Committee on Immunization Practices recommends annual influenza vaccination for all healthcare workers [283]. CDC guidelines include four Level I recommendations to help increase rates of vaccination [284]:

- Offer influenza vaccine annually to all eligible healthcare workers.

- Provide influenza vaccination to healthcare workers at the work site and at no cost as one component of employee health programs. Use strategies that have been demonstrated to increase influenza vaccine acceptance, including vaccination clinics, mobile carts, vaccination access during all work shifts, and modeling and support by institutional leaders.

- Monitor influenza vaccination coverage and declination of healthcare workers at regular intervals during influenza season and provide feedback of ward-, unit-, and specialty-specific rates to staff and administration.

- Educate healthcare workers about the benefits of influenza vaccination and the potential health consequences of influenza illness for themselves and their patients, the epidemiology and modes of transmission, diagnosis, treatment, and nonvaccine infection control strategies, in accordance with their level of responsibility in preventing healthcare-associated influenza.

In addition, the Joint Commission began including vaccination programs in its accreditation standards in 2007 [285].

Despite these guidelines, not all healthcare personnel are being vaccinated for influenza. During the 2017–2018 influenza season, vaccination coverage among healthcare personnel was 78.4%, similar to the 78.6% coverage observed during the 2016–2017 season [283]. By occupation, vaccination rates were highest among physicians (96.1%), pharmacists (92.2%), and nurse practitioners (87.8%). Vaccination coverage was higher among personnel working in hospitals (91.9%) than for those working in long-term care facilities (67.4%) [283].

Healthcare workers have given many reasons for not being vaccinated, and the reasons vary among categories of healthcare professionals [287]. Across all categories, shortage of the vaccine is the primary reason for not being vaccinated; other reasons include concern about side effects, inconvenience, and forgetfulness [287]. Many reasons for receiving the vaccine have also been identified, including [283,287]:

- Fear of getting influenza

- Fear of transmitting influenza to patients

- Belief that the vaccine is safe

- Belief that the vaccine is effective

- Convenience

The CDC reports that vaccination rates are highest among healthcare personnel whose employers require (85.8%) or recommend (68.4%) that they be vaccinated, compared with personnel whose employers who do not recommend or have a policy recommending vaccination (43.4%) [283]. Efforts to increase the vaccination rate among healthcare workers are ongoing. The APIC issued a position paper acknowledging the problem and highlighting suggestions to improve vaccination rates [288].

PRECAUTIONS AND ISOLATION TECHNIQUES

The CDC guidelines for isolation precautions in hospitals, updated in 2007, synthesize a variety of recommendations for precautions based on the type of infection and the route of transmission [22]. As defined by the CDC, Standard Precautions represent measures that should be followed for all patients in a healthcare facility, regardless of diagnosis or infection status. Standard Precautions apply to blood; all body fluids, secretions, and excretions except sweat, regardless of whether or not they contain visible blood; nonintact skin; and mucous membranes [22]. For patients who are known to have or are highly suspected to have colonization or infection, Contact Precautions should be followed. This type of precaution is designed to reduce exogenous transmission of micro-organisms through direct or indirect contact from healthcare workers or other patients. Airborne Precautions are used for patients who have or are highly suspected of having infection that is spread by airborne droplet nuclei, such as tuberculosis, measles, or varicella. Droplet Precautions target infections that are transmitted through larger droplets generated through talking, sneezing, or coughing, such as invasive Haemophilus influenzae type b disease, diphtheria (pharyngeal), pertussis, group A streptococcal pharyngitis, influenza, mumps, and rubella [22].

The CDC guidelines include descriptions of all the elements involved in the four types of precautions, including hand hygiene; the use of personal protection equipment (gloves, gown, and face protection); handling of patient-care equipment; environmental services and occupational health; and placement of the patient. A new element of Standard Precautions added to the 2007 guidelines is respiratory hygiene/cough etiquette [22]. Recommendations in this area address the importance of educating healthcare workers about adherence to measures to control the transmission of respiratory pathogens, especially during seasonal outbreaks of viral respiratory tract infections. In addition, the guidelines state that efforts should be made to contain respiratory secretions in patients and other individuals who have signs and symptoms of a respiratory infection, beginning at the point of initial encounter in a healthcare setting. Signs should be posted to instruct patients and visitors with symptoms of respiratory infection to cover their mouths/noses when coughing or sneezing, to use and dispose of tissues, and to perform hand hygiene after contact with respiratory secretions. Masks should be offered to coughing patients and other individuals with symptoms, and such persons should be encouraged to maintain an ideal distance of at least 3 feet from others in common waiting areas.

PREVENTION OF ANTIBIOTIC-RESISTANT INFECTION

Managing the problem of emerging drug-resistant microbial infection is a crucial aspect of an institution's infection control program. Any use of an antibiotic exerts selective pressure that can lead to the development of drug-resistance. The growing prevalence of antibiotic resistance is a serious problem for hospitals and for public health. Studies show that treatment indication, choice of antibiotic, or duration of therapy can be incorrect in up to 30% of instances in which antibiotics are prescribed. The national effort to promote antibiotic stewardship is intended to slow the development of resistance, help prevent untreatable infection, and extend the useful lifetime of the most urgently needed antibiotics [14].

Updated guidelines for the management of MRSA and other drug-resistant micro-organisms were published by the CDC in 2006 and the SHEA in 2014; the guidelines focus on the prevention of drug-resistant infections and the judicious use of antibiotics (antimicrobial stewardship) (Table 18) [22,30,38,72].

Table 18: SUMMARY OF STRATEGIES FOR PREVENTION OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS AND OTHER DRUG-RESISTANT MICRO-ORGANISMS

Conduct MRSA risk assessment and implement an MRSA monitoring programa

System to identify patients with MRSA colonization or infection

Feedback of information to cliniciansa

Education

Hand hygiene

Environmental decontamination

Dedicated equipment

Contact precautions

Masksb

Cohortingc

Antimicrobial stewardship

Active surveillance testingc

Decolonization therapyd

Compliance with hand hygiene

Compliance with cleaning protocolse

Compliance with Contact Precautionsa

aNot discussed in the guidelines by the Society for Healthcare Epidemiology of America (SHEA).

bRecommended in SHEA guidelines but not in guidelines by the Centers for Disease Control and Prevention (CDC).

cRecommended by the CDC only for specific subpopulations or circumstances.

dRecommended by both CDC and SHEA only for specific subpopulations or circumstances.

eNot discussed in the SHEA guidelines and recommended by the CDC only for specific subpopulations or circumstances.

Source: [22,30,38,72]

The CDC's Be Antibiotics Aware program provides fact sheets, pocket cards, posters, and slide sets for a variety of patient populations, including hospitalized adults, individuals to have surgery, patients receiving dialysis, long-term care patients, and hospitalized children [319]. All of the resources are available on the CDC website at https://www.cdc.gov/antibiotic-use/week/toolkit.html.

The IHI defines five components of a program to reduce the risk of infection with drug-resistant micro-organisms [289]:

- Hand hygiene

- Decontamination of the environment and equipment

- Active surveillance

- Contact precautions for infected and colonized patients

- Bundled interventions to prevent intravascular device-related bloodstream infections and ventilator-associated pneumonia

Universal surveillance of MRSA at hospital admission has been suggested as a measure to help prevent the transmission of this infection in the healthcare setting; however, the CDC guidelines state that the evidence on universal surveillance is limited and recommends surveillance only in specific subpopulations, defined in the context of the infection characteristics of the facility [22].

Since the publication of the guideline, conflicting data have been reported. In a prospective study of surgical patients at a Swiss teaching hospital, a rapid MRSA screening test at the time of hospital admission did not reduce the rate of MRSA infections [290]. In contrast, a universal MRSA screening program at a three-hospital organization in the United States led to a large reduction in MRSA infection during hospitalization and at 30 days after discharge [291]. Rates of MRSA infection have been reduced when universal MRSA surveillance was incorporated into a bundle of interventions that included adherence to Standard Precautions and recommendations for hand hygiene, adherence to Contact Precautions for patients who have MRSA-positive cultures, and efforts to change the environmental culture through briefings on patient care units, leadership involvement, and other similar strategies [289]. In one study, implementation of such a bundle resulted in significant decreases in transmission of MRSA (from 5.8 per 1,000 bed-days to 3.0 per 1,000) and overall MRSA HAIs (from 2.0 per 1,000 bed-days to 1.0 per 1,000), as well as a 65% decrease in MRSA surgical site infections after orthopedic operations [172]. Three independent factors have been found to correlate with previously unknown MRSA carriage: recent treatment with antibiotics, history of hospitalization, and age older than 75 years. Predictive models with these factors may enhance MRSA screening by better targeting patients at risk for MRSA carriage [292].

Antimicrobial Stewardship

The principles underlying the judicious use of antibiotics are the limitation of unnecessary antibiotics, obtaining timely culture and sensitivity data, selecting the most appropriate treatment, and prescribing the appropriate dose [293]. In addition, studies have shown that antimicrobial use can be decreased by using explicit criteria to identify patients with HAIs as well as those at highest risk for infection [294]. Antibiotic stewardship programs provide guidance to clinicians and have been shown to improve patient outcomes, reduce the burden of antibiotic resistance, and save healthcare dollars [14,286].

In their "Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship," SHEA and IDSA recommend that two core strategies of such a program are a prospective audit with intervention and feedback and formulary restriction and preauthorization [71]. Other elements of an effective antimicrobial stewardship program include [71]:

- Education to supplement interventions

- Guidelines and clinical pathways that incorporate local microbiology and resistance patterns

- Antimicrobial order forms

- Policy to avoid routine antimicrobial cycling

- Selective use of combination therapy

- Streamlining or de-escalation of therapy

- Dose optimization

- Systematic plan for parental-to-oral conversion

The goal of phase four of the CDC national HAI Action Plan is to "slow the emergence of resistant bacteria and prevent the spread of resistant infection" (Table 19) [14]. The CDC is coordinating stewardship activities among federal agencies, public health, and healthcare systems in order to achieve the following goals by 2020 [14]:

- Establishment of antibiotic stewardship programs in all acute care hospitals and improved stewardship across all healthcare settings

- Reduction of inappropriate antibiotic use by 50% in outpatient settings and by 20% in inpatient settings

- Establishment of Antibiotic Resistance Prevention Programs in all 50 states

Table 19: CDC'S CORE ELEMENTS FOR ANTIBIOTIC STEWARDSHIP PROGRAMS IN HOSPITALS, NURSING HOMES AND OUTPATIENT FACILITIES

Core Element

Definition

Leadership commitment

Dedicating necessary human, financial and information technology resources

Accountability

Appointing a single leader responsible for program outcomes. Experience with successful programs show that a physician leader is effective.

Drug expertise

Appointing a single pharmacist leader responsible for working to improve antibiotic use

Action

Implementing at least one recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e., "antibiotic time out" after 48 hours)

Tracking

Monitoring antibiotic prescribing and resistance patterns

Reporting

Regular reporting of information on antibiotic use and resistance to doctors, nurses and other relevant staff

Education

Educating clinicians about resistance and optimal prescribing

Source: [14]

EDUCATION FOR HEALTHCARE PROFESSIONALS

Education on best practices is a crucial aspect of preventing HAIs and is a recommendation in all infection control guidelines. Education should highlight the effect of prevention measures on the rates of HAIs, enhance knowledge about currently available guidelines, and provide instruction on carrying out guideline recommendations. Research has also suggested that education about prevention strategies may be more effective if patterns of care and levels of risk are incorporated into recommendations [295]. Numerous studies have shown that knowledge and practices related to HAIs and guidelines are improved after educational programs. The combination of a self-study module (with pretest and post-test), inservice lectures, posters, and fact sheets on the prevention of intravascular device-related bloodstream infections and appropriate practices led to substantial reductions in the prevalence of such infections [258,296,297]. A small study showed that ICU nurses' knowledge and practices were enhanced by education on the prevention of ventilator-associated pneumonia [235]. A Canadian study demonstrated that rates of nosocomial MRSA infection significantly decreased after a mandatory infection control education program on MRSA that included discussion of hospital-specific MRSA data and case-based practice [298].

Because increasing knowledge is not sufficient for effecting behavior change, theoretical models for behavior change should be considered when designing improvement initiatives [280,299]. Among effective model-related strategies are the following [280,299]:

- Education and discussion of barriers to adherence (cognitive model)

- External reinforcements, incentives, and reminders (behavioral model)

- Consensus, leadership, and role models (social influence model)

- Quality improvement teams, process redesign, and fostering of a safety-oriented culture (organizational model)

Healthcare facilities should explore innovative ways to develop quality improvement initiatives. In an effort to enhance adherence to the CDC guidelines on hand hygiene, a group of three hospitals used the Six Sigma approach with success. Six Sigma is a process established in the business world to achieve and sustain excellence in general operations and service [300]. The healthcare facility used the process to organize the knowledge, opinions, and actions of physicians, nurses, and other staff in four ICUs at the facilities, resulting in an increase in compliance from 47% to 80% [301].

Given the low rates of influenza vaccination among healthcare workers, education on the importance of this measure is also needed. Two literature reviews have shown high rates of misconceptions or lack of knowledge about influenza, the role of healthcare professionals in transmitting influenza to patients, and the importance and risks of vaccination [302,303]. Education on vaccination should be targeted to address these attitudes and beliefs. In addition, some studies have indicated that self-protection is a primary reason healthcare professionals decide to be vaccinated, and education that focuses on this aspect may help improve vaccination rates [303].

EDUCATION FOR PATIENTS AND FAMILIES

Education for patients and families is an important component of an overall prevention strategy, and the U.S. Department of Health and Human Services notes that such education is a critical part of the national effort on preventing HAIs [14]. Many national-level initiatives have been launched to encourage individuals to become more active in their health care and to be their own advocates, and patients, family members, and hospital visitors should be encouraged to become partners in preventing the transmission of infection in the healthcare setting [22].

Hospitals should engage patients in their own care by discussing infection control measures for hand hygiene practices, respiratory hygiene practices, and contact precautions (according to the patient's condition) with the patient and his or her family members on the day the patient enters the hospital or as soon as possible thereafter. For patients who are to have surgery, healthcare professionals should describe the measures that will be taken to prevent adverse events. This information may be provided in any form of media, and the patient's understanding of the information should be evaluated and documented.

Physicians and other healthcare professionals should educate patients and families about ways to prevent infection, especially with regard to their specific factors (e.g., surgery, insertion of a urinary catheter). Clinicians should also explain the importance of the appropriate use of antibiotics, including the need to complete the recommended antibiotic treatment course; the relationship between the inappropriate use of antibiotics and the increasing prevalence of drug-resistant bacteria; and the implications of drug-resistant bacteria. Patients should be encouraged to help promote adequate hand hygiene by asking their healthcare providers if they have washed their hands. The IHI has addressed this topic with the "It's OK to Ask" campaign, and patient educational pamphlets can be downloaded from the IHI website (http://www.ihi.org). The CDC has developed a video for newly admitted patients on the topic of hand hygiene, which is available on its website (https://www.cdc.gov/handhygiene/campaign/index.html). The SHEA and the CDC collaborated to develop a series of patient guides on the top five HAIs, as well as on MRSA and VRE, and the guides are available on the SHEA website (http://www.shea-online.org/index.php/practice-resources/patients).

The ability to understand health information and make informed health decisions, known as health literacy, is integral to good health outcomes [304]. Yet, the National Assessment of Adult Literacy estimated that only 12% of adults have "proficient" health literacy and 14% have "below basic" health literacy [305]. Rates of health literacy are especially low among ethnic minority populations and individuals older than 60 years of age [304]. Compounding the issue of health literacy is the high rate of individuals with limited English proficiency. According to the U.S. Census Bureau data from 2017, more than 64.2 million Americans speak a language other than English in the home, with more than 25.6 million of them (8.5% of the population) speaking English less than "very well" [306].

Clinicians should assess their patients' literacy level and understanding and implement interventions as appropriate. Healthcare professionals should use plain language in their discussions with patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding. Reinforcement with the use of low-literacy or translated educational materials may be helpful.

Translation services should be provided for patients who do not understand the clinician's language. "Ad hoc" interpreters (family members, friends, bilingual staff members) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, clinicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [307]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [307]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [308]. Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [309,310,311].

The American Medical Association offers several health literacy resources for healthcare professionals on its website (https://www.ama-assn.org), and the U.S. Department of Health and Human Services offers valuable information on cultural competency from the Health Resources and Services Administration (HRSA) (https://www.hrsa.gov/culturalcompetence) and the Office of Minority Health (http://www.thinkculturalhealth.org).

PREPAREDNESS AND CONTROL OF OUTBREAKS

Another responsibility of an infection control team is establishing response plans for outbreaks and epidemics and controlling them should they occur. An outbreak is defined by the WHO as "an unusual or unexpected increase of cases of a known nosocomial infection or the emergence of cases of a new infection" [15]. The number of individuals affected can vary from a few to 100 or more. Outbreaks and epidemics account for approximately 5% to 10% of HAIs, and most hospitals lack adequate equipment, isolation space, and staff to treat a large increase in the number of patients with an infectious disease [39,87]. The two primary concerns are to confirm the existence of the outbreak and to establish control measures to confine the spread.

An outbreak should be identified and investigated as early as possible to prevent morbidity and mortality. Any healthcare professional who suspects an outbreak should notify infection control staff, and an outbreak team should be established. Investigating an outbreak involves [15,312]:

- Establishing the existence of an outbreak

- Verifying the diagnosis

- Defining and identifying cases

- Describing and orienting the data in terms of time, place, and person

- Developing and evaluating hypotheses

- Refining hypotheses and carrying out additional studies

- Implementing control and prevention measures

- Communicating findings

The outbreak team should collaborate with all appropriate healthcare workers to identify either the carriers or the common sources of the infection and to review aseptic practices and disinfectant use for a breach in compliance. Data on potential cases should be reviewed and a case definition should be developed. The case definition should include [15,312]:

- Unit of time and place

- Specific biologic and/or clinical criteria

- Inclusion/exclusion criteria

- Gradient of definition (definite, probable, or possible)

- Differentiation between colonization and infection

- Specific criteria to identify the index case, if relevant information is available

Data should be collected from all available sources, such as patient charts, microbiology reports, pharmacy reports, and log books from patient units. Describing the outbreak in terms of individuals, place, and time helps to create an epidemic curve, which shows the distribution of cases by time of onset [15]. An attack rate can then be defined as the number of people at risk who are infected compared with the total number of people at risk.

Developing and evaluating hypotheses will yield the source of the outbreak and/or the index case. The data should be reviewed carefully to evaluate the characteristics and similarities among affected individuals. The team must then determine the extent of the outbreak. Cohort isolation is implemented as needed (Table 20) [22,313]. Throughout the investigation, the team should communicate routinely with hospital administration. At completion, data on the outbreak should be documented and published, as the information can provide valuable education to the healthcare community at large and can help staff prepare for future outbreak investigations [314].

Table 20: TYPE AND DURATION OF PRECAUTIONS REQUIRED FOR INFECTIONS WITH POTENTIAL FOR OUTBREAKS

Infection/Condition

Precaution Type

Precaution Duration

Notes

Anthrax (cutaneous or pulmonary)

Standard

Ongoing

Use Contact Precautions if there is large amount of uncontained drainage from lesions.

Aspergillosis

Standard

Ongoing

Use Contact Precautions and Airborne Precautions if there is massive soft-tissue infection with copious drainage.

Botulism

Standard

Ongoing

Not transmitted person-to-person.

Diphtheria (cutaneous or pharyngeal)

Contact, Droplet

Until antibiotic therapy is completed and two cultures taken at least 24 hours apart are negative

—

Ebola (viral hemorrhagic fever)

Standard, Contact, Droplet

Duration to be determined on case-by-case basis, in conjunction with local, state, and federal health authorities

Single patient room with the door closed preferred. Maintain log of all people entering the patient's room. Use barrier protection against blood and body fluids upon entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields). Use additional protective wear (double gloves, leg and shoe coverings) during final stages of illness when hemorrhage may occur. Use dedicated disposable (preferred) medical equipment for patient care. Clean/disinfect all nondedicated, nondisposable equipment. Limit use of needles, sharps as much as possible. Limit procedures, tests. Avoid aerosol-generating procedures. Notify public health officials immediately if Ebola is suspected.

Clostridium difficile gastroenteritis

Contact

Duration of illness

Discontinue antibiotics if appropriate. Use soap and water for hand-washing, as antiseptic handrubs lack sporicidal activity. Do not share equipment (e.g., electronic thermometers). Ensure consistent environmental cleaning and disinfection.

Influenza, seasonal

Droplet

5 days after onset of symptoms

Single patient room preferred or cohort. Use mask on patient when he or she is transported out of room. Use gown and gloves according to Standard Precautions. The duration of precautions for immunocompromised patients cannot be defined. Refer to CDC guidance (https://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm).

Influenza, pandemic

Droplet

5 days after onset of symptoms

Refer to CDC guidance (http://www.cdc.gov/flu/pandemic-resources).

Influenza, avian

Droplet

Duration of illness

Refer to CDC guidance (http://www.cdc.gov/flu/avianflu).

Malaria

Standard

Ongoing

Install screens in windows and doors in endemic areas.

Measles (rubeola), all presentations

Airborne

4 days after onset of rash (duration of illness for immunocompromised patients )

Use Airborne Precautions for exposed susceptible patients. Susceptible healthcare staff should not enter the room if immune caregivers are available. Exclude susceptible healthcare staff from duty from day 5 after first exposure to day 21 after last exposure, regardless of post-exposure vaccine.

Meningitis (Haemophilus influenzae or Neisseria meningitidis [meningococcal] known or suspected)

Droplet

Until 24 hours after initiation of effective therapy

—

Meningococcal pneumonia

Droplet

Until 24 hours after initiation of effective therapy

—

Norovirus

Standard

Duration of illness

Cohorting of affected patients to separate airspaces and toilet facilities may help interrupt transmission during outbreaks. Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control outbreaks. Ensure consistent environmental cleaning and disinfection, with focus on restrooms even when apparently unsoiled. Persons who clean heavily contaminated areas may benefit from wearing masks as virus can be aerosolized.

Plague, bubonic

Standard

Ongoing

—

Plague, pneumonic

Droplet

Until 48 hours after initiation of effective therapy

Antimicrobial prophylaxis should be given to exposed healthcare staff.

Pneumonia caused by:

Adenovirus

Legionella

Meningococcal

Mycoplasma (primary atypical pneumonia)

Droplet, Contact

Standard

Droplet

Droplet

Duration of illness Ongoing until 24 hours after initiation of effective therapy Duration of illness

—

Scabies

Contact

Until 24 hours after initiation of effective therapy

—

Staphylococcus aureus, skin, wound, or burn

Major: no dressing or dressing does not contain drainage adequately

Minor or limited: dressing covers and contains drainage adequately

Contact

Standard

Duration of illness Ongoing

—

Group A streptococci, skin, wound, or burn (major: no dressing or dressing does not contain drainage adequately)

Contact, Droplet

Until 24 hours after initiation of effective therapy

—

Toxoplasmosis

Standard

Ongoing

—

Toxic shock syndrome (staphylococcal or streptococcal disease)

Standard

Ongoing

—

Tuberculosis, extrapulmonary (draining lesion)

Airborne, Contact

Only when therapy is effective, patient is clinically improving, and the cultures of 3 consecutive sputum smears, collected on different days, are negative

Examine for evidence of active pulmonary tuberculosis. (If evidence exists, additional precautions are necessary.)

Tuberculosis, extrapulmonary, (no draining lesion, meningitis)

Standard

Ongoing

Examine for evidence of pulmonary tuberculosis. (If evidence exists, additional precautions are necessary.)

Tuberculosis, pulmonary or laryngeal disease (confirmed)

Airborne

Only when therapy is effective, patient is clinically improving, and the cultures of 3 consecutive sputum smears, collected on different days, are negative

—

Tuberculosis, pulmonary or laryngeal disease (suspected)

Airborne

Only when the likelihood of infectious disease is negligible and the cultures of 3 consecutive sputum smears, collected on different days, are negative

—

Tuberculosis, latent (skin-test positive with no evidence of current pulmonary disease)

Standard

Ongoing

—

Varicella zoster (chickenpox)

Airborne, Contact

Until all lesions are crusted (10 to 21 days) Susceptible healthcare staff should not enter the room if immune caregivers are available.

Whooping cough (pertussis)

Droplet

Until 5 days after initiation of effective therapy

—

Source: [22,313]

Case Example

The following case outlines an investigative process and illustrates that the source of an outbreak may be unusual [315].

A cardiac surgeon noticed a cluster of cases of sternal wound dehiscence among his patients who had had surgery. Specimens from the wounds were obtained for culture. Microbiologic evaluation indicated that the infections were predominantly caused by Enterobacter cloacae, and molecular typing and serotyping demonstrated that the isolates were similar. No infections had developed after operations the surgeon had performed at other hospitals. No breach in aseptic technique was identified. All of the infected patients had been operated on in the same operating room, and the environment was screened. No source was found. Further questioning of the surgeon's operative practice revealed one difference from other cardiac surgeons: he used semi-frozen sodium lactate solution to achieve cardioplegia. Swabbing of the freezer used for the solution identified E. cloacae of the same typing as that found in the wound infections. The hypothesis was that contamination of the freezer led to contamination of the ice/slush solution, and the micro-organism was transmitted to the patients. The freezer was replaced, a rigorous cleaning schedule was instituted, and no further cases have occurred.

Potential Outbreaks

The following are overviews of selected potential outbreaks. Identification and early action in the case of any of these outbreaks will limit the adverse effects.

Group A Streptococci

Most outbreaks of group A streptococci involve surgical wounds, and the source can usually be traced to an asymptomatic carrier in the operating room or on the wound care team [87,316]. Standard Precautions are sufficient if the wound is minor; if it is major, Contact Precautions should be instituted and followed for 24 hours after initiation of effective therapy [22]. The healthcare worker should receive antimicrobial therapy as appropriate and leave the setting until completion of therapy.

Pulmonary Tuberculosis

Dealing with pulmonary tuberculosis involves prompt identification of the disease and determining the susceptible individuals who were exposed to the patient before isolation [87]. Airborne Precautions should be instituted and remain in place until the patient is receiving effective therapy, is improving clinically, and the culture results for three consecutive sputum specimens, collected on different days, are negative. Comprehensive information is available in the CDC guidelines for preventing the transmission of tuberculosis in healthcare facilities [317].

Legionella

The source of HAI with Legionella pneumonia is usually contaminated water [87]. Implementation of Standard Precautions for the patient is sufficient [22]. Laboratory-based surveillance for nosocomial Legionella should be performed, and samples of tap water should be obtained for culture. If the culture is positive, it is best to obtain cultures from patients who have healthcare-associated pneumonia. There are more than 40 known types of Legionella species, but most outbreaks are caused by Legionella pneumophila serotypes 1 and 6.

Antibiotic-Resistant Micro-Organisms

Outbreaks of antibiotic resistance have involved MRSA, VRE, and, most recently, vancomycin-resistant S. aureus [318]. In such outbreaks, it is important to identify patients with colonization or infection early and isolate them or cohort them. Contact Precautions should be implemented and carried out until antibiotic therapy has been completed and cultures are negative [22]. The importance of adhering to proper hand hygiene and other elements of Contact Precautions should be emphasized. Healthcare workers who were involved with patients before isolation should be evaluated for colonization and infection and treated appropriately.

Other Outbreaks

The potential for other outbreaks or epidemics vary, and the CDC website, http://www.bt.cdc.gov, offers resources on emergency preparedness for outbreaks or epidemics caused by potential agents of bioterrorism, including anthrax and viral hemorrhagic fever. A Bioterrorism Readiness Plan template is also available (https://emergency.cdc.gov/bioterrorism/pdf/13apr99APIC-CDCBioterrorism.pdf). Many aspects should be considered when planning for bioterrorism preparedness, and each department of a healthcare facility can play an important role.

7. CONCLUSION

Infections acquired in the healthcare setting raise a great risk for patients, leading to high rates of morbidity and mortality. Many of the deaths caused by HAIs could be prevented by following evidence-based guidelines and consensus statements on prevention strategies. Several institutions have implemented campaigns to enhance the quality of health care and patient safety by focusing on measures to reduce the most common HAIs: catheter-associated urinary tract infection, surgical site infection, pneumonia, intravascular device-related bloodstream infection, and C. difficile infection. The single most effective infection control measure is appropriate hand hygiene, and all efforts to reduce the rate of HAIs must focus on enhancing compliance with this measure in conjunction with other prevention strategies. Along with hand hygiene, meticulous attention to aseptic technique when preparing for invasive procedures or using invasive devices is also essential for reducing the prevalence of HAIs. Prevention measures specific for each of the most common types of HAIs have been recommended in evidence-based guidelines and consensus statements (Table 21).

Table 21: SUMMARY OF PREVENTION MEASURES FOR THE MOST COMMON HEALTHCARE-ASSOCIATED INFECTIONS

Type of Infection

Evidence-Based Recommended Measures

Other Suggestions

All infections

Appropriate hand hygiene

Meticulous aseptic technique for devices and equipment

—

Catheter-associated urinary tract infection

Indwelling catheters only when needed

Proper securing of catheter

Closed sterile drainage system

Unobstructed urine flow

Removal of catheter as soon as possible

Alternative to indwelling catheter (suprapubic, condom)

Antimicrobial-coated catheter

Hand-held bladder scanners

Pneumonia (without mechanical intubation)

Deep breathing

Frequent coughing

Early movement (in bed and/or walking)

Limited use of narcotic agents

Incentive spirometry (for patients at high risk)

—

Ventilator-associated pneumonia

Elevation of the head of the bed (30 degrees)a

Daily interruptions of sedation and assessment of readiness to extubatea

Prophylaxis of peptic ulcer diseasea

Prophylaxis of deep venous thrombosisa

Endotracheal tube with a dorsal lumen

Noninvasive ventilation

Surgical site infection

Appropriate antibiotic prophylaxis

Avoidance of preoperative shaving

Maintaining adequate glycemic control

Maintaining a warm body temperature

Performance feedback to surgeons

Intravascular device-related bloodstream infections

Maximal barrier precautionsa

2% chlorhexidine solution for skin antisepsisa

Selection of optimal site for the catheter (subclavian vein preferred for nontunneled catheters)a

Daily review of the need for the line, with prompt removal if line is deemed unnecessarya

Catheter with antimicrobial coating

Performance feedback to personnel

Clostridium difficile-associated diarrhea

Judicious use of antibiotics

Barrier precautions (gowns and gloves, dedicated or disposable equipment, cohorting of patients and/or staff)

Handwashing with soap and water (alcohol is not effective against C. difficile spores)

Appropriate disinfectant for surfaces and devices

—

aComponent of a bundle of interventions that, when implemented together, has lowered the rate of infection.

Source: Compiled by Author

The common pathogens, diagnosis, and treatment vary among these infections and even within each type of infection. The CDC has detailed diagnostic criteria for each type of infection, and consensus statements and guidelines have also proposed such criteria. The treatment of HAIs varies according to the pathogen and the anatomic site. The prevailing principle is to use antibiotics judiciously, as the inappropriate use of antibiotics has led to an increasing number of resistant strains of bacteria. When using empiric antibiotic therapy, physicians should select an antibiotic on the basis of known pathogens in the healthcare facility as a whole, as well as on the specific unit within the facility.

An effective infection control team is critical to reducing the incidence of HAIs in a healthcare facility. All departments within a healthcare facility should be represented on this team to ensure widespread adherence to prevention measures. The responsibilities of an infection control team are to conduct surveillance of infections; ensure compliance with infection control guidelines, including those for management of drug-resistant organisms; and establish response and control plans for outbreaks and epidemics. Most important is the development of an organizational culture that fosters a focus on patient safety and emphasizes education on HAIs and infection control for healthcare workers and patients and their families.

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35110 • Clinical Use of Neuromuscular Blocking Agents

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired)

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Neuromuscular blocking agents (drugs that paralyze skeletal muscle) have been used in anesthesia since the 1930s. Their use in the intensive care unit, emergency department, and prehospital care (e.g., ground and air ambulances) is somewhat more recent, though still well-established. Despite the fact that these drugs are commonly administered to critically ill patients, many practitioners have only the most rudimentary knowledge regarding the proper selection of these agents, their broad classifications, their dosages, the monitoring technique necessary for their use, and other crucial aspects of this class of drugs. Indeed, a number of potentially lethal side effects from the acute or chronic administration of these agents may occur, resulting in significantly increased morbidity and mortality among patients receiving them.

Table of Contents

35110 • Clinical Use of Neuromuscular Blocking Agents

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. A BRIEF HISTORY OF NEUROMUSCULAR BLOCKERS

3. THE NEUROMUSCULAR JUNCTION

MOTOR NEURONS

THE NEUROMUSCULAR JUNCTION

ACETYLCHOLINE AND THE NICOTINIC ACETYLCHOLINE RECEPTOR

MECHANISM OF SKELETAL MUSCLE CONTRACTION

THE CLINICAL IMPORTANCE OF THESE MECHANISMS AND STRUCTURES

4. NEUROMUSCULAR BLOCKING AGENTS

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS: AMINO-STEROID AGENTS

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS: BENZYLISOQUINOLINIUM AGENTS

DEPOLARIZING NEUROMUSCULAR BLOCKERS

5. MONITORING NEUROMUSCULAR BLOCKADE

6. REVERSAL OF NEUROMUSCULAR BLOCKADE

ANTI-ACETYLCHOLINESTERASE AGENTS

SUGAMMADEX

7. COMMON USES OF NEUROMUSCULAR BLOCKING AGENTS AND AREAS OF CONCERN FOR THE PRACTITIONER

POST-ANESTHESIA CARE UNIT

PREHOSPITAL ADVANCED CARE PROVIDERS (PARAMEDICS AND PREHOSPITAL NURSES)

ANESTHESIA

THE INTENSIVE CARE UNIT

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

35110 • Clinical Use of Neuromuscular Blocking Agents

Education Category. Pharmacology

Release Date. 04/01/2020

Expiration Date. 03/31/2023

Course Overview

Neuromuscular blocking agents (drugs that paralyze skeletal muscle) have been used in anesthesia since the 1930s. Their use in the intensive care unit, emergency department, and prehospital care (e.g., ground and air ambulances) is somewhat more recent, though still well-established. Despite the fact that these drugs are commonly administered to critically ill patients, many practitioners have only the most rudimentary knowledge regarding the proper selection of these agents, their broad classifications, their dosages, the monitoring technique necessary for their use, and other crucial aspects of this class of drugs. Indeed, a number of potentially lethal side effects from the acute or chronic administration of these agents may occur, resulting in significantly increased morbidity and mortality among patients receiving them.

Audience

This course is designed for nurses, nurse practitioners, and other allied health professionals in a variety of settings, including the intensive care unit, emergency department, acute care, prehospital settings, critical care, and post-anesthesia care.

Course Objective

The purpose of this course is to provide intensive care, emergency, and prehospital providers with the clinical knowledge to administer neuromuscular blocking agents in a safe and effective fashion, as well as to know how such agents can be effectively monitored and, ultimately, safely and efficiently reversed.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review the pertinent history surrounding the discovery and early administration of neuromuscular blocking agents.

2. Outline the anatomy and physiology of the neuromuscular junction.

3. Identify commonly used neuromuscular blockers.

4. Discuss the use and effects of benzylisoquinolinium nondepolarizing neuromuscular blocking agents.

5. Describe the use and effects of amino steroid nondepolarizing neuromuscular blockers.

6. Identify the crucial effects and side effects of succinylcholine, listing both relative and absolute contraindications to its use.

7. Analyze approaches to monitoring neuromuscular blockade.

8. Evaluate the effects and use of traditional agents used to reverse neuromuscular blockade.

9. Discuss the reversal agent sugammadex.

10. Analyze the role of neuromuscular blockers in various patient populations.

Faculty

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), is a retired nurse anesthetist and prehospital registered nurse (instructor) who has published extensively in various areas of healthcare research while providing clinical care in arenas ranging from academic medical centers to austere environments in the third world during both wartime and peacetime. He has a bachelor’s degree in nursing from Georgetown University, Master’s degrees in education (Boston University) and nursing specializing in anesthesia (State University of New York in Buffalo and U.S. Army), and a PhD from the University of South Carolina. He is a retired lieutenant colonel in the U.S. Army Nurse Corps. He has taught nursing anesthesia, pharmacology, and physiology; mentored students in doctoral programs; and used advanced patient simulation to train students. Dr. Haas has worked in clinical, administrative, education, and research roles. He continues to work as an independent consultant, while taking more time to enjoy life with his wife of nearly 50 years and their children and grandchildren.

Faculty Disclosure

Contributing faculty, Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

For those who administer drugs, the emphasis on the five "rights" (i.e., right dose, right drug, right patient, right time, and right route) has been emphasized beginning in the earliest days of instruction. There is, however, one class of drugs—neuromuscular blocking agents—that has the potential to end a patient's life each time they are administered, no matter how scrupulously the "five rights" are followed. The body's ability to move in order to flee adverse stimuli; to seek food, warmth, and shelter; and even to breathe has many redundant motor pathways, emphasizing the importance of motor function in the maintenance of homeostasis. The interruption of motor function by neuromuscular blocking agents places the patient's life in the hands of the practitioner administering the drug. With this in mind, the following continuing education course is designed to make the skilled practitioner aware of the problems that can occur with the administration of these agents, guide selection of the best agent for a particular intervention, and provide guidelines for monitoring a relaxed (i.e., paralyzed) patient and reversing the effects of these drugs.

2. A BRIEF HISTORY OF NEUROMUSCULAR BLOCKERS

The history of neuromuscular blockers, and how they came into day-to-day clinical use, is a fascinating one. Curare (Chondrodendron tomentosum) is the archetypal neuromuscular blocking agent, becoming popular in the 1930s, though it is no longer commonly used in practice in the United States [1]. Several authors describe the first "discoverer" of curare as Sir Walter Raleigh, though at least one expert disputes this idea [2,3,4]. Raleigh witnessed the natives in Guyana making a poison and applying it to the tips of their arrows when hunting monkeys. The slightest wound resulted in death to the monkey. In 1804, Charles Waterton (1782–1865) left England for his family's sugar estates in Guyana, and there he observed native Guyanese men hunting with curare. Encouraged by English scientists to find the secret of these poison arrows, Waterton brought curare back to England in 1812 for further study, thinking it might be especially useful in the treatment of rabies (then called hydrophobia) [5]. In the course of his time in Guyana, he witnessed an event that affected him profoundly: the death of a native man who was accidentally hit by his own arrow after missing the monkey at which it was aimed. His eyewitness description is [2]:

"Never," he (the Indian) said to his companion in a broken voice, and having looked at his bow while he spoke, "will I bend this bow again." Having spoken these words, he removed from his shoulder the small bamboo box that contained the poison, and having placed his bow and arrows on the ground, he lay down, said goodbye to his companion, and never spoke again. "It will be a consolation for tender souls," remarked Waterton, "to know that the victim did not suffer, because 'wourali' take life gently."

Waterton continued his research in curare, as did others, most notably the physiologist Claude Bernard (1813–1878), who in 1840 discovered that the cause of death of the drug was neuromuscular paralysis [4]. One of Bernard's early experiments involved the application of a piece of dried curare beneath the skin of a frog [2]. Bernard reported the following [6]:

On opening the poisoned frog, I saw that its heart continued to beat. Its blood became red on exposure to the air and appeared physiologically normal. I then used electrical stimuli as the most convenient method of provoking a reaction in the nerves and muscles. Stimulating the muscle directly produced violent contractions in every part of the body, but on stimulating the nerves there was no reaction. The nerves, that is, the bundles of nervous tissue, were completely dead, while the other bodily components, the muscles, the blood, the mucous membranes, retained their physiological properties for a number of hours, as one sees in cold-blooded animals.

Bernard then linked the effects of curare to its ability to paralyze skeletal muscle while allowing smooth muscle and cardiac muscle to continue to function. Though Bernard died in 1878, the clinical utility of his findings and their use in the care of patients did not begin to occur until the early 20th century. In 1932, West described numerous proposed uses of curare, though most of his uses differ diametrically from the reasons that neuromuscular blocking agents are administered today [7]. Indeed, West's efforts focused on the degree to which the side effects of curare could be best used in patient care. He explained making the drug itself from the raw material, which he describes as "a resinous mass of the consistency of hard toffee…incompletely soluble in water" [7]. The mass was sterilized and placed in glass ampoules of 2–20 mg designed for clinical administration. He injected the drug "hypodermically" into 30 patients and observed patients had no effects at 10 minutes, at which point a feeling of "giddiness" and "feeling stupid or fuddled" along with nystagmus began to occur. Blood pressure fell 20 to 30 mm Hg, and the hypotension was accompanied by both bradycardia and by a headache that could be "entirely relieved by administering 5 or 10 minims of adrenalin with or shortly after the curare injection" [7]. In retrospect, the "giddiness" and "fuddled" feelings could be the result of hypoxia, though ventilatory responses to the drug were not measured. His subsequent attempts to treat hypertension with curare resulted in elevations in blood pressure of 10 to 16 mm Hg, most likely associated with a sympathetic discharge associated with hypoxia, although again, no records of ventilatory response were obtained [7]. It is easy now, after 80 years of research, to be critical of West's findings. However, he helped advanced the research of the use of neuromuscular blockers when he stated, "There is the possibility of the myoneural junction being a more selective apparatus than it is usually considered to be. I have in mind a structure upon which curare could actually act selectively, removing discharges of certain electrical patterns, while allowing others to pass" [7]. In fact, he was describing the nicotinic acetylcholine receptor on the posterior neuromuscular junction far before it was discovered.

The researchers who best directed use of neuromuscular blockers into what they have become today are Griffith and Johnson who, in 1942, reported on the use of a new tool for general anesthesia: curare [8]. They reported that the use of curare in doses of "10–20 mg per 20 lbs. of body weight" improved skeletal muscle relaxation in their first cohort of 25 patients to whom it was administered. They described its effect in many of their patients, but it is important to note that in all of these cases, patients breathed spontaneously and required no "artificial respiration" [8]. In a particularly descriptive part of the paper, the authors described the surgeon's difficulty in closing an abdominal wound after an appendectomy. The administration of 5 mL of Incostrin (the trade name for curare) resulted in the patient's abdomen being "soft as dough" within one minute [8].

While curare began to take its place in the armamentarium of anesthesia through the 1940s, some disturbing data, most of it anecdotal, began to appear. Practitioners were finding that individuals receiving curare during surgery were dying at higher rates than those who did not. This led to the groundbreaking 1954 study of Beecher and Todd in which they reviewed 599,548 patients administered anesthetics between 1948 and 1952 [9]. The study placed a special emphasis on the curares, as described by the authors when they state, "The muscle relaxants have been singled out from the other agents and technics [sic] for particular discussion because of their newness, because of their greatly increasing use, and because their employment appears to be associated with certain anesthetic hazards not yet entirely clear, nor completely appreciated" [9]. Could it be that these new agents, in clinical use for less than two decades, would be removed from practice? Indeed, they found a six-fold increase in death rate when "curares" were used, as compared to when they were withheld [9]. The researchers, however, placed the responsibilities for these deaths not on the drug itself, but rather stated [9]:

The data presented strongly suggest that great caution in the use of the muscle relaxants is indicated, that the agents available at present be considered as on trial, and that they be employed only where there are clear advantages to be gained by their use, that they not be employed for trivial purposes, or as a corrective for generally inadequate anesthesia.

This is the best possible advice to all practicing clinicians when it comes to the use of neuromuscular blockade; it is only administered after careful risk/benefit considerations, and its use is not trivial. Though there are historical developments that occur after this, they are mainly in the creation of various types of agents.

3. THE NEUROMUSCULAR JUNCTION

The neuromuscular junction has been the subject of intense research over the past 50 years. The work of Griffith and Johnson in introducing curare into clinical practice prompted the work of two generations of bench scientists to uncover the secrets of this structure [8]. In order to understand why neuromuscular blocking agents work the way they do, it is vital to understand the structural anatomy and physiology related to the neuromuscular junction.

MOTOR NEURONS

The cells in the brain communicate with those in the rest of the body by sending and receiving small electric impulses (called action potentials) along nerves from one area of the body to another. When one wishes to move, specialized areas in the brain send action potentials along specific motor neurons that descend through the spinal cord. Bundles of neurons, running together within an anatomic sheath, are called nerves. The neurons comprising the nerves are myelinated; that is, each neuron is wrapped in a series of Schwann cells, increasing the speed of transmission of a muscle action potential along the nerve through a process called saltatory conduction [10]. There are small spaces between the Schwann cells called the nodes of Ranvier, and the underlying nerve is exposed at these points. These exposed areas of the nerve allow the action potential to skip from space to space, significantly increasing the speed of transmission of the impulse [10]. The point at which two nerves meet is called a synapse.

The neuron that sends the signal by releasing a neurotransmitter is called a first-order or, more commonly, a prejunctional neuron. The neuron or muscle cell that receives the action potential can be referred to as a second-order or postjunctional neuron. These second-order neurons, or the second nerve in a series of connecting nerves (bundles of which are called peripheral nerves), exit the ventral horn of the spinal cord and begin branching, creating 10 to 300 separate nerve fibers, traveling throughout the body, and finally ending in skeletal muscle fibers [11]. The point at which the nerve meets the muscle is referred to as the neuromuscular junction, and the muscle fiber is the postjunctional area (Figure 1). Though the nerve terminal (or endpoint of the motor nerve) approaches each individual muscle fiber, it does not contact it. Instead, the terminal ending of the nerve sits in a highly specialized invagination of the muscle fiber called the neuromuscular junction. Each muscle fiber has its own neuromuscular junction.

Figure 1: THE NEUROMUSCULAR JUNCTION

1. Presynaptic terminal

2. Sarcolemma

3. Synaptic vesicles

4. Acetylcholine receptors

5. Mitochondrion

Source: [147]

THE NEUROMUSCULAR JUNCTION

The neuromuscular junction is a complex of numerous anatomic structures and is itself a synapse. At any synapse, some ligand (an intracellular substance) is released from a prejunctional neuron, crosses a synaptic space, and binds with a receptor on a postjunctional neuron (or postjunctional muscle). As noted, the terminal nerve ending does not touch the muscle fiber itself. Rather, there is a small space between the two structures, referred to as the synaptic cleft or the synaptic space [10,11]. The terminal nerve ending consists of thousands of small synaptic vesicles that contain the neurotransmitter acetylcholine. When an action potential leaves the spinal cord via a lower motor neuron and travels to the terminal nerve ending, the amount of voltage within the nerve changes as the impulse passes. When the action potential (electric impulse) arrives at the prejunctional nerve terminal, the resting membrane potential (i.e., the electric "charge" inside the cell) suddenly increases from a resting level of -90 millivolts to a depolarizing level of +50 millivolts [11]. This change in voltage activates small receptors in the prejunctional neurons called voltage-gated calcium channels. These channels are specialized proteins that open and close, creating a tube through which calcium ions (Ca2+) can flow when open [10]. Because there is 10,000 times more calcium outside of the nerve cell than inside, Ca2+ rushes through these tubes into the prejunctional nerve cell [10]. The entry of calcium effects a change in the vesicles, causing them to move toward and fuse with the cell membrane. After the fusion takes place, the vesicles are opened to the extracellular space, resulting in thousands of molecules of acetylcholine being released from the prejunctional neuron and entering the synaptic space [10].

ACETYLCHOLINE AND THE NICOTINIC ACETYLCHOLINE RECEPTOR

Acetylcholine is one of the most important neurotransmitters in the human body. It is crucial for the function of both the autonomic and motor nervous systems. This course will focus on acetylcholine's role in ultimately making skeletal muscle contract.

Acetylcholine is synthesized in the neuron in both the soma and the terminal nerve ending [10]. It is the product of acetyl-coenzyme-A, produced by the mitochondria, and choline from dietary sources. These substances are combined in the presence of the enzyme choline acetyl-transferase and then placed in the vesicles.

After being released from the vesicles, acetylcholine molecules travel a short distance across the synaptic cleft, where they bind to the nicotinic acetylcholine receptor (Figure 2) [11,12]. This receptor is crucially important to neuromuscular function and has been intensively studied. The receptor is a large protein that spans from the cytosol outside the muscle cell to the cytoplasm on the inside of the cell [13]. The protein has five major subunits: two alpha, two beta, and one delta. There are two acetylcholine binding sites on the receptor. Once bound, the receptor undergoes a change in shape and creates an opening through which sodium ions (Na+) can pass. As Na+ passes into the muscle cell, the electrical charge in the muscle rises, causing a muscular action potential, similar to the neuronal action potential.

Figure 2: THE NICOTINIC ACETYLCHOLINE RECEPTOR

Source : Author

MECHANISM OF SKELETAL MUSCLE CONTRACTION

Muscle cells have their own electrical charge when at rest—in this case, approximately -90 millivolts [14]. When Na+ enters the muscle, this potential rises and causes the depolarization of the cell, sending an action potential into the muscle fiber. Muscles, however, are anatomically thicker than neurons, and the action potential must activate the fibers inside a mass of muscle (Figure 3) in the same manner it activates those closer to the surface. The t-tubules accomplish this, as they dive deep into the muscle and allow the action potential to spread. In the presence of this action potential, a series of vesicular structures called the sarcoplasmic reticula become permeable to Ca2+. This happens via specific channels on the sarcoplasmic reticulum called ryanodine receptors. Figure 4 illustrates the entry of Ca2+ into the skeletal muscle, which then binds with the ryanodine receptor, releasing more Ca2+ from the sarcoplasmic reticulum and allowing a buildup of Ca2+ in the cell [15]. Ca2+ is important in beginning and maintaining the contraction of skeletal muscle.

Figure 3: SKELETAL MUSCLE

Source : [148]

Figure 4: CALCIUM RELEASE IN SKELETAL MUSCLE

1. Calcium enters the cytoplasm after the opening of voltage-gated calcium channels.

2. Calcium opens ryanodine receptors on sarcoplasmic reticulum (SR), allowing the release of stored Ca2+ from calsequestrin inside the SR.

3. Ca2+ accumulates in skeletal muscle cytoplasm.

VGCC=voltage-gated calcium channel.

Source: Author

The operant part of the skeletal muscle is the interdigitation of actin and myosin fibers within the muscle cell. Actin has binding sites for the myosin heads of the myosin fibers, but at rest, these are covered by a structure called the troponin-tropomyosin complex. The tropomyosin portion of this complex is tightly wound around the actin fiber and covers the actin-binding sites [10]. Once covered, the myosin heads remain quiescent, unable to bind with the sites. In the presence of increased Ca2+ levels, such as those that occur after an excitatory muscle potential, the binding sites are uncovered. The Ca2+ binds with one part of the troponin-tropomyosin complex called troponin C. Once bound, the tropomyosin undergoes a conformational change and "rolls" off the actin binding sites. Myosin heads, in the presence of magnesium (Mg2+) and adenosine triphosphate (ATP), bind with the actin binding sites. As the ATP dissociates into adenosine diphosphate (ADP) and a free phosphate ion, the head of the myosin assumes an acute angle, and the myosin head binds with the now-exposed actin-binding site, releasing the ADP and phosphate ion. The myosin head has been compared to a "cocked spring" [10]. Once bound to actin, the spring releases, causing the head to change to a more acute angle, thus pulling the actin fibers closer together. In the presence of ATP, the myosin releases from the actin-binding site. Ca2+ is actively pumped back into the sarcoplasmic reticulum and pumped outside the muscle cell, and the process is free to begin again. Indeed, the muscle stiffness called rigor mortis seen in individuals who have died is the result of a lack of ATP allowing the myosin heads to release from the actin fibers.

THE CLINICAL IMPORTANCE OF THESE MECHANISMS AND STRUCTURES

Understanding the nature by which muscle contracts in the face of the stimulation of the neuromuscular junction is at the heart of understanding how to safely administer neuromuscular blocking agents. As described, there are two binding sites for acetylcholine on the alpha subunits of the neuromuscular junction.

Some neuromuscular blockers, called depolarizing agents, have structures similar to acetylcholine. These agents bind with the neuromuscular junction, causing it to discharge and initiating random depolarization of skeletal muscle, similar to acetylcholine. The difference is that these agents remain bound to the receptor and do not allow the muscle to repolarize. In short, the muscle shortens, then relaxes, and then remains relaxed for a longer period than it would if the depolarization was caused by acetylcholine [15].

Other agents, called nondepolarizing agents, bind with the receptor but do not cause it to be activated. These are considered true antagonists, because they interact with the receptor but the interaction results in no downstream activity. In the case of these agents, the muscles progressively weaken as impulses through the neuromuscular junction are halted. As drug molecules redistribute to other tissues and/or undergo degradation, their numbers decrease, which again allows acetylcholine to function normally and muscle to contract and relax [15,16].

Motor nerves themselves will still conduct motor action potentials; it is only at the point where the nerve meets the muscle that contractility of the skeletal muscle fibers is obtunded. Further, administration of reversal agents, which either increases the amount of acetylcholine or surrounds the neuromuscular blocking agent molecules to render them inert, will result in the accelerated return of normal neuromuscular function [16].

4. NEUROMUSCULAR BLOCKING AGENTS

As noted, there are two major classes of neuromuscular blocking agents: depolarizing and nondepolarizing. These agents interfere with the normal transmission of messages from the prejunctional neuron to the postjunctional muscle fiber.

There is only one depolarizing agent currently available for use in the United States—succinylcholine [16]. As discussed, the nicotinic acetylcholine receptor has two binding sites, one on each alpha subunit. When bound to these sites, succinylcholine causes an uncontrolled depolarization of the muscle cell, resulting in random muscle movement (fasciculation). The binding of succinylcholine with these sites prevents the repolarization of the muscle, causing paralysis.

There are numerous nondepolarizing agents, which are subsequently broken down into two major subgroups: benzylisoquinoliniums and amino steroids [16,17]. However, both of these groups have the same mechanism of action when it comes to blocking neuromuscular transmission. Upon injection, they travel to the nicotinic receptor and bind with one of the two receptors. As can be recalled, in order for a neuromuscular action potential to be passed from the nerve to the muscle, both binding sites on the receptor must be occupied by acetylcholine [10]. As the binding of a nondepolarizer to one of the two binding sites will prevent this, neuromuscular excitation is precluded and no muscular contraction will occur.

During the testing and development of neuromuscular blocking agents, a dose that results in some level of paralysis in a representative sample of patients is established. If the dose results in an effect in 95% of the patients tested, that dose is referred to as the ED_95 or the estimated dose at which 95% of patients receive the desired effect (i.e., paralysis) [16]. Though an agent may have an ED_95, there is often a significant time lapse between the time of administration and peak effect. During endotracheal intubation and airway management, time is of the essence. The prolonged onset of these agents in lower doses may be deleterious, so most agents used for endotracheal intubation are administered to patients at two to three times the ED_95 [14,17]. This increased dose speeds the onset of action, though it is important for the practitioner to remember that the increased dose also prolongs the effect of the injected agent. Table 1 shows the typical ED_95 dose as well as the intubating dose of commonly used neuromuscular blocking agents [17].

Table 1: NEUROMUSCULAR BLOCKING AGENT DOSAGES

Agent

Approximate ED_95

Factor to Calculate Intubating Dose (× ED_95)

Intubating Dose

Intubating Dose For A Healthy 80-Kg Male

Atracurium

0.25 mg/kg

2

0.5 mg/kg

40 mg

Cisatracurium

0.05 mg/kg

5

0.3 mg/kg

24 mg

Mivacurium

0.07 mg/kg

2

0.15 mg/kg

12 mg

Pancuronium

0.07 mg/kg

1.5

0.1 mg/kg

8 mg

Rocuronium

0.3 mg/kg

4

1.2 mg/kg

100 mg

Succinylcholine

1 mg/kg

1.5

1.5 mg/kg

120 mg

Vecuronium

0.05 mg/kg

4

0.2 mg/kg

16 mg

Source: [17]

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS: AMINO-STEROID AGENTS

There are a number of amino-steroid agents on the market today, most of them routinely used. These agents all have a quaternary amine structure, which prevents them from crossing the blood-brain barrier and interacting with cholinergic receptors in the brain. They are also highly water-soluble, allowing them to move quickly from central circulation to the peripheral neuromuscular junctions on skeletal muscle. In nearly all cases, these agents are metabolized in the liver and excreted by the kidneys.

Pancuronium Bromide

Pancuronium bromide is a long-acting, nondepolarizing neuromuscular blocking agent. It is an older agent (as are most neuromuscular blockers) first synthesized in 1966 [16]. The agent can be used for long procedures in the operating room, prolonged air or ground transport during which paralysis is required for patients who are mechanically ventilated, and in the intensive care unit (ICU) for patients requiring immobility for long periods of time [18]. Table 2 provides the dosing regimens for pancuronium.

Table 2: PANCURONIUM DOSING AND CHARACTERISTICS

ED_95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion Dose

0.07 mg/kg

0.1 mg/kg

0.02 mg/kg

2 to 3 minutes

60 to 90 minutes

0.03–0.22 mg/kg/hra

aThis use was only reported in children.

Source: [14,16,19]

Cardiovascular Effects

Pancuronium bromide is noted for its cardiovascular stability, with a slight propensity to cause minor tachycardia in higher doses. This mechanism is related to a combination of blockade of muscarinic receptors and blockade of the re-uptake of norepinephrine in the periphery [20,21]. In one study of patients undergoing open-heart surgery, pancuronium increased heart rate an average of 8 beats per minute (from 53 to 61) while changing neither arterial blood pressure nor cardiac index [22]. Indeed, the authors stated this mild increase in heart rate may be "beneficial" [22].

Hepatic Effects

As pancuronium undergoes 40% to 60% of its degradation in the liver, patients with cirrhosis may expect prolonged time to recovery [16]. The key to determining the duration of pancuronium's effects is a patient's hepatocyte status. Laboratory indications of destruction of hepatic parenchyma should lead to caution in the administration of pancuronium, as its action may be substantially lengthened [23]. In the presence of patients taking other drugs that undergo extensive degradation by the liver (e.g., phenytoin), the upregulation of microsomal enzymes may result in a substantial decrease in the duration of action [16,24].

Renal Effects

Pancuronium is 85% eliminated by the kidneys [25]. In patients with renal failure, the substantial need for renal degradation of the agent combined with decreased glomerular filtration rate can result in prolonged duration of action [17]. In the elderly patient with decreased cardiac output, glomerular filtration rate, and hepatic blood flow, one may expect to see these comorbid conditions combine to result in a prolongation of the drug's effects [16]. Pancuronium clearance time in the patient with renal disease is doubled, resulting in prolonged action [26]. At least two case studies involving three patients reported prolonged paralysis after the administration of pancuronium to patients with renal disorders, in one case for nine days [27]. In the other two cases, patients with comorbid kidney disease who received pancuronium as part of an anesthesia plan for open-heart coronary artery bypass surgery. In these two patients, one remained paralyzed for two days after the administration of pancuronium, the other for six days [28].

Ophthalmologic Effects

During ophthalmologic cases, pancuronium does not change intra-ocular pressure and may be considered for prolonged surgical cases involving the eye [29].

Effects of Pancuronium in Special Populations

Pediatric Patients. Pancuronium may be safely administered to pediatric patients (including neonates), though one should expect a somewhat shorter duration of action. Its duration in pediatric patients is approximately 60 minutes [16]. Pancuronium is especially useful in the pediatric population, as heart rate rather than stroke volume is a key indicator of cardiac output. Cote describes pancuronium as "an appropriate choice" in pediatric patients in whom maintaining an elevated heart rate is particularly important [30]. Pancuronium may also be used in the pediatric intensive care unit (PICU). In one study of 25 pediatric patients receiving pancuronium for three to five days in the PICU, no signs of residual weakness were reported after discontinuation of the of the drug [19].

Elderly Patients. Initial research on pancuronium revealed that despite having both decreased clearance and a prolonged elimination half-life, pancuronium administered to healthy elderly patients has a profile that does not differ markedly from that of young adults [31]. More recent reports recommend caution with the use of pancuronium in the elderly, especially in those with known age-related decrements in hepatic or renal function [32].

Evidence Based Practice Recommendation

The Society of Critical Medicine suggests that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular blocking agents doses for obese patients.

https://journals.lww.com/ccmjournal/Fulltext/2016/11000/Clinical_Practice_Guidelines_for_Sustained.16.aspx

Last Accessed: March 23, 2020

Strength of Recommendation: Weak

Obese Patients. Dosing of any drug is always a challenge in the obese patient. Research has varied, with some clinicians using total body weight and others using ideal body weight or the patient's body surface area to calculate dose [14,16,17,33,34]. The best clinical method of dosing the extremely obese patient with pancuronium is to begin with the ideal-body-weight dose and then modify the dose upward, if needed, based on neuromuscular blocking results [17]. The induction dose may need to be increased if speed of onset is crucial for patient safety. As obese patients frequently present with complex airway problems, a long-acting agent such as pancuronium may be best replaced with one of the shorter-acting agents. The presence of prolonged neuromuscular blockade, combined with a "can't intubate/can't ventilate" scenario with the obese patient, may result in severe comorbidity or death.

Rocuronium Bromide

Rocuronium is the most recently developed neuromuscular blocking agent, introduced in 1992 and developed as a short- to intermediate-acting nondepolarizing agent with an extremely rapid, dose-based onset (Table 3) [14,16,17]. This agent is primarily used as an induction and maintenance agent in anesthesia or when neuromuscular relaxation is needed for a comparatively short period in the non-surgical venue. Rocuronium is typically used in the prehospital environment to facilitate endotracheal intubation by paramedics in the field [35]. Its rapid onset has placed it as a nondepolarizing alternative to succinylcholine; however, doses sufficient to speed onset to this degree come with long durations of action. In the patient whose airway is difficult and in whom the chance of failure to rapidly intubate may lead to a comorbid or mortal event, succinylcholine remains the criterion standard. This circumstance, however, has changed with the introduction of sugammadex to clinical practice in the United States (as will be discussed in more detail later in this course). This novel reversal agent works by surrounding the molecules of rocuronium, precluding it from binding to the nicotinic acetylcholine receptor [36]. Following an intubating dose of rocuronium, administration of sugammadex allows the complete recovery of neuromuscular function in a shorter time than an equipotent dose of succinylcholine. This innovation has dramatically increased the use of rocuronium, making it ideal for the prehospital environment.

Table 3: ROCURONIUM DOSING AND CHARACTERISTICS

ED_95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion

0.3 mg/kg

0.6–1.2a mg/kg

0.1 mg/kg

45 to 90 seconds

60 to 90 minutes

9–12 mcg/kg/min

a1.2 mg/kg allows intubating conditions in 45 to 60 seconds.

Source: [14,16,17]

Cardiovascular Effects

Rocuronium is a very cardiovascularly stable neuromuscular blocking agent [16,37]. In one study in which it was compared with atracurium, rocuronium was significantly more cardiovascularly stable, with no change in heart rate and significantly less decrease in mean arterial pressure [38]. In another study of 80 healthy adults, rocuronium and cisatracurium were found to have equal cardiovascular stability when the parameters of heart rate, mean arterial pressure, cardiac index, and stroke index were measured [39]. The study showed that during a 90-minute monitoring period, mean arterial pressure and heart rate were essentially unchanged throughout the surgical procedures. Additionally, cardiac index varied less than 0.4 L/min/m^2, from a high of 3.4 L/min/m^2 to a low of 3.0 L/min/m^2 [39]. Finally, its use in managing the airways of prehospital trauma patients also speaks to its stability in the injured patient [35].

Hepatic Effects

Degradation of the liver in any fashion prolongs the effects of rocuronium [40]. In one study of 50 patients, patients with cirrhosis showed a slower and more variable return to neuromuscular function and impaired elimination of the drug [41]. In another study of 38 patients, 17 of whom had mild or moderate cirrhosis, researchers found a definite prolongation of duration of rocuronium in patients with liver impairment, with a mean increase in total duration of more than 30 minutes compared with healthy controls [42].

Renal Effects

Rocuronium is eliminated 20% to 35% unchanged in the urine and 55% to 80% unchanged in the bile [15,37]. It is, therefore, dependent on renal clearance for its subsequent elimination from the body. In one study comparing patients with renal disease to healthy controls, equipotent doses of rocuronium had clinical durations approximately 18 minutes longer in those patients with kidney failure, and the recovery time for patients with renal impairment was 30 minutes longer than for those with normal kidneys [43].

Respiratory Effects

Rocuronium does not have a significant histamine release and may be safely administered to patients with reactive airway disease [37].

Effects of Rocuronium on Special Populations

Pediatrics Patients. Rocuronium has been safely administered to pediatric patients both perioperatively and in the ICU. In its usual dose of 0.6 mg/kg, children will experience 90% degradation of the first twitch (T1) in a train of four (TOF) series within 90 seconds [44]. While rocuronium may be used as a rapid sequence induction agent for children as well, it is important to remember that as dose speeds onset, it also increases the duration of the block. Bock and colleagues successfully used priming doses of rocuronium, administered to children premedicated with oral midazolam in subclinical doses of 0.045–0.06 mcg/kg prior to a subsequent intubating dose of 0.405–0.504 mg/kg [44]. They found they were able to decrease the time required for maximal suppression of T1 from a maximum of 90 seconds in the control group to 40 seconds while increasing the maximum duration of the block less than 10 minutes [44]. Rocuronium has not been reported to change heart rate or blood pressure in children in doses of two times the ED_95 (0.6 mg/kg) [45]. It is important to note that in the operating room environment, the concomitant administration of the volatile anesthetic sevoflurane may prolong the effect of rocuronium in children [46].

Elderly Patients. Rocuronium is well tolerated by the elderly population, and there have been no reports of significant change in hemodynamic variables. Elderly patients have inherent decreases in cardiac output, hepatic blood flow, and both renal blood flow and glomerular filtration rate. One might expect a longer time until onset with any agent, but the literature reports different findings. One study reveals rocuronium's onset was the same in the elderly as in younger patients, but the duration of action was markedly increased, from an average of 82 minutes in younger patients to 98 minutes in the elderly after a standard double ED_95 dose of the agent [25]. A second study showed that the onset of rocuronium administered at a dose of 1 mg/kg (slightly more than three times the ED_95) was, on average, 18 seconds longer compared with younger adult patients [47]. This 18-second difference may or may not be clinically significant to practitioners, depending on the circumstance of use. During times when gaining control of the airway in an elderly patient is crucial, this relatively short prolongation of onset may have dramatic effects on clinical outcomes. As rocuronium undergoes both hepatic and renal degradation and excretion, this prolonged effect is expected [48]. At least one source suggests that recovery from rocuronium after the administration of sugammadex as a reversal agent may also be prolonged when compared with a younger adult patient [48].

Obese Patients. Rocuronium dosage modification in obese patients is similar to that necessary for other neuromuscular blockers. Specifically, it is important to consider whether to dose by ideal body weight, actual body weight, or some value between the two. In their review of dosing morbidly obese patients, Ingrande and Lemmons recommend using ideal body weight in order to preclude prolongation of the effects [49]. Their recommendation is confirmed by other sources [37,50]. In one reported case study of bariatric surgery on a super-obese patient (77 kg, body mass index [BMI] 66), rocuronium was successfully administered based on ideal body weight [51].

Trauma Patients. The cardiovascular stability and rapid onset offered by rocuronium provide superior advantages in its use in emergency rapid sequence induction and intubation in the traumatically injured patient. It is crucial, however, that these advantages be balanced against the disadvantage of a prolonged neuromuscular blockade coupled with failed airway management. The latter results in the necessity for rapid surgical management of the airway (quite difficult in the prehospital environment and never routine outside of the operating room). If the airway can be safely obtained in the prehospital setting, the duration of rocuronium works to the advantage of care providers during transport, as the patient will not be able to move and inadvertently remove the endotracheal tube [52].

Vecuronium Bromide

Introduced in 1980, vecuronium is an intermediate-acting nondepolarizing neuromuscular blocker that is quite potent; this can be expected, as it is a monoquaternary analogue of pancuronium. As a result, in larger doses one would expect to see prolonged duration, though in normal doses (Table 4) it is classed as intermediate-acting [15]. Further, vecuronium is unstable as an aqueous solution, so the agent is produced as a dry white powder that must be reconstituted prior to its administration [15,16,37]. Vecuronium undergoes elimination in the liver and is excreted in the bile and urine [14]. One of vecuronium's metabolites, 3-desacetyl vecuronium, is active and cleared more slowly than vecuronium, which may result in prolongation of action in patients with liver and kidney disorders.

Table 4: VECURONIUM DOSING AND CHARACTERISTICS

ED_95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion

0.05 mg/kg

0.1–0.2 mg/kg

0.02 mg/kg

2.4 minutes

20 to 50 minutes

0.8–1.0 mcg/kg/min

Source: [14,16,17]

Cardiovascular Effects

Vecuronium's hemodynamically stable profile has contributed to its popularity. In one study, vecuronium administered in a dose of 0.1 mg/kg showed no significant changes in heart rate or blood pressure throughout the surgical case, during which both the narcotic remifentanil and volatile inhaled agent sevoflurane were also administered [53]. In another study of 60 adult patients with limited comorbidity undergoing laparotomy, vecuronium administered by infusion was noted to result in no significant changes in hemodynamic status. In this study, the average change in heart rate throughout the case was three beats per minute [54]. In a study of patients undergoing coronary artery bypass graft, Shah and colleagues found vecuronium somewhat less stable than rocuronium [55]. There was no difference in postoperative outcomes, despite vecuronium resulting in greater changes in heart rate and mean arterial pressure as well as higher pulmonary vascular resistance and decreased stroke volume [55].

Hepatic Effects

Vecuronium's primary route of excretion is via the biliary tract, with 40% to 80% of the drug being eliminated in the bile and the rest excreted in the urine [16,26]. In patients with hepatic cirrhosis, onset is slower at lower doses (0.1 mg/kg) compared with healthy controls [26]. When the dose is increased to 0.2 mg/kg, the opposite effect occurs; onset becomes more close to normal controls, but duration is markedly lengthened [26]. In all patients with significant hepatic disorder, the elimination half-life and the duration of any dose of vecuronium is markedly increased [17]. Additionally, doses of vecuronium tend to accumulate, making the administration of multiple doses even more likely to lead to prolonged neuromuscular blockade in these patients [56].

Renal Effects

Though the primary route of excretion for vecuronium is the biliary route, a significant portion of the agent is also excreted renally. Renal clearance is the primary mechanism of excretion of the drug from the blood. A prolonged effect of vecuronium should be expected in patients with renal disease. In one study, duration of the agent increased approximately 35% in patients with chronic renal failure versus those with normal renal function [57]. The extent to which this prolongation can be seen is described in a case study of a woman (61 years of age) who, after losing consciousness in her home, was transported to the hospital, placed in the ICU, and paralyzed with vecuronium for mechanical ventilation and sedation for 15 hours [58]. The patient did not recover central nervous system function and was diagnosed brain dead, allowing her to serve as an organ donor. The paralyzing effects of vecuronium lasted for 64 hours after its cessation, an extreme duration of action attributed to polycystic kidney disease resulting in renal insufficiency and decreased clearance [58]. Naturally, this is an extreme case, but the prolonged duration of vecuronium in patients with renal disease, including renal failure, is confirmed by other studies [37,59].

Effects of Vecuronium on Special Populations

Pediatric Patients. Vecuronium may be safely administered to infants and children. Its cardiovascular stability results in no change in heart rate. However, the concomitant administration of narcotics or high doses of volatile agents may result in a decreased heart rate and resultant hypotension [16,37]. Although these effects are not caused by vecuronium, they could be ameliorated with an agent that increases heart rate (e.g., pancuronium). The United Kingdom Paediatric Intensive Care Society Sedation, Analgesia, and Neuromuscular Blockade Working Group has recommended vecuronium as one of a small group of agents acceptable for administration to children in the ICU [60]. As with patients in renal failure, neonates and infants may have reduced renal clearance of vecuronium, resulting in a prolonged action [30].

Elderly Patients. Elderly patients have less circulating body water than young adults. As monoquaternary agents are hydrophilic in nature, elderly patients will require a lower dose of vecuronium (generally decreased by about 35%) to obtain the same paralyzing effect as in younger adults [37,48,61]. Additionally, the decreased reserve manifested by these elderly patients results in the need for special care to be taken in ensuring that vecuronium has either been adequately reversed or allowed to completely wear off before a patient is considered stable and capable of maintaining his or her airway without assistance [16,37,48].

Obese Patients. Obese patients may safely receive vecuronium at an ideal-body-weight dosage, assuming there are no significant liver or kidney comorbidities [50]. In one study, researchers found that 0.015 mg/kg of vecuronium administered as an intravenous bolus, based on actual body weight, resulted in a faster onset in women than in men [62]. They attributed this difference to the greater body fat percentage in female patients compared with male patients. In a subsequent observation, they compared the onset times of the agent in obese and non-obese women, finding a faster onset in the obese group [62]. Other authors, however, have recommended using ideal body weight in the dosing of neuromuscular blocking drugs [34,49].

Trauma Patients. Vecuronium is an excellent agent for muscle relaxation in trauma patients. Its cardiovascular stability coupled with its ability to be administered for longer periods as an infusion make it ideal for patients requiring mechanical ventilation in the ICU. In the prehospital literature, at least one source suggests the use of longer-acting agents such as vecuronium to prevent excess movement during transport, particularly air transport [63].

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS: BENZYLISOQUINOLINIUM AGENTS

As opposed to the amino-steroid neuromuscular blockers, there are primarily two benzylisoquinolinium-based agents on the market in the United States, and one of these (cisatracurium) is used far more than the other (atracurium). These agents have a bis-quaternary amine structure, which prevents them from crossing the blood-brain barrier and interacting with cholinergic receptors in the brain; the same properties are present in monoquaternary amino-steroids [37]. However, benzylisoquinoliniums were developed for a specific purpose, and their structure is closely related to that purpose. In the 1980s, Stenlake and colleagues developed a neuromuscular blocking agent that could be administered to patients with hepatic and renal comorbidities and still undergo predictable degradation [16,64]. The discovery of the application of the Hofmann elimination process in 1956, by which the drug "splits" into inactive parts in the presence of normal blood temperature and pH, and subsequent 25 years of testing and research resulted in the development of atracurium, followed by its cis isomer cisatracurium [15,16,65]. These agents are both classed as "intermediate-duration" nondepolarizing neuromuscular blocking agents [14,17].

A third benzylisoquinolinium-based agent—mivacurium—was developed in the 1980s but removed from the market in 2006 [149]. This agent was then reintroduced in 2016, though its use has remained limited.

Atracurium Besylate

As noted, atracurium besylate was the first of its class, introduced into clinical practice in the United States in the early 1980s. It rapidly gained popularity due to its reliability of degradation even in patients with severe hepatic disease, renal disease, or a combination of both. The dosing details for atracurium can be seen in Table 5.

Table 5: ATRACURIUM DOSING AND CHARACTERISTICS

ED_95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion

0.25 mg/kg

0.5–0.6a mg/kg

0.1 mg/kg

3 minutes

45 minutes

4–12 mcg/kg/min

aIn patients who have atopic tendencies, the release of histamine at this dosage level may result in a hypersensitivity response that, in its most severe form, may progress to anaphylaxis.

Source: [14,16,17]

Cardiovascular Effects

Atracurium has been characterized as being hemodynamically stable, except when administered in doses resulting in histamine release. In other words, the drug itself provides good stability in the absence of an atopic response on the part of the patient at doses of 0.4 mg/kg and lower [16,64]. In one study of healthy adult patients (American Society of Anesthesiology [ASA] Class I or II), the administration of atracurium in a dose of twice the ED95 (0.5 mg/kg) resulted in an average of a 10-mm Hg drop in mean arterial pressure and an average increase of heart rate of approximately 10 beats per minute [38]. These changes were correlated with a peak plasma histamine increase 700 pg/mL higher than in an equivalent group receiving rocuronium. This represented a doubling of the average plasma histamine level before administration of the drug [38]. In another study comparing atracurium at a dose of 0.5 mg/kg with vecuronium at 0.1 mg/kg and a combination of both agents (atracurium 0.25 mg/kg and vecuronium 0.05 mg/kg), there was no significant difference in heart rate or blood pressure measured perioperatively between the atracurium group and the vecuronium group [66]. Of interest, however, is that the group that combined both agents showed greater hemodynamic stability than either one given alone [66]. In another study comparing benzylisoquinolines to amino-steroid blockers, a dose of 0.6 mg/kg of atracurium resulted again in a doubling of plasma histamine levels within two minutes after a five-second bolus injection of the agent [67]. These levels were accompanied by significant hemodynamic changes, including pulse elevation and decreased blood pressure [67]. Contrary to this, one study describes the administration of atracurium to ASA class III and IV patients (those with significant and life-threatening comorbidities) diagnosed with sepsis and inherent cardiovascular instability in which no mention was made of drug-induced instability [68]. One phenomenon that seems to be receiving greater scrutiny is long QT syndrome, in which a triggering agent or condition results in the polymorphic ventricular tachycardia torsade des pointes [69]. Atracurium is not a triggering agent for this phenomenon and may be safely administered [69].

Hepatic Effects

A significant part of atracurium's raison d'être is to better treat patients with hepatic disease [14,15,16]. It has been shown to reliably metabolize in patients with severe liver disease at the same rate as in healthy controls [23]. In one study of six patients with acute hepatic and renal failure, a dose of atracurium 0.7 mg/kg resulted in a mean plasma elimination half-life of 22 minutes, compared with 21 minutes in healthy controls [70]. Another case study described the administration of multiple doses of atracurium to a patient with severe hepatic disease [71]. The agent degraded reliably, and the patient's remaining neuromuscular block was reversed at the end of the case without difficulty [71]. In one particularly interesting case, a woman (37 years of age, primigravida) presented for emergency cesarean delivery with the diagnoses of twin pregnancy, pre-eclampsia, and acute fatty liver of pregnancy syndrome with elevated liver function tests, as well as fetal decelerations [72]. General anesthesia was administered using atracurium for muscle relaxation, and the resulting extubation and recovery postoperatively was described as "uneventful" [72]. Other authors have also recommended the perioperative use of atracurium during surgery for pregnant patients with liver disease [73].

Renal Effects

Atracurium was also developed to assist in the effective treatment of patients with renal dysfunction. In a manner analogous to that of hepatic function, the Hofmann elimination aspects of the drug make it very attractive for use in the patient with kidney disease, removing renal excretion from the degradation pathway [15,16,59]. Atracurium is valued for its use in the critically ill patient, as it does not possess the accumulative properties leading to prolonged blockade, and is preferred over the amino-steroids for this class of patients [74]. One concern is the partial production of laudanosine, one of the metabolites of Hofmann elimination. This metabolite, in large doses, has rarely been associated with central nervous system disorders in the form of seizure activity [16,74]. In a study comparing the effects of atracurium in patients with renal failure against those of healthy controls, Della Rocca and colleagues found that there was no difference in onset, duration, or recovery from 25% blockade recovery to 80% blockade recovery [57]. Atracurium is also indicated in renal transplant surgery [59,75].

Effects of Atracurium on Special Populations

Pediatric Patients. Atracurium may be administered to pediatric patients, but it is important to bear in mind the significance of histamine release if administered quickly or in high doses. Neonates and infants have decreased renal clearance of anesthetic drugs, so classes of agents that do not rely on renal excretion are helpful in the care of these patients [30]. The onset of atracurium in neonates is more rapid than in children [45]. A standard induction dose of 0.5 mg/kg administered to children establishes sufficient muscle relaxation for intubation in 1.2 minutes; in neonates, these same conditions occur at 0.9 minutes [45]. In children, compared with neonates and infants, atracurium has a more rapid clearance rate [60].

Elderly Patients. In general, muscle relaxants, like other drugs, have longer onsets (usually associated with decreased cardiac output) and longer durations (associated with degraded performance of the hepatic and renal systems) when administered to elderly patients. The duration of atracurium follows this model, in spite of its lack of reliance on hepatic and renal systems [61]. The ED_50 needed for neuromuscular blockade was slightly higher in the elderly when compared with younger controls (137 mcg/kg vs. 126 mcg/kg), and the difference in dose to reach ED_95 was higher still (249 mcg/kg vs. 226 mcg/kg) [25]. Some research, however, has found no difference in recovery from atracurium [48].

Obese Patients. As discussed, the decision of dosing the obese patient by actual body weight, ideal body weight, or some scaled body weight between the two can be difficult. Van Kralingen and colleagues compared two different atracurium dosing protocols on morbidly obese patients in their study [76]. A group of 20 patients was randomized to receive either atracurium 0.5 mg/kg based on ideal body weight or the same dose based on actual body weight. The researchers measured the onset in terms of time to 100% blockade of a TOF and return to 5%, 25%, 75%, and 95% of the control value before atracurium administration [76]. They found that dosing on ideal body weight resulted in a predictable return to function identical to that of a non-obese patient of the same weight, while the total-body-weight-dosing group had longer and unpredictable durations [76]. Their findings coincide with those of other researchers, advising the practitioner to dose on an ideal body weight basis, monitor results carefully, and be prepared to provide supplemental doses as needed [33,49].

Trauma Patients. While the traumatically injured patient may receive atracurium acutely, those requiring prolonged mechanical ventilation in the ICU should not. The buildup of the metabolite laudanosine, which is not easily cleared by those with renal impairment or decreased glomerular filtration, may result in seizure activity [37]. In the prehospital setting, atracurium can easily be replaced by other agents that will provide a more rapid onset of muscle relaxation. Further, at the dose needed for a rapid onset, atracurium may cause histamine release accompanied by hemodynamic instability and reactive airway response that is especially deleterious in the trauma patient. In one study of 566 patients at two tertiary care centers, 287 of whom received neuromuscular blockers, atracurium was not administered to any of the patients requiring airway management, while rocuronium and succinylcholine were administered 70.4% and 29.6% of the time, respectively [35].

Cisatracurium Besylate

Cisatracurium was developed and approved in the mid-1990s as an alternative to atracurium and is one of atracurium's 10 stereoisomers [16,17]. After numerous reports of problems with atracurium's propensity to result in release of histamine, cisatracurium was designed to result in less likelihood of histamine release and to increase potency. The increased potency allows prolonged administration of the agent via infusion, with less buildup of the toxic metabolite laudanosine [37]. Its use of Hofmann elimination as the primary pathway of degradation has contributed to its popularity in clinical use. The dosing characteristics of cisatracurium are outlined in Table 6.

Table 6: CISATRACURIUM DOSING AND CHARACTERISTICS

ED_95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion

0.05 mg/kg

0.15–0.2 mg/kg

0.02 mg/kg

5 minutes

45 to 60 minutes

1–2 mcg/kg/min

Source: [14,16,17]

Cardiovascular Effects

Cisatracurium has demonstrated hemodynamic stability in both the operating room and in the ICU [16]. In a study of 70 patients undergoing myocardial revascularization, patients received a dose of cisatracurium of 0.1 mg/kg (approximately two times the cited ED_95) [77]. Cisatracurium was administered over 60 seconds in one group, over 30 seconds in a second group, and over 5 to 10 seconds in a third group. None of the groups had hemodynamic changes greater than or equal to 20% of baseline [77]. These results were replicated in a similar study in which 79 patients diagnosed with coronary artery disease undergoing elective bypass received a cisatracurium dose of either two or four times the ED_95 [78]. No hemodynamic instability was noted in any of the patients, regardless of dose. In another study of 60 patients who received an intubating dose of 0.25 mg/kg of cisatracurium (roughly five times the ED_95), there were no significant changes in hemodynamic status noted [79]. A study of 80 patients receiving either rocuronium or cisatracurium for general anesthesia, combined with either intravenous propofol or inhaled sevoflurane, showed no significant changes in heart rate, mean arterial blood pressure, or cardiac index [80]. Finally, a group of researchers compared two doses of cisatracurium administered to patients in respiratory failure in the ICU for periods ranging from 1.6 to 650 hours [81]. Dose was maintained via infusion pump and monitoring TOF at the orbicularis oculi to obtain either 0 or 2 out of 4 twitches. The researchers reported that, even after long durations of the infusion, no patients had evidence of hemodynamic instability [81].

Hepatic Effects

As with atracurium, cisatracurium was designed for patients with either hepatic or renal comorbidities. The Hofmann elimination process is applicable to cisatracurium [16]. In patients with cirrhosis, cisatracurium is a muscle relaxant of choice, although the fluid retention found in patients with cirrhosis necessitates an increased dose to obtain a similar effect as in non-cirrhotic patients [82]. However, a study assessing the effects of cisatracurium on patients with a Child-Pugh Score of A or B (the lowest and intermediate indicators of hepatic disease) found the dose response curve to be "clinically insignificant" when compared to normal controls [83]. Based on the evidence at hand, cisatracurium is also favored for hepatic resection secondary to tumor excision [84].

Renal Effects

In a study comparing various neuromuscular blockers in patients with renal disorders, there were no significant differences in onset, duration, or supplemental doses, but offset from 25% recovery to 75% recovery was roughly doubled (from 9 minutes in healthy controls to 18 minutes in the renal disease group), and offset from 25% recovery to 80% recovery was slightly longer in patients with renal disease (20 minutes vs. 16 minutes in healthy patients) [57].

Effects of Cisatracurium on Special Populations

Pediatric Patients. Cisatracurium may be safely administered to pediatric patients [16]. In a comparison of all neuromuscular blockers, cisatracurium was noted to have no cardiovascular effects and no histamine-releasing effects in children [85]. In a study of 75 children, cisatracurium doses of 0.1 mg/kg resulted in significantly longer onset; larger doses (0.15 mg/kg and 0.2 mg/kg) did not [86]. No significant difference in recovery time was found at the highest two doses, and no evidence of cardiovascular instability was noted at any dose. In a study of intubating conditions in 181 infants and children 1 month to 12 years of age, a dose of 0.15 mg/kg produced "acceptable intubating conditions" in two minutes [87].

Elderly Patients. Cisatracurium's pharmacodynamics are similar in both elderly and younger adult populations [37,61]. This assumes that the elderly have only the normal renal changes brought on by aging rather than renal comorbidities [25].

Obese Patients. Cisatracurium may be safely administered to patients who are obese. In a study of 20 obese women with BMIs greater than 40, cisatracurium was administered based either on actual or ideal body weight [88]. There was no difference in onset time between the actual-body-weight group and non-obese controls, though the ideal-body-weight group had an onset delayed by 50 seconds on average. The duration of the block to 25% recovery was approximately 30 minutes longer in the actual-body-weight patients when compared with ideal-body-weight patients [88]. One report of anesthesia for a super-obese patient (BMI: 70.7) used cisatracurium at a dose of 0.2 mg/kg using an ideal body weight of 80 kg (compared with an actual body weight of 219 kg) [89]. The authors reported the patient recovered uneventfully after reversal of the neuromuscular blockade [89].

Trauma Patients. There is no reference to the use of cisatracurium in the prehospital role in the professional literature. In the traumatized patient in the ICU, it is crucial that the demands made upon the patient's liver and kidneys be minimized to the extent possible. Not infrequently, patients with severe cardiovascular stressors decrease both hepatic and renal blood flow [74]. As this is the case, agents not relying on these routes for degradation would seem preferable to those that do require hepatic or renal elimination. Further, the absence of inherent cardiovascular instability makes cisatracurium desirable in this setting [90].

DEPOLARIZING NEUROMUSCULAR BLOCKERS

Succinylcholine

Despite the plethora of nondepolarizing neuromuscular blocking agents currently in use in modern healthcare practice, there remains one depolarizing agent—succinylcholine chloride. As new drugs are brought to the market, succinylcholine still has a place in modern practice, despite its invention in the 1950s [16]. The drug has numerous effects and side effects that stand among its principal purpose, which is to rapidly induce neuromuscular paralysis and nearly as rapidly have it wear off again. Succinylcholine differs in its mechanism of action significantly from the nondepolarizing agents.

Succinylcholine, like its nondepolarizing counterparts, works at the postsynaptic neuromuscular junction. Upon injection, it rapidly distributes throughout the body, binding to the acetylcholine receptors on the postsynaptic muscle tissue. Instead of preventing muscular contraction, it causes a random and uncoordinated firing of these receptors, resulting in the physical manifestation of anything from minor twitching to tonic contraction of major muscle groups. These fasciculations are an indicator that the drug is working. After the muscle groups tighten, they relax, but the presence of the drug on the receptors does not allow the muscle tissue to immediately repolarize [16]. The subsequent relaxation of the skeletal muscle results in a transient paralysis that quickly dissipates. The pharmacodynamic characteristics of succinylcholine are described in Table 7.

Table 7: SUCCINYLCHOLINE DOSING AND CHARACTERISTICS

ED95

Intubating Dose

Supplemental Doses

Onset

Return to Normal after Intubating Dose

Infusion

0.5–0.6 mg/kg

1.0–1.5 mg/kg

0.5–0.6 mg/kga

1 minute

9 to 13 minutes

0.5–10 mg/kg/mina

aAt doses exceeding 5 mg/kg, patients may transition into a phase II block, which unpredictably prolongs the action of succinylcholine.

Source: [14,15,16,17]

Succinylcholine has been intensively studied since its introduction into clinical practice in the 1960s. A small molecule that is the functional analog of two acetylcholine molecules joined together, succinylcholine is degraded in the blood by plasma cholinesterase (also referred to as butyrylcholinesterase or pseudocholinesterase) [14,17]. In patients with normal physiology, the abundance of this enzyme allows rapid breakdown of succinylcholine into succinylmonocholine and choline, with approximately 10% being excreted in the urine [91]. This agent has been successfully used in all areas of clinical care, including prehospital, intensive care, anesthesia/surgery, and surgical obstetric practice, and on all age groups. Perhaps due to this longevity, it has been subjected to many clinical trials and research studies. In light of this research, succinylcholine has been found to have numerous side effects and post-administration sequelae. Before addressing these, however, it is important to stress that succinylcholine still has a role in clinical practice. Succinylcholine is the criterion standard for rapid relaxation of skeletal muscle and for its ability to degrade allowing the rapid return of muscular function [15,16,17,37]. When skeletal muscle relaxation is needed quickly, such as for rapid-sequence induction for intubation, succinylcholine remains an excellent choice. Its ability to wear off quickly also ensures that failed intubation does not result in serious comorbidity or, in the presence of a "can't intubate/can't ventilate" scenario, possible patient death due to hypoxia. These facts being accepted, there are many times when succinylcholine may cause complications, some of which are quite serious.

Succinylcholine Side Effects

Post-Administration Myalgias. Patients receiving succinylcholine may complain of a diffuse musculoskeletal pain after recovering from its use. These muscle pains are believed to be the result of generalized inflammation following uncoordinated muscular fasciculations [56]. Numerous interventions have been developed to decrease this pain, which may be severe. The foremost technique is the use of a defasciculating dose of nondepolarizing agents two to three minutes before the administration of succinylcholine, resulting in visibly decreased fasciculations [16]. A meta-analysis assessed a broad compendium of possible treatments to decrease post-administration myalgias, including decreasing the succinylcholine dose and the co-administration of vitamin C, calcium gluconate, lidocaine, and aspirin and nonsteroidal analgesics [92]. Most of the treatments decreased reported pain, but none proved to be ideal. In one study of 393 patients, authors administered lidocaine, d-tubocurarine in a defasciculating dose, a combination of the two, or a placebo prior to the administration of succinylcholine [93]. The authors found that the combination of lidocaine and d-tubocurarine resulted in 8% of the patients having postoperative myalgias, compared with 41.3% reporting myalgias in the placebo group [93].

Hyperkalemia. When muscle and nerve cells depolarize, sodium ions enter the cell, followed by a release of potassium ions during repolarization [10]. The action of the sodium potassium pump then moves these ions against their concentration gradient to ensure the re-equilibration of the ions in their correct concentrations both inside and outside of the cell. However, the administration of succinylcholine, with its accompanying massive depolarization of skeletal muscle, may cause the elevation of serum potassium levels, usually about 0.5–1.0 mmol/L [16,56]. This is especially important in patients with prolonged immobility, neuromuscular weakness as a result of stroke, and/or paralysis secondary to injury [16]. These patients undergo a physiologic change in which they upregulate the number of receptors at their neuromuscular junctions [94]. A 2012 study sought to determine the degree to which hyperkalemia becomes problematic in the critically ill. In a study of 131 critically ill patients who were intubated 158 times (some requiring second intubation in the course of their care), using succinylcholine as the muscle relaxant of choice increased potassium levels an average of 0.4 mmol/L [94]. The primary impact on the elevation in potassium in this study was the length of stay in the ICU. However, in some patients, succinylcholine can cause potassium to rise precipitously. In a case study of a male adolescent (16 years of age) with Klebsiella pneumoniae-associated sepsis, the administration of succinylcholine to facilitate intubation resulted in an increase in his potassium level from 3.19 mmol/L to 8.64 mmol/L [95]. The patient developed cardiac arrest and was aggressively resuscitated. The patient's illness before intubation resulted in him being on bed rest for 15 days prior to the episode, illustrating the impact of immobility on the upregulation of the receptors [95]. Practitioners should make a careful risk/benefit analysis involving any use of succinylcholine. In each case of its use, the question is whether the short onset and, perhaps more importantly, the short duration of this agent overcome the possibility of creating a critical hyperkalemia in an immobile patient.

Masseter Muscle Spasm. One of the primary uses of succinylcholine is to temporarily paralyze the patient to ease the performance of laryngoscopy and endotracheal intubation. Occasionally, the administration of succinylcholine will result in the spasm of the masseter muscle in the jaw, resulting in a patient with a tightly clenched mouth and jaw [16,37]. This condition results in extraordinarily difficult airway manipulation. In one case study, a man became unconscious after an overdose of oral clonidine and the decision was made to intubate him [96]. The patient received 30 mg of etomidate to obtund consciousness, followed by 1.5 mg/kg of succinylcholine. With the jaw rigidly closed, two subsequent attempts at intubation failed, relieved only by the administration of the nondepolarizer vecuronium 10 mg, resulting in sufficient relaxation to allow successful intubation [96]. In a more extreme case, a man presented via ambulance to the emergency room after significant hypovolemia secondary to upper and lower gastrointestinal bleeds [97]. In the face of impending respiratory failure, rapid sequence intubation was selected, and the patient received etomidate 20 mg and succinylcholine 100 mg, after which he rapidly developed a masseter spasm so tight the mouth could not be opened nor could the mandible be moved. Following these findings, a repeat dose of succinylcholine 100 mg was administered without effect [97]. The neck was subsequently prepped and, after a failed nasal fiber optic attempt at intubation, a cricothyrotomy performed with the successful placement of a 5.0 endotracheal tube. It is vital to anticipate the possibility of masseter muscle spasm in patients receiving succinylcholine. Deepening sedation or the administration of a nondepolarizing agent will ameliorate this condition [56].

Cardiovascular Effects. The acetylcholine-based structure of succinylcholine may activate the muscarinic receptors in the parasympathetic nervous system, resulting in bradycardia and bradyarrhythmias. This is most common in patients with high vagal tone and could be of concern in patients requiring an elevated pulse rate to maintain cardiac output [16,17,99]. It is not uncommon to see these effects after large initial doses of succinylcholine or supplemental doses after an initial intubating dose (e.g., in the case of an initial failure of intubation). The slowing of heart rate may result in the generation of ventricular dysrhythmias, which are further aggravated by elevations in potassium [37]. The administration of an anticholinergic such as atropine or glycopyrrolate will ameliorate both the bradycardia and excessive secretions in the mouth and upper airway (another problem of cholinergic stimulation) [15].

Hepatic Effects. As succinylcholine is primarily metabolized by circulating plasma cholinesterases, one would not imagine variations in liver function to be of much concern. However, plasma cholinesterase is produced in the liver, and its levels can be used as proxy indicators of hepatic function [91]. Hepatic abnormalities, ranging from hepatitis to cirrhosis, and normal changes of pregnancy may result in decreased production of plasma cholinesterase [16,37,56].

Genetic Issues. Certain genetic disorders result in abnormal cholinesterases that will degrade succinylcholine far more slowly. This genetic predisposition can be assessed using the dibucaine test, which provides a dibucaine number based on the total activity of cholinesterase and its modified activity in the presence of the local anesthetic dibucaine. Table 8 shows the relationship between dibucaine activity and the ability of cholinesterase to degrade succinylcholine. Dibucaine numbers less than 70 indicate genetic variation that may result in prolonged activity of succinylcholine [37,91].

Table 8: CHANGES IN SUCCINYLCHOLINE ACTION BASED ON DIBUCAINE TEST RESULTS

Type of Cholinesterase

Prevalence in Population

Genetic Identifier

Dibucaine Number

Succinylcholine Duration

Normal

96%

Homozygous U (typical)

70–80

Normal

Atypical

3%

Heterozygous atypical

50–69

Lengthened 50% to 100%

Fluoride-resistant, silent, and other variants

1%

Homozygous atypical

16–30

Markedly prolonged (4 to 8 hours)

Source: [14,15,16,17,91]

Unfortunately, for some patients, this genetic predisposition only becomes evident after the first administration of succinylcholine. A prolonged response is usually followed by genetic testing, and the patient can then have the information placed in their medical records. In extreme cases (such as the "silent" variant), patients may obtain an alert bracelet to warn emergency medical service providers of their altered response to succinylcholine.

Renal Effects. Hyperkalemic effects of succinylcholine can be even more severe in the patient with acute or chronic renal failure. Ordinarily, ingested potassium exceeds requirements, so the kidney excretes excess potassium in the urine. The principal cells in the kidney secrete potassium into the filtrate via specialized channels [100]. Because this loss of potassium is dependent upon glomerular filtration in the kidney, decreased or absent blood flow in the kidney will result in increased potassium levels. One study indicated that while succinylcholine can be safely administered to patients in renal failure, patients with comorbidities or with a predisposition toward hyperkalemia should not receive the drug without a careful risk/benefit analysis [101].

Malignant Hyperthermia. Malignant hyperthermia is a rare genetic disorder occurring in both adults and children, characterized by an uncontrolled release of cellular calcium creating a hypermetabolic state [102,103]. In extreme cases, the patient's temperature can rise as high as 110 degrees Fahrenheit [102]. The syndrome is triggered by the administration of volatile anesthesia inhalation agents or succinylcholine. A prior history of masseter muscle spasm has been noted in 20% to 30% of those with malignant hyperthermia and decreases the onset time of symptoms [103]. Though symptoms can occur immediately after the administration of a triggering agent, there can also be a significant delay. One 2014 study reviewing 477 reported cases of malignant hyperthermia showed its onset from 10 minutes to 75 minutes after the administration of succinylcholine [103]. The initial onset is characterized by an unexplained tachycardia, elevation of end tidal carbon dioxide, and elevation of body temperature. A history of malignant hyperthermia is an absolute contraindication to the use of succinylcholine.

Effects of Succinylcholine on Special Populations

Pediatric Patients. The use of succinylcholine in pediatric patients has generated a great deal of controversy over the past 20 years. In a healthy child with no comorbidities, succinylcholine works well, with the added advantage of being able to be administered intramuscularly. In the event of laryngospasm during the inhalation induction of general anesthesia, succinylcholine may be used in small intramuscular doses to allow muscular relaxation and reopening of the glottis. Infants require somewhat larger doses of succinylcholine; 2 mg/kg is the dose most efficacious for quick blockade [30]. Because both infants and children are dependent on heart rate for cardiac output and tend to have higher vagal tone than adults, an anticholinergic agent should be administered to offset succinylcholine's cholinergic action (and resultant bradycardia) [16,30].

There have been a significant number of case reports of hyperkalemia leading to death in children receiving succinylcholine. One review cites 13 patients with no previous report of neuromuscular disorders, almost all of whom were 8 years of age or younger, who experienced hyperkalemic cardiac arrest after exposure to succinylcholine [104]. All of these patients had underlying Duchenne muscular dystrophy or Becker muscular dystrophy, leading to upregulation of nicotinic receptors. This problem reached sufficient severity to prompt the U.S. Food and Drug Administration to place a "black-box" warning on the succinylcholine product insert. Part of this warning reads as follows [105]:

When a healthy-appearing infant or child develops cardiac arrest soon after administration of succinylcholine, not felt to be due to inadequate ventilation, oxygenation, or anesthetic overdose, immediate treatment for hyperkalemia should be instituted. This should include administration of intravenous calcium, bicarbonate, and glucose with insulin, with hyperventilation. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. However, extraordinary and prolonged resuscitative efforts have resulted in successful resuscitation in some reported cases. In addition, in the presence of signs of malignant hyperthermia, appropriate treatment should be instituted concurrently.

Based on these findings, a nondepolarizing agent should be strongly considered. Bearing this in mind, succinylcholine has been successfully administered to children in the prehospital environment with success, with no reports of malignant hyperthermia-like symptoms [106]. Succinylcholine should be reserved for cases in which rapid onset and short action are crucial to the success of the larger plan of care.

Elderly Patients. The normal degradation of organ systems that accompany aging should be considered when administering any neuromuscular blocker, and succinylcholine is not an exception to this rule. While no difference in duration of action has been found, the elderly may experience longer onsets when their decreased cardiac output is considered [25,61].

Obese Patients. Obese patients frequently have airways that are difficult to manage, whether in the inpatient environment, in the operating room, or in the field during prehospital rescue or resuscitation. Succinylcholine has been used to help facilitate endotracheal intubation in these patients primarily because of its ability to wear off quickly in the event of failed airway management, allowing the patient to breathe spontaneously [16,49]. Succinylcholine should be administered to adult patients using total body weight, rather than ideal body weight, at a dose of 1 mg/kg [33,49]. This use of total body weight to calculate dose is also appropriate for obese adolescents [107]. It is important to remember that these doses result in both rapid onset and somewhat prolonged activity, with duration increasing to approximately 12 minutes [49].

Trauma Patients. In both the inpatient emergency setting and the prehospital setting, succinylcholine has been successfully administered to facilitate intubation of the critically ill or injured patient. In the Eastern Association for the Surgery of Trauma practice guideline, succinylcholine is described as the neuromuscular blocking agent of choice for use in securing the airway via emergency intubation in the prehospital setting [108]. However, European literature has recommended rocuronium, which, with the advent sugammadex, can be readily reversed in a period as short as (or shorter than) the degradation period of succinylcholine [109].

Burn Patients. The burn patient, like the immobilized patient, presents with special concerns regarding the administration of succinylcholine. Patients who have been burned within the last 24 hours usually have had insufficient time to upregulate nicotinic receptors and will not demonstrate the hyperkalemia associated with patients extensively burned more than 24 to 48 hours prior [16,98]. The quick onset and offset of succinylcholine may be of benefit for patients whose emergent burn injuries involve or are near the head and face, so the airway may be rapidly and reliably secured despite any anatomic anomalies. Indeed, inhalation of smoke and superheated air affects the delicate oropharyngeal and nasopharyngeal mucosa, and intubation should be attempted at the earliest practical moment. Patients with burns will frequently return for various grafts and wound maintenance. For these cases, and for airway management in the burn unit, nondepolarizing agents represent the safest choice for neuromuscular blockade [16,17,98].

5. MONITORING NEUROMUSCULAR BLOCKADE

Neuromuscular blocking agents are different from other classes of agents in many ways, but perhaps most exceptional is the ability to accurately and precisely track levels and degrees of neuromuscular blockade [15]. With most other agents, the patient's description is relied upon to determine efficacy (e.g., "My pain is less" or "My nausea is better"). Using a simple nerve stimulator (or "twitch monitor"), an anesthetized surgical patient or sedated intensive care patient can be precisely evaluated. Note that the sedation aspect in the description of these patients is important—as the frequency of the impulse rises, so does the degree of pain. An impulse of 50 Hz administered to produce tetany is quite painful, so patients being tested in such a fashion should be sedated or deemed insensate to pain secondary to severe injury or illness.

Peripheral nerve stimulators (PNSs) have been used for more than 40 years to monitor neuromuscular blockade, although its routine use is not as ubiquitous as might be expected [11,16]. In a 2015 editorial, Rodney and associates reported that a PNS was routinely used by only 18% of those in anesthesia practice in Europe and 34% of those in the United States [110]. This low use rate is despite the fact that the monitor is small and easy to use and that the patient who is inadequately recovered from neuromuscular blockade is at risk for severe complications, including death [111,112,113]. The average PNS (Image 1) is roughly 2–3 inches wide, 1 inch deep, and 4–6 inches long. It has two wires, a positive and negative, which, when attached to gel-filled pads (e.g., electrocardiogram pads), provides a mechanism by which to apply small electrical impulses down a nerve, simulating the electrical synapses that would ordinarily cause the contraction of skeletal muscle. They range in complexity from extremely simple (a twitch switch, a tetany switch, and little else) to very complex (multiple settings, ability to select the exact frequency needed, automatic settings for various techniques of monitoring). Most are less than $300 in price.

The PNS has several settings that are helpful to the clinician and can be activated by pressing the correct button. In this example, there are several modes available by which the degree of neuromuscular blockade can be monitored. In the upper left side of the control panel is the "standby" switch, which stops all electrical impulse generation while maintaining the PNS in the "on" state. Next is the "TEN SEC" button, which will generate one impulse every ten seconds. To the right is the "ONE SEC" button, which will generate one twitch per second. The "TWO HZ" button increases the frequency of the twitch from 1 Hz to 2 Hz. In the second row on the left is the "100 HZ" button, which delivers a high-intensity tetanic pulse for as long as the button is pressed. To the right is the "50 HZ" button, which will also deliver a tetanic stimulation, albeit at half the frequency, for as long as it is pressed. The next button to the right is the "TOF" (train of four) button, which will activate a single series of four impulses. Next is the "TET" button, meaning tetany. Finally, there is the "BATTERY" button. If pressed, how much battery power is left in the device will be displayed. Other, more advanced PNSs may have other controls. For example, some have a control marked "DBS" for double-burst stimulation. The blank screen would show exactly how many Hz are being administered during the production of electric impulses. It is important to remember that the PNS shown in Image 1 is just one example of a PNS; they vary a great deal in complexity, utility, and cost. At a minimum, all should provide single twitches and tetany.

Image 1: PERIPHERAL NERVE STIMULATOR WITH PADS

Source : Author

Monitoring of neuromuscular blockade could conceivably occur anywhere that a motor nerve is close enough to the skin that it may be stimulated [16]. Most practitioners, however, use either the adductor pollicis muscle in the patient's forearm and wrist (Image 2) or the orbicularis oculi muscles surrounding the eye in the face (Image 3). Both Image 2 and Image 3 show the correct placement of the electrodes on the forearm (in the case of the adductor pollicis) or over the temporal branch of the facial nerve (cranial nerve VII), stimulation of which results in twitches around the eye. In addition, Image 2 shows a comparison of the thumb in the relaxed mode and the contracted mode. The orbicularis oculi may be used if the practitioner cannot gain access to the patient's arms (e.g., due to injury or positioning for surgery). The use of the orbicularis oculi has been shown to be as effective as the adductor pollicis in determining adequate muscle relaxation for endotracheal intubation [114].

Image 2: PLACEMENT OF THE PNS MONITORING PADS TO SIMULATE THE ADDUCTOR POLLICIS

Source : Author

Image 3: PAD PLACEMENT TO STIMULATE THE ORBICULARIS OCULI

Source : Author

Evidence Based Practice Recommendation

The Society of Critical Medicine suggests that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment.

https://journals.lww.com/ccmjournal/Fulltext/2016/11000/Clinical_Practice_Guidelines_for_Sustained.16.aspx

Last Accessed: March 23, 2020

Strength of Recommendation: Weak

The most commonly used method of neuromuscular blockade monitoring is the TOF, which will fire four 2-Hz impulses every half second for two seconds [115]. If there is no neuromuscular blocking agent present, one should see four muscular contractions of equal intensity [16,115]. The impulses should be a monophasic, square type, and last no longer than three milliseconds [115].

When activating the PNS to produce a 1-Hz impulse each second, a tracing similar to the one seen in Figure 5 could be produced. Using this figure as an example, consider a patient who has received a dose of neuromuscular blocking agent at the time indicated in Figure 5. As the agent reaches the nicotinic receptors, the degree of muscular contraction, represented by the height of the lines, will diminish. As the muscle relaxant is degraded, the height of the twitch returns to its original pre-block height. Figure 6 shows the effect of the neuromuscular blocker on the twitch height, and the specific measures showing how efficacious the agent is (after a normal dose, to what extent paralysis occurs), its onset (how long it took to reach the maximum point of twitch suppression), and its duration (how long it took to fully degrade and allow twitch height to return to normal). These types of diagrams are ordinarily used in research studies and occasionally by clinicians fortunate enough to have a complex accelerometer available for monitoring time.

Figure 5: CHANGE IN TWITCH HEIGHT AFTER NONDEPOLARIZER AND REVERSAL AGENT

Source : Author

Figure 6: TWITCH HEIGHT SUPPRESSION AND RETURN

Source : Author

The average neuromuscular stimulator, however, does not have this level of complexity. Instead, the clinician uses either a series of four single twitches, observed visually and/or using tactile senses, repeatedly administered one second apart (the TOF). The TOF tells the clinician the approximate number of receptors occupied by the neuromuscular blocker at the point in time when the clinician activates the stimulator. As previously mentioned, the stimulator administers four 2-Hz impulses to the patient. By simply counting the number of muscular contractions produced by the electrical impulses, the practitioner can estimate the degree to which neuromuscular blockade is in force. The TOF looks different in patients receiving succinylcholine than it does in all of the nondepolarizing agents.

Figure 7 shows the height of TOF muscular twitches, represented by lines reaching a certain height in the patient receiving a nondepolarizing neuromuscular blocker. In clinical practice, one would equate the height of these lines with the degree of muscular contraction. Therefore, a tall line is indicative of a strong muscular contraction, a short line is a weak contraction, and no line indicates no response to the stimulus. A patient is tested before receiving an initial dose of neuromuscular blocking agent (after receiving sedation in the ICU or an induction dose of intravenous or inhalation anesthesia). Following the establishment of this baseline, the nondepolarizing agent is administered, a short amount of time (i.e., 30 to 60 seconds) is permitted to pass, and the patient is again retested. Note that all of the twitches are reduced, with the first twitch being strongest and the fourth being weakest. Subsequent tests show further diminution of these twitch heights, until finally only the first twitch is manifested. As the block wears off, the twitches return in ascending height from first to fourth, until, after reversal or significant time for degradation, all four twitches are equal in height and equal to the test conducted before block administration. The interpretation of these twitches is outlined in Table 9 [13,16,116].

Figure 7: TRAIN OF FOUR RESPONSE TO NONDEPOLARIZING NEUROMUSCULAR BLOCKERS

Source : Author

Table 9: INTERPRETATION OF TWITCHES DURING TRAIN OF FOUR STIMULATION AFTER THE ADMINISTRATION OF A NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUG

Number of Twitches Seen

Clinical Interpretation

0

100% of the neuromuscular junctions are blocked. It is possible that the concentration of drug is so high that the amount available exceeds the amount needed for a maximal response.

1

90% of the neuromuscular junctions are blocked. This degree of relaxation is ordinarily suitable for most surgical or intensive care patients.

2

80% of the neuromuscular junctions are blocked. The patient may be readily reversed with the administration of reversal agents.

3

75% of the neuromuscular junctions are blocked. This patient may have inadequate blockade for some types of surgery and/or may attempt to breathe over the ventilator.

4

Less than 70% of the neuromuscular junctions are blocked. The patient may breathe adequately but may still be in a weakened state.

Source: [13,16,116]

Figure 8 shows the TOF response one sees when succinylcholine is administered. The stair-step appearance of the height of the twitches seen with a nondepolarizing agent is no longer present. The depolarizing action of this blocker suppresses muscle response equally, resulting in all twitch heights diminishing to the same degree until the relaxant sets up, at which point they are completely abolished. The twitches return in the same manner in which they were ablated, with four twitches of the same height increasing in contractility until a return to normal function.

Figure 8: TRAIN OF FOUR RESPONSES TO DEPOLARIZING NEUROMUSCULAR BLOCKERS

Source : Author

The degree to which a patient is relaxed may also be determined by administering a tetanic impulse of 50–100 Hz for a given period of time, usually five seconds. For most practitioners, the presence of five seconds of sustained tetany is used as a proxy measure for adequate muscle contraction needed for spontaneous and effective ventilation. However, the transmission of these impulses may provide a clouded picture of the patient's blocked status. Consider the patient who has received a nondepolarizing neuromuscular blocking agent. The practitioner administers TOF stimulation, but notes zero twitches out of four. After waiting a short period (i.e., one minute), the practitioner administers five seconds of tetany, followed almost immediately by a TOF stimulation, after which two of four twitches can be seen. This latter reading is inaccurate, as the tetanic impulse caused the temporary release of large amounts of acetylcholine from the presynaptic neuron. This transient efflux results in a brief period during which it appears the neuromuscular blockade has dissipated. If one re-tests the TOF after four to five minutes, during which the transiently increased release of acetylcholine is redistributed and/or broken down, the TOF will return to zero of four twitches.

Double-burst stimulation is also useful, though it should be noted that the higher impulses used by this technique increase its painfulness and patients who are sedated but not anesthetized may react to this testing method. The double-burst stimulation technique involves firing either two or three 50-Hz impulse bursts, followed by a delay of 750 milliseconds [117]. A second two- or three-burst series follows. The goal is to feel the degree of muscular contraction of the first burst compared to the second burst in terms of both strength of the contraction and lack of fade (or sustained contractility throughout the electric impulse). If the contraction on the second set of bursts indicates fade, the patient patient's TOF ratio (current values compared to baseline values) are 40% to 60%, indicating the patient has residual weakness [117].

A final way of measuring neuromuscular function is the use of post-tetanic count. As with the double-burst stimulation, this is a painful technique and patients who are not anesthetized may view this as a noxious stimulus. It should be used with great discretion in the ICU and prehospital arenas. In this technique, 50 Hz is applied for five seconds, followed after three seconds of no impulse with a 1-Hz twitch. The presence of a twitch indicates the patient is not completely (100%) blocked [117]. It also gives an indication of the time to the return of the first twitch in TOF stimulation; after post-tetanic count, the presence of a twitch during vecuronium or atracurium relaxation indicates a return of T1 in a TOF within seven to eight minutes [117].

For most patients receiving nondepolarizing agents as part of anesthesia for surgical procedures, as well as for most patients in the ICU requiring paralysis, the return of the first twitch only in a series provided by the TOF indicates the presence of a therapeutic degree of neuromuscular blockade. It is possible (and a common, though not desirable, occurrence) that a dose of neuromuscular blocking drug can completely extinguish all twitches in a TOF. Though indicative of a completely paralyzed patient, this level of relaxation is, in most cases, both unneeded and undesirable. In such cases, one must attempt to anticipate how long it will take the block to wear off in an environment of supersaturation. In other words, the amount of neuromuscular blocking agent exceeds the amount needed for a therapeutic effect; there is excessive drug present even as the body starts to break down the initial dose. This is analogous to a "standing-room only" crowd. When one patron leaves his/her seat, another person is waiting to take it; no longer can the number of patrons be estimated by counting the seats.

There are rare cases in the ICU, post-anesthesia care unit (PACU), operating theatre, and prehospital arena in which the benefits gained by the patient being utterly immobile exceed the benefits of the knowledge gained by seeing one twitch and knowing when offset will occur. However, these occasions should be carefully planned and should not happen as a default administration of neuromuscular blocking drugs. No patient should receive a relative overdose of any agent unless there is benefit to be gained by the use of that larger dose [113].

Evidence Based Practice Recommendation

If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia.

https://journals.lww.com/ccmjournal/Fulltext/2016/11000/Clinical_Practice_Guidelines_for_Sustained.16.aspx

Last Accessed: March 23, 2020

Strength of Recommendation: Good Practice

Note that this applies only to nondepolarizing agents. Complete ablation of the TOF is common with the depolarizing agent succinylcholine and is a good indicator of adequate blockade. This reflects the fact that succinylcholine, when administered to a patient with normal plasma cholinesterase levels and function, has a short duration, resulting in the patient's rapid return to normal neuromuscular function [118]. The absence of any twitches only becomes problematic in patients with pathologic responses to the drug (e.g., atypical plasma cholinesterases) or in those developing a phase 2 block. For the most part, such occasions are quite rare, and succinylcholine reliably degrades very quickly, obviating the need for one-twitch maintenance [118].

6. REVERSAL OF NEUROMUSCULAR BLOCKADE

One of the properties that makes nondepolarizing muscle relaxants so useful is their ability to be reversed. In comparison, depolarizing blockers cannot be reversed; the agent must run its natural course and degrade spontaneously. As discussed, it is vital to dose the agent correctly. In nearly all cases, this means leaving a minimum of one twitch in the TOF (for nondepolarizing agents). The biggest concern with reversing neuromuscular blocking drugs is the fact that reversal agents work at both the nicotinic and muscarinic receptor sites. As the nicotinic receptor and its activity have been discussed in detail in a previous section, this section will provide a brief review of the muscarinic receptor.

Muscarinic receptors are found ubiquitously throughout the body, though its main areas of concern when reversing neuromuscular blockade are its effects in the heart, vasculature, upper airway, conducting airways, and nervous system. The autonomic nervous system (Figure 9) is composed of two major divisions: the sympathetic (or adrenergic) nervous system and the parasympathetic (or cholinergic) nervous systems. The sympathetic nervous system is associated with the "fight-or-flight" phenomenon, while the parasympathetic system is associated with the "rest-and-digest" functions. Both of these nervous systems are further divided into the preganglionic neurons and the postganglionic neurons.

Figure 9: THE AUTONOMIC NERVOUS SYSTEM

Source : Author

In the reversal of neuromuscular blockade, concerns revolve around the inadvertent and excessive activation of the parasympathetic nervous system and its attendant muscarinic receptor activation. This is because classic neuromuscular blockade reversal agents work by deactivating acetylcholinesterase, the enzyme primarily responsible for inactivating acetylcholine. Lack of acetylcholinesterase causes increased levels of acetylcholine to build up. These acetylcholine molecules compete with nondepolarizing drug molecules for the acetylcholine receptor site at the nicotinic receptor on the postsynaptic neuromuscular junction membrane. This is a therapeutic action, resulting in the return to normal functioning of skeletal muscle.

Unfortunately, elevated levels of acetylcholine will also bind with muscarinic receptors. Muscarinic receptors are a family of receptor subtypes that are primarily responsible for carrying out the physiologic effects associated with the parasympathetic nervous system [16]. When activated by acetylcholine, muscarinic receptors have a wide range of physiologic responses that can be deleterious to the patient, including bradycardia, bronchospasm, increased nasal and oral secretions, and hypotension [37,116]. In patients with reactive airway disease, cholinergic responses can result in full-blown asthma attacks. The solution is to administer a concomitant dose of an anticholinergic agent, which will work at the muscarinic receptor to block the attachment of acetylcholine while not affecting the nicotinic receptors. It is crucial that an adequate dose of anticholinergic drug, either glycopyrrolate or atropine, is administered with the anti-acetylcholinesterase agent. Failure to administer an anticholinergic may result in severe cardiovascular collapse, pulmonary failure, and, in extreme cases, death [119]. Fortunately, these drugs are easy to administer.

ANTI-ACETYLCHOLINESTERASE AGENTS

Upon release from the prejunctional neuron at the neuromuscular junction, acetylcholine rapidly crosses the synaptic space and binds with the nicotinic acetylcholine receptor on the muscle membrane. The synaptic cleft, however, is also lined with acetylcholinesterase that has the function of breaking down acetylcholine. This breakdown happens very quickly, usually within 80 to 100 microseconds [116]. In order to overcome this rapid breakdown and to allow the neurotransmitter sufficient time to build up to a level at which it can compete with the nondepolarizing drug, the acetylcholinesterase must be temporarily degraded. There are three commonly used anti-acetylcholinesterase agents that will accomplish this task: edrophonium, neostigmine, and pyridostigmine. Of these three, neostigmine is the one used most frequently for the reversal of neuromuscular blockade induced by a nondepolarizing agent.

Neostigmine

Injecting neostigmine intravenously results in the drug quickly binding with acetylcholinesterase. This binding process accomplishes two actions. First, the acetylcholinesterase is inactivated, and then the neostigmine itself is hydrolyzed, deactivating the action of the drug as well [116]. These actions raise the concentration of acetylcholine in the synapse of the neuromuscular junction, resulting in a return to normal function of the skeletal muscle [15]. The kidney excretes approximately 50% of neostigmine, so its effects may be prolonged in the patient with renal disease [116]. Of the remaining drug, 30% undergoes degradation in the plasma via cholinesterases, and the rest in the liver [120]. Neostigmine has a quick onset (i.e., 1 minute) but a slower peak activity (approximately 10 minutes) after injection [119,121]. A dose of 0.07 mg/kg (maximum: 5 mg) has been deemed sufficient to provide reversal for patients who manifest at least one twitch in a TOF; however, more recent research has called this into question [15,16]. A standard dose of neostigmine does not reflect the pharmacologic standard of varying drug doses with patient needs. The ability to monitor patients receiving neuromuscular blockers allows one to determine the extent of the blockade and thus modify the dose of reversal agent required. In Table 10, the works of several researchers have been combined to provide dosage guidance for the administration of neostigmine in the face of neuromuscular block monitoring [11,17,113,119,121].

Table 10: DOSAGE GUIDELINES FOR NEOSTIGMINE REVERSAL OF NEUROMUSCULAR BLOCKADE

Twitches in TOF

Dose of Neostigmine

0

Delay reversal until TOF = 2

1

0.05–0.07 mg/kg

2

0.05–0.07 mg/kg

3

0.05–0.07 mg/kg

4 (with fade)

0.04–0.05 mg/kg

4 (without fade)

0.015–0.025 mg/kg

Source: [17,116,121,122]

Edrophonium

This agent is a short-acting anti-acetylcholinesterase with a more rapid onset than neostigmine. While the administration of neostigmine results in the degradation of the acetylcholinesterase enzyme, edrophonium merely binds and then releases, leaving the enzyme intact [116]. The dose of edrophonium is 0.5–1.0 mg/kg, and, like neostigmine, it must be administered with an anticholinergic agent [16,116].

Pyridostigmine

Pyridostigmine has a somewhat longer duration of action than neostigmine and, like neostigmine, degrades the acetylcholinesterase enzyme. Pyridostigmine is not as effective as either neostigmine or edrophonium at doses of 0.38 mg/kg [123]. A review of the literature reveals the nearly total absence of use of this agent as a reversal drug, and it is included here solely in the interest of being complete.

Correct Administration

As with every other medication, the patient's underlying comorbidities, pathology, and circumstances regarding its administration should be considered. The most common way of administering neuromuscular reversal agents is to mix them together in a syringe of adequate size, usually 10 mL in capacity. To prepare the medication for injection, the clinician first aseptically draws up 5 mL of either atropine (in a concentration of 400 mcg/mL; total dose 2 mg) or glycopyrrolate (in a concentration of 200 mcg/mL; total dose 1 mg). Having filled the syringe halfway with anticholinergic, the practitioner fills the remaining 5 mL of the syringe with 5 mg of neostigmine, resulting in a 10-mL syringe filled with 5 mg of neostigmine in a concentration of 0.5 mg/mL, and either 2 mg of atropine at a concentration of 200 mcg/mL or 1 mg of glycopyrrolate at a concentration of 100 mcg/mL. The drugs are now ready for administration. Referring to Table 9, consider a 60-kg patient with two twitches on a TOF being reversed with glycopyrrolate and neostigmine. The correct dose for reversal is 0.05–0.07 mg of neostigmine per kilogram of body weight. This calculates to a dose of 3.5–4.2 mg of neostigmine. The dose of 3.5 mg is selected. As the syringe contains 0.5 mg neostigmine per mL, 7 mL of the mixed agents is required; this will give a concomitant dose of 700 mcg of glycopyrrolate. Glycopyrrolate will ameliorate the adverse cardiovascular and pulmonary side effects of neostigmine, while the therapeutic effects of increasing acetylcholine at the neuromuscular junction will continue, resulting in the reversal of neuromuscular blockade. This technique also works with atropine, though atropine's ability to cross the blood-brain barrier (which is not present in glycopyrrolate) has resulted in its use as a part of the reversal mixture decreasing over time.

Occasionally, patients may experience a brief episode of bradycardia if neostigmine binds with muscarinic receptors before the anticholinergic can occupy and block those same muscarinic receptors. If it is important that the patient not become bradycardic (e.g., cardiac valvular disease with regurgitant flow), the practitioner can mix the neostigmine and anticholinergic in two different syringes. A small dose of the anticholinergic is then administered first, and, upon seeing an increase in heart rate, the practitioner can then inject the anti-acetylcholinesterase agent and the remaining anticholinergic agent.

SUGAMMADEX

Sugammadex is the newest reversal drug to come on the market, and it has been described as "revolutionary" [36]. It was approved for use in the United States by the FDA in 2015 [36]. Prior to this, it was used successfully in Europe for nearly a decade. Sugammadex is described as a cyclodextrin with a hydrophobic interior and hydrophilic exterior [124]. Its structure allows other hydrophobic agents to enter the center of the molecule and prevent the agent from binding with the receptor. The drug was designed to have a specific affinity for the nondepolarizing agents rocuronium and vecuronium [125]. It differs from other neuromuscular block reversal agents in that it inactivates the nondepolarizing drug while leaving acetylcholinesterase unaffected. As sugammadex combines with the amino-steroid nondepolarizers, there are fewer free nondepolarizing agent molecules available to bind with the nicotinic receptor. This in turn allows the increased binding of acetylcholine and a return to normal muscle function [36]. One of the shortcomings of this drug is that it does not work to reverse blocks from cisatracurium, atracurium, or succinylcholine [36].

The most crucial impact of sugammadex is that, when combined with the nondepolarizing agent rocuronium, it offers an alternative to succinylcholine in a patient who requires both a rapid onset and a rapid offset of muscle relaxation. This is even more important when coupled with the fact that the duration of time the block has been in effect, the presence or absence of twitches, and the dose of the block are immaterial to its reversal [124]. As an example of the efficacy of this reversal agent, consider the effects of a dose of 0.6 mg/kg of rocuronium, which should last approximately 40 minutes. After the administration of a dose of 8 mg/kg of sugammadex, neuromuscular function returns to normal in less than two minutes [124]. A dose of conventional neuromuscular block reversal agent, such as neostigmine, would have been ineffective until two twitches of the TOF had recurred (approximately 20 minutes), and then the reversal agent itself would have taken another 10 minutes to peak. The recovery profile of sugammadex coupled with rocuronium exceeds that of succinylcholine in terms of onset and offset [113].

The dose of sugammadex varies depending on the time delay between the administration of the nondepolarizing agent and the subsequent reversal dose of the drug. The doses of sugammadex for shallow, moderate, and deep levels of neuromuscular blockade are 2 mg/kg, 4 mg/kg, and 16 mg/kg, respectively [113,119]. The latter dose of 16 mg/kg is referred to as a rescue dose and can reverse doses of rocuronium as high as 1.2 mg/kg in as little as three to five minutes [113].

Sugammadex is eliminated via the kidney, with 95% of the drug being eliminated unchanged in the urine [126]. The drug has not been associated with any pulmonary or cardiovascular side effects, despite initial concerns that its administration could aggravate long QT syndrome [126].

7. COMMON USES OF NEUROMUSCULAR BLOCKING AGENTS AND AREAS OF CONCERN FOR THE PRACTITIONER

POST-ANESTHESIA CARE UNIT

Neuromuscular blockers are commonly administered in the operating room, and nurses in the PACU will frequently receive patients who either still have neuromuscular blocking drugs on board or who have just undergone reversal. It is important for the PACU nurse to rapidly and accurately determine the patient's neuromuscular blockade status, as the inadequate reversal of neuromuscular blockade combined with an extubated patient may result in hypoxemia, the need for emergent reintubation, cardiac dysrhythmias, and, in extreme cases, death [112,113]. While using the PNS to determine the degree of relaxant remaining in the patient would be of greatest use, this is somewhat difficult unless the patient arrives in the PACU sedated and intubated, as the PNS tests may be painful. Fortunately, other tests can be done to determine the degree to which the patient's neuromuscular function has returned [111,113,121]. These tests include:

- A sustained head lift for longer than five seconds: This tests the core muscles of the patient and mimics the "five seconds of tetany" produced by the PNS. The drawback of this test is it may be impossible for certain patients (e.g., those who have undergone abdominal surgery).

- Protrusion of the tongue for longer than five seconds: The tongue is the most likely anatomic structure to occlude the upper airway. Patients who can stick their tongue out and hold it for five seconds reassure the practitioner that they can clear their own airway. Additionally, the five-second period shows prolonged muscular activity is possible.

- Firm handgrip for longer than five seconds: This test offers the added benefit of determining the patient's level of mentation and his or her ability to respond appropriately to verbal stimulus. As with the first two tests, the five-second period shows the ability of the patient for prolonged muscular contraction.

- An inspiratory force exceeding -25 cm H2O: The ability of the patient to breathe deeply is the prime reason all of the other tests are performed. The ability to generate this level of negative pressure (as measured by spirometry) indicates the return of muscular function of the diaphragm.

- Tidal volume of 5 mL/kg and a vital capacity of greater than 15 mL/kg: These tests are ordinarily performed by respiratory therapy during a pulmonary function test but may be performed at the bedside if the patient is intubated. The ability to generate these values on command is indicative of sufficient respiratory function to allow normal breathing. It is important to note these values may be modified in patients with significant pulmonary comorbidities.

PREHOSPITAL ADVANCED CARE PROVIDERS (PARAMEDICS AND PREHOSPITAL NURSES)

The prehospital arena presents numerous problems for practitioners. There is a consistent dynamic tension between the option of staying on scene longer to stabilize the patient prior to transport and loading the patient for rapid transport to a hospital for definitive care. The area in which these two schools of thought converge is that of time management. The "golden hour" applies not just to traumatically injured patients, but to those suffering from cardiovascular issues (e.g., myocardial infarction) or cerebrovascular issues (e.g., stroke). In all of these cases, perfusion of the damaged tissue with oxygenated blood is among the highest priorities. Providing supplemental oxygen via facemask, nasal cannula, or even continuous positive airway pressure may not be sufficient to meet the patients' needs. In these cases, the airway must be secured, either with a supraglottic device blindly inserted or via endotracheal intubation.

Administration of neuromuscular blockers can relax the musculature of the jaw and oropharynx and speed endotracheal intubation. The same relaxation that makes endotracheal intubation easier comes with the downside of increasing the likelihood of vomiting and aspiration. As early as 1998, researchers have sought to determine the extent to which succinylcholine would ease intubations in the emergency department [127]. Though not in the prehospital venue as such, most prehospital policies emanate from emergency departments. In this study, researchers found that the administration of succinylcholine decreased the number of intubations defined as "difficult" and advocated for the use of the drug [127]. This study was followed by a second confirming the utility of neuromuscular blockers in the hands of non-anesthesia personnel in the emergency room, again using succinylcholine [128]. The rates of complications such as esophageal intubation, aspiration, and airway trauma were reduced after the administration of succinylcholine for airway management.

Other studies conducted in the late 1990s began to branch into the use of neuromuscular blocking agents in the field by non-physician providers. One such study advocated the use of succinylcholine, along with lidocaine, oxygen, and midazolam, for patients receiving aeromedical evacuation [129]. The researchers found an increased rate of successful intubation, moving from 69.6% success in non-medicated patients to 97.5% in those receiving paralysis [129]. A particularly interesting study dealt with the paramedic administration of succinylcholine to critically ill and injured children. As discussed, succinylcholine may lead to significant problems in children, such as bradycardia and hyperkalemia, the latter complication in those with undiagnosed muscle disorders. Despite these possible concerns, the study found that paramedics, under close medical direction, could use succinylcholine to successfully intubate pediatric patients, with a reduced prevalence of airway complications and no episodes of bradycardia [130]. This theme was echoed by researchers determining the utility of neuromuscular blockade assisted intubation in patients with severe head injuries [131]. They used succinylcholine followed by rocuronium after endotracheal tube placement to provide ease in ventilation during transport. Severely hypoxic patients had statistically higher mortality rates than those without hypoxia, and the success rate for oral tracheal intubation was 84.5% [131]. Another study in which paramedics intubated patients with severe traumatic brain injury using succinylcholine showed increased rates of favorable neurologic outcome six months after the injury [132].

As prehospital care continued to develop, the use of other types of medications for neuromuscular blockade were researched. As with succinylcholine, early research seeking to use rocuronium as a substitute was performed in the emergency department. In a study comparing the use of succinylcholine and rocuronium for airway management in a tertiary care facility, both agents were found to be equally efficacious, though succinylcholine was preferred by the clinicians, presumably due to its fast offset [133]. It is important to note that during the time of this study (2009) sugammadex was not yet approved for use in the United States. In a later review article, the author suggested rocuronium be substituted for succinylcholine for the prehospital provider [63]. The availability of sugammadex takes the problem of prolonged paralysis out of the equation while also eliminating the plethora of side effects associated with succinylcholine. In short, neuromuscular blocking agents used by well-trained field personnel decrease the likelihood of airway complication, facilitate airway management in the field, and, when accompanied by appropriate sedation protocols, prevent the patient from fighting restraints and mechanical ventilation during transport.

ANESTHESIA

The most common use of neuromuscular blocking agents is during surgical procedures. Neuromuscular blocking agents allow the anesthesia provider the muscular relaxation needed to facilitate manipulation of the patient's airway, direct or indirect exposure of the glottic opening, and placement of an endotracheal tube to facilitate perianesthesia ventilation and maximally protect the patient's airway during the procedure. Additionally, in the majority of surgical cases, relaxation of skeletal muscle aids the surgeon's visualization of the organs and results in the administration of lower doses of other anesthetics. As discussed, neuromuscular blocking agents work peripherally at the neuromuscular junction rather than centrally in the motor cortex of the brain. It is, however, possible to decrease patient movement and decrease the tension in skeletal muscle by deepening the level of other anesthetic agents, particularly the inhaled (volatile) anesthetic agents. Years of experience have revealed that the dose of inhalation agent required to accomplish this is quite high and affects not only the brain but also mechanisms at the spinal cord [134]. It is dramatically higher than the amount of inhaled agents needed to obtund consciousness and obliterate the patient's memory during the surgical procedure [134]. As this is the case, neuromuscular blocking agents provide a quiet surgical field, increase the patient's tolerance of mechanical ventilation, and quickly reverse the patient at the end of the case, shortening the perianesthesia period.

The anesthetist is well placed to measure the degree of neuromuscular blockade continuously throughout the anesthetic and surgical procedure. With rare exceptions, the anesthetist has access to either the patient's forearm (to stimulate adductor pollicis muscles) or head (to stimulate orbicularis oculi muscles). As this continuous monitoring is both quick and easy to quantify, the guidelines recommend that only intermediate-acting neuromuscular blockers be administered and that the long-acting neuromuscular blockers (e.g., pancuronium) be removed from anesthesia practice [113]. Further, the anesthetist should endeavor, whenever clinically possible, to maintain a minimum of one twitch in a TOF series. These two practices, both of which are easily accomplished, have the potential to decrease the problems with prolonged or inadequately reversed neuromuscular blockade. Long-acting muscle relaxants may still have a place in anesthesia practice for patients who require a long recovery, intensive care hospitalization, and prolonged post-procedure ventilation. As surgical practice moves more and more toward "fast-tracking" the patient's recovery, these cases will probably be less common.

THE INTENSIVE CARE UNIT

Note: There are many types of ICUs, some generalized in nature and some only accepting specific patients. In this course, the term ICU includes any unit in which critically ill or injured patients require extensive monitoring and in which mechanical ventilation is used.

Critically ill patients in the ICU may be unable to breathe for themselves secondary to severe injury, extensive surgery, or respiratory failure secondary to cardiac or pulmonary comorbidities. In cases such as this, intubated patients (or those with tracheotomy) may require mechanical ventilation. While such ventilation is possible with the co-administration of neuromuscular blocking drugs, some forms of mechanical ventilation will be difficult for the patient to tolerate. For example, as the mechanical ventilator inflates the lungs, a volume will be reached that triggers the Hering-Breuer response [135]. This reflex ordinarily stops negative pressure inspiration in the normally breathing adult; however, in the mechanically ventilated patient, it may cause the patient to violently attempt to cough, more commonly known as "bucking" on the ventilator. This phenomenon may be attenuated by either sedation or narcotic analgesia, but the doses of such medications may result in prolonged inhibition of normal respiration and delay extubation. Further, in patients with either acute lung injury or adult respiratory distress syndrome (sometimes referred to as noncardiogenic pulmonary edema), the administration of neuromuscular blockade can decrease oxygen consumption [74]. In one study of 340 patients requiring mechanical ventilation secondary to adult respiratory distress syndrome, a group that received a 15-mg bolus dose of cisatracurium followed by an infusion of 37.5 mg/hour for 48 hours resulted in a 90-day mortality rate of 31.6%, compared with a mortality rate of 40.7% in those not receiving the protocol [136]. While the importance of the judicious use of neuromuscular blockers in the critically ill cannot be understated, one study provides clear and convincing evidence of the importance of a sufficient level of sedation that must also be given to these patients. In their study, patients were more likely to develop delirium in the absence of or inadequacy of sedation [137]. In their research, 64.4% of mechanically ventilated patients experienced delirium and had a 30-day mortality rate of 30.3%, compared with a rate of 11.9% in those not experiencing delirium [137]. Clinicians should always keep in mind the concept that neuromuscular blockers offer no diminution of central nervous system function whatsoever, and there can be few things as terrifying as being paralyzed and wide awake.

With the use of a PNS and the co-administration of sedation, the ICU staff can closely monitor a patient's degree of neuromuscular blockade. Indeed, one author has referred to the use of the PNS as the "criterion standard" in musculoskeletal monitoring [138]. Patients requiring prolonged neuromuscular blockade in the ICU are best treated with intravenous infusions of intermediate-acting agents. As with all hospitalized patients, the goal is to treat the underlying disease or injury as quickly as possible, and then wean the patient from the ventilator in a quick and efficient manner. While intermittent boluses of neuromuscular blockers will prevent patient movement, they may impede the reversal and weaning process. A large loading dose of neuromuscular blocking drug, given to ensure quick onset, has the disadvantage of exceeding the therapeutic dose levels and extinguishing the TOF response (no twitches). Until the dose begins to degrade, the clinician is "flying blind," as there is no way to determine the extent of neuromuscular blockade. Indeed, there may be a supramaximal dose, resulting in prolonged blockade. The infusion dose, though taking a bit longer to set up, stops at the desired point. The lack of peaks and nadirs ensures the correct dose throughout the administration of the drug, easing recovery from neuromuscular blockade. Finally, the administration of large bolus doses of neuromuscular blocking agents in the ICU has been associated with prolonged blockade [138]. This is attributed primarily to those agents degraded by the liver and eliminated by the kidney. During the peak stages of the patient's illness or injury, hepatic and/or renal function may decrease. Agents such as pancuronium and vecuronium, with significant hepatic breakdown, active metabolites, and diminished renal excretion, have been associated with prolonged neuromuscular blockade lasting days or weeks after the cessation of administration [138]. This phenomenon appears especially linked to those patients presenting with sepsis. One group of researchers speculated the aggravating effects of neuromuscular blockers in these patients may also be due to degraded renal function [139].

Evidence Based Practice Recommendation

The Society of Critical Medicine suggests against the routine administration of a neuromuscular blocking agents to mechanically ventilated patients with status asthmaticus.

https://journals.lww.com/ccmjournal/Fulltext/2016/11000/Clinical_Practice_Guidelines_for_Sustained.16.aspx

Last Accessed: March 23, 2020

Strength of Recommendation: Weak

Another significant problem that may occur in ICU patients receiving muscle relaxants is the phenomenon of ICU-acquired weakness. This weakness may be nerve-centered (critical illness polyneuropathy) or muscle-centered (critical illness myopathy) [140]. One study reports an incidence of between 24% and 77% in patients with stays in the ICU as short as one week, and men appear to be twice as likely to experience this as women [140,141]. The nature and role of neuromuscular blocking in aggravating or preventing this weakness is still under consideration. One study, for example, found that cisatracurium had no effect on the development or exacerbation of ICU-acquired weakness [140]. A contrary view states that the risk of myopathy increases with the concomitant administration of corticosteroids and neuromuscular blockers [138]. From this perspective, the institution of "drug-free holidays" during which neuromuscular blockers are allowed to completely wear off, as verified by the PNS, may be warranted. Their findings were echoed by other researchers, who identified prolonged neuromuscular blockade as a risk factor for prolonged weakness [141]. These researchers recommended the same drug-free holidays, as well as the use of an infusion to keep the dose at a sufficient level to allow a TOF of two twitches, with regular PNS monitoring.

8. CONCLUSION

Neuromuscular blockers have a specific and carefully defined place in health care. The primary warning that comes with each of the agents is that an individual who is an expert in airway management should always be immediately available prior to their administration. The practitioner should always consider carefully the comorbidities of the patient receiving these agents. Further, every patient who receives these agents should receive some form of sedation, preferably deep sedation, to prevent him or her from consciously experiencing the terrifying phenomenon of being awake and paralyzed. Finally, patients who have received neuromuscular blocking agents should always be carefully monitored and, with rare exceptions, the minimum dose to achieve the therapeutic goal administered. Following these guidelines will result in patient care that is safe and comfortable.

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130. Brownstein D, Shugerman R, Cummings P, Rivera F, Copass M. Prehospital endotracheal intubation of children by paramedics. Ann Emerg Med. 1996;28(1):34-39.

131. Davis DP, Dunford JV, Poste JC, et al. The impact of hypoxia and hyperventilation on outcome after paramedic rapid sequence intubation of severely head-injured patients. J Trauma. 2004;57(1):1-8.

132. Bernard SA, Nguyen V, Cameron P, et al. Prehospital rapid sequence intubation improves functional outcome for patients with severe traumatic brain injury. Ann Surg. 2010;22(6):959-965.

133. Mallon WK, Keim SM, Shoenberger JM, Walls RM. Rocuronium vs. succinylcholine in the emergency department: a critical appraisal. J Emerg Med. 2009;37(2):183-188.

134. Perouansky M, Pearce RA, Hemmings HC Jr. Inhaled anesthetics. In: Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Cohen NH, Young WL (eds). Miller's Anesthesia. 8th ed. Philadelphia, PA: Elsevier Saunders: 2015; 614-637.

135. Hall J. Regulation of respiration. In: Hall JE, Guyton AC (eds). Guyton and Hall's Textbook of Medical Physiology. 13th ed. Philadelphia, PA: Elsevier, Inc.; 2016; 539-549.

136. Yegneswaran B, Murugan R. Neuromuscular blockers and ARDS: thou shalt not breathe, move, or die! Crit Care. 2011;15(5):311.

137. Shehabi Y, Riker RR, Bokesch PM, et al. Delirium duration and mortality in lightly sedated, mechnically ventilated intensive care patients. Crit Care Med. 2010;38(12):2311-2318.

138. Pandit L, Agrawal A. Neuromuscular disorders in critical illness. Clin Neurol Neurosurg. 2006;108(7):621-627.

139. Schefold JC, Bierbrauer J, Weber-Carstens S. Intensive care unit-acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock. J Cachexia Sarcopenia Muscle. 2010;1(2):147-157.

140. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011;10(10):931-941.

141. Linos K, Foot C, Ziegenfuss M, Freeman WD, Tan KM. Critical illness weakness: common questions. Curr Anaesth Crit Care. 2007;18(5-6):252-260.

142. Kim TK, Obara S, Johnson KB. Basic principles of pharmacology. In: Miller RD (ed). Miller's Anesthesia. 8th ed. Philadelphia, PA: Elsevier/Saunders; 2015: 590-613.

143. Ortiz-Gómez JR, Carrascosa F, Pérez-Cajaraville JJ, Percaz-Baldos JA, Añez C. Comparative study of intubating conditions at the first minute with suxamethonium, rocuronium and different priming. Eur J Anesthesiol. 2005;22(4):263-268.

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95150 • Responsible and Effective Opioid Prescribing

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

95150 • Responsible and Effective Opioid Prescribing

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

ACUTE PAIN

CHRONIC PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

RISK ASSESSMENT TOOLS

PERIODIC REVIEW AND MONITORING

CONCURRENT USE OF BENZODIAZEPINES

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

8. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

STIGMA OF ADDICTION

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95150 • Responsible and Effective Opioid Prescribing

Education Category. Pharmacology

Release Date. 05/01/2017

Review Date. 09/15/2019

Expiration Date. 04/30/2021

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all physicians, osteopaths, physician assistants, and nurses who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

Upon completion of this course, you should be able to:

1. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

2. Create comprehensive treatment plans for patients with pain that address patient needs as well as drug diversion prevention.

3. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Describe the available treatment modalities for opioid use disorder.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Ronald Runciman, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. SCOPE OF THE PROBLEM

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in pain patients, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-dependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2].

The current extent of opioid analgesic use in the United States is unprecedented in the country's history and unparalleled anywhere in the world. Before 1990, physicians in the United States were skeptical of prescribing opioids for chronic noncancer pain. But as of 2017, 1 of 25 adults is prescribed an opioid such as oxycodone and hydrocodone for chronic pain, and sales of opioid analgesics now total more than $9 billion each year [3].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2009 consumption of 39 tons (35,380 kg); 99% of this was consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 77 tons (69,853 kg) in 2009, of which 62 tons (56,245 kg or 81%) were consumed in the United States [3]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [4]:

- 99% of all hydrocodone

- 80% of all oxycodone

- 58% of all methadone

- 54% of all hydromorphone

- 49% of all fentanyl

- 43% of all meperidine

This disproportionate rate of opioid consumption reflects sociocultural and economic factors and standards of clinical medicine.

Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time non-medical opioid analgesic users 12 to 17 years of age increased 542% [4]. It is interesting to note that while opioid prescribing has increased precipitously among adults in the United States, the rate remained low and steady for children between 1996 and 2012 [5]. To assist in monitoring the public health problem associated with prescribed opioids, numerous governmental, non-profit, and private sector agencies and organizations are involved in collecting, reporting, and analyzing data on the abuse, addiction, fatal overdose, and treatment admissions related to opioid analgesics.

Before it was halted in 2011, the Drug Abuse Warning Network (DAWN) provided estimates of the health consequences of nonmedical use of individual drugs, including opioid medications [6]. DAWN indicates that opioid abuse is a growing problem in the United States. In 2005 and 2011, hydrocodone and its combinations accounted for 51,225 and 97,183 emergency department visits, respectively. Oxycodone and its combinations resulted in 42,810 visits to the emergency department in 2005; this number increased to 175,229 visits in 2011 [7,8]. Visits for nonmedical use of all opioids increased from 217,594 to 420,040 during the six-year period.

3. PAIN MANAGEMENT APPROACHES

Healthcare professionals should know the best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy [9,10]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [11].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [10]. However, it is important to note that this guideline is based on emergency department prescribing guidelines for non-traumatic non-surgical pain [12]. It may be necessary to prescribe for longer periods in patients with acute severe pain.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [13,14,15].

CHRONIC PAIN

Nonpharmacologic therapy and non-opioid pharmacologic therapy are the preferred first-line therapies for chronic pain. Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Implantable intrathecal opioid infusion and/or spinal cord stimulation may be options for severe, intractable pain. Both options require that devices or ports be implanted, with associated risks. With intrathecal opioid infusion, the ability to deliver the drug directly into the spine provides pain relief with significantly smaller opioid doses, which can help to minimize side effects (e.g., drowsiness, dizziness, dry mouth, nausea, vomiting, and constipation) that can accompany systemic pain medications that might be delivered orally, transdermally, or through an IV [90]. However, use of opioid infusion has traditionally been limited to cancer pain. With spinal cord stimulation therapy, the most challenging aspect is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months [91].

If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient [10].

Opioid therapy for chronic pain should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,10]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [1,10]. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting opioid formulations [10].

The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression. Prescribers should carefully reassess evidence of benefits and risks when increasing the dosage to ≥50 mg morphine equivalent dose (MED) per day. Decisions to titrate dose to ≥90 mg MED/day should be avoided or carefully justified [10].

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [16].

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented [27]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [27,28,29,30,31,32,33,34,35,36].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [37]. This reluctance is related to a variety of attitudes and beliefs [27,37]:

- Fear of addiction to opioids

- Worry that if pain is treated early, there will be no options for treatment of future pain

- Anxiety about unpleasant side effects from pain medications

- Fear that increasing pain means that the disease is getting worse

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [38]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [27]. It is also helpful to note the difference between addiction and physical dependence.

There are several other ways clinicians can allay patients' fears about pain medication:

- Assure patients that the availability of pain relievers cannot be exhausted; there will always be medications if pain becomes more severe.

- Acknowledge that side effects may occur but emphasize that they can be managed promptly and safely and that some side effects will abate over time.

- Explain that pain and severity of disease are not necessarily related.

Encouraging patients to be honest about pain and other symptoms is also vital. Clinicians should ensure that patients understand that pain is multidimensional and emphasize the importance of talking to a member of the healthcare team about possible causes of pain, such as emotional or spiritual distress. The healthcare team and patient should explore psychosocial and cultural factors that may affect self-reporting of pain, such as concern about the cost of medication.

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [27,34,37,39,40,41]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [37,39,41,42]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [37,39].

Clinicians require a clear understanding of available medications to relieve pain, including appropriate dosing, safety profiles, and side effects. If necessary, clinicians should consult with pain specialists to develop an effective approach.

Strong opioids are used for severe pain at the end of life [30,34,43,44]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States [45]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. For an opioid-naïve patient or a patient who has been receiving low doses of a weak opioid, the initial dose should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled.

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and so may not be appropriate for patients with unstable pain [34]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [34].

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1). Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [10,26].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

Definable physical pathology with objective signs and reliable symptoms

Clinical correlation with diagnostic testing, including MRI, physical examination, and interventional diagnostic techniques

With or without mild psychologic comorbidity

With or without minor medical comorbidity

No or well-defined and controlled personal or family history of alcoholism or substance abuse

Age 45 years or older

High levels of pain acceptance and active coping strategies

High motivation and willingness to participate in multimodal therapy and attempting to function at normal levels

Medium Risk

Significant pain problems with objective signs and symptoms confirmed by radiologic evaluation, physical examination, or diagnostic interventions

Moderate psychologic problems, well controlled by therapy

Moderate coexisting medical disorders that are well controlled by medical therapy and are not affected by chronic opioid therapy (e.g., central sleep apnea)

Develops mild tolerance but not hyperalgesia without physical dependence or addiction

Past history of personal or family history of alcoholism or substance abuse

Pain involving more than three regions of the body

Defined pathology with moderate levels of pain acceptance and coping strategies

Willing to participate in multimodal therapy, attempting to function in normal daily life

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

History of alcoholism or drug misuse, abuse, addiction, diversion, dependency, tolerance, or hyperalgesia

Major psychologic disorders

Age younger than 45 years

HIV-related pain

High levels of pain exacerbation and low levels of coping strategies

Unwilling to participate in multimodal therapy, not functioning close to a near normal lifestyle

HIV = human immunodeficiency syndrome, MRI = magnetic resonance imaging.

Source: [17]

Evidence Based Practice Recommendation

Despite limited evidence for reliability and accuracy, screening for opioid use is recommended by the American Society of Interventional Pain Physicians, as it will identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf

Last Accessed: September 17, 2019

Level of Evidence: Limited (Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality trials, important flaws in trial design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.)

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [10,16].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [17].

RISK ASSESSMENT TOOLS

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [18].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [19].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [20].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Tool

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment tool is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [21]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [22]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

Informed Consent and Treatment Agreements

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,23]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [24]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [24]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [25].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in chronic pain patients. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [26]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with chronic pain patients receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [46]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [22].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [47]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [10]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [47]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONCURRENT USE OF BENZODIAZEPINES

In 2015, 23% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [87]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers avoid prescribing benzodiazepines concurrently with opioids whenever possible [10]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. A commonly used tapering schedule is a reduction of the benzodiazepine dose by 25% every one to two weeks [10].

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [48].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [16]. A copy of this form may be accessed online at https://www.fda.gov/media/86281/download.

When prescribing opioids, clinicians should provide patients with the following information [16]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [49]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [50]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [50]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [49]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,10].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by chronic pain patients receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [48].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2015 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [51]. Among persons 12 years of age or older, 40.5% obtained their prescription opioids from a friend or relative for free, 34.0% got them through a prescription from one doctor (vs. 17.3% in 2009–2010), 9.4% bought them from a friend or relative, and 3.8% took them from a friend or relative without asking [51]. Less frequent sources included a drug dealer or other stranger (4.9%); multiple doctors (1.7%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.2% in 2009–2010) [51].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 pain patients treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [52]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion, but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [53].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [48,54,55]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with a lower level of evidence for their association with opioid misuse include [48,54,55]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [49]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [49]. If available, it is also best practice to periodically request a report from the state's prescription reporting program to evaluate the prescribing of opioids to your pahttp://www.netce.com/tients by other providers [49].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [49,56]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [56].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that physicians have an obligation to support continuity of care for their patients. While physicians have the option of withdrawing from a case, they should notify the patient (or authorized decision maker) long enough in advance to permit the patient to secure another physician and facilitate transfer of care when appropriate [57]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [58].

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [24].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [59]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The U.S. Drug Enforcement Administration (DEA) is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [60].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [61]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

STATE-SPECIFIC LAWS AND RULES

Most states have established laws and rules governing the prescribing and dispensing of opioid analgesics. It is each prescriber's responsibility to have knowledge of and adhere to the laws and rules of the state in which he or she prescribes.

Arkansas Laws and Rules

An excerpt from the Arkansas Code rules and regulations relating to the regulation of controlled substances is available by clicking here.

Colorado Laws and Rules

An excerpt from the Colorado Revised Statutes relating to the electronic prescription drug monitoring program, and the full Guidelines for the Safe Prescribing and Dispensing of Opioids are available by clicking here.

New Mexico Laws and Rules

An excerpt from the New Mexico Administrative Code Title 16, Chapter 10, Part 14: Management of Pain and Other Conditions with Controlled Substances is available by clicking here.

New York Laws and Rules

An excerpt from the New York Code, Rules, and Regulations relating to the regulation of controlled substances is available by clicking here.

Vermont Laws and Rules

Information on use of the Vermont Prescription Monitoring System (VPMS) is available by clicking here.

Wisconsin Laws and Rules

The Wisconsin Medical Examining Board Opioid Prescribing Guideline is available by clicking here.

Washington Laws and Rules

Laws governing the prescribing of opioids in the state of Washington are available by clicking here.

Michigan Laws and Rules

A summary of 2017 legislation enacted in Michigan to curb substance abuse and drug diversion is available by clicking here.

Nebraska Laws and Rules

An excerpt reprinted from the Nebraska Revised Statutes 71-2454 and 71-2455 is available by clicking here.

8. MANAGEMENT OF OPIOID USE DISORDER

Management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [62]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient’s body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [62].

CRISIS INTERVENTION

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [63]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [63]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. It is available in a ready-to-use 4-mg single-dose sprayer [64,65].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [66]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [66].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [67,68]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [68,69]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [62,68].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [67].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [67]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [70]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [67]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [70].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [70,71]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms is lofexidine [86]. In studies, lofexidine resulted in less severe withdrawal symptoms and greater treatment retention than placebo.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [70].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [70]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [70]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [72,73].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [74]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [75].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [76]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [76]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [62].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [62]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [62]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [62]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [62].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [67]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient’s attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [67].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [77]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [77].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [67]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [67].

As of 2018, there were 1,519 treatment programs including opioid replacement therapy in the United States [78]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [67]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [79].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [62].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine’s advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [62].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [80]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [80]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [81].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [81].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [82]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [83].

STIGMA OF ADDICTION

Many terms used in discussions of opioid use and misuse may have ambiguous meanings, and the absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions. These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. This, coupled with pervasive stereotypes about what an opioid addict “looks” like, can negatively impact willingness to receive treatment or seek help and impair the patient’s self-worth and mental health. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids [88,89]. It is important for all healthcare professionals to remember that addiction can affect any patients, regardless of age, sex, socioeconomic status, education, ability, or race.

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [84]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [85].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [76].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [76].

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat patients with opioids. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

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31. Blinderman CD, Homel P, Billings JA, Portenoy RK, Tennstedt SL. Symptom distress and quality of life in patients with advanced congestive heart failure. J Pain Symptom Manage. 2008;35(6):594-603.

32. Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009;38(1):115-123.

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36. Godfrey C, Harrison MB, Medves J, Tranmer JE. The symptom of pain with heart failure: a systematic review. J Card Fail. 2006;12(4):307-313.

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39. D'Arcy Y. Nursing2008 pain management survey report. Nursing 2008. 2008;38(6):42-49.

40. Zerzan J, Lee CA, Haverhals LM, Nowels CT. Exploring physician decisions about end-of-life opiate prescribing: a qualitative study. J Palliat Med. 2011;14(5):567-572.

41. Fineberg IC, Wenger NS, Brown-Saltzman K. Unrestricted opiate administration for pain and suffering at the end of life: knowledge and attitudes as barriers to care. J Palliat Med. 2006;9(4):873-883.

42. Mezei L, Murinson BB, Johns Hopkins Pain Curriculum Development Team. Pain education in North American medical schools.J Pain. 2011;12(12):1199-1208.

43. Adler ED, Goldfinger JZ, Park ME, Meier DE. Palliative care in the treatment of advanced heart failure. Circulation. 2009;120:2597-2606.

44. Douglas C, Murtagh FE, Chambers EJ, Howse M, Ellershaw J. Symptom management for the adult patient dying with advanced chronic kidney disease: a review of the literature and development of evidence-based guidelines by a United Kingdom Expert Consensus Group. Palliat Med. 2009;23(2):103-110.

45. Pergolizzi JV Jr, Mercadante S, Echaburu AV, et al. The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus. Curr Med Res Opin. 2009;25(6):1517-1528.

46. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26:552-561.

47. Atluri SL, Akbik H, Sudarshan G. Prevention of opioid abuse in chronic non-cancer pain: an algorithmic, evidence-based approach. Pain Physician. 2012;15:ES177-ES189.

48. National Institute on Drug Abuse. Minimizing the Misuse of Prescription Opioids in Patients with Chronic Nonmalignant Pain. Available at https://www.drugabuse.gov/nidamed/centers-excellence/resources/minimizing-misuse-prescription-opioids-in-patients-chronic-nonmalignant-pain. Last accessed September 17, 2019.

49. American College of Preventive Medicine. Use, Abuse, Misuse and Disposal of Prescription Pain Medication Patient Guide. Available at https://www.acpm.org/page/UseAbuseRx_PatGuide. Last accessed September 17, 2019.

50. Office of National Drug Control Policy. Proper Disposal of Prescription Drugs. Available at https://www.ncjrs.gov/ondcppubs/publications/pdf/prescrip_disposal.pdf. Last accessed September 17, 2019.

51. Substance Abuse and Mental Health Services Administration. Prescription Drug Use and Misuse in the United States: Results from the 2015 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm. Last accessed September 17, 2019.

52. Sekhon R, Aminjavahery N, Davis CN Jr, et al. Compliance with opioid treatment guidelines for chronic non-cancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). Pain Med. 2013;14(10):1548-1556.

53. Meier B. Increase in Urine Testing Raises Ethical Questions. Available at https://www.nytimes.com/2013/08/02/business/increase-in-urine-testing-raises-ethical-questions.html?_r=0. Last accessed September 17, 2019.

54. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84:593-601.

55. Holliday S, Hayes C, Dunlop A. Opioid use in chronic non-cancer pain. Part 2: prescribing issues and alternatives. Australian Family Physician. 2013;42:104-111.

56. U.S. Department of Justice Office of Diversion Control. Don't Be Scammed By A Drug Abuser. Available at https://www.deadiversion.usdoj.gov/pubs/brochures/drugabuser.htm. Last accessed September 17, 2019.

57. American Medical Association. Code of Ethics: Opinion 1.1.5 Terminating the Patient-Physician Relationship. Available at https://www.ama-assn.org/sites/ama-assn.org/files/corp/media-browser/code-of-medical-ethics-chapter-1.pdf. Last accessed September 17, 2019.

58. U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services. A Prescriber's Role in Preventing the Diversion of Prescription Drugs. Available at https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Provider-Education-Toolkits/Downloads/prescriber-role-drugdiversion.pdf. Last accessed September 17, 2019.

59. Centers for Disease Control and Prevention. Risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR. 2012;61(26):493-497.

60. Hannon K. The Prescription Drug Crisis in New York State: A Comprehensive Approach. Available at https://www.scribd.com/doc/82474334/Prescription-Drug-Abuse-Crisis-in-NYS-Comprehensive-Approach-New. Last accessed September 17, 2019.

61. U.S. Drug Enforcement Administration. Drug Scheduling. Available at https://www.dea.gov/drug-scheduling. Last accessed September 17, 2019.

62. van den Brink W, Haasen C. Evidence-based treatment of opioid-dependent patients. Can J Psychiatry. 2006;51(10):635-646.

63. Cassels C. FDA Okays Handheld Autoinjector for Opioid Overdose. Available at https://www.medscape.com/viewarticle/823039. Last accessed September 17, 2019.

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65. U.S. Food and Drug Administration. FDA Moves Quickly to Approve Easy-To-Use Nasal Spray to Treat Opioid Overdose. Available at https://wayback.archive-it.org/7993/20180125101447/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Last accessed September 17, 2019.

66. Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health. 2003;80(2):189-200.

67. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med. 2004;164(3):277-288.

68. Substance Abuse and Mental Health Services Administration. Federal Guidelines for Opioid Treatment Programs. HSS Publication No. (SMA) PEP15-FEDGUIDEOTP. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

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70. Kaye AD, Gevirtz C, Bosscher HA, et al. Ultrarapid opiate detoxification: a review. Can J Anaesth. 2003;50(7):663-671.

71. American Society of Addiction Medicine. National practice guideline for the use of medications in the treatment of addiction involving opioid use. Available at https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf. Last accessed September 17, 2019.

72. Amato L, Minozzi S, Davoli M, Vecchi S, Ferri M, Mayet S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2008;(4):CD005031.

73. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2011;9:CD005031.

74. Fiellin DA, O'Connor PG. Office-based treatment of opioid-dependent patients. N Engl J Med. 2002;347(11):817-823.

75. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004;56(1):793-802.

76. Wasan AD, Correll DJ, Kissin I, O'Shea S, Jamison RN. Iatrogenic addiction in patients treated for acute or subacute pain: a systematic review. J Opioid Manag. 2006;2(1):16-22.

77. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments. Clin Infect Dis. 2006;43(Suppl 4):S173-S177.

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82. Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR. Alternative reinforcer response cost impacts cocaine choice in humans. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):189-193.

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Evidence-Based Practice Recommendations Citations

1. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116. Available at https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf. Last accessed September 17, 2019.

34160 • Iron: Impact on Health and Wellness

Evangeline Y. Samples, MS, RDN, LD, EdD

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Iron plays an essential role in human health by participating in a variety of metabolic processes. The constant interaction between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis. Disruption of homeostasis is the basis for many iron-associated disorders and can lead to decreased absorption of dietary iron. Most dietary iron is derived from heme sources (e.g., meat, seafood, poultry). Certain medical conditions can inhibit iron absorption and lead to iron-deficiency anemia. Treatment of iron deficiency, either orally or parenterally, can replenish body iron stores and prevent the consequences of iron deficiency.

Table of Contents

34160 • Iron: Impact on Health and Wellness

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. FUNCTIONS OF IRON IN THE BODY

3. IRON HOMEOSTASIS

IRON ABSORPTION AND LOSS

4. DIETARY IRON

FACTORS THAT PROMOTE/INHIBIT IRON ABSORPTION

RECOMMENDED DAILY ALLOWANCES FOR IRON

5. IRON DEFICIENCY

SIGNS AND SYMPTOMS OF IRON DEFICIENCY

DIAGNOSING IRON DEFICIENCY

IRON DEFICIENCY IN WOMEN

IRON DEFICIENCY IN THE PEDIATRIC POPULATION

IRON DEFICIENCY IN OTHER POPULATIONS

6. TREATMENT OF IRON DEFICIENCY

7. IRON TOXICITY

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

34160 • Iron: Impact on Health and Wellness

Education Category. Infection Control / Internal Medicine

Release Date. 12/01/2019

Expiration Date. 11/30/2022

Course Overview

Iron plays an essential role in human health by participating in a variety of metabolic processes. The constant interaction between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis. Disruption of homeostasis is the basis for many iron-associated disorders and can lead to decreased absorption of dietary iron. Most dietary iron is derived from heme sources (e.g., meat, seafood, poultry). Certain medical conditions can inhibit iron absorption and lead to iron-deficiency anemia. Treatment of iron deficiency, either orally or parenterally, can replenish body iron stores and prevent the consequences of iron deficiency.

Audience

This course is designed for nurses and allied health professionals in all practice settings.

Course Objective

The purpose of this course is to provide nurses with information about the importance of iron for human health so they can identify patients at risk of iron deficiency and provide nutrition counseling and education about recommended iron intake.

Learning Objectives

Upon completion of this course, you should be able to:

1. Identify the functions of iron in the human body.

2. Discuss the underlying processes involved in maintaining iron homeostasis.

3. List the daily recommended intakes of iron by age, gender, and life stage.

4. Classify levels of iron deficiency and identify groups at risk for iron deficiency.

5. Describe iron toxicity and conditions that lead to iron toxicity.

Faculty

Evangeline Y. Samples, MS, RDN, LD, EdD, is a dietitian and writer who has worked for decades teaching patients and students about good nutrition. She earned her Masters of Science degree in Dietetics from Marshall University and earned her Doctor of Education degree from Northcentral University. Ms. Samples has an adjunct professor of nutrition, and has written numerous articles on fitness and nutrition for the lay public. She is currently a clinical dietitian practicing in West Virginia.

Faculty Disclosure

Contributing faculty, Evangeline Y. Samples, MS, RDN, LD, EdD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The role of iron in human health and disease has long been recognized. Iron had early medicinal uses for Egyptians, Hindus, Greeks, and Romans [1]. During the 17th century, iron was used to treat chlorosis (the "green disease"), a condition that often resulted from iron deficiency [2]. In 1932, the importance of iron was settled when it was established that it was needed for hemoglobin synthesis [3].

This course will provide nurses and other healthcare professionals with information about the impact of iron on health and wellness, including its role in a variety of metabolic processes; how iron equilibrium is regulated; sources of dietary iron and recommendations for daily iron intake; the causes, signs, and symptoms of iron deficiency and identification of populations at risk for this condition; treatment recommendations for iron deficiency; and the dangers of iron toxicity.

2. FUNCTIONS OF IRON IN THE BODY

Iron participates in a variety of metabolic processes, including oxygen and electron transport and DNA synthesis. Iron is also necessary for proper function of the heart [4]. Studies have reported an increased incidence of heart failure in patients with iron deficiency [5,6,7].

The body requires iron for the synthesis of hemoglobin and myoglobin and for the formation of heme and other enzymes involved in electron transfer. Iron is also a cofactor for enzymes in the brain [8,9]. Approximately 60% of the body's iron is found in hemoglobin in circulating erythrocytes; 25% is contained in a mobilizable iron store; and the remaining 15% is bound to myoglobin in muscle tissue [10,11,12].

Iron also plays a role in dopamine signaling. Iron deficiency is associated with a disturbance in dopamine metabolism, reduced activity of the dopamine transporter, and abnormal activity of dopamine D1 and D2 receptors in the basal ganglia of the brain [12,13]. Dopamine regulates cognition and emotion and the reward and pleasure centers in the brain, and it controls the release of hormones. Dopamine is active in the prefrontal cortex to promote cognitive control of executive functions, such as planning, working, memory, and sustained attention [14].

3. IRON HOMEOSTASIS

The average adult's total body iron is 3–4 grams. The body absorbs 1 mg iron daily, but the internal requirement is 20–25 mg (20 mg for hemoglobin synthesis and degradation and 5 mg for other requirements). While most of this iron passes through the plasma for reutilization, iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin [4,15,16]. The constant interaction between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis [17].

Hepcidin, a hormone secreted by the liver, functions as master regulator of systemic iron homeostasis by coordinating iron use and storage with acquisition [18]. Ferroportin is an iron transporter expressed in macrophages, duodenal enterocytes, and hepatocytes [19]. Hepcidin acts by binding to ferroportin, causing its internalization and degradation [20,21]. Loss of ferroportin from the cell surface prevents iron entry into plasma, resulting in low transferrin saturation and less iron delivered to developing erythroblasts. Conversely, decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption [18,20]. Disturbances in this process are the basis for many iron-associated disorders, including anemia and iron-overload-related disorders [22,23].

IRON ABSORPTION AND LOSS

Iron in the diet is either heme or nonheme iron [15,16,24]. Heme iron, derived from hemoglobin and myoglobin of animal food sources (i.e., meat, fish, poultry), is the most easily absorbable form and contributes 10% or more of total absorbed iron. Nonheme iron is derived from plants and iron-fortified foods and is less well absorbed [24].

Approximately 2 mg of iron is absorbed daily in the duodenum and jejunum. This is balanced by losses resulting from desquamation of skin, sloughing of intestinal epithelial cells, and blood loss [16]. Losses also occur due to hemorrhage, problems absorbing iron, and other medical conditions (e.g., end-stage renal disease) [25].

Diminished absorption is commonly due to insufficient intake of absorbable dietary iron [15]. Most dietary iron absorption depends on the physical state of the iron atom. At physiologic pH, iron exists in the oxidized ferric (Fe3+) state. To be absorbed, it must be in the ferrous (Fe2+) state or bound by a protein such as heme. The low pH of gastric acid in the duodenum allows the ferric reductase enzyme, duodenal cytochrome B reductase (Dcytb), to convert dietary ferric iron to the more soluble ferrous state. The protein divalent metal cation transporter 1 (DMT1) (on the membrane of enterocytes) then transports iron across the membrane and into the cell. Ferrous iron then enters the iron pool, where it can be used for heme synthesis, sequestered into ferritin, or transported into the body [24].

4. DIETARY IRON

As stated, dietary iron may be heme or nonheme. The richest sources of dietary heme iron include lean meats and seafood. Dietary sources of nonheme iron include nuts, beans, vegetables, and fortified grain products. Dairy products, while recommended as part of a healthy eating pattern, are poor sources of iron (Table 1) [26].

Table 1: SELECT SOURCES OF DIETARY IRON (HEME AND NONHEME)

Food

Amount Per Serving

Percent Daily Value (DV)a

Breakfast cereals, fortified with 100% of DV for iron

18 mg

100%

Oysters, 3 oz

8 mg

44%

White beans, canned, 1 cup

8 mg

44%

Beef liver, 3 oz

5 mg

28%

Spinach, boiled, ½ cup

3 mg

17%

Tofu, firm, ½ cup

3 mg

17%

Sardines, oil-packed, 3 oz

2 mg

11%

Beef, bottom round, 3 oz

2 mg

11%

Green peas, boiled, ½ cup

1 mg

6%

Chicken, roasted with skin, 3 oz

1 mg

6%

Cheese, cottage, 2% milk fat, ½ cup

0 mg

0%

Milk, 1 cup

0 mg

0%

aAccording to the U.S. Food and Drug Administration.

Source: [26]

FACTORS THAT PROMOTE/INHIBIT IRON ABSORPTION

Nutritional adequacy depends on both intake and bioavailability, and the bioavailability of iron is higher when it comes from animal- versus plant-based foods [26]. The bioavailability of iron is approximately 14% to 18% from mixed diets that include substantial amounts of meat, seafood, and vitamin C (which enhances the bioavailability of nonheme iron), and 5% to 12% from vegetarian diets [27,28]. Phytates (in grains and beans) and certain polyphenols (in cereals and legumes) have the opposite effect [28]. It is believed that calcium might reduce the bioavailability of both heme and nonheme iron. However, because the effects of iron absorption enhancers and inhibitors are often reduced by the mixed western diet, they have little effect on the iron status of most individuals [29].

A variety of medical conditions can decrease iron absorption, including celiac disease, inflammatory bowel disease, gastrointestinal (GI) surgery (e.g., bariatric/weight-loss surgery), and rare genetic conditions (e.g., TMRPSS6 gene mutation, which causes overproduction of hepcidin) [25]. While both men and women can inherit hemochromatosis (an autosomal recessive disorder associated with iron overload), women are typically diagnosed after menopause, as blood loss from menstruation yields a significant loss of iron [84,85]. Infections and inflammation (e.g., from congestive heart failure) also may inhibit nonheme iron absorption [11].

RECOMMENDED DAILY ALLOWANCES FOR IRON

The recommended daily allowance (RDA) is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97% to 98%) healthy individuals [29]. The RDA for iron varies by age, sex, and life stage. Table 2 lists current iron RDAs for nonvegetarians. The RDAs for vegetarians are 1.8 times higher than for people who eat meat [29].

Table 2: RECOMMENDED DAILY ALLOWANCES FOR IRON

Age

Male

Female

Pregnancy

Lactation

Birth to 6 months

0.27 mga

0.27 mga

—

—

7 to 12 months

11 mg

11 mg

—

—

1 to 3 years

7 mg

7 mg

—

—

4 to 8 years

10 mg

10 mg

—

—

9 to 13 years

8 mg

8 mg

—

—

14 to 18 years

11 mg

15 mg

27 mg

10 mg

19 to 50 years

8 mg

18 mg

27 mg

9 mg

51+ years

8 mg

8 mg

—

—

aFor this age group, adequate intake (a level assumed to ensure nutritional adequacy) is used because evidence is insufficient to develop an RDA.

Source: [29]

Total iron (heme and nonheme) bioavailability from the U.S. diet has been estimated to be 18% [30]. However, the results of at least one investigation found this figure to be much lower [30]. Using data from the National Health and Nutrition Examination Survey (NHANES) MyPyramid database, researchers found that the average unadjusted nonheme iron absorption for all participants (6,631) was only 3.7%. It was higher in females (5.6%) than in males (2.6%) and lower in non-Hispanic whites (3.5%) than in Mexican Americans (4.5%) and non-Hispanic blacks (4.4%) [30].

5. IRON DEFICIENCY

Iron deficiency affects the health of more than 1 billion people worldwide, with an estimated 10 million affected in the United States [31]. The greatest burden of disease occurs in lesser-developed countries among children and women of reproductive age and is the result of both nutritional and infectious causes [31]. Iron deficiency diminishes the capability of affected individuals to perform physical labor, and it diminishes growth and learning in children [15]. Iron deficiency is the main cause of anemia, which has an estimated global prevalence of 24.8% [32].

In developing countries, iron deficiency is caused by a combination of poor iron intake and parasitic infections, specifically malaria and hookworm [31]. Malaria causes intravascular hemolysis and the loss of iron from hemoglobin in the urine. Once in the GI tract, hookworms can stay for several years and release eggs into the stool. In the small intestine, adult hookworms ingest blood, rupture erythrocytes, and degrade hemoglobin, leading to anemia. Antiparasitic drugs can reverse iron-deficiency anemia caused by hookworm [11].

SIGNS AND SYMPTOMS OF IRON DEFICIENCY

Signs of iron-deficiency anemia include koilonychia, cheilosis, pale/sallow skin, and atrophic glossitis [25]. With koilonychia, the nails (usually fingernails) are abnormally thin and may be spoon-shaped or concave [33]. Cheilosis is an abnormal condition of the lips characterized by surface scaling and fissures in the corners of the mouth [34,35]. Pale, sallow skin may be a result of low levels of hemoglobin. With atrophic glossitis, the tongue appears to be smooth and glossy with a red or pink background [36]. Each of these conditions is reversible with correction of the iron deficiency.

Symptoms of iron-deficiency anemia include [5,14,25,32,37,38,39]:

- Chest pain, irregular heartbeat (sign of a more serious deficiency)

- Fatigue

- Cognitive deficits

- Headache

- Dizziness

- Dyspnea

- Pica

- Restless legs syndrome

As noted, anemia is a common, serious comorbidity in heart failure, with a prevalence ranging from 10% to 79%. While the cause of anemia in heart disease is not fully understood, it is believed to be associated with iron deficiency, comorbid chronic kidney disease, and blunted erythropoietin production [37,40,41]. Fatigue and cognitive deficits are also common [14,42,43,44]. As stated, iron deficiency impairs the metabolism of dopamine, leading to poor inhibitory control, poor executive functioning, and altered social-emotional behavior [14].

Pica, the compulsive consumption of non-nutritive food items (e.g., dirt, paper), is often associated with iron deficiency [45]. Pica is observed most frequently in children and is the most common eating disorder in individuals with developmental disabilities. It also has been observed in women during pregnancy; among high-risk pregnancies, 5.7% reported pica [46]. Physical signs and symptoms include nausea, vomiting, tearing of the stomach, and bowel obstruction. Dental manifestations (e.g., severe tooth abrasion) also may be present [45]. Approximately one-half of patients with moderate iron-deficiency anemia develop pagophagia, a particular form of pica characterized by the ingestion of ice, freezer frost, or iced drinks [15,47,48,49].

Central hypoxia may lead to symptoms of headache, tinnitus, and vertigo in some patients with iron deficiency. Other patients may experience restless legs syndrome [32,47,50]. Patients with iron deficiency have been found to have a 30% higher frequency of restless legs syndrome than those without, and the severity of iron deficiency correlates with the severity of restless legs syndrome symptoms [50].

Anemia is a common manifestation and complication of inflammatory bowel diseases, such as Crohn disease and ulcerative colitis. Patients with inflammatory bowel disease are commonly found to have impaired iron absorption due to tissue inflammation and iron-deficiency anemia secondary to chronic blood loss. Not all patients with iron deficiency manifest signs and symptoms; therefore, it is important to regularly monitor hemoglobin levels in patients with inflammatory bowel disease [34].

DIAGNOSING IRON DEFICIENCY

Iron deficiency develops in stages. Stage 1 is characterized by decreased iron stores in bone marrow and serum ferritin levels <20 ng/mL. Iron absorption increases, causing an increase in transferrin level. Erythropoiesis is impaired in stage 2. Although transferrin level is increased, the serum iron level decreases and the transferrin saturation decreases. Anemia develops during stage 3 (with indices that appear normal). Microcytosis and then hypochromia develop in stage 4. In stage 5, iron deficiency affects tissues, with resulting signs and symptoms [51].

Laboratory studies are used to confirm iron deficiency. The World Health Organization (WHO) defines anemia as a hemoglobin level <13.0 g/dL in adult men, <12.0 g/dL in nonpregnant adult women, and <11.0 g/dL in pregnant women. Mild anemia is defined as a hemoglobin level of 11.0–11.9 g/dL in nonpregnant women and 11.0–12.9 g/dL in men [52].

Serum ferritin is an early and highly specific indicator of iron deficiency. The WHO defines low serum ferritin as 12 mcg/L for children younger than 5 years of age and 15 mcg/L for children older than 5 years of age [52]. Limited data suggest that a serum ferritin level of <15 mcg/L is a specific, but not sensitive, cutoff; however, there is considerable variation in serum ferritin cutoff recommendations [53]. Additionally, the concentration of serum ferritin increases with age and in the presence of inflammatory disease [54].

As noted, functional iron deficiency may be observed in infectious, inflammatory, and malignant diseases [55]. Serum ferritin is a commonly used diagnostic marker of functional iron deficiency [56]. A serum ferritin level <100 mcg/L in nondialyzed patients is associated with a high likelihood of iron deficiency and potentially good response to repletion with supplemental iron. A serum ferritin level <12 mcg/L indicates absent iron stores [55]. Mean cell hemoglobin and mean cell volume are useful at diagnosing functional iron deficiency over weeks or months but are of no use in assessing acute changes in iron availability secondary to therapy with erythropoiesis-stimulating agents. The percentage of hypochromic red cells is the best-established variable for the identification of functional iron deficiency [55].

Laboratory values differ in patients with kidney disease. A serum ferritin level <200 mcg/L in patients undergoing chronic hemodialysis is associated with a high likelihood of iron deficiency and a potentially good response to iron therapy. However, due to extensive biologic variability, serum ferritin should be used with caution when guiding iron supplementation in patients with chronic kidney disease [56].

IRON DEFICIENCY IN WOMEN

More than 20% of women experience iron deficiency at some point in their reproductive lives, and blood lost during menstruation places women at risk for iron deficiency [57,58]. Women with normal menses lose an average of 1 mg of iron per cycle. However, women with menorrhagia menstruate for an average of six days and lose an average of 5.2 mg of iron per cycle [58].

Iron-deficiency anemia has been found to influence cognitive function in women. In one cross-sectional study of healthy women 18 to 35 years of age, those with iron-deficiency anemia scored lower on measures of attention than those with no iron deficiency [42].

Iron Deficiency in Pregnancy

The estimated prevalence of iron deficiency in pregnant women is 18.6%; of these, 16.2% also have anemia [59]. One study of 1,311 pregnant women found that approximately 21% of women in their third trimester and 4% of women in their first trimester had anemia [60]. Factors that increase a pregnant woman's risk for iron-deficiency anemia include a diet lacking in iron-rich foods, GI disease, medications (e.g., antacids) that can decrease iron absorption, and a short interval between pregnancies. Non-Hispanic black and Mexican American women have higher prevalence rates of iron deficiency than white women [59]. Iron-deficiency anemia also is associated with adverse neonatal outcomes.

A hemoglobin level <11 g/dL in the first or third trimester or a hemoglobin level <10.5 g/dL in the second trimester indicates iron-deficiency anemia in the pregnant woman [61]. A maternal hemoglobin level <6 g/dL has been associated with abnormal fetal oxygenation resulting in non-reassuring heart tracings, low amniotic fluid volumes, fetal cerebral vasodilation, and fetal death [62,63].

As noted, pregnant women require 27 mg of iron per day. However, one cross-sectional study found little difference between the food consumption of pregnant and nonpregnant women; inadequate intake of iron, folate, and calcium was observed in both groups [64]. Nonpregnant women consumed an average of 12.4 mg of iron per day, while pregnant women consumed an average of 13.6 mg of iron per day [64]. Another study performed among women in South Korea also found that iron intake from food was inadequate during pregnancy [65]. These results suggest that pregnant women are unlikely to meet their elevated iron needs from diet alone. The addition of daily prenatal vitamins is necessary, as these vitamins often include a low dose (30 mg) of elemental iron [59].

IRON DEFICIENCY IN THE PEDIATRIC POPULATION

Neonates

An essential goal of neonatal care is to deliver adequate oxygen to meet tissue demand. Increasing fetal hemoglobin by placental transfusion is an effective method of enhancing arterial oxygen content and improving oxygen delivery. Placental transfusion can increase the neonate's iron stores at birth, and it can be accomplished in one of three ways: delayed cord clamping; intact umbilical cord milking; and cut-umbilical cord milking [11,62,65,66,67].

Depending on the time of clamping and the infant's position relative to the mother's, the neonate can receive a placental transfusion of 20–30 mL/kg of blood (15–25 mg/kg of additional iron). In one study, a 30- to 120-second delay in clamping was found to improve iron status during the first two to three months of life in both full-term and preterm infants [62,68].

With intact umbilical cord milking, the cord is grasped and blood is pushed, or stripped, toward the infant two to four times prior to clamping. Cord milking before clamping improves pulmonary blood flow immediately at birth and assists with lung expansion at the onset of respirations. If performed, it is recommended that the cord be milked five times for infants born at term and four times for preterm infants [65].

Cut-umbilical cord milking involves clamping and cutting a long segment of the cord immediately at birth and passing it and the baby to the pediatric provider who then untwists the cord and milks the entire contents into the neonate [65]. This practice is more commonly done in Asia. At least one study found that cord milking in preterm (born at less than 32 weeks' gestation) infants was associated with severe intraventricular hemorrhage [86].

One study was conducted to assess the effect of placental transfusion on serum ferritin levels in preterm neonates of 30 to 33 weeks' gestation. Interventions included delayed (by 60 seconds) cord clamping or cord milking compared with early (within 10 seconds) cord clamping [66]. The authors found that the median serum ferritin at discharge was significantly higher in the placental transfusion group than in the early cord clamping group, and that the incidence of anemia by 3 months of age was less in the placental transfusion group than in the early cord clamping group [66].

Infants and Children

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for iron-deficiency anemia in children ages 6 to 24 months.

https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/iron-deficiency-anemia-in-young-children-screening

Last Accessed: November 12, 2019

Strength of Recommendation: I (Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.)

Among infants, risk factors for iron deficiency include a mother with mild-to-moderate iron-deficiency anemia, low birth weight, premature birth, lead exposure, exclusive breastfeeding beyond 4 months of life, and weaning to whole milk and complementary foods without iron-fortified foods [62]. Low food security and low maternal education also may be associated with an increased risk of anemia in low-income family infants [69].

The American Academy of Pediatrics recommends universal screening for iron-deficiency anemia in all children at 1 year of age [70]. The Centers for Disease Control and Prevention also recommends screening children from low-income or newly immigrated families at 9 to 12 months of age. Preterm and low-birth-weight infants should be considered for screening before 6 months of age if they are not given iron-fortified formula [71].

Adolescents

Adolescents have an increased iron requirement due to increased demand resulting from expanded blood volume, myoglobin for higher muscular mass, and enzymes needed for growth [72,73]. Iron requirements in girls begin to increase after menarche, with typical 30–40 mL blood loss and 15–30 mg iron loss during each menstruation. In boys, testosterone secretion and increased muscular mass development increase iron requirements [72,73].

Iron deficiency is the most common cause of anemia in children and adolescents with inflammatory bowel disease, although the exact prevalence is unknown [74]. One small study sought to estimate the prevalence by following patients with inflammatory bowel disease for 15 years. The study included children 1 to 17 years of age; the average patient age at diagnosis of inflammatory bowel disease was 13.3 years. At diagnosis, 76.8% of patients had iron deficiency and 43.5% had iron-deficiency anemia. At one-year follow-up, 68.1% of the participants had iron deficiency and 21.7% had iron-deficiency anemia [74].

Persistent Effects of Early Iron Deficiency

Iron deficiency experienced early in life has persistent effects. Children who were iron-depleted at 12 months of age have lower developmental scores in self-help at 6 years of age [75]. Iron deficiency in infancy has been linked to deficits in attentional control at 10 years of age and heightened risk taking in adolescence [38]. Iron deficiency assessed in children soon after adoption predicts low intelligence quotient (IQ) scores and poor executive function performance [43].

In one study, participants with chronic iron deficiency in infancy were compared to those who were iron-sufficient before and/or after iron therapy [39]. Of those who were iron deficient in infancy, 58.1% did not complete secondary school, 76.1% were not pursuing further education, and 83.9% were single. In contrast, of those who were iron-sufficient, 24.4% did not complete secondary school, 33.8% were not pursuing further education, and 23.7% were single [39]. Those with untreated iron deficiency early in life reported poorer emotional health, more negative emotions, feelings of dissociation and detachment, and physical symptoms of depression.

IRON DEFICIENCY IN OTHER POPULATIONS

Iron deficiency is also prevalent among athletes. Among male triathletes and runners, the incidence of a hemoglobin <14 g/L occurred at least once in 87.5% of triathletes and 31.3% of runners. A hemoglobin <12 g/L in women occurred at least once in 20% of triathletes, but 0% of runners [76]. Researchers also observed iron deficiency in 2,749 athletes from 25 different teams at one National Collegiate Athletic Association Division I institution [77]. Among girls/women, 30.9% had iron deficiency without anemia and 2.2% had iron-deficiency anemia. Among boys/men, 2.9% had iron deficiency without anemia and 1.2% had iron-deficiency anemia [77].

Iron deficiency also does not occur evenly throughout the world. In underdeveloped areas, there is an estimated fivefold increase in prevalence [11]. In some regions, the prevalence of anemia among young children is between 50% and 100% [78]. In these same regions, an estimated 40% to 50% of the entire population is anemic at all ages, with the exception of nonelderly men [79].

6. TREATMENT OF IRON DEFICIENCY

Treatment of iron-deficiency anemia depends on its cause and severity. Because the major cause of iron deficiency is overt or occult blood loss, the first step should be to identify and treat the source of the iron or blood loss, which should improve hemoglobin levels and symptoms of anemia. Any medications that may be blocking iron absorption should be discontinued. In cases of malnutrition or non-drug-induced impaired GI absorption of iron, supplementation may be indicated. Treatment may include oral supplementation or parenteral iron therapy [25]. Oral iron is the most common treatment, but it has a few adverse effects, including vomiting, constipation, darkening of the urine and stool, and staining of teeth and gums [59]. An oral therapy regimen of three to six months is typically required to replenish iron stores [25]. If oral therapy alone does not replenish body stores, or if the patient does not tolerate oral iron, parenteral therapy may be recommended [25,59,80]. Parenteral iron causes a more rapid therapeutic response and often takes only one or a two sessions to replenish body iron stores; however, it can cause adverse effects, such as allergic or infusion reactions [54,80]. Both oral and parenteral iron therapy should be continued for at least six months after the hemoglobin has normalized to replenish iron stores [80].

7. IRON TOXICITY

The tolerable upper intake level is the highest amount of a nutrient that healthy people can consume daily without adverse effects [29]. Beginning at 14 years of age and continuing through adulthood, the upper intake level for iron is 45 mg per day. In children from birth through 13 years of age, the limit for iron is 40 mg per day [81]. Iron may reach a toxic level in the body when ingested above the upper limit.

Iron poisoning is a significant cause of death among children, especially those younger than 6 years of age. In 2017, the American Association of Poison Control Centers (AAPCC) reported 4,400 single exposures to iron and iron salts, with 2,181 in children younger than 6 years of age. The AAPCC additionally reported 9,640 single exposures to multiple vitamins with iron, with 7,926 in children younger than 6 years of age [82]. Iron supplements are routinely administered to postpartum women, and the presence of iron supplements in the home may place young children at risk for accidental iron toxicity via ingestion [83]. The toxic effects of iron may occur at doses of 10–20 mg/kg of elemental iron [83]. In children, diagnosis of iron toxicity is based on symptoms, imaging studies, and laboratory analysis. An abdominal x-ray will show if iron tablets were consumed [83].

Normal serum iron levels are 50–120 mcg/dL. Mild-to-moderate systemic iron toxicity is possible when serum iron levels are 350–500 mcg/dL. Hepatotoxicity is usually observed at levels higher than 500 mcg/dL, and levels higher than 800 mcg/dL are associated with severe toxicity. Patients with serum iron levels exceeding 1,000 mcg/dL require age-appropriate intensive care [82]. Excessive iron has a corrosive effect on the GI tract leading to nausea, vomiting, diarrhea, melena, and hematemesis. Iron overload can damage organs, such as the liver, heart, and pancreas, as well as endocrine glands and joints.

8. CONCLUSION

Iron plays an essential role in human health by participating in a variety of metabolic processes. Constant interaction between iron uptake, transport, storage, and utilization is required to maintain iron homeostasis. Disruption of homeostasis is the basis for many iron-associated disorders and can lead to decreased absorption of dietary iron. Certain medical conditions can also inhibit iron absorption and lead to iron-deficiency anemia. The greatest burden of iron-deficiency anemia occurs in women of reproductive age and children and is usually caused by a combination of poor iron intake and parasitic infections, particularly in underdeveloped parts of the world. Persistent effects of early iron deficiency include lower than average developmental scores and poor executive functioning in children, and poorer emotional health in adults. Treatment of iron deficiency, either orally or parenterally, can replenish body iron stores and prevent the consequences of iron deficiency.

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42. Cook RL, O'Dwyer NJ, Parker HM, et al. Iron-deficiency anemia, not iron deficiency, is associated with reduced attention in healthy young women. Nutrients. 2017;9(11):E1216.

43. Doom JR, Gunnar MR, Georgieff MK, et al. Beyond stimulus deprivation: Iron deficiency and cognitive defects in postinstitutionalized children. Child Dev. 2014;85(5):1805-1812.

44. Fugelstad AJ, Georgieff MK, Iverson SL, et al. Iron-deficiency after arrival is associated with general cognitive and behavioral impairment in post-institutionalized children adopted from Eastern Europe. Matern Child Health J. 2013;17(6):1080-1087.

45. Ellis CR. Pica. Available at https://emedicine.medscape.com/article/914765-overview. Last accessed November 7, 2019.

46. Santos AM, Benute G, Yamamoto Nomura RM, Santos NO. Pica and eating attitudes: a study of high-risk pregnancies. Mat Child Health J. 2015;20(3).

47. Leung AKC, Hon KL. Pica: a common condition that is commonly missed: an update review. Curr Pediatr Rev. 2019; [Epub ahead of print].

48. Borgna-Pignatti C, Zanella S. Pica as a manifestation of iron deficiency. Expert Rev Hematol. 2016;9(11):1075-1080.

49. Bhatia MS, Kaur N. Pagophagia: a common but rarely reported form of pica. J Clin Diagn Res. 2014;8(1):195-196.

50. Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev. 2012;5:CD007834.

51. Merck Manual. Iron-Deficiency Anemia. Available at https://www.merckmanuals.com/professional/hematology-and-oncology/anemias-caused-by-deficient-erythropoiesis/iron-deficiency-anemia. Last accessed November 7, 2019.

52. World Health Organization. Serum Ferritin Concentrations for the Assessment of Iron Status and Iron Deficiency in Populations. Geneva: World Health Organization; 2011.

53. Daru J, Colman K, Stanworth SJ, DeLaSalle B, Wood EM, Pasricha SR. Serum ferritin as an indicator of iron status: what do we need to know? Am J Clin Nutr. 2017;106(Suppl 6):1634S-1639S.

54. Joosten E. Iron deficiency in older adults: a review. Geriatr Gerontol Int. 2018;18(3):373-379.

55. Thomas DW, Hinchliffe RF, Briggs C, et al. Guidelines for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013;161(5):639-648.

56. Gaweda AE. Makers of iron status in chronic kidney disease diagnosing iron deficiency. Hemodial Int. 2017;21(Suppl 1):S21-S27.

57. Percy L, Mansour D, Fraser I. Iron deficiency and iron-deficiency anaemia in women. Best Pract Res Clin Obstet Gynaecol. 2017;40:55-67.

58. Napolitano M, Dolce A, Celenza G, et al. Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses. Ann Hematol. 2014;93(4):557-563.

59. Siu AL, U.S. Preventive Services Task Force. Screening for iron-deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(7):529-536.

60. Vandevijere S, Amsalkhir S, Van Oyen H, Egli I. Moreno-Reyes R. Iron status and its determinants in a nationally representative sample of pregnant women. J Acad Nutr Diet. 2013;113(5):659-666.

61. Rigby FB. Anemia and Thrombocytopenia in Pregnancy. Available at https://emedicine.medscape.com/article/261586-overview. Last accessed November 7, 2019.

62. Short MW, Domgalski JE. Iron-deficiency anemia: evaluation and management. Am Fam Physician. 2013;87(2):98-104.

63. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 95: anemia in pregnancy. Obstet Gynecol. 2008;112(1):201-207.

64. Sato AP, Fujimori AP, Szarfarc SC, Borges AL, Tsunechiron MA. Food consumption and iron intake of pregnant and reproductive aged women. Rev Lat Am Enfermagem. 2010;18(2):247-254.

65. Katheria AC, Lakshminrusimha S, Rabe H, McAdams R, Mercer JS. Placental transfusion: a review. J Perinatol. 2017;37(2):105-111.

66. Das B, Sundaram V, Kumar P, Mordi WT, Dhaliwal LK, Das, R. Effect of placental transfusion on iron stores in moderately preterm neonates of 30–33 weeks gestation. Indian J Pediatr. 2018;85(3):172-178.

67. Rao R, Georgieff MK. Iron in fetal and neonatal nutrition. Semin Fetal Neonatal Med. 2007;12(1):54-63.

68. van Rheenen P, Brabin BJ. Late umbilical cord-clamping as an intervention for reducing iron-deficiency anaemia in term infants in developing and industrialised countries: a systematic review. Ann Trop Paediatr. 2004;24(1):3-16.

69. Metallinos,-Katsaras E, Colchamiro R, Edelstein S, Siu E. Household food security status is associated with anemia risk at age 18 months among low-income infants in Massachusetts. J Acad Nutr Diet. 2016;116 (11):1760-1766.

70. Baker RD, Greer FR; Committee on Nutrition, American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics. 2010;126(5):1040-1050.

71. Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR. 1998;47(RR3):1-29.

72. Urrechaga E, Izquierdo-Alvarez S, Llorente MT, Escanero JF. Prevalence of iron deficiency in health adolescents. Ann Nutr Disord Ther. 2016;3(2):1036.

73. Sekhar DL, Murray-Kolb LE, Wang L, Kunselman AR, Paul IM. Adolescent anemia screening during ambulatory pediatric visits in the United States. J Community Health. 2015;40(2):331-338.

74. Carvalho FSG, de Medeiros IA, Antunes H. Prevalence of iron-deficiency anemia and iron deficiency in a pediatric population with inflammatory bowel disease. Scand J Gastroenterol. 2017;52(10):1099-1103.

75. Thorisdottir AV, Gunnarsdottir I, Palsson GI, Gretarsson SJ, Thorisdottir I. Iron status and developmental scores in 6-year-olds highlights ongoing need to tackle iron deficiency in infants. Acta Paediatr. 2013;102(9):914-919.

76. Coates A, Mountjoy M, Burr J. Incidence of iron deficiency and iron-deficiency anemia in elite runners and triathletes. Clin J Sport Med. 2017;27(5):493-498.

77. Parks RB, Hetzel SJ, Brooks MA. Iron deficiency and anemia among collegiate athletes: a retrospective chart review. Med Sci Sports Exerc. 2017;49(8):1711-1715.

78. Lutter CK, Iron deficiency in young children in low-income countries and new approaches for its prevention. J Nutr. 2008;138(12):2523-2528.

79. Mclean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005. Public Health Nutr. 2009;12(4):444-454.

80. Merck Manual. Anemia in Pregnancy. Available at https://www.merckmanuals.com/professional/gynecology-and-obstetrics/pregnancy-complicated-by-disease/anemia-in-pregnancy. Last accessed November 7, 2019.

81. Institute of Medicine Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001.

82. Spanierman CS. Iron Toxicity. Available at https://emedicine.medscape.com/article/815213-overview#a5. Last accessed November 7, 2019.

83. Boyle JS. Pediatric Iron Toxicity. Available at https://emedicine.medscape.com/article/1011689-overview. Last accessed November 7, 2019.

84. Porter JL, Bhimji SS. Hemochromatosis. Treasure Island, FL: StatPearls Publishing; 2017.

85. Geissler C, Singh M. Iron, meat, and health. Nutrients. 2011;3(3):283-316.

86. Katheria A, Reister F, Essers J. Association of umbilical cord milking vs. delayed umbilical cord clamping with death or severe intraventricular hemorrhage among preterm infants. JAMA. 2019;322(19):1877-1886.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Iron-Deficiency Anemia in Young Children: Screening. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/iron-deficiency-anemia-in-young-children-screening. Last accessed November 12, 2019.

94150 • The Coronavirus Disease (COVID-19) Pandemic

John M. Leonard, MD

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Table of Contents

94150 • The Coronavirus Disease (COVID-19) Pandemic

Course Overview

Attention

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. BACKGROUND

CORONAVIRUS

HUMAN CORONAVIRUS INFECTION

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

SEVERITY AND PROGRESSION OF ILLNESS

SYSTEMIC COMPLICATIONS OF COVID-19

RECOVERY FROM COVID-19

LATE SEQUELAE OF COVID-19

4. COVID-19 IN CHILDREN

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

5. DIAGNOSTIC TESTING FOR SARS-COV-2

ANTIBODY TESTING

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

INVESTIGATIONAL THERAPEUTICS

COVID-19 VACCINES

DURATION OF IMMUNITY AND REINFECTION

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

VARIANT STRAINS OF SARS-COV-2

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

9. OTHER AVAILABLE RESOURCES

Works Cited

94150 • The Coronavirus Disease (COVID-19) Pandemic

Education Category. Infection Control / Internal Medicine

Release Date. 02/01/2020

Review Date. 01/15/2023

Expiration Date. 02/28/2023

Course Overview

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Attention

This outbreak is ongoing. As the situation evolves, the course is being revised to reflect new information. The last update was done May 27, 2022.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may identify or educate patients regarding coronavirus infection.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals an overview of the 2019–2020 global outbreak of novel human coronavirus (SARS-CoV-2) infection, including background epidemiology, clinical features, mode of transmission, epidemic potential, and the clinical and public health measures recommended to limit the spread of infection and control the outbreak.

Learning Objectives

Upon completion of this course, you should be able to:

1. Differentiate between the common, ubiquitous strains of human coronavirus and novel (outbreak) strains with respect to epidemiology, modes of transmission, spectrum of illness, and public health implications.

2. Characterize the clinical and public health experience gained from the two prior novel human coronavirus epidemics, SARS and MERS, and how that informs our understanding and response to the current pandemic.

3. Recognize clinical manifestations of COVID-19 and anticipate systemic complications associated with a dysregulated immune response, and discuss the dynamics of transmission and advise patients regarding prevention of infection and the role of COVID-19 vaccines, with special attention to those at risk for severe disease.

4. Implement guideline recommendations for diagnostic testing and management of patients with recent exposure to, suspected infection with, or newly diagnosed COVID-19.

Faculty

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. BACKGROUND

CORONAVIRUS

Coronaviruses (a subfamily of Coronaviridae) are enveloped, single-stranded RNA viruses that are broadly distributed among humans, other mammals, and birds. Under electron microscopy, the outer envelope of the virion shows club-like surface projections that confer a crown-like appearance to the virus, which accounts for the name given to this family of viruses. The nucleocapsid is a long, folded strand that tends to spontaneous mutations and recombination of genomic material. When virus circulation (and replication) is high, the number of random changes within the genome grows, increasing the likelihood that such changes may impact transmissibility and pathogenicity.

In addition to four specific subtypes of coronavirus commonly found in humans, other strains are specific to many different species of animals, including bats, cats, camels, and cattle. On rare occasions, an animal coronavirus is responsible for zoonotic infection in humans, meaning that a new (novel) coronavirus is transmitted from an animal host to one or more humans, producing clinical illness that may result in secondary spread among persons in close contact. The wide distribution, genetic diversity, and frequent shifts in the genome, combined with unique human-animal interface activities, are considered important factors in the periodic emergence of new coronavirus outbreaks in human populations [1,2].

HUMAN CORONAVIRUS INFECTION

Common Strains

Human coronavirus (HCoV) was first identified in 1965, isolated from a patient with what was described as the common cold [3]. Subsequently, four types of HCoV have been detected commonly in respiratory secretions of children and adults in scattered regions of the globe, labeled HCoV-229E, -NL63, -OC43, and -HKU1. These agents are a cause of common mild-to-moderate upper respiratory illness, including the common cold, bronchitis, bronchiolitis in infants and children, and asthma exacerbation. Rarely, HCoVs have been implicated in cases of lower respiratory tract infection (viral pneumonia), a complication more common to persons with underlying cardiopulmonary disease or weakened immune systems.

Novel Coronavirus Outbreaks

In addition to the seasonal infections caused by the ambient, adaptive HCoVs described, widespread outbreaks of novel coronavirus infection have occurred in each of the past two decades, and the 2019–2020 Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale [1,4]. The epidemiologic feature common to these outbreaks is an initial point source cluster of zoonotic infection followed by secondary spread of the virus via human-to-human transmission. Among the factors thought to be conducive to the emergence of such outbreaks are the following: genomic recombination in an animal CoV capsid that renders the virus better adapted to human infection (and perhaps more virulent); and dietary practices and cultural determinants that bring humans into close contact with livestock or raw meat and carcasses of wild animals and birds, thereby facilitating transmission from an infected animal host to humans. After infection is established, secondary viral transmission occurs through close person-to-person contact by way of droplet nuclei propelled into the air during coughing and sneezing. The first two known novel coronavirus outbreaks, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, are considered to be zoonotic in origin and were associated with serious, sometimes fatal illness.

Severe Acute Respiratory Syndrome (SARS-CoV)

Infection with SARS-CoV was first recognized in China in November 2002, and signs of an outbreak in Asia were evident by February 2003 [3]. Epidemiologic investigation found that early cases of SARS-CoV were zoonotic infection involving transmission from civet cats to humans. Over the next several months, SARS-CoV spread to countries in North America, South America, Europe, and other parts of Asia before the global outbreak was contained later in the same year.

SARS-CoV infection began with fever, headache, malaise, and arthralgia/myalgia followed in two to seven days by cough, shortness of breath, and signs of pneumonia [3].

According to the World Health Organization (WHO), the 2002–2003 outbreak caused 8,098 probable cases of SARS worldwide and 774 deaths. Just eight cases were identified in the United States. Since 2004, there have been no additional known cases of SARS-CoV infection reported anywhere in the world [3].

In response to the 2003 global SARS outbreak, the Centers for Disease Control and Prevention (CDC), working in concert with the WHO, developed a strategy for controlling the epidemic that included the following elements [3]:

- Activated the Emergency Operations Center to provide around-the-clock coordination and response.

- Committed more than 800 medical experts and support staff to work on the SARS response and to assist with ongoing investigations around the world.

- Provided assistance to state and local health departments in investigating possible cases of SARS in the United States.

- Conducted extensive laboratory testing of clinical specimens from patients with SARS to identify the cause of the disease.

- Initiated a system for distributing health alert notices to travelers who may have been exposed to cases of SARS.

This experience informed the rapid public health response to the 2019–2020 coronavirus outbreak in China.

Middle East Respiratory Syndrome (MERS-CoV)

MERS-CoV was first reported in Saudi Arabia in 2012, and all cases to date have been linked to countries in or near the Arabian Peninsula. Travel-associated cases of MERS-CoV infection have been reported in many countries, including two imported cases diagnosed in the United States in 2014 involving unlinked healthcare providers recently returned from Saudi Arabia. Two modes of transmission have been identified: zoonotic infection from an animal reservoir to humans (with camels acting as the intermediate host), and person-to-person transmission via close contact with an index case, as described in association with a family case cluster and a nosocomial outbreak [5,6,7].

Most persons with confirmed MERS-CoV infection have had moderately severe respiratory illness manifest by fever, cough, and shortness of breath, often complicated by pneumonia and respiratory failure. The case-fatality rate approaches 40%. Most deaths have been in patients with pre-existing chronic conditions such as diabetes, cancer, or heart, lung, or renal disease. Sporadic cases of MERS-CoV continue to appear in various parts of the Middle East [3].

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

In December 2019, Chinese physicians in Hubei Province, China, began an investigation of a cluster of cases of severe viral pneumonia in area hospitals. In the weeks following, it became evident that a large outbreak of respiratory illness was rapidly emerging within Wuhan City and nearby communities, reaching the thousands by mid-January.

On January 24, Chinese scientists reported the results of viral diagnostic studies conducted on bronchoalveolar lavage specimens obtained from three Wuhan City patients hospitalized in December with severe bilateral interstitial, alveolar pneumonia [2]. The investigation identified a viral genome matched to lineage B of the genus betacoronavirus, showing more than 85% match with a SARS-like CoV genome previously described in bats. Ultrathin sections of infected human airway epithelial cells showed inclusion bodies filled with virus particles in membrane-bound vesicles in the cytoplasm. The morphology of the virion on electron microscopy is consistent with the Coronaviridae family.

This newly identified coronavirus, the etiologic agent responsible for the Wuhan outbreak, was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease caused by the infection is referred to as COVID-19. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is a betacoronavirus that likely had its origin in bats, with one or more animals serving as the intermediate host. The actual source and timing of initial human infection is unclear. According to CDC reports, virus sequences from initial imported cases in the United States were similar to the one posted by China, indicating emergence of this virus from a point-source in Wuhan, China [12].

The rapid accumulation of many new COVID-19 cases in Wuhan City during December 2019 and January/February 2020, combined with evidence of spread to nearby provinces in central China and reports of acute infection in healthcare workers, indicated that facile human-to-human transmission of SARS-CoV-2 was the key factor responsible for propagation of the outbreak. This has been proven true throughout the pandemic. During the first six months of 2020, outbreaks of COVID-19 spread to countries in every part of the world. As of May 2022, the global COVID-19 disease burden totaled 487 million confirmed cases and more than 6 million deaths, of which 80 million cases and more than 1 million deaths have been reported in the United States [132].

Despite the availability of effective COVID-19 vaccines beginning in December 2020, the scope of the pandemic remained undiminished in Europe and the United States throughout the summer and fall of 2021, primarily because of two complimentary developments: the slow rollout and limited acceptance of COVID-19 vaccines in certain regions and population groups, and the emergence of a SARS-CoV-2 variant strains that are three to four times more infectious and spread faster than the original virus strain. By July 2021, the SARS-CoV-2 Delta variant accounted for 99% of all COVID-19 cases reported in the United States; in December 2021, Delta was rapidly supplanted by the less severe but highly infectious Omicron variant [132].

A viral variant has one or more mutations within the genome that differentiate it from other strains of the virus. Closely genetically related variants derived from a common ancestor are designated a lineage. In response to concerns that emerging SARS-CoV-2 variants may have the potential to circumvent COVID-19 countermeasures, a SARS-CoV-2 Interagency Group (SIG) was established to characterize variants and monitor their impact on transmission, disease severity, risk of reinfection, and potential to evade vaccine-induced immunity [123]. The CDC’s national genomic surveillance program identifies SARS-CoV-2 variants by genetic sequencing and tracks the proportion and distribution of COVID-19 cases caused by variants. As of April 2022, the SARS-CoV-2 Omicron lineage (subvariants BA.1, BA.2, BA.3) accounts for an estimated 100% of new cases of COVID-19 in the United States [123,124].

3. CLINICAL MANIFESTATIONS OF COVID-19

The incubation period of SARS-CoV-2 infection is 5 to 7 days on average, with a range of 2 to 14 days. It is estimated that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of infection [15,18]. The onset and progression of illness is variable, with most patients experiencing some combination of fever, cough, fatigue, anorexia, myalgias, and shortness of breath. Less common presenting symptoms include rhinorrhea, sudden loss of smell (anosmia) and/or taste (ageusia), and sore throat. Atypical presentations have been described whereby some patients experience diarrhea or nausea and vomiting prior to the onset of fever and respiratory symptoms and signs. As with other infections, elderly persons may present with weakness and confusion. Older adults and persons with medical comorbidities may have delayed onset of fever and respiratory symptoms [15].

In a study designed to better characterize the symptom profiles of patients with COVID-19 in the United States, especially among nonhospitalized patients, the CDC used an optional questionnaire to collect detailed information from a sample of confirmed COVID-19 cases reported from 16 participating states [60]. Among 164 symptomatic patients with onset of illness between January 14 and April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Of 57 hospitalized adult patients, 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Each of the following symptoms was reported by more than half of patients: cough (84%), fever (80%), myalgia (63%), chills (63%), fatigue (62%), headache (59%), and shortness of breath (57%). Gastrointestinal symptoms were relatively common, most frequently diarrhea (38%) and least frequently vomiting (13%). Shortness of breath was more common in patients who required hospitalization (82%) than in nonhospitalized patients (38%). Anosmia and ageusia were reported by a higher percentage of nonhospitalized patients (22%) than hospitalized patients (7%) [60].

An array of cutaneous symptoms and signs has been described in patients with COVID-19. Although the exact frequency remains unknown, reports have ranged from 0.2%, early in the pandemic, to as high as 20.4% [15]. In addition to the exanthems common to many viral infections, pernio-like lesions have been described [105]. Pernio (chilblains) is a superficial inflammatory vascular response that occurs on acral skin, usually after cold exposure. In patients with COVID-19, these lesions appear as discolored edematous plaques on the toes and fingers. An international registry was organized early in the pandemic to characterize the diversity of dermatologic manifestations. In a study of 171 registry patients with confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) [106]. Morbilliform rashes were often pruritic and involved the trunk. Pernio morphologies were often painful/burning and involved the hands/feet. Pernio-like lesions were generally observed in patients with mild disease, whereas retiform purpura was seen exclusively in critically ill patients. Cutaneous manifestations usually appeared at the onset of or after other COVID-19 symptoms. However, in 12% of cases skin lesions occurred before other COVID-19 symptoms or signs [106]. Images of cutaneous findings are available from the American Academy of Dermatology at https://www.aad.org/public/diseases/coronavirus/covid-toes.

Although most symptomatic patients with COVID-19 experience a mild-to-moderate illness with slow convalescence, there is substantial risk of progression to bilateral pneumonia complicated by respiratory failure and death. In February 2020, the overall case fatality rate for confirmed cases of COVID-19 reported from China was approximately 3%. As the pandemic has progressed, reported case fatality rates have varied considerably among countries and regions, ranging from 3% to as high as 14%. Multiple factors account for this variance, including available health resources and access to care, differences in public health mitigation strategies, lack of uniformity in the way deaths are attributed to COVID, and the extent to which testing and contact tracing identifies asymptomatic infections. Based on reported cases and attributable deaths through mid-July 2020, the COVID-19 case fatality rate during the first six months of the pandemic was 3.6% in the United States [8]. It is more useful to consider age-adjusted case fatality rates, which range from less than 1% in persons younger than 20 years of age to more than 15% for those older than 75 years of age.

SEVERITY AND PROGRESSION OF ILLNESS

The first report describing the clinical features of hospitalized patients with COVID-19-related pneumonia in Wuhan City was published online January 24, 2020 [9]. As of January 2, 41 admitted patients had been identified as having laboratory-confirmed 2019-nCoV infection; 30 (73%) were men and 27 (66%) had been exposed to the open-air Huanan Seafood Market. The median age was 49 years, and fewer than half of the patients had a history of underlying chronic disease. Common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%). Dyspnea developed in 22 patients (55%), with a median time from illness onset to dyspnea of eight days. Common laboratory abnormalities included leukopenia, lymphopenia, and mild hepatic enzyme elevations. All 41 patients were reported to have pneumonia, and all save one had radiographic evidence of bilateral involvement. The typical findings on chest computed tomography (CT) images of intensive care unit (ICU) patients were bilateral multilobar and segmental areas of consolidation. Acute respiratory distress syndrome developed in 12 (32%) patients, 13 (32%) were admitted to an ICU, and 6 died (15%).

A larger retrospective study examined the clinical characteristics of COVID-19 in a cohort of 1,099 hospitalized patients in China during the first two months of the outbreak [17]. The most common symptoms were fever (43.8% on admission, 88.7% during hospitalization), cough (67.8%), and fatigue (38.1%) [17]. The most common patterns on chest CT were ground-glass opacification (36.4%) and bilateral patchy shadowing (51.8%). Some degree of radiographic or CT abnormality was evident in 82% of patients with nonsevere disease and 97% of patients with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Sixty-seven patients (6.1%) were admitted or transferred to the ICU, 2.3% required mechanical ventilation, and 1.4% died [17].

In a summary of 72,314 cases reported to the Chinese Center for Disease Control and Prevention, the severity of illness ranged from mild to critical with approximately the following distribution [15,23]:

- Mild to moderate (mild symptoms up to mild pneumonia): 81%

- Severe (dyspnea, hypoxia or >50% lung involvement on imaging): 14%

- Critical (respiratory failure, shock, or multiorgan dysfunction): 5%

The majority of cases (81%) were characterized as mild, with no or mild pneumonia [23]. The overall case-fatality rate was 2.3%, with higher rates among patient subgroups. Specifically, the case-fatality rate was 49% among critical patients, and all reported deaths occurred in critical patients [23].

Risk Factors

Risk factors for severe disease include advanced age, obesity (body mass index ≥30), and comorbidities such as hypertension, diabetes, cardiovascular disease, cancer, and chronic lung disease. Among more than 70,000 cases reported in China through February 11, 2020, 87% occurred in persons 30 to 79 years of age [23]. The proportion of case fatalities among patients 70 to 79 years of age was 8%, and among those 80 years of age or older, the rate was 14.8%. Case fatality for patients with comorbidities was elevated as well, specifically for those with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%). Only 2% of cases were in persons younger than 20 years of age, and no deaths were reported in those younger than 10 years of age.

Atypical presentations have been described, and older adults and persons with medical comorbidities may have delayed presentation of fever and respiratory symptoms [15]. Headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, and diarrhea have been reported but are less common (<10%). Some persons with COVID-19 have experienced gastrointestinal symptoms such as diarrhea and nausea prior to developing fever and lower respiratory tract signs and symptoms. Anosmia or ageusia preceeding the onset of respiratory symptoms has been anecdotally reported, but more information is needed to understand its role in identifying COVID-19. Several studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (presymptomatic) [15].

In June 2020, the CDC issued an epidemiologic report on 1,320,488 laboratory-confirmed COVID-19 cases in the United States and territories, reported to CDC between January 22 and May 30, 2020 [55]. Cumulative incidence (403.6 cases per 100,000 persons) was similar among males (401.1) and females (406.0), highest among persons 80 years of age or older (902.0), and lowest among children younger than 9 years of age (51.1). Among 599,636 cases with known information on both race and ethnicity, 36% of persons were non-Hispanic white, 33% were Hispanic, 22% were black, 4% were Asian, and 1.3% were American Indian or Alaska Native. Among 287,320 cases with sufficient data on underlying health conditions, the most frequently reported were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU, and 71,116 (5%) died. The hospitalized rate was six times higher among patients with a reported underlying condition (45.4%) than among those without reported underlying conditions (7.6%). The mortality rate was 12 times higher among patients with reported underlying conditions (19.5%) compared with those with none reported (1.6%). Approximately 4% of reported cases were asymptomatic. Among 373,833 cases with data on individual symptoms, 70% noted fever, cough, or shortness of breath; 36% reported muscle aches; and 34% reported headache. Overall, 31,191 (8%) persons reported loss of taste or smell [55].

During the course of the COVID-19 pandemic in the United States, obesity has emerged as an important independent risk factor for severe disease, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, have consistently found that severe obesity (body mass index >35) is associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [77,78]. The risk varies directly with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology and sleep apnea, severe obesity is associated with immune dysfunction (depression of anti-inflammatory signaling and increased pro-inflammatory signaling), alterations in vascular endothelium, and renin-angiotensin stimulation, which together may worsen lung inflammation and alveolar damage [78].

Although the absolute risk of severe COVID-19 is low among people of child-bearing age, the risk of severe illness and complications is substantial when infection is acquired during pregnancy. Evidence for this comes from an analysis of 409,462 women (15 to 44 years of age) with symptomatic COVID-19 reported to the CDC between January 22 and October 3, 2020 [107]. Of the total, 23,434 women (5.7%) were pregnant at the time of infection. Pregnant patients were admitted to an ICU more frequently than nonpregnant patients (10.5 versus 3.9 per 1,000 cases) and were more likely to receive invasive ventilation (2.9 versus 1.1 per 1,000 cases) or extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases). The mortality rate was 1.5 per 1,000 cases for pregnant women compared with 1.2 per 1,000 cases for nonpregnant women. Older pregnant patients (35 to 44 years of age) with symptomatic COVID-19 were nearly four times more likely to require invasive ventilation and twice as likely to die than were nonpregnant patients of the same age [107].

Following the emergence of the Delta variant and 2021 summer surge of COVID-19, the risk for unvaccinated pregnant individuals infected with SARS-CoV-2 became even more serious. A retrospective cohort study comparing COVID-19 outcomes among unvaccinated pregnant patients infected in the pre-Delta period with those infected during the Delta surge found that proportions of severe-critical illness and ICU admissions were three-fold higher among patients in the Delta cohort than those in the pre-Delta cohort [149]. The need for intubation and mechanical ventilation was also greater among those with Delta variant infection. Maternal COVID-19 from SARS-CoV-2 Delta infection also had an adverse effect on perinatal outcomes; rates of cesarean delivery, stillbirth, preterm birth, and neonatal intensive care unit admission were all higher during the period of Delta predominance [149].

SYSTEMIC COMPLICATIONS OF COVID-19

At the cellular level, infection by a virus requires some affinity of the virion for the host cell combined with a mechanism that facilitates attachment and entry into the cell. Cell entry of SARS-CoV-2 depends on binding of the viral surface spike protein to angiotensin-converting enzyme (ACE2) receptors and activation of the spike protein by host cell transmembrane protease serine 2 [30]. ACE2 is highly expressed by epithelial cells in the nasopharynx and type II alveolar cells in the lung. ACE2 is also expressed in the heart, kidney, vascular endothelium, and intestinal epithelium, which may explain, in part, the propensity for multiorgan dysfunction and vascular complications increasingly recognized in patients with severe COVID-19. In an autopsy series of 27 patients reported from Germany, SARS-CoV-2 was detected in multiple organs, including the lungs, pharynx, kidney, heart, liver, and brain [31]. In a further analysis of renal involvement, SARS-CoV-2 viral load was detected in all kidney compartments examined, with preferential targeting of glomerular cells.

Based upon recent reports from clinical centers caring for a high volume of hospitalized patients, renal and cardiac complications are relatively common in severe COVID-19. In a retrospective study from China, 251 of 333 (75%) hospitalized patients with COVID-19 pneumonia exhibited some degree of renal involvement, as evidenced by proteinuria or hematuria, and 35 (10%) met criteria for acute kidney injury [32]. In another case series of 138 hospitalized COVID-19 patients, 7% overall and 22% of those admitted to the ICU developed elevated troponin levels or electrocardiogram abnormalities indicative of myocarditis or cardiac injury some time during hospitalization [33]. Myocardial injury affects more than one-quarter of COVID-19 cases classified as critical and presents in two patterns: acute myocardial injury and dysfunction on presentation, and myocardial injury developing as illness severity intensifies [34]. While headache and confusion are seen in some patients presenting with severe COVID-19, there is no indication that SARS-CoV-2 causes primary infection of the central nervous system (e.g., encephalitis). In an autopsy series of 18 consecutive patients who died 0 to 32 days after onset of COVID-19, histopathologic examination of brain specimens did not show encephalitis or other specific brain changes referable to the virus [56].

Coagulopathy

Hospitalized patients with advanced COVID-19 may have laboratory signs of a coagulopathy and increased risk for arterial and venous thromboembolic complications [15,39,40]. The pathogenesis is unknown but likely involves some combination of systemic inflammation, endothelial dysfunction, platelet activation, immobility, and stasis of blood flow [40]. The earliest abnormalities are elevated D-dimer levels and mild thrombocytopenia; with disease progression, fibrin degradation products are elevated and prothrombin time becomes prolonged. Laboratory measure of coagulation factors in a patient hospitalized with COVID-19 provides a way to track disease severity. The presence of an elevated D-dimer on admission carries a poor prognosis and has been associated with increased risk of requiring mechanical ventilation, ICU admission, and mortality [40,41]. The most frequently reported complications of COVID-19 coagulopathy are deep venous thrombosis (DVT) and pulmonary emboli (PE). In a prospective study of 150 critically ill patients from two centers in France, 25 patients developed PE and 3 developed DVT despite prophylactic anticoagulation [42]. In a report of 184 patients with severe COVID-19 from three centers in the Netherlands, the cumulative incidence of venous thromboembolism was 27%, including PE in 80% of the cases affected [43]. Other centers have reported lower rates. Among 393 patients from New York, venous thromboembolism was diagnosed in only 13 patients (3.3%), 10 of whom were on mechanical ventilation [44]. These differences point to the need for studies that control for clinical severity, underlying comorbidities, prophylactic regimen, and COVID-19-related therapies. At present, there are limited data available to inform clinical management around prophylaxis or treatment of venous thromboembolic complications in patients with COVID-19 [15]. One source of interim guidance recommends regularly monitoring hemostatic markers—namely D-dimer, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low-molecular-weight heparin in all hospitalized patients, unless there are contraindications [40]. The National Institutes of Health has developed guidelines for antithrombotic therapy in patients with COVID-19, available at https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy.

RECOVERY FROM COVID-19

Convalescence following SARS-CoV-2 infection follows a variable course, and symptomatic recovery from severe COVID-19 may take weeks to months. A report from Italy describes a cohort of 143 patients with moderate-to-severe COVID-19, 87% of whom had persistent symptoms two months or more after discharge from hospital [68]. The mean duration of hospitalization was 13.5 days; 73% had evidence of interstitial pneumonia, 15% received noninvasive respiratory support, and 5% required mechanical ventilation. Follow-up clinical assessment was conducted a mean of 60 days after onset of the first COVID-19 symptom. At evaluation, 18 (13%) were symptom free; of the remaining participants, 32% had one or two symptoms and 55% had three or more symptoms. The most common persistent symptoms were fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%). None had fever or signs of acute illness. Of the total, 44% reported persistence of the decline in quality of life imposed by COVID-19.

"Long COVID" is the term applied to the syndrome of persistent symptoms four weeks or later after recovery from acute COVID-19. The majority of reported cases are adults in the 35-to-69-year age group, and women are 30% more likely to get long COVID than men [133]. The range of complaints includes residual cough, fatigue, loss of smell or taste, shortness of breath, headache, and "brain fog." The prevalence of post-COVID-19 cognitive impairment and association with disease severity was investigated in 740 adult patients with no prior history of dementia. Study participants were 38 to 59 years of age, prior COVID severity ranged mild to severe, and evaluations were performed an average of 7.6 months after diagnosis. Deficits were found in processing speed (18%), executive functioning (16%), phonetic fluency (15%) and category fluency (20%), memory encoding (24%), and memory recall (23%) [134]. Executive functioning, processing speed, and memory encoding and recall impairments were predominant among hospitalized patients.

A multistate survey conducted by the CDC found that persistent symptoms three weeks after diagnosis of SARS-CoV-2 infection was common among outpatients with milder illness [69]. Of 270 respondents who were symptomatic at diagnosis, 95 (35%) had not returned to their usual state of health 14 to 21 days from the test date, including 26% of those 18 to 34 years of age and 47% of those older than 50 years of age. Among respondents reporting cough, fatigue, or shortness of breath at the time of COVID-19 diagnosis, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview [69].

A cohort study of long-term symptoms among healthcare professionals found that after mild COVID-19, 26% of participants reported at least one moderate-to-severe symptom lasting two months and 15% reported at least one moderate-to-severe symptom lasting eight months [108]. The most common symptoms were anosmia, fatigue, ageusia, and dyspnea. These studies show that low-risk adults with mild COVID-19 commonly experience a slow convalescence with diverse long-term symptoms that may disrupt work and social activity.

LATE SEQUELAE OF COVID-19

In addition to lingering functional impairments represented by long COVID syndrome, there is growing evidence that beyond acute infection, SARS-CoV-2 may have late adverse effects on critical organ function that increase the subsequent burden of cardiovascular disease and diabetes. The lung/vascular/heart involvement of acute-phase moderate-to-severe COVID-19 reflects the trophism of SARS-CoV-2 and is augmented by a dysregulated (hyperimmune) inflammatory response to infection; this can lead to multiple complications. Microvascular dysfunction and endothelial injury may precipitate thromboembolic events. Myocarditis may impair cardiac function; acute coronary syndromes from vasculitis and plaque instability may cause myocardial ischemic injury and heart failure. Parenchymal lung injury and microvascular thrombosis may lead to interstitial fibrosis and hypoxemia, adding to the cardiac workload and subsequent risk of clinical or subclinical heart failure [159].

The cardiovascular sequelae of post-acute COVID-19 were analyzed using the databases of the U.S. Department of Veterans Affairs to build a cohort of 153,769 individuals with COVID-19, as well as cohorts of contemporary and historical controls. The study was designed to estimate risks and one-year burdens of a set of prespecified incident cardiovascular outcomes. The analysis showed that beyond the first 30 days after infection, individuals with COVID-19 were at increased risk of subsequent cardiovascular diseases spanning several categories, including dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease [160]. The increased risk and added burden were evident among hospitalized and nonhospitalized patients. Overall, the impact increased in graded fashion according to the clinical care setting. In a separate report, using the same database and study protocol, investigators also found that the risks and 12-month burdens of incident diabetes and antihyperglycemic use were increased among people who survived COVID-19, compared to a contemporary control group who had not contracted SARS-CoV-2 [161]. The post-acute diabetes risks and disease burdens increased in graded fashion according to severity of the acute phase of COVID-19.

Chronic, persistent SARS-CoV-2 infection following COVID-19 has been reported in patients with hematologic malignancies and immunodeficiency disorders. The common features are protracted virus shedding, fluctuating symptoms, and failure of humeral immunity many months after acute infection. In addition to the burden of ongoing symptoms and added cost of care, these patients often have to endure prolonged self-isolation and inability to resume productive lives. COVID-19 vaccines may be beneficial in such cases; in a reported case study, mRNA COVID-19 vaccination elicited humoral and cellular immune responses to SARS-CoV-2, which had failed in response to ongoing infection itself, followed by viral clearance [162].

4. COVID-19 IN CHILDREN

The CDC provides information for pediatric healthcare providers and guidance for the evaluation and care of neonates at risk for COVID-19 [45]. Acute SARS-CoV-2 infection in childhood tends to be asymptomatic or relatively mild, consisting of transient fever, cough, and other signs common to an upper respiratory viral syndrome. Severe manifestations of COVID-19 have been reported in children of all ages, though the incidence is far less common than in adults and fatalities following acute childhood infection are rare. Among more than 2,000 pediatric cases in China, 4% were asymptomatic, 51% had mild symptoms, 39% were moderately ill with some evidence of pneumonia, and 5% were severely ill with dyspnea, hypoxia, and central cyanosis [45]. Only 0.6% developed respiratory failure, shock, or multi-organ dysfunction.

Children younger than 18 years of age account for 22% of the U.S. population and represent 19% of cumulative COVID-19 cases reported since the onset of the pandemic [136]. As of April 2022, more than 12.8 million children have tested positive for COVID-19, including 7.8 million child cases added since September 2021. Severe illness from SARS-CoV-2 infection is uncommon. Among states reporting, children account for 1.2% to 4.6% of COVID-19-related hospitalizations and less than 1.5% of all child COVID-19 cases result in hospitalization. The childhood COVID-19 case fatality rate is less than 0.03% [46,136]. As in adults, children with underlying medical conditions and special healthcare needs, including genetic, neurologic, and metabolic disorders or congenital heart disease are at increased risk for severe illness from COVID-19.

Coinciding with increased circulation of the highly infectious SARS-CoV-2 Omicron variant, COVID-19-associated hospitalization rates increased rapidly among children 0 to 4 years of age, a group not yet eligible for vaccination. During the period December 2021 to February 2022, weekly hospitalizations among children 0 to 4 years of age peaked at 14.5 per 100,000, a level fivefold higher than that during the previous six months (Delta predominance) [163]. During Omicron predominance, 63% of hospitalized infants and children had no underlying medical conditions. Monthly ICU admission rates were approximately 3.5 times higher during the Omicron predominance peak in January 2022 than during the Delta predominance peak in September 2021 [163].

Long COVID has also been described in children, though to a lesser degree than in adults. Adolescents and teenagers account for the majority (70%) of reported cases [133]. In a study of 151 children with documented SARS-CoV-2 infection, 8% had post-acute COVID-19 symptoms lasting three to eight weeks [135]. The most common symptoms were residual cough and/or fatigue. On follow-up survey at six months, all 151 children had fully recovered.

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

Reports from the United Kingdom, Italy, and New York describe a serious inflammatory disorder in children linked to COVID-19, with many features common to Kawasaki disease and toxic shock syndrome [46,47,48]. The term applied to this condition is multisystem inflammatory syndrome in children (MIS-C). Kawasaki disease is an acute vasculitis of unknown cause that affects infants and young children, first described in Japan and thought to involve an aberrant immune response to an unidentified pathogen in persons with a genetic predisposition [47]. Children with COVID-related MIS-C present with signs of a diffuse inflammatory disorder, including persistent fever, abdominal complaints, rash, leukocytosis, elevated C-reactive protein, and evidence of single or multiple organ dysfunction [49]. Hypotension on presentation is common, and myocarditis and other cardiovascular changes (e.g., mitral regurgitation, coronary artery dilatation) may be seen. The majority of patients have tested positive for recent SARS-CoV-2 infection by molecular diagnostic and/or antibody testing. The onset of MIS-C may come days or weeks after what appears to have been an asymptomatic or mild case of COVID-19.

During a 10-day period in mid-April 2020, pediatricians at an intensive care hospital in England noted an unprecedented cluster of eight children with hyperinflammatory shock and other clinical features similar to atypical Kawasaki disease [47]. All had been previously well, and five of the children were boys. Four of the children had known family exposure to SARS-CoV-2. Clinical presentations were similar, with unrelenting fever, variable rash, conjunctivitis, peripheral edema, and warm shock refractory to volume repletion and eventually requiring vasopressors. No clinical or virologic evidence of lower respiratory involvement was observed. All patients were treated with IV immunoglobulin (IVIG); seven recovered and one died following arrhythmia, shock, and cerebral infarction. During the course of the COVID-19 epidemic in northern Italy, physicians in Bergamo observed 10 children (median age: 7.5 years) in the span of two months with a severe form of Kawasaki-like disease, a 30-fold increase in incidence when compared to the previous five years [48]. All were positive for recent SARS-CoV-2 infection. As of June 3, 2020, the New York State Department of Health was investigating 195 reported cases of MIS-C and 3 deaths in children. Of these patients, 28% are younger than 5 years of age and 69% are between 5 and 19 years of age [46]. Of the 195 cases, 93% have tested positive for COVID-19. A targeted surveillance for MIS-C in pediatric health centers across the United States identified 186 cases in 26 states during a five-week period between March and May [61]. The median age was 8.3 years, 165 (62%) were male, and 131 (70%) tested positive for SARS-CoV-2 infection by rT-PCR or serologic antibody test.

The clinical features in the MIS-C cases investigated by the New York Department of Health have been reported [62]. Of 191 patients in the study, all presented with fever and tachycardia, 80% were admitted to the ICU, and 62% required vasopressor support. Abdominal complaints and gastrointestinal symptoms were common (62%), as was rash (60%), conjunctival injection (56%), and mucosal changes (27%). Laboratory markers of inflammation included elevated levels of C-reactive protein in all patients, positive D-dimer (91%), and elevated troponin (71%). Evidence of myocarditis was present in 53% of patients. At least one echocardiogram was obtained for 93 patients (94%); 51 (52%) had some degree of ventricular dysfunction, 32 (32%) had pericardial effusion, and 9 (9%) had a documented coronary artery aneurysm. The majority of patients were treated with IVIG and/or glucocorticoids in addition to vasopressors. The median duration of hospitalization was six days. Two patients died. As in Italy, MIS-C cases in New York followed the peak of the COVID-19 epidemic in that state and nearly all patients tested seropositive for recent SARS-CoV-2 infection [62].

Early recognition of MIS-C and prompt referral to an inpatient unit of care is essential. Approximately 50% to 60% of children and adolescents with MIS-C present with signs of cardiovascular involvement leading to warm shock and a need for vasopressor support, compared with about 5% of children with Kawasaki's disease [61,62]. Cardiac abnormalities are common, including a 9% incidence of coronary artery aneurysm. Echocardiography is recommended in all patients presenting with MIS-C, and until more is known about long-term cardiac sequelae of MIS-C, providers should consider follow-up imaging at one to two weeks and four to six weeks after treatment [61]. Clinical evaluation should include inquiry as to recent COVID-19 illness or known exposure to persons with COVID-19. There are currently no published guidelines or CDC recommendations regarding treatment for MIS-C and no studies comparing efficacy of various treatment options. Based on published reports, principles of care include close observation, correction of hemodynamic instability, diagnostic evaluation to exclude serious bacterial infection (e.g., streptococcal or staphylococcal sepsis, toxic shock syndrome), and consideration of treatment with IVIG. The CDC recommends that patients younger than 21 years of age meeting MIS-C criteria be reported to local, state, and territorial health departments. The CDC case definition for MIS-C is [49]:

- An individual younger than 21 years of age presenting with fever (>38.0°C for at least 24 hours), laboratory evidence of inflammation (including, but not limited to, one or more of the following: an elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin-6, elevated neutrophils, reduced lymphocytes, and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (at least two) organ involvement; AND

- No alternative plausible diagnoses; AND

- Positive for current or recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms

All individuals should be reported if they meet the case definition for MIS-C, regardless of whether they fulfill criteria for Kawasaki disease. In addition, MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.

The CDC tracks case reports of MIS-C associated with COVID-19. As of March 2022, the number of patients meeting the case definition of MIS-C in the United States totaled 7,885, with 66 deaths [137]. The median age of reported cases was 9 years, and half of children with MIS-C are 5 to 13 years of age. Of the total MIS-C cases reported, 58% are Hispanic/Latino or non-Hispanic Black, 60% are male, and 98% had a positive test for recent SARS-CoV-2 infection [137].

Vaccination with mRNA vaccine is highly effective in preventing COVID-19-associated MIS-C in children 12 to 18 years of age. A case-control study across 24 pediatric hospitals in 20 states comparing 124 patients with MIS-C with 181 hospitalized controls found that the estimated effectiveness against MIS-C following two doses of Pfizer-BioNTech vaccine was 91% [164]. Ninety-five percent of patients hospitalized with MIS-C were unvaccinated, and all 38 MIS-C patients requiring life support were unvaccinated.

5. DIAGNOSTIC TESTING FOR SARS-COV-2

There are two types of diagnostic tests for determining active SARS-CoV-2 infection: molecular tests that use the real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect viral RNA, and antigen tests that detect specific proteins on the surface of the virion. The most widely used and reliable of these is RT-PCR, which can be applied to mucus specimens from the upper or lower respiratory tracts and to serum samples. SARS-CoV-2 viral RNA can be detected more readily in secretions taken by swab from the nasopharynx than in samples obtained by throat swab [15]. RT-PCR testing of deep nasopharyngeal swab specimens has become the standard procedure for the laboratory diagnosis of active SARS-CoV-2 infection [79,80]. This test is highly accurate and results can be obtained within one or two days. Antigen tests for the diagnosis of active SARS-CoV-2 infection are also performed on nasal or throat swab specimens and have the advantage of providing results much faster than the RT-PCR test (often less than one hour) [80]. However, antigen tests are less sensitive than molecular tests, which detect viral nucleic acids, and the amount of antigen in a sample decreases as the duration of illness increases. Specimens collected more than seven days after onset of illness are considered more likely to be negative compared to a RT-PCR assay [80]. Thus, a positive antigen test result is highly reliable, but a negative test may need to be confirmed with RT-PCR. Updated CDC guidance for healthcare providers who order antigen tests, receive antigen test results, or perform point-of-care testing in the community is available online at https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html.

The availability of safe, reliable, and timely SARS-CoV-2 diagnostic testing is essential for effective public health measures to control the COVID-19 pandemic. The nasopharyngeal swab specimen collection method involves close interaction between healthcare workers and patients, requires personal protective equipment, and entails a measure of discomfort for the test subject—all disadvantages to community drive-through diagnostic testing and contact tracing. Self-collected saliva could prove to be a simple, less expensive alternative that alleviates the need for personal protective equipment. There is growing evidence that the molecular test detection rate in saliva specimens from symptomatic and asymptomatic SARS-CoV-2 infected individuals is comparable to deep nasopharyngeal swab specimens. Yale investigators found that among 70 inpatients with confirmed COVID-19 and 495 asymptomatic healthcare workers, the use of self-collected saliva specimens for SARS-CoV-2 molecular diagnostic testing compared favorably with nasopharyngeal swab specimens collected by personnel [81]. In another study of 354 patients presenting to a drive-through testing center with at least one symptom consistent with COVID-19, the SARS-CoV-2 positivity rate was 22.6% for nasopharyngeal swab specimens compared with 22.9% for salivary specimens [82]. Between nasopharyngeal swab specimens and salivary specimens, the positive percent agreement was 93.8% and the negative percent agreement 97.8%.

COVID-19 diagnostic testing in the United States is available at all state and local public health laboratories and at commercial laboratories authorized by the U. S. Food and Drug Administration (FDA) [16,80]. Although in some cases viral nucleic acid can be detected in nasopharyngeal specimens for weeks after infection, studies show that SARS-CoV-2 viral cultures are usually negative within 8 to 10 days after onset of infection. Shedding of live virus may persist longer in severely ill, hospitalized patients (median range of viral shedding: 12 to 20 days) [15]. Information on specimen collection, handling, and storage is available online at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html.

ANTIBODY TESTING

SARS-CoV-2 antibody assays are useful for epidemiologic investigation of prevalence in the general population and to identify groups at risk for infection. Unlike RT-PCR and antigen detection tests that identify acute infection, antibody tests determine whether there is evidence of prior infection, even if the person being tested never developed symptoms. The FDA has not authorized the use of serology to detect active SARS-CoV-2 infection, and the CDC does not recommend antibody testing for routine diagnosis of acute infection [79]. However, antibody testing in conjunction with viral RT-PCR may be used to support clinical assessment of persons who present late in the course of COVID-19, or a patient suspected of having a post-infectious syndrome caused by recent SARS-CoV-2 infection (e.g., MIS-C).

Following SARS-CoV-2 infection, IgM and IgG antibodies appear almost simultaneously in the serum within two to three weeks after symptom onset, at which time infectiousness likely is greatly decreased and some degree of immunity from future infection has developed [83]. Thus, early IgM assay without IgG testing is of little value. The duration of detectable antibody is unknown, and the absence of detectable IgM or IgG antibodies does not necessarily rule out previous infection. Several commercially marketed serologic assays for SARS-CoV-2 have emergency use authorization (EUA) by the FDA, which has independently reviewed their performance. A list of all tests authorized for emergency use under EUA is maintained on the FDA website [84]. All currently authorized tests are qualitative (providing a result that is positive, negative, or indeterminate) rather than quantitative (providing a quantitative assessment of antibody levels). It is important to minimize false-positive test results by choosing an assay with high specificity and by testing individuals with an elevated likelihood of previous exposure to SARS-CoV-2 [83].

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

There is no simple, safe, and highly effective antiviral therapy for the routine treatment of COVID-19. Care is supportive and should be provided in a controlled environment under Isolation Precautions. Effective vaccines for prevention of SARS-CoV-2 began distribution at the end of 2020.

After China published the viral genome on a public database in mid-January 2020, the National Institutes of Health immediately began research efforts to improve diagnostics, identify effective treatments, and develop vaccines against SARS-CoV-2 [10]. As noted, the CDC and commercial laboratories developed a reliable diagnostic test based on genetic sequencing of the virus. Two antiviral agents—remdesivir, a drug tried unsuccessfully in the Ebola outbreak, and lopinavir/ritonavir (Kaletra), a combination antiviral used for treatment of human immunodeficiency virus (HIV)—were provided on a compassionate use basis in China. However, one study of hospitalized patients with COVID-19 in China found no difference in time to clinical improvement or outcome with lopinavir/ritonavir treatment [20].

Following successful development and clinical trials of vaccines against SARS-CoV-2 in the summer and fall of 2020, an accelerated effort was launched in the United States and other countries to implement an immunization strategy against COVID-19.

INVESTIGATIONAL THERAPEUTICS

Antiviral Therapy

Remdesivir is the only drug approved by the FDA for the treatment of COVID-19. Ritonavir-boosted nirmatrelvir (Paxlovid), molnupiravir, and certain SARS-CoV-2 monoclonal antibodies have received EUA from the FDA for treatment of COVID-19. The NIH Treatment Guidelines Panel provides updated information on these and other drugs of interest for the management of COVID-19, including recommendations for patient selection and use of specific anti-viral regimens [57].

Remdesivir

Remdesivir, an investigational antiviral drug that inhibits viral RNA polymerases, has been shown to have in-vitro activity against SARS-CoV-2 [15]. An early report described the clinical outcomes for a cohort of patients with COVID-19 who were treated with a 10-day course of intravenous remdesivir as part of a compassionate use program [26]. The study enrolled patients from the United States, Canada, Europe, and Japan who were hospitalized with confirmed SARS-CoV-2 infection and signs of lower respiratory tract disease severe enough to require some degree of oxygen supplementation and/or ventilatory support. Of 53 patients with sufficient data for analysis, 32 (68%) showed significant improvement in oxygen support status with use of remdesivir; the overall mortality was 13% over a median follow-up of 18 days, including 18% among those who were receiving invasive ventilation and 5% among those who were receiving noninvasive oxygen support. The authors observed that while there was no randomized control group and the patients in this study are not directly comparable, the observed mortality was considerably less than that reported contemporaneously in other COVID-19 case series and reports [26].

On October 22, 2020, the FDA approved remdesivir for use in adult and pediatric patients 12 years of age and older (weighing at least 40 kg) for the treatment of COVID-19 when hospitalization is required [90]. In April 2022, this approval was expanded to include children 28 days of age and older weighing at least 3 kilograms [177]. The approval was supported by an analysis of three randomized, controlled clinical trials that showed remdesivir shortens the time to recovery and decreases progression of respiratory illness in adult patients hospitalized with COVID-19 [90]. The data analysis included final results from an NIH-sponsored study, a double-blind, placebo-controlled remdesivir trial involving hospitalized patients with moderate-to-severe COVID-19 [35]. In this study, a total of 1,062 patients were randomized to receive intravenous remdesivir or placebo for 10 days. The primary outcome was time to recovery, defined by discharge from hospital or resolution of need for clinical care (hospitalization for infection-control purposes only). The median time to recovery was 10 days for the remdesivir group, compared with 15 days for the placebo group. In an analysis of secondary outcomes, patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15. The proportion of serious adverse events related to respiratory failure and the need for higher levels of respiratory support were lower among patients in the remdesivir group. Kaplan-Meier estimates of mortality showed a trend in favor of the treatment group: 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% versus 15.2% by day 29 [35].

The NIH Treatment Guidelines Panel (NIH Panel) recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 <94% on ambient air or those who require supplemental oxygen, and in patients who need any form of mechanical ventilatory support [57]. The recommended duration of treatment and the advisability of combining remdesivir with a glucocorticoid vary in relation to severity of illness and level of ventilatory support. For patients who require supplemental oxygen but have no need for delivery of oxygen through a high-flow device, the recommended regimen is remdesivir 200 mg IV for one day, followed by 100 mg daily for four days or until hospital discharge, whichever comes first. The duration of remdesivir therapy may be extended up to 10 days when there is no substantial clinical improvement by day 5.

A three-day course of remdesivir has received FDA approval for use in nonhospitalized COVID-19 patients in settings where intravenous therapy and close patient monitoring are feasible. In a randomized, placebo-controlled clinical trial among nonhospitalized adults (mean age: 50 years) with symptomatic COVID-19 and at least one risk factor for disease progression, a three-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than placebo [165]. COVID-19-related hospitalizations and deaths from any cause occurred in 2 patients (0.7%) in the remdesivir group and 15 patients (5.3%) in the placebo group.

Oral Anti-SARS-CoV-2 Agents

Two oral antiviral drugs, molnupiravir and nirmatrelvir-ritonavir, have received FDA EUA for early treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at risk of disease progression. Mulnupiravir is the prodrug of a ribonucleoside with broad antiviral activity against RNA viruses. Uptake by viral RNA-dependent RNA polymerases causes mutations that are lethal to the virus. In clinical trials, 800-mg molnupiravir twice daily for five days reduced the rate of hospitalization or death among patients with COVID-19 by 30% compared with placebo [57]. Molnupiravir is not recommended for use in pregnant patients due to concerns about potential fetal toxicity. The NIH Panel recommends using molnupiravir only when nirmatrelvir-ritonavir, remdesivir, and selective monoclonal antibody therapy are not available or cannot be used, because molnupiravir has lower efficacy than the other options [57].

Nirmatrelvir is a protease inhibitor active against a constitutive protein (protease) essential for virus replication. It has demonstrated antiviral activity against all human coronaviruses [57]. Nirmatrelvir is used in combination with ritonavir, a pharmacokinetic booster required to increase nirmetrelvir concentration into therapeutic range. Because ritonavir is a potent P450 3A4 inhibitor, nirmatrelvir-ritonavir has significant potential drug-drug interactions; the patient’s concomitant medications should be reviewed before clinical use. The available formulation (Paxlovid) uses nirmatrelvir 300 mg plus ritonavir 100 mg orally twice daily for five days in those older than 12 years of age and weighing more than 40 kg. Treatment should be initiated as soon as possible and within five days of symptom onset. Paxlovid is indicated for early treatment of select patients who are at high risk of severe disease and complications from COVID-19 [57]. In a randomized, placebo-controlled clinical trial of nirtrelvir-riyonavir among symptomatic, unvaccinated, nonhospitalized adults at risk for severe disease, the incidence of progression to severe COVID-19 (hospitalization or death) was 89% lower in the treatment group than in the placebo group [166]. The incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths.

There is some evidence of a COVID-19 recurrence following treatment with nirmatrelvir-ritonavir [176]. Limited information currently available from case reports suggests that persons treated with ritonavir-boosted nirmatrelvir who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed in cases where COVID-19 rebound is suspected. Patients with a COVID-19 recurrence should be advised to re-isolate for at least five days to prevent further transmission of the virus.

Hydroxychloroquine

In-vitro studies show that chloroquine phosphate and hydroxychloroquine sulphate (commonly used to treat malaria) interfere with the replication cycle of coronaviruses, including SARS-CoV-2, and thus may offer some therapeutic efficacy for treatment of COVID-19 [21]. Randomized controlled clinical trials of hydroxychloroquine are underway in the United States. Based on small case studies and anecdotal reports of possible efficacy, many clinicians have been inclined to administer hydroxychloroquine to patients with COVID-19 who are so ill as to require hospitalization and having risk factors for severe disease (i.e., age older than 65 years, underlying medical conditions, and/or signs of viral pneumonia). On March 28, 2020, the FDA issued an EUA that allowed chloroquine phosphate or hydroxychloroquine sulphate to be used for the treatment of patients hospitalized with COVID-19 when clinical trials are not available or participation is not feasible [36]. However, this letter was revoked in June 2020 [58]. If used, hydroxychloroquine is generally preferred as it is better tolerated. The suggested dosage regimen is hydroxychloroquine sulphate administered orally in a loading dose of 400 mg twice daily (for one day) then 200 mg twice daily for four days [22]. Potential adverse effects include cardiac conduction QT-prolongation and a number of drug-drug interactions.

An observational study examined the association between hydroxychloroquine use and clinical outcomes, analyzing data from 1,376 consecutive patients with COVID-19 admitted to a clinical center in New York City between March 7 and April 8, 2020 [37]. To assess potential benefit or detrimental effect, the primary end point selected was a composite of intubation or death in a time-to-event analysis, comparing outcomes in patients who received hydroxychloroquine with those who did not. A total of 811 patients (59%) were treated with hydroxychloroquine for a median of five days, 60% of whom also received azithromycin. After adjusting for severity of illness, the investigators found no significant difference in the rate of the composite end point of intubation or death over a median follow-up of 22.5 days. Thus, the risk of intubation or death was not significantly different among hospitalized patients with COVID-19 who received hydroxychloroquine than among those who did not [37].

Randomized, controlled clinical trials to assess efficacy of hydroxychloroquine in patients hospitalized with COVID-19 have not shown a benefit. A multicenter study of hospitalized patients with mild-to-moderate COVID-19 found that hydroxychloroquine, alone or in combination with azithromycin, was no more effective than standard care in improving clinical status at 15 days [70]. Preliminary analysis of data from a multicenter, randomized trial in the United Kingdom found no reduction in 28-day mortality among those treated with hydroxychloroquine when compared with the control group [71]. Hydroxychloroquine use was associated with increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation. An NIH-sponsored, controlled clinical trial was halted (after the fourth interim analysis) because hydroxychloroquine was found unlikely to be beneficial to hospitalized patients with COVID-19 [72]. As of November 2021, multiple randomized, controlled trials have failed to demonstrate any significant benefit for hydroxychloroquine in outpatient treatment of mild COVID-19 or as primary or secondary prophylaxis against SARS-CoV-2 infection.

On June 15, 2020, the FDA revoked the EUA that allowed for chloroquine and hydroxychloroquine donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was not available or feasible [58]. This decision was based on an ongoing analysis of emerging data indicating that these drugs are unlikely to be effective for patients hospitalized with COVID-19. As of July 2020, the NIH Panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 except in a clinical trial [57].

Ivermectin

Ivermectin is an antiparasitic drug approved by the FDA for the treatment of several tropical diseases (e.g., onchocerciasis, helminthiases, scabies) and under investigation for the prevention of malaria transmission. Ivermectin is poorly absorbed from the intestinal tract, which enhances its effectiveness against parasitic infections confined largely to the intestinal tracts of humans and large mammals (e.g., sheep, cattle, horses). Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response. In addition, ivermectin docking may interfere with the attachment of the SARS-CoV-2 spike protein to the human cell membrane. Although ivermectin inhibits SARS-CoV-2 replication in vitro (cell culture), the effect is dose-dependent, meaning that inhibition is observed when the concentration of ivermectin is raised to a certain level. Furthermore, the ivermectin concentration required for in vitro inhibition of SARS-CoV-2 is 50 to 60 times higher than can be achieved in humans by standard oral doses of the drug. Pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.

In 2021, ivermectin dispensing by retail pharmacies increased dramatically, as did the use of available over-the-counter veterinary formulations not intended for human consumption. The number of ivermectin prescriptions dispensed in the United States increased from 3,600 per week at the pre-pandemic baseline to more than 88,000 per week in August 2021 [167]. During the same period, state poison control centers across the country reported a fivefold increase in consultations for human exposures to ivermectin [167,168]. Misuse of prescription ivermectin by excess dosage or duration can have adverse effects. Veterinary formulations intended for use in horses and cattle are often highly concentrated and unsafe for ingestion by humans. Clinical signs of ivermectin toxicity include gastrointestinal upset, confusion, ataxia, hypotension, disturbances of vision, hallucinations, seizures, and coma.

Ivermectin is not authorized or approved by FDA for prevention or treatment of COVID-19. Clinical studies regarding the use of ivermectin to treat or prevent COVID-19 have been conflicting, and many studies had incomplete information and significant methodological limitations. Among 400 patients with mild COVID-19, a double-blind, randomized, placebo-controlled trial of ivermectin 300 mg/kg twice daily for five days found that ivermectin had no significant effect on time to resolution of symptoms compared with placebo [169]. A larger, double-blind, randomized, placebo-controlled trial of early ivermectin treatment for COVID-19 (679 patients in each comparator group) found that ivermectin did not lower incidence of admission to hospital (progression of disease) or duration of time required for emergency department observation [170]. In a randomized, placebo-controlled trial among patients hospitalized with mild-to-moderate COVID-19, treatment with ivermectin on admission had no beneficial effect on the rate of disease progression (21.6%) compared with standard care (17.3%) [171]. The rates of COVID-19-associated ICU admission, mechanical ventilation, and mortality were not significantly different for the ivermectin group than the control group. Due to the lack of reliable and accurate data, the NIH Panel does not recommend either for or against the use of ivermectin for the treatment of COVID-19 [57].

Baricitinib

In May 2022, the FDA issued an EUA for baricitinib to treat COVID-19 in hospitalized pediatric patients 2 to 17 years of age requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [175]. The recommended dosage of baricitinib under the EUA is 4 mg once daily for patients 9 years of age and older or 2 mg once daily for patients 2 to 8 years of age. Treatment should continue for 14 days or until hospital discharge, whichever occurs first [175].

Before initiating therapy, baseline glomerular filtration rate, liver enzyme level, and complete blood count should be assessed, as modifications in approach are necessary with abnormalities in any of these values. Baricitinib is not recommended for patients with active tuberculosis, who are on dialysis, have end-stage renal disease, or have acute kidney injury [175].

Other Agents

Several other approaches to antiviral therapy have been explored for the treatment of COVID-19, with poor results. The NIH guidelines for the treatment of COVID-19 recommend against the use of nitazoxanide, lopinavir/ritonavir, and other HIV protease inhibitors to manage or prevent COVID-19 outside of clinical trials [57].

Approaches to Disease Modification

Severe SARS-Cov-2 infection results in progressive interstitial-alveolar pneumonia and respiratory failure. The disease process is closely linked to activation of the innate immune system and dysregulation of adaptive immune responses, with release of proinflammatory cytokines and chemokines. Death from COVID-19 is often preceded by signs of a hyperimmune inflammatory response ("cytokine storm") that leads to ARDS, multi-organ dysfunction, and circulatory collapse. Laboratory markers of heightened inflammation include elevated C-reactive protein, ferritin, and interleukin-6. Novel approaches to disease management seek to modify disease progression and prevent or ameliorate pulmonary and systemic complications of cytokine storm, in hope of reducing mortality from COVID-19.

COVID-19 Convalescent Plasma

Passive immunization with plasma obtained from surviving patients has been used in the past to treat life-threatening infections absent specific therapy. There is emerging evidence that intravenous transfusion of convalescent plasma with high-titer antibody directed against SARS-CoV-2 is effective in reducing mortality in hospitalized patients with COVID-19 pneumonia. In a preliminary, uncontrolled case series of five critically ill Chinese patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status, including resolution of ARDS in four patients at 12 days after transfusion [27].

Convalescent plasma treatment has been widely utilized in the United States since early April 2020 under the Mayo Clinic's Expanded Access Protocol (EAP). A report from the Mayo EAP involving 35,322 registered patients found that plasma infusion is relatively safe and may reduce COVID-19 mortality when administered early after hospitalization [76]. A subset analysis showed a gradient of mortality in relation to IgG antibody levels in transfused plasma. The risk of dying from COVID-19 was lower among patients who received convalescent plasma units containing high titer anti-SARS-CoV-2 antibody than among those who received plasma containing low antibody levels. The pooled relative risk reduction among patients transfused with high antibody level plasma units versus low-level antibody plasma was 35% at 7 days and 23% at 30 days. The Mayo EAP report is an analysis of registry data and not a randomized controlled study.

On August 23, 2020, the FDA granted an EUA to COVID-19 convalescent plasma for treatment of patients hospitalized with COVID-19 [73]. This decision was based on historical evidence derived from the use of plasma in prior outbreaks of respiratory virus infection, small case series, and non-randomized clinical trials conducted during the current outbreak. As of December 2020, the only double-blind, placebo-controlled clinical trial of convalescent plasma did not demonstrate a reduction in mortality or improvement in other clinical outcomes [93]. In this study, 333 patients with severe COVID-19 pneumonia were randomized in a 2:1 ratio to receive convalescent plasma (228 subjects) or placebo (105 subjects). Of the total, 68% were men and 65% had a coexisting condition at entry into the trial. The median time from onset of COVID-19 symptoms to enrollment was eight days. More than 90% were receiving oxygen and glucocorticoids at the time of entry into the trial. The infused convalescent plasma had a median titer of 1:3,200 of total SARS-CoV-2 antibodies. At 30 days, the clinical status of patients in the convalescent plasma group did not differ significantly from that of patients in the placebo group. The proportion of ICU admissions and invasive ventilatory support requirements were similar in both groups. Overall mortality was 11.43% in the placebo group and 10.96% in the convalescent plasma group. In a subset analysis, no differences favoring convalescent plasma were noted in a group of 39 patients who received the intervention within 72 hours of symptom onset [93]. Of note, all patients in this study had signs of severe pneumonia; thus, no firm conclusion can be drawn as to the potential efficacy of COVID-19 convalescent plasma initiated earlier in the disease. At present, IDSA and NIH guidelines recommend that convalescent plasma therapy be used only in the context of a clinical trial [10,57].

Although convalescent plasma therapy has no clear benefit for hospitalized patients with COVID-19 pneumonia, treatment with high-titer convalescent plasma early in the course of illness has been shown to reduce the risk of progression to severe disease. Evidence for this comes from a randomized, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 administered to older adults within 72 hours after onset of mild COVID-19 symptoms. In the cohort of patients who received high-titer plasma therapy, 13 of 80 (16%) patients progressed to severe respiratory disease, compared with 25 of 80 patients (31%) who received placebo [109]. This corresponds to a relative risk reduction of 48%. The study population consisted of adults 75 years of age or older, or between 65 and 74 years of age with at least one coexisting condition.

The FDA provides a COVID-19 convalescent plasma fact sheet with guidance for healthcare providers [73]. Patients recovering from COVID-19 who wish to donate convalescent plasma can also find information at the FDA website [28]. Persons who have fully recovered from COVID-19 are candidates for plasma donation. COVID-19 convalescent plasma can only be collected from recovered individuals if they are eligible to donate blood. A potential donor must have had a prior diagnosis of COVID-19 documented by a laboratory test and meet other donor criteria. Complete resolution of symptoms for at least 28 days is required before an individual may donate plasma, or alternatively have had no symptoms for at least 14 days prior to donation and have a negative lab test for active COVID-19 disease [28]. Persons interested in becoming donors should contact the American Red Cross or ask the local blood center about options to donate convalescent plasma in their area.

On April 10, 2020, the FDA granted EUA for an extracorporeal blood purification system to treat adult patients with COVID-19 admitted to an ICU with confirmed or imminent respiratory failure [29]. This device filters the blood for removal of cytokines and other inflammatory mediators associated with cytokine storm, then returns filtered blood to the patient.

Monoclonal Antibody to SARS-CoV-2

Modern immunologic techniques enable the identification of pathogen-specific memory B cells and recovery of immunoglobulin genes that can be expressed to produce monoclonal antibodies [85]. The clinical application of monoclonal antibodies has been relatively safe. FDA-approved monoclonal antibody products are available to treat or prevent respiratory-syncytial virus, anthrax, and Clostridioides difficile. Several laboratories have used B cells from patients recovering from COVID-19 to produce neutralizing monoclonal antibodies to SARS-CoV-2. These antibodies are directed against surface spike glycoprotein, preventing entry of virus into host cells. Passive immunization with monoclonal antibodies has potential for preventing COVID-19 in vulnerable people and for early augmentation of the immune response (to block disease progression) in COVID-19 patients at risk for severe illness. Given the long half-life of immunoglobulin (approximately three weeks), a single infusion of monoclonal antibodies to SARS-CoV-2 should suffice for either prevention or treatment of COVID-19 [85]. In a phase 2 randomized clinical trial involving outpatients with mild or moderate COVID-19, a single infusion of bamlanivimab (a monoclonal neutralizing antibody) was associated with rapid decline in viral load and reduced need for further medical attention [94]. Subsequent COVID-related hospitalization or visit to an emergency room was required in 1.6% of patients in the monoclonal antibody group, compared with 6.3% in the placebo group.

As of March 2022, three monoclonal antibody products (bamlanivimab plus etexevemab, casirivimab plus imdevimab, and sotrovimab) have received EUAs from the FDA for the treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease. In placebo-controlled clinical trials for these agents, anti-SARS-CoV-2 monoclonal antibodies reduced the risk of hospitalization or death by 70% to 85% [57]. At present, sotrovimab is recommended over the other two products because in vitro studies indicate that only sotrovimab exhibits acceptable activity against the Omicron variant, the predominant SARS-CoV-2 variant in all regions of the United States as of May 2022 [57]. Outpatient monoclonal antibody therapy is reserved for at-risk symptomatic patients and should be administered soon after confirmation of SARS-CoV-2 infection, within 7 to 10 days of symptom onset. Patients with symptomatic COVID-19 who meet one of the following criteria are eligible for treatment:

- Body mass index >35

- Diabetes

- Chronic kidney disease

- Immunosuppressive disease or current immunosuppressive treatment

- Age 65 years or older or 55 years or older with underlying cardiovascular disease, hypertension, or chronic lung disease

Specific guidance that addresses patient selection criteria, authorized dosage, and treatment precautions, is provided at the NIH Panel website [57,96].

Dexamethasone

Preliminary results of a large multicenter therapeutic trial show that dexamethasone (a glucocorticoid) improves survival in patients hospitalized with COVID-19 who require some degree of respiratory support [63]. In this ongoing study platform, patients are randomly assigned to a group of different therapies and efficacy is assessed using a single end-point: mortality within 28 days after randomization. A total of 2,104 patients were assigned to receive dexamethasone at a dose of 6 mg daily, and 4,321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1,110 patients (25.7%) in the usual care group died within 28 days after randomization. The observed differences in mortality varied according to the level of respiratory support patients required upon entry to the study. Among patients receiving mechanical ventilation, the 28-day mortality was significantly lower in the dexamethasone group (29.3%) than that in the usual care group (41.4%). Among patients receiving supplemental oxygen without mechanical ventilation, the observed benefit was less pronounced but also significant, 23.3% in the dexamethasone group and 26.2% in the usual care group. There was no demonstrable benefit from dexamethasone treatment in patients who did not require oxygen.

The NIH Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen but not mechanical ventilation [57]. If dexamethasone is not available, equivalent doses of another glucocorticoid may be used, such as prednisone 40 mg/day or methylprednisolone 32 mg/day. Dexamethasone is the preferred glucocorticoid to use in pregnant women with COVID-19 who require respiratory support, because of the potential benefit of decreased maternal mortality and the known low risk of fetal adverse effects associated with short-course maternal dexamethasone therapy [57]. Patients receiving dexamethasone at the time of hospital discharge should be given a prescription to complete the specified 10-day course. The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen.

Potential adverse effects of glucocorticoid use include hyperglycemia and opportunistic infection. Clinicians should be aware that Strongyloides hyperinfection syndrome has been reported as a complication of modest-dose and short-duration dexamethasone regimens [75]. Patients who may be at risk are those who have previously resided in South America, the Caribbean, the Middle East, Africa, or Asia. Clinical clues to subclinical or unrecognized Strongyloides infection include peripheral eosinophilia and unexplained gram-negative bacteremia [75].

Tocilizumab

Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been used to mitigate cytokine storm syndrome associated with COVID-19. A retrospective cohort study of hospitalized patients who required ICU support found that treatment with tocilizumab was associated with reduced mortality [74]. Of 630 patients selected for analysis, 358 (57%) died—102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. The primary multivariable Cox regression analysis showed an association between receiving tocilizumab and decreased hospital-related mortality. This association was also noted among subgroups requiring mechanical ventilation and with baseline C-reactive protein of 15 mg/dL or higher. In contrast to findings from this and other observational studies of COVID-19 pneumonia, randomized clinical trials have not reported a mortality benefit from tocilizumab therapy [91]. Tocilizumab has been reported to reduce the requirement for mechanical ventilation in some patient populations, thereby alleviating the demand on ICU-level care for management of severe COVID-19. A published editorial assessment concluded that newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy [91]. As of August 2021, the NIH Panel guidelines recommend adding IV tocilizumab for the treatment of hospitalized patients with evidence of systemic inflammation and who require delivery of oxygen through a high-flow device or either noninvasive or mechanical ventilation [57]. Tocilizumab should only be used in combination with dexamethasone, as trials have shown the clinical benefit of tocilizumab was seen among patients who were receiving this agent in combination with a glucocorticoid [57]. Clinicians may consider assessing the patient's response to dexamethasone before deciding whether adding tocilizumab is necessary.

COVID-19 VACCINES

The effort to develop vaccines against coronavirus began following the 2002–2004 SARS outbreak, but was halted when SARS-CoV began to disappear from the human population. These earlier preclinical studies did clarify the antigenic target for coronavirus and laid the groundwork for current SARS-CoV-2 vaccine development. Coronaviruses encode for one large surface glycoprotein, the spike protein, which is responsible for receptor binding and membrane fusion [97]. As noted, SARS-CoV-2 spike protein binds to ACE2 receptors on host cells and facilitates release of the viral genome into the cytoplasm for replication of new virions. Antibodies that bind to the spike protein prevent attachment and neutralize the virus [97]. On the basis of these observations, the spike protein is an antigenic target for development of vaccines against SARS-CoV-2.

As of December 2020, more than 180 potential vaccines were in preclinical studies worldwide, and several candidate vaccines had entered into clinical trials designed to assess immunogenicity and safety. The range of vaccine platforms includes inactivated-virus and live-virus vaccines, recombinant protein vaccines, vectored vaccines, and novel RNA and DNA vaccines [97]. Three vaccines showed promising early results and were advanced to phase 3 clinical trials in August 2020; two are messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna, and the third is an adenovirus-vectored vaccine developed by Astra-Zeneca and the University of Oxford. Pfizer and the German company BioNTech have reported preliminary results of an ongoing phase 1 mRNA vaccine trial in 45 healthy adults 18 to 55 years of age. Participants received one of three vaccine doses (25, 100, or 250 mcg) given as two inoculations 28 days apart [64]. All participants developed an immune response. Following the second dose, antibody titers increased and serum neutralizing antibody activity was comparable to levels measured in a control panel of SARS-CoV-2 convalescent serum. Adverse events such as fatigue, myalgia, feverishness, and pain at injection site were reported in half the participants, more commonly after the second injection and at the highest dose. The study group concluded that immunogenicity and safety findings supported expansion of the trial to include older adults and advancement of this vaccine to later-stage clinical trials. In a follow-up report of 40 older adults (50% 56 to 70 years of age and 50% older than 70 years of age) administered the mRNA vaccine, the safety profile and immunogenicity were comparable to results in the younger cohort of participants [86]. Enrollment in a phase 3 trial began in late July 2020.

A report from the University of Oxford described early results of a clinical trial using a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCov-19) that expresses a full-length version of the SARS-CoV-2 spike protein [65]. In a phase 1/2 randomized controlled trial, 1,077 healthy adults received either the candidate vaccine or a meningococcal conjugate vaccine as control. Following a single dose, ChAdOx1 nCoV-19 elicited spike-specific T-cell responses that peaked on day 14 and measurable anti-spike IgG antibody by day 28. Strong humoral and cellular immune responses persisted at day 56 of the ongoing trial. Neutralizing antibody was detected in 32 (91%) of 35 participants after a single dose, and in 10 (100%) of 10 participants who received a booster dose. Adverse events such as discomfort at injection site, fever, malaise, and headache were common but mild or moderate and self-limiting. There were no serious adverse reactions. Progression into phase 2 and 3 trials is underway, recruiting older age groups with comorbidities, healthcare workers, and those at higher risk for SARS-CoV-2 exposure [65].

COVID-19 mRNA Vaccines

COVID-19 mRNA vaccine represents a new vaccine technology that has important public health advantages. The vaccine can be produced completely in vitro, which enables facile purification and rapid production of individual vaccine doses. The COVID-19 mRNA vaccine consists of a nucleoside-modified messenger RNA inside a lipid-laden nanoparticle. The vaccine mRNA encodes for SARS-CoV-2 surface spike protein. The lipid envelope not only facilitates vaccine delivery into host cells but also enhances stability and may augment the immune response. Following intramuscular inoculation, host myocytes utilize vaccine mRNA to express SARS-CoV-2 antigen on cell surfaces, which in turn elicits neutralizing antibody and cellular immune responses to SARS-CoV-2. The vaccine mRNA does not enter the host cell nucleus and cannot become part of the vaccinee's own DNA.

Preliminary results of phase 3 clinical trials demonstrate that both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines are safe and 94% to 95% effective [98,99]. In the Pfizer-BioNTech vaccine trial, 43,448 adults were randomized to receive vaccine (21,720 participants) or placebo (21,728 participants) in two doses 21 days apart [98]. The primary outcomes were safety and the incidence of symptomatic COVID-19 at least seven days after the second dose. The interim analysis included the first 170 cases of symptomatic COVID-19 diagnosed in the study population and covered a median of two months of safety data. Of the total, eight cases of COVID-19 were observed in the vaccine group and 162 cases in the placebo group. This corresponds to a vaccine efficacy of 95.0%. Vaccine efficacy was similar across subgroups defined by age, sex, race, body mass index, and coexisting medical conditions. Ten cases of severe COVID-19 occurred with onset after the first dose, of which nine were in placebo recipients. Post-vaccination reactions included mild-to-moderate localized pain at the injection site and transient systemic reactions such as fatigue, fever, and headache. Systemic reactions occurred more commonly in younger vaccine recipients (16 to 55 years of age) and after the second dose [98]. The Moderna phase 3 vaccine trial results were equally favorable [99]. In this trial, 30,420 adult participants were randomly assigned to receive either two doses of vaccine or placebo 28 days apart. Of 196 confirmed cases of symptomatic COVID-19 with onset at least 14 days after the second inoculation, 185 cases were in the placebo group and 11 in the vaccine group, a vaccine efficacy of 94.1%. Severe COVID-19, including one fatality, occurred in 30 participants, all of whom were in the placebo group. Transient local and systemic post-vaccination reactions occurred commonly; no safety concerns were identified [99]. In mid-December 2020, following independent verification of safety and efficacy data, the FDA issued an EUA to the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines for use in adults and older adolescents.

COVID-19 Adenovirus Vector Vaccine

In February 2021, Johnson and Johnson (Janssen Pharmaceuticals) received an EUA for use of the Janssen COVID-19 vaccine in adults [110]. This is a recombinant, replication-incompetent adenovirus vector vaccine encoded for the SARS-CoV-2 prefusion spike glycoprotein. Based on interim data from an international phase 3 clinical trial, a single dose of Janssen COVID-19 vaccine is highly effective in preventing COVID-19-associated hospitalization and death [110]. The phase 3 study enrolled 43,783 participants across three regions, 44% from United States, 41% from Latin America, and 15% from South Africa. One-third of the participants were older than 60 years of age and 41% had underlying chronic health conditions. At 14 days following vaccination, the Janssen vaccine was 66% effective in preventing symptomatic COVID-19. After 28 days, the vaccine was 85% effective against severe disease and 93% effective in preventing hospitalization. Among participants in South African, where 95% of COVID-19 cases were caused by the B.1.351 variant, vaccine efficacy against severe disease was 89%. There were no COVID-19 deaths in the vaccine group compared with seven in the placebo group. Vaccine administration side effects were mild-to-moderate, and adverse events were rare and manageable; no anaphylaxis was encountered [110].

COVID-19 Protein Subunit Vaccine

In July 2022, the FDA issued an EUA for the Novavax COVID-19 Vaccine, Adjuvanted for individuals 18 years of age and older [178]. The vaccine contains purified SARS-CoV-2 spike protein and Matrix-M adjuvant. The vaccine was the subject of an ongoing randomized, blinded, placebo-controlled study conducted in the United States and Mexico. The effectiveness of the vaccine was assessed in clinical trial participants 18 years of age and older who did not have evidence of SARS-CoV-2 infection through six days after receiving the second vaccine dose. Among these participants, approximately 17,200 received the vaccine and approximately 8,300 received saline placebo. Overall, the vaccine was 90.4% effective in preventing mild, moderate, or severe COVID-19, with 17 cases of COVID-19 occurring in the vaccine group and 79 cases in the placebo group [178]. No cases of moderate or severe COVID-19 were reported in participants who received the vaccine, compared with nine cases of moderate COVID-19 and four cases of severe COVID-19 reported in placebo recipients. In the subset of participants 65 years of age and older, the vaccine was 78.6% effective. However, it is important to note that the clinical trial was conducted prior to the emergence of Delta and Omicron variants [178].

Vaccine Distribution

Because initial supplies of vaccine were limited, the Advisory Committee on Immunization Practices (ACIP) and the CDC have provided interim recommendations for allocation of COVID-19 vaccines, updated January 1, 2021 [100]. The recommended plan called for prioritization of vaccine distribution based upon risk of exposure to SARS-CoV-2 and potential for severe illness. In Phase 1a, healthcare workers and residents and staff of long-term care facilities were offered vaccination. The next priority group (Phase 1b) consisted of front-line essential workers (e.g., first-responders, teachers, Postal Service employees, grocery workers) and people older than 75 years of age. In Phase 1c, vaccine was offered to persons 65 to 74 years of age and 14 to 64 years of age with high-risk conditions, and other essential workers. Phase 2 included all other persons 16 years of age and older who were not offered the vaccine in Phase 1.

The ACIP has issued interim considerations for the use of Pfizer-BioNTech, Moderna, and Janssen (Johnson & Johnson) COVID-19 vaccines, available at the CDC website [101]. This guidance includes vaccine dose, timing of second inoculation, contraindications, anticipated side effects, and COVID-19 vaccination of pregnant persons and those with underlying medical conditions. Adolescents 16 to 17 years of age were included among those initially eligible to receive the Pfizer-BioNTech COVID-19 vaccine under the EUA. Following review of efficacy and safety data in spring 2021, Pfizer mRNA COVID-19 vaccine received FDA EUA for use in adolescents 12 to 18 years of age. In November 2021, FDA issued a EUA and CDC/ACIP recommended Pfizer COVID-19 vaccine use, at reduced dosage, in children 5 to 11 years of age. Providers should counsel vaccine recipients to expect local reactions (e.g., injection site pain, swelling, erythema, localized axillary lymphadenopathy) and systemic symptoms such as fever, fatigue, headache, or myalgias. Most post-vaccination symptoms are mild-to-moderate and resolve within one to three days of onset.

Data from clinical trials indicate that it is safe to offer vaccination to persons with evidence of a prior SARS-CoV-2 infection, and the CDC recommends doing so 90 days or more after infection [101]. Interestingly, the natural immunity that follows SARS-CoV-2 infection is greatly enhanced by vaccination. In one study, anti-spike antibody titers increased more than 140-fold from peak pre-vaccine levels following a single dose of mRNA vaccine [111]. In a small cohort of persons previously infected, a single dose of vaccine was also shown to substantially increase neutralizing activity against the important SARS-CoV-2 variants circulating in the United States [112].

COVID-19 Vaccine Booster Dose

Following initial rollout in December 2020, COVID-19 vaccines were nearly 100% effective against severe disease, hospitalization, and death, and about 95% effective in preventing SARS-CoV-2 infection. Six months later, and coinciding with emergence of the Delta variant in May/June 2021, protection against severe illness and hospitalization remained strong (92% to 95%) while efficacy against infection had declined to about 70%. An analysis of reported COVID-19 hospitalizations during the period January to May 2021, during which 100 million persons were vaccinated against SARS-CoV-2, found that 600 vaccinated adults had developed breakthrough COVID-19 severe enough to require hospitalization. Of this group, 74% were older than 65 years of age and 130 died (all deaths were patients 71 to 89 years of age) [154].

In fall 2021, the CDC noted that vaccine effectiveness against SARS-CoV-2 infection and mild illness was gradually diminishing among healthcare and other frontline workers, most likely because of decreased immune protection and greater infectiousness of the Delta variant. Small clinical trials demonstrated that booster doses of COVID-19 vaccines enhanced the anti-SARS-CoV-2 immune response in participants who were immunized months earlier [155]. In response, the CDC recommended everyone 5 years of age and older receive an interval-appropriate booster after completing the initial COVID-19 vaccine series. The recommended timing is six months after completion of Pfizer or Moderna mRNA vaccination or two months after Johnson & Johnson vaccination. The choice of vaccine booster is open, meaning that one may “mix and match” dosing for booster shots. One of the two mRNA vaccines is preferred. Effective April 1, 2022, the CDC has authorized a second booster dose of COVID-19 vaccine for persons older than 50 years of age and those at high risk of severe illness because of underlying medical conditions. Updated guidance and COVID-19 vaccine schedules are provided at the CDC website.

As of April 2022, COVID-19 vaccines have been in use in the United States for 16 months; more than 560 million COVID-19 vaccine doses have been administered and 217.6 million people are fully vaccinated, comprising 65.5% of the total population and 85.3% of those 65 years of age and older [124]. About 50% of those fully vaccinated have received an interval-appropriate booster dose. Vaccine efficacy in reducing the incidence of SARS-CoV-2 infection and protecting against severe outcomes (hospitalization and death) has been demonstrated in clinical trials and confirmed by real-world observational studies. One such study, which analyzed data from a multistate hospital network comprising 7,544 patients enrolled between March 11, 2021, and January 24, 2022, found that receipt of two or three doses of COVID-19 mRNA vaccine conferred 90% protection against COVID-19-related invasive mechanical ventilation or in-hospital death [172]. Vaccine effectiveness was consistent throughout the periods of Delta and Omicron predominance; protection against mechanical ventilation and death was higher (94%) among those who received a third (booster) dose during the period of Omicron predominance.

COVID-19 Vaccine Safety

COVID-19 Vaccines and Pregnancy, Lactation, and Fertility

As noted, observational data demonstrate that pregnant persons have an increased risk of severe illness and complications from COVID-19, including ICU admission and mechanical ventilation [107]. Related concerns include the possibility that COVID-19 during pregnancy may increase the risk for adverse pregnancy outcomes (e.g., pre-eclampsia, coagulopathy, preterm birth) [101]. Any currently authorized COVID-19 vaccine can be administered to pregnant or lactating people; the ACIP does not state a product preference [101,149].

Vaccination reduces the risk of getting COVID-19 and protects patient and fetus from severe consequences. Vaccination while pregnant has the added benefit of providing transplacental maternal antibody protection to the newborn for some months after delivery. Studies show that maternal neutralizing antibodies directed against SARS-CoV-2 are present in umbilical cord blood of newborn infants and in breast milk [138].

There was no expectation that COVID-19 vaccines would pose a risk to pregnant persons or the fetus based on current knowledge of human coronaviruses and the science of COVID-19 vaccine development. The authorized COVID-19 vaccines in use are non-replicating vaccines; they do not contain intact virus and cannot cause infection in either the mother or fetus [101]. No reproductive, fetal developmental, or safety concerns were demonstrated in preclinical vaccine studies in animals, nor were any adverse pregnancy-related outcomes, including fetal outcomes, determined to be related to previous use of an adenovirus vector platform in a large-scale Ebola virus vaccine trial [101].

The CDC has three national surveillance programs in place to monitor the safety and efficacy of COVID-19 vaccination in pregnant persons [139]. As of October 25, 2021, more than 169,000 participants enrolled in the CDC v-safe Health Checker indicated they were pregnant when vaccinated against COVID-19. The COVID-19 Vaccination Registry, a subset of 5,100 participants enrolled within 30 days of vaccination, provides direct contact and detailed surveillance, including access to medical records. To date there are no reports of increased risk of pregnancy loss, adverse effects on fetal growth and development, or other safety concerns among pregnant or lactating individuals. An analysis of outcomes among registry participants vaccinated before 20 weeks' gestation found no increased risk of miscarriage in association with COVID-19 vaccine use early in pregnancy [140]. A case-control analysis of outcomes from Norwegian registries on first-trimester pregnancies also found no evidence of an increased risk for early pregnancy loss after COVID-19 vaccination [141]. In general, there is no difference in the incidence of pregnancy loss, preterm birth, delayed gestational growth, congenital abnormalities, and neonatal death among pregnant persons who have received mRNA vaccine compared with the known background incidence of these events in unvaccinated pregnant persons.

The Academy of Breastfeeding Medicine does not recommend cessation of breastfeeding for individuals who are vaccinated against COVID-19 [142]. The Academy considers it unlikely that vaccine lipid would enter the blood stream and reach breast tissue, and if it did, even less likely that either the intact nanoparticle or mRNA would transfer into milk. In the unlikely event mRNA is present in milk, it would be digested by the child and be unlikely to have any biological effects. In a study of seven breastfeeding mothers who received either Pfizer or Moderna COVID-19 vaccine, analysis of 13 samples of breastmilk obtained 4 to 48 hours after vaccination found no detectable mRNA or any other vaccine-related particles in any of the samples tested [143].

On September 14, 2021, the Society for Maternal and Fetal Health and the American College of Obstetrics and Gynecology, along with 18 other professional organizations representing nurse practitioners, nurse-midwives, pediatricians, infectious disease specialists, and public health professionals, issued a joint Statement of Strong Medical Consensus for Vaccination of Pregnant Individuals Against COVID-19 [144]:

As the leading organizations representing experts in maternal care and public health professionals that advocate and educate about vaccination, we strongly urge all pregnant individuals—along with recently pregnant, planning to become pregnant, lactating, and other eligible individuals—to be vaccinated against COVID-19.

A conversation between the patient and clinical team may assist with decisions about the selection and timing of a COVID-19 vaccine during pregnancy, though a discussion with a healthcare provider is not required before vaccination [101]. When making a decision, patient and provider should consider the level of SARS-CoV-2 community transmission, the patient's personal risk of contracting COVID-19, the risks of COVID-19 to the patient and potential risks to the fetus, the efficacy and side effects of the vaccine, and current data about the COVID-19 vaccine use during pregnancy [101]. Pregnant persons who choose to receive COVID-19 vaccine are encouraged to enroll in the CDC's v-safe registry, established to follow outcomes among people who are vaccinated [113].

Concerning infertility, there is no scientific basis for COVID-19 vaccines having any impact on fertility, and no scientific evidence that these vaccines cause sterility in either women or men. Claims that vaccine-derived antibodies directed against SARS-CoV-2 spike protein would cross-react with uterine syncytin-1 protein and cause damage to the developing trophoblast, thereby preventing embryo implantation, are unfounded. A study comparing implantation and sustained pregnancy success rates among individuals receiving frozen embryo transfer found no differences among vaccine seropositive, infection seropositive, and seronegative participants. Rates of sustained embryo implantation for seronegative, vaccine seropositive, and infection seropositive patients were 52.3%, 65.7%, and 47.4%, respectively, and were consistent with pre-COVID-19 success rates [150]. Seropositivity to the SARS-CoV-2 spike protein, derived from either vaccination or infection, had no adverse effect on embryo implantation or early pregnancy development.

There are no studies showing COVID vaccination reduces sperm concentration or motility. Among 45 volunteers for baseline and post-vaccination measure of sperm parameters, no significant differences in semen volume, sperm counts, or sperm motility were found after two doses of mRNA COVID-19 vaccine [151]. On the other hand, male sexual dysfunction and related fertility issues have been reported as potential late complications of symptomatic COVID-19 [152].

Adverse Reactions to COVID-19 mRNA Vaccines

Early side effects, such as soreness at injection site, fatigue, and headache, occur in about 50% of vaccine recipients; feverishness is less common, and all side effects usually resolve in 12 to 36 hours. Immediate, severe allergic reactions (anaphylaxis) do occur rarely within 15 minutes after injection, as with influenza vaccine. Anaphylaxis was not observed during clinical trials, in part because potential participants who had experienced reactions to vaccines were excluded. However, according to a review of SARS-CoV-2 vaccine safety, several cases of anaphylaxis associated with the Pfizer mRNA vaccine were reported following vaccination of 2 million healthcare workers in the United States [102]. For most vaccines in common use, vaccine-associated anaphylaxis has been a rare event, at about one case per million injections. The estimated risk of anaphylaxis associated with use of the Pfizer mRNA vaccine is 1 in 100,000 inoculations—10 times higher [102]. The explanation for this is unclear. One component unique to mRNA vaccines is a polyethylene glycol (PEG) 200 lipid conjugate used to stabilize the nanoparticle carrier system. PEG is a stabilizing compound commonly used in medications and other products and has been implicated in IgE-mediated reactions and recurrent anaphylaxis [102]. This has raised concern that individuals sensitized by past exposure to PEG (or its polysorbate derivative) in commercial products may be at risk of anaphylactic reactions from mRNA vaccination. Anaphylaxis is an acute allergic reaction that can lead to upper airway obstruction, bronchospasm, and circulatory collapse. Prompt recognition and treatment with epinephrine is necessary to prevent life-threatening complications.

A detailed discussion of contraindications and precautions to be observed with mRNA vaccine administration is included in the guidance provided by the CDC [101]. The history of any one of the following reactions is considered a contraindication to vaccination with either the Pfizer-BioNTech or Moderna COVID-19 vaccines [101]:

- Severe allergic reaction (e.g., anaphylaxis) after a previous dose of an mRNA vaccine or any of its components

- Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG)

- Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG)

Persons with an immediate allergic reaction to the first dose of an mRNA vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines [101]. Healthcare providers who participate in mRNA vaccine administration should be familiar with signs and symptoms of hypersensitivity reactions and have access to medications and supplies needed for assessing and managing anaphylaxis. The CDC has provided interim guidance on preparation for the potential management of anaphylaxis after COVID-19 vaccination [103].

Delayed-onset local reactions have been reported after mRNA vaccination in some individuals beginning a few days through the second week after the first dose [101,114]. The suspected cause is delayed-type or T-cell-mediated hypersensitivity, and reactions resolve within a few days. In a small series report, the recurrence rate following the second dose was less than 50% [114]. Vaccinees with only a delayed-onset local reaction (e.g., erythema, induration, pruritis) around the injection site do not have a contraindication or precaution to the second dose of vaccine. The CDC recommends these individuals receive the second dose using the same vaccine product as the first dose at the recommended interval, preferably in the opposite arm [101].

Immune Thrombotic Thrombocytopenia and Adenovirus-Vectored Vaccines

On April 13, 2021, after more than 6.8 million doses of the Janssen COVID-19 vaccine had been administered in the United States. the FDA placed a pause on use of this vaccine while the CDC investigated six reports of severe intravascular clotting events that occurred within two weeks following vaccination [127]. In these cases, a rare form of blood clot (cerebral venous sinus thrombosis) combined with thrombocytopenia was observed between the 6th and 13th day after vaccination. All cases were women 18 to 48 years of age, one of whom died. The pause was for purposes of further analysis and so health professionals could become familiar with the diagnostic and management implications. Treatment of this type of clotting disorder is different from treatment that might typically be administered to patients with thrombosis. Usually, the anticoagulant drug heparin is used to treat blood clots. However, in this setting the administration of heparin may be dangerous, and alternative therapies are needed [127]. The risk of cerebral venous thrombosis following Jenssen COVID-19 vaccination is approximately 1 in 1,000,000 vaccinees.

AstraZenica COVID-19 vaccine, the other primate adenovirus-vectored vaccine used in Europe, has also been linked to thrombotic events in vaccinees. In two separate reviews (11 cases from Germany and Austria, and 5 cases from Norway), patients presented 5 to 16 days after vaccination with thrombocytopenia and signs of vascular thrombosis at unusual sites [128,129]. In patients with one or more thrombotic events, there were 13 instances of cerebral venous thrombosis, 4 of splanchnic-vein thrombosis, 2 of pulmonary embolism, and 4 involving other sites. The patient age range was 22 to 54 years, and 13 of 16 cases were women. The timing of events and character of clinical features were similar to that observed in cases of severe autoimmune heparin-induced thrombocytopenia, suggesting an antibody-mediated thrombotic thrombocytopenia triggered by the vaccine. All patients in each series had high levels of antibodies directed against antigenic complexes of platelet factor 4 (PF4). None of the patients had previously received heparin. This disorder is thought to represent vaccine-induced immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4 [128,129].

These reports, and the action taken by the FDA and the CDC, have important implications for health professionals. The few cases among millions of vaccine doses administered indicates the incidence is rare and the risk low. The risk may be highest in women younger than 50 years of age. Vaccinees who are beyond three weeks from date of vaccination are not considered at risk for thrombotic complications. Individuals who develop any of the following new-onset symptoms within three weeks of vaccination should be evaluated for severe headache, abdominal pain, swelling or pain in the leg, chest pain, or shortness of breath. The evaluation should include a platelet count and imaging studies appropriate to clinical exam findings. Patients with thrombocytopenia and suspicion of a thrombotic event should not be treated initially with a heparin product. A diagnostic screening immunoassay for antibodies against PF4-heparin, or an enzyme-linked immunosorbent assay for antibodies against PF4-polyanion should be ordered. Hematology consultation is advisable. Potential treatment options include high-dose immunoglobulins and certain non-heparin anticoagulants [128,130].

Another rare adverse event reported after Janssen COVID-19 vaccination is Guillain-Barré syndrome (GBS). As of June 30, 2021, approximately 12.6 million doses of Janssen COVID-19 vaccine had been administered in the United States, with 100 reports of GBS with disease onset 3 to 42 days after vaccination [145]. The median age of reported cases was 57 years, and 61 were male. The GBS reporting rate for all recipients was 7.8 cases per million doses administered; among men 50 to 64 years of age, the rate is 15.6 cases per million doses [145].

Myocarditis/Pericarditis and mRNA COVID-19 Vaccines

Myocarditis and pericarditis have been reported more frequently than expected following receipt of either the Pfizer or Moderna mRNA COVID-19 vaccine, usually within seven days after the second dose of vaccine. The majority were male adolescents or young adult, and most cases were mild, responded well to treatment, and improved rapidly without evident long-term effects. Because a background level of seasonal myocarditis/pericarditis is associated with several common viral infections, at issue is whether and how many additional (excess) cases are precipitated by COVID vaccination. Following a nationwide vaccination program, a one-to-one comparison study with 800,000 subjects each in the vaccinated and control groups found that mRNA COVID-19 vaccine was associated with an excess risk of myocarditis (2.7 events per 100,000 persons) [146]. SARS-CoV-2 infection in the same time period was associated with a higher incidence of myocarditis (11 events per 100,000 persons). In a follow-up report, the estimated incidence of vaccine-associated myocarditis among males 16 to 29 years of age was 10 events per 100,000 vaccinees; among females 16 to 29 years of age, 0.3 events per 100,000 vaccinees; and among males 30 years of age of older, 2 events per 100,000 [153].

Data from a network of 40 healthcare systems (subserving 15 million people) found the risk of cardiac complications (myocarditis/pericarditis) was significantly higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination in all age groups evaluated. For example, among males 12 to 17 years of age, the incidence rate of myocarditis/pericarditis was 50 to 65 cases per 100,000 after infection, 2 to 3 cases per 100,000 after the first dose of vaccine, and 22 to 36 after the second dose; among males 18 to 29 years of age, the corresponding incidence rates (cases per 100,000) were 55 to 100 after infection, to -8 after the first and 7 to 15 after the second dose of vaccine. Among young children 5 to 11 years of age, the incidence of myocarditis/pericarditis was considerably lower. After infection, the rate was 13 to 18 cases per 100,000 among males and 5 to 11 cases per 100,000 among females; after COVID-19 vaccination, the rate was 0 to 4 cases per 100,000 among males and 0 cases among females [173]. These findings show that the risk of myocarditis/pericarditis in adolescent and young adult males is 5 to 8 times higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination.

On July 22, 2021, the ACIP reviewed updated benefit-risk analyses after Janssen and mRNA COVID-19 vaccination and concluded that the benefits of COVID-19 vaccination outweigh the risks for rare serious adverse events after COVID-19 vaccination [145]. In reaching this conclusion, the ACIP reviewed population-level considerations, including that COVID-19 cases were rising in the United States, the predominance of the highly transmissible Delta variant, and the importance of providing options for the type of COVID-19 vaccines offered in relation to epidemiologic considerations. The Department of Health and Human Services, American Academy of Pediatrics, American Heart Association, and other health professional organizations issued a joint statement concurring with the ACIP findings and recommended COVID-19 vaccination of all eligible persons [147].

DURATION OF IMMUNITY AND REINFECTION

More than two years into the COVID-19 pandemic, there is limited information on duration of immunity following SARS-CoV-2 infection and COVID-19 vaccination. Despite the scope of the pandemic and burgeoning number of COVID-19 cases, reports of reinfection were uncommon before the emergence of SARS-CoV-2 variants. Natural immunity to SARS-CoV-2 appears to be quite durable for protection against reinfection by the original infecting strain, but less robust or predictable for protection against reinfection by variant strains of the virus.

As with most viral infections, pathogen-specific IgG antibody assays in the weeks following onset of COVID-19 are useful for diagnostic purposes but not for measuring the durability of immunity provided by (unmeasured) neutralizing antibody and memory T-cell immune responses, which often persist for months to years. In a population-based study designed to assess durability of humoral immune responses to SARS-CoV-2, serum samples from 1,107 seropositive persons were collected up to four months after diagnosis of COVID-19. Antiviral Ig-antibody titers increased during the first two months and had not declined four months after infection [116]. In a longitudinal study of healthcare workers at the University of Oxford Hospitals undergoing periodic SARS-CoV-2 testing, the presence of antibodies in persons with previous asymptomatic or symptomatic COVID-19 substantially reduced the risk of reinfection [117]. Workers were offered nasopharyngeal SARS-CoV-2 PCR testing every two weeks and antibody testing at two-month intervals. Among 11,364 workers who were initially seronegative, 223 subsequently acquired SARS-CoV-2 infection, evidenced by a positive PCR. Among 1,265 workers who were seropositive, 2 subsequently developed an asymptomatic reinfection, evidenced by a positive PCR. During eight months surveillance, no symptomatic SARS-CoV-2 reinfections were detected among workers who had serologic evidence of prior SARS-CoV-2 infection [117].

Population-based studies also indicate that reinfection with SARS-CoV-2 is uncommon and occurs in less than 1% of individuals who have previously tested positive by SARS-CoV-2 PCR. Using a PCR-test data set from 4 million inhabitants of Denmark, researchers analyzed infection rates across separate surges of COVID-19 to estimate the degree of protection afforded by natural immunity against SARS-CoV-2 reinfection more than seven months later [118]. Among 11,068 persons who tested PCR-positive during the first COVID-19 surge (March to May 2020), 72 (0.65%) tested positive again during the second surge (September to December 2020). By comparison, the rate of infection among uninfected persons who became PCR-positive during the second surge was 3.27%. Thus, the estimate of protection against SARS-CoV-2 reinfection was 80.5%. However, protection against reinfection among persons older than 65 years of age was lower (47%). The authors note the limitations of this study, including absence of information about severity of infection and the possibility individuals infected during the first COVID-19 surge may have altered subsequent behavior affecting exposure risk. These estimates of protection do highlight the importance of administering SARS-CoV-2 vaccines to previously infected individuals, especially the elderly [118].

Durable protective immunity after SARS-CoV-2 infection or COVID-19 vaccination consists of a repertoire of immune responses referred to collectively as "immunological memory" [119]. Measurable components of immune memory include pathogen-specific antibody level, memory B cells, CD4+ T cells, and/or memory CD8+ T cells. Immune memory against SARS-CoV-2 provides the basis of protection against reinfection and determines the quality and duration of vaccine efficacy. An analysis of 254 blood samples from 188 COVID-19 cases, including some samples up to eight months after infection, found that substantial immune memory involving all four types of immune response was retained in 95% of subjects over the six- to eight-month period of observation [119]. Antibodies against SARS-CoV-2 spike and receptor binding domains declined over eight months, and memory B cell activity increased between one month and eight months after infection. Circulating antibody titers were not predictive of memory T-cell activity. The authors concluded that simple serologic tests for SARS-CoV-2 antibodies do not reflect the quality and durability of immune memory to the virus [119].

COVID-19 vaccines also produce durable cellular immunity against SARS-CoV-2 infection. Studies show persistence of memory B cells and strong CD4+ T cell immune responses at least six to eight months after mRNA COVID-19 vaccination [156]. Furthermore, vaccine-induced cellular immune responses impacting cell binding with SARS-CoV-2 variants are superior to infection-induced natural immunity. This may explain in part the epidemiologic evidence that COVID-19 vaccination provides greater protection against subsequent Delta variant COVID-19 than prior SARS-CoV-2 infection. An analysis of hospitalizations for COVID-19-like illness during January–September 2021 found the adjusted odds of laboratory-confirmed COVID-19 were five-fold higher among unvaccinated patients with documented previous SARS-CoV-2 infection than among mRNA COVID-19 vaccinated patients with no previous SARS-CoV-2 infection [157].

Natural immunity augmented by COVID-19 vaccination against SARS-CoV-2 may provide the strongest, most durable protection against subsequent COVID-19. In a retrospective cohort study, using data from national health registries subserving the entire population of Sweden, investigators analyzed the impact of natural immunity on risk of SARS-CoV-2 reinfection and COVID-19 hospitalization, and potential further benefit from COVID-19 vaccination (hybrid immunity). Natural immunity from SARS-CoV-2 infection was associated with a 95% lower risk of reinfection and 87% lower risk of COVID-19 hospitalization up to 20 months follow-up. One- and two-dose hybrid immunity was associated with a lower risk of SARS-CoV-2 reinfection than natural immunity up to nine months follow-up. One-dose hybrid immunity conferred a 94% lower risk of subsequent COVID-19 hospitalization than natural immunity alone, though differences in absolute numbers were small [174].

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

Beginning in January 2020, and in association with travel to and from China, cases of confirmed SARS-CoV-2 infection began to be reported from multiple countries around the world, including the United States. In the initial weeks of the outbreak, cases reported in countries outside China were occurring primarily in returning travelers who had visited Wuhan City or nearby locales in central China. Soon, however, the extent of person-to-person transmission unrelated to travel became increasingly clear from contact tracing and rapid community spread. By November 2021, 224 countries and territories around the world had been impacted by the COVID-19 pandemic, SARS-CoV-2 infections were on the increase in 53 countries, and the global case report total exceeded 250 million, with more than 5 million deaths [120].

The WHO monitors developments and tracks the progress of the epidemic, providing daily Situation Reports at its website [8]. In an effort to curb the spread of infection, the WHO and national agencies have developed public health measures and clinical criteria to guide the evaluation and management of persons with significant exposure and/or compatible illness.

Advice to the Public

The WHO has posted standard recommendations for the general public designed to reduce exposure to, and transmission of SARS-CoV-2 [11]. In addition, the CDC has developed guidelines for the public on how to best protect themselves and others [24]:

- Wash hands often with soap and water for at least 20 seconds, especially after having been in a public place or after coughing, sneezing, or blowing your nose. If soap and water are not readily available, a hand sanitizer that contains at least 60% alcohol may be used.

- Avoid touching eyes, nose, and mouth with unwashed hands.

- Avoid close contact with people who are sick, and stay home as much as possible

- Put distance (at least 6 feet) between yourself and other people.

- Cover your mouth and nose with a cloth face cover when around others (i.e., in public). Note: This recommendation does not apply to children younger than 2 years of age, persons with breathing difficulties, or those who are unable to remove the mask unassisted.

- Cover coughs and sneezes.

- Clean and disinfect frequently touched surfaces daily, including tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks.

WHO and CDC guidance on the use of a face covering, whether by prefabricated mask or fashioned from cloth, is predicated on the growing evidence that asymptomatic and presymptomatic individuals infected with SARS-CoV-2 can transmit the virus to others in close proximity [54]. Therefore, anyone out in public should consider that he or she could, unwittingly, be an agent of transmission to others. The simple act of coughing, sneezing, talking, singing, or forceful breathing can release virus-laden droplets and respiratory particles into the air and onto nearby environmental surfaces. Multi-layered cloth masks block 50% to 70% of fine droplets and particles and limit the forward spread of those not captured [104]. Although the primary function of a face covering is to prevent inadvertent transmission to others ("source control"), it may also provide a degree of barrier protection for the one wearing it. The CDC recommends wearing cloth face coverings in public settings in which other social distancing measures are difficult to maintain (e.g., grocery stores, pharmacies), especially in areas experiencing significant community-based transmission. Detailed guidance on the construction, proper usage, and cleaning of cloth face coverings is provided on the CDC website [12].

As public health restrictions are lifted, professional and social interactions in the community present more opportunities for spread of SARS-CoV-2. The risk of transmission varies in proportion to how closely a person interacts with an infected individual and for how long. In a scientific brief updated November 20, 2020, the CDC summarized the experimental and epidemiologic data supporting community masking to reduce the spread of SARS-CoV-2 and concluded that the prevention benefit of masking is derived from the combination of source control and personal protection for the mask wearer [104]. Studies confirm that wearing face masks or double-layer cloth face coverings reduces the risk of transmission for medical personnel, patients, and the general public when in social and community settings, especially when social distancing is not possible [66,67]. A CDC report of a contact investigation involving a hair salon where universal face covering was practiced is illustrative. Two stylists with COVID-19 symptoms had worked closely with 139 clients over an eight-day period before learning of the COVID-19 diagnosis, yet there was no evidence of secondary transmission [67]. None of the clients developed COVID-19 symptoms and of 67 individuals tested for SARS-CoV-2, all were negative. Both stylists and 98% of of the clients interviewed had followed posted company policy and city ordinance requiring face coverings by employees and clients in businesses providing personal care services.

The CDC issued an order, effective February 1, 2021, requiring passengers to wear a mask on all public conveyances (e.g., airplanes, ships, ferries, subways, buses, taxis, ride-shares) when traveling into, within, or out of the United States [121]. Masks are required upon entering or while on the premises of a transportation hub and when waiting, boarding, and disembarking from public conveyances. People must wear masks that completely cover the mouth and nose.

Although highly effective in preventing severe illness, hospitalization, and death, COVID-19 vaccines are not 100% effective at preventing SARS-CoV-2 breakthrough infection. Most breakthrough infections in immunized individuals are asymptomatic or mild, having little public health import unless local transmission rates are high. In order to reduce such risks, the CDC website provides updated public health recommendations for vaccinated people [131]. As of October 2021, the CDC recommends fully vaccinated persons wear a mask indoors in public if local SARS-CoV-2 transmission is sustained or high, and get tested for COVID-19 if experiencing symptoms or within five to seven days after exposure to someone with known or suspected COVID-19. Vaccinated people may resume domestic and international travel and refrain from testing before and after travel and from self-quarantine after travel [131].

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

The rapidity with which the outbreak spread locally in China provided early evidence that human-to-human transmission from close contact with persons having mild, nonspecific symptoms is the primary means by which SARS-CoV-2 spreads within the community. Epidemiologic studies suggest that infected droplet nuclei expelled during coughing, sneezing, loud talking, or singing is the primary mode of transmission. Sustained close personal contact (being within 6 feet for at least 15 minutes) with an infected person increases the risk of transmission. Limiting the time and lengthening the distance reduces the risk [87]. Recovery of replication-competent virus from the upper respiratory tract begins to decline after onset of symptoms. For patients with mild-to-moderate COVID-19, replication-competent virus has not been recovered after 10 days following symptom onset [88]. Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some patients with severe COVID-19.

Unlike the 2003 SARS-CoV, whereby replication occurred mostly in the lower respiratory tract and virus shedding is temporally associated with symptom onset, SARS-CoV-2 is characterized by high levels of replication and virus shedding was the upper respiratory tract, even during the pre-symptomatic phase of infection [38]. Newly infected individuals are most infectious one to two days before and for a few days after the onset of symptoms. This means that persons with asymptomatic and pre-symptomatic SARS-CoV-2 infection may have high viral loads in nasopharyngeal secretions that render them efficient vectors of person-to-person transmission. Therefore, a strategy for prevention that relies solely on symptom-based detection and isolation of COVID-19 cases is likely to have limited effectiveness. In a study of skilled nursing facility residents infected with SARS-CoV-2 from a healthcare worker, half were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing [15].

These considerations have important public health implications. Close personal contact implies touching and the sharing of common utensils; it is also defined by a proximity of 6–8 feet—the distance respiratory droplets travel after coughing or sneezing. As noted, the risk of infection is greatest for persons who have prolonged, unprotected close contact (i.e., within 6 feet for 15 minutes or longer) with someone recently diagnosed with SARS-CoV-2 infection, regardless of whether the patient has symptoms [89]. A CDC contact investigation demonstrated that even brief periods of unprotected close contact, if repeated and cumulative (exceeding 15 minutes) over the course of a day, significantly increases the risk [92]. This highlights the importance of avoiding congregate settings (e.g., assisted living facilities, college dormitories, family gatherings, indoor dining and bars) because of the increased likelihood of repetitive or sustained close contact. People can reduce the community spread of SARS-CoV-2 by practicing social distancing, wearing face coverings in public, and washing their hands.

On October 21, 2020, the CDC definition of "close contact" was revised for purposes of contact investigation [59]. Close contact describes someone who was within 6 feet of an infected person for a cumulative total of 15 minutes within a 24-hour period starting from two days before illness onset (or, for asymptomatic patients, two days prior to test specimen collection) until the time the patient is isolated. The cumulative 15-minute exposure refers to any combination of individual exposures (e.g., three 5-minute exposures) over a 24-hour period. Factors to consider when assessing close contact include proximity, duration of exposure, whether the individual has symptoms (as the period around onset of symptoms is associated with highest levels of viral shedding), whether the infected person was likely to generate aerosols (e.g., was coughing, shouting, singing), and other environmental factors (e.g., crowding, adequacy of ventilation, whether exposure was indoors or out of doors) [59].

Several emerging reports and epidemiologic studies indicate that children younger than 10 years of age may play only a small role in transmission of SARS-CoV-2. An investigation of 36 childhood COVID-19 cases in China found that 89% acquired the infection from exposure to an older household family member [50]. A population-based surveillance study in Iceland, drawing from a nationwide random sample, found that of 848 children younger than 10 years of age, none tested positive for SARS-CoV-2, whereas 100 of 12,232 (0.8%) adolescents and adults tested positive [51]. Contact tracing in relation to a cluster of COVID-19 among family and friends in France revealed that despite several days of potential exposure to a symptomatic pediatric case, there was no evidence of secondary transmission among 172 school contacts [52]. One possible explanation for these observations is the finding that gene expression of ACE2 in nasal epithelium is age-dependent; it is significantly lower in young children and increases as one develops into adulthood [53]. Lower ACE2 expression in children relative to adults could impact transmission dynamics and may help explain why COVID-19 is less prevalent in children.

Assumptions about childhood transmission of COVID-19 have been tempered somewhat since emergence of the highly transmissible SARS-CoV-2 Delta and Omicron variants in 2021. Compared with original strain infection, nasal and pharyngeal virus shedding is significantly higher; persons with Delta or Omicron infection are two and four times more infectious, respectively. Consequently, transmission now occurs more readily among children and from child to adult. Because most children were unvaccinated, symptomatic childhood infection has increased and with it the need for hospitalization. COVID-19-associated hospitalization rates among children and adolescents in the United States increased five-fold from June 2021 to mid-August 2021 [148]. Hospitalization rates were 10 times higher among unvaccinated than among vaccinated adolescents.

The stability of SARS-CoV-2 on environmental surfaces has been studied in an effort to assess whether surface contamination (fomites) could play a role in virus transmission. After application of aerosols containing a standard dose of SARS-CoV-2, viable virus was detected up to 72 hours on plastic and stainless steel, though the virus titer was greatly reduced; on cardboard, no viable SARS-CoV-2 was measured after 24 hours [19]. These data should be interpreted with caution, as it is unclear to what extent environmental detection of virus in much reduced titer at a given interval, experimentally, can be equated with actual risk of transmission from common environmental surfaces. In an April 2021 scientific brief, a CDC analysis of quantitative microbial risk assessment studies concluded the risk of SARS-CoV-2 infection via the fomite transmission route is less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection [122].

The public health strategy of mitigation (preventing spread within communities) has become paramount in order to decisively limit spread and blunt the COVID-19 epidemic curve, pending development and distribution of effective vaccines. These measures include the following: suspension or cancellation of events having large public gatherings, such as cinema, theatre, concerts, and collegiate and professional sports competition; closure of schools and cancellation of classes at colleges and universities; the practice of social distancing in smaller venues such as restaurants and churches; the wearing of masks or cloth face coverings at indoor commercial venues and social gatherings. By slowing the degree and pace of virus transmission, effective mitigation helps to protect those most vulnerable and to ensure that the clinical case load does not overwhelm local hospital and critical care resources.

VARIANT STRAINS OF SARS-COV-2

In late 2020, variant strains of SARS-CoV-2 began to appear in countries with high COVID-19 case rates. Widespread circulation of SARS-CoV-2 combined with spontaneous mutations in the genome increases the probability that mutations affecting transmissibility will lead to emergence of a variant strain. As indicated, the CDC’s national genomic surveillance program identifies SARS-CoV-2 variants and tracks the proportion and distribution of COVID-19 cases attributable to variants [123,124]. SARS-CoV-2 variants circulating in the United States are characterized as variants of concern (VOC) or variants of interest (VOI). In spring 2021, three VOCs accounted for 40% of COVID-19 cases in the United States: B.1.1.7, B.1.351, P.1, and California (B.1.351, 427/429) [123]. The defining characteristics of VOC include increased transmission (B.1.1.7), increased disease severity (B.1.1.7), and decreased neutralization by monoclonal antibody therapeutics (P.1, B.1.351, 427/429). By June/July 2021, these variants had been superseded by a single highly transmissible VOC: B.1.617.2 (Delta) variant [132].

Delta Variant

Compared with the original SARS-CoV-2 strain, Delta variant is more infectious, spreads faster, and causes more severe illness in unvaccinated people than previous variants [132]. First detected in December 2020, the Delta variant spread rapidly to 43 countries across six continents. In spring 2021, the COVID-19 surge in the United States had receded to the lowest point of the pandemic; the seven-day moving average of daily new cases was 12,000. By mid-July, the daily average of new cases had again surged to more than 60,000, of which 98% were caused by the SARS-CoV-2 Delta variant [132].

During the period of Delta predominance, breakthrough infection (usually asymptomatic or mild) occurred in vaccinated persons, but the majority of hospitalizations and deaths caused by Delta variant COVID-19 were in unvaccinated people. During the summer COVID-19 surge in Los Angeles County, unvaccinated individuals were five times more likely to acquire Delta variant infection and 29 times more likely to be hospitalized than persons who had been fully vaccinated [158]. The principal risk of secondary household and community transmission was also attributable to unvaccinated people, who were much more likely to become infected and thus shed the virus. Fully vaccinated individuals with breakthrough Delta infection did spread virus to others, but to a lesser degree and for a shorter period of time [132]. An investigation of virologic characteristics among healthcare workers with Delta variant breakthrough COVID-19 found that illness was uniformly mild; shedding of virus from the nose and throat was either unmeasurable or rapidly dissipated within one to three days [115].

Omicron Variant

In mid-November 2021, a new SARS-CoV-2 strain (the Omicron variant) emerged in South Africa among children, college students, and international travelers. Within 10 to 14 days’ time, cases of Omicron variant COVID-19 were identified in 50 countries, indicating a high level of transmission. Early clinical reports indicated that Omicron-associated COVID is mild (characterized mainly by nasal congestion, cough, and fatigue). with rates of hospitalization less than half that seen with the Delta variant. Cases of SARS-CoV-2 Omicron were first reported in the United States in December; by end of that month, Omicron had replaced Delta as the predominant variant and principal cause of COVID-19 in the United States [123,124].

Omicron is unique because of the number of genomic mutations and substitutions identified--50 overall and more than 30 in the spike protein, some of which are known to be associated with reduced susceptibility to monoclonal antibody therapeutics or reduced neutralization by convalescent and vaccinee sera [123]. Omicron is highly transmissible and spreads two to four times more rapidly than the original SARS-CoV-2 and Delta variant. COVID-19 cases tend to be less severe, though this can be misleading, as many patients are children or vaccinated adults, groups expected to experience mild illness. Health providers should expect the Omicron COVID-19 clinical profile to be similar to that associated with previous strains; the risk of serious illness is lower but still significant for unvaccinated persons, especially the elderly and those with underlying health conditions.

It was expected that the Omicron variant might evade immune protection gained from prior SARS-CoV-2 infection or COVID-19 vaccination. There is a three- to eightfold increased risk of Omicron reinfection among people who have had prior COVID-19. Studies show the initial two-dose mRNA vaccines (Pfizer, Moderna) lose their effectiveness against Omicron infection after four to six months (though protection against severe illness and hospitalization is largely preserved). Evasion of vaccine immunity is reversed following a booster dose in people who previously received the primary COVID-19 vaccine series; an interval-appropriate third (booster) dose increases neutralizing antibody levels 25- to 60-fold, reduces risk of breakthrough infection by 75%, and provides more than 90% protection against severe illness and hospitalization.

Rapid, wide-spread circulation has led to emergence of Omicron subvariants, one of which (BA.2) is more transmissible than the parent variant and slowly becoming the predominant version. Apart from heightened transmissibility, severity of illness appears to be unchanged and the benefit derived from previous natural and boosted vaccine immunity appears to be as robust as that against the parent variant.

The emergence of Delta and Omicron demonstrates that SARS-CoV-2 variants can impact transmission, disease severity, risk of reinfection, and vaccine efficacy. At issue is the extent to which adaptive immunity (CD4+ and CD8+ T cell responses) in COVID-19 convalescent patients and vaccinees recognize (target) conserved epitopes on SARS-CoV-2 variants of concern. Fortunately, studies to date have demonstrated that SARS-CoV-2 T cell epitopes are not appreciably affected by the mutations found in newly described variants [125,126]. Overall, CD4+ and CD8+ T cell responses in convalescing COVID-19 patients or COVID-19 mRNA vaccinees remain effective against VOC presently circulating in the United States, including Delta and Omicron variants.

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

As of May 2022, more than 82 million cases and more than 1 million deaths from COVID-19 have been reported in the United States and territories [124]. Ethnic populations appear to be disproportionately affected. The CDC monitors COVID-19 epidemiologic data and provides updated clinical guidance for healthcare providers, laboratories, health facilities, and public health professionals [124]. Included are recommendations for the evaluation of persons/patients under investigation, laboratory specimen transport, and protection of healthcare workers. Recommendations for patient assessment and care in hospitals and other healthcare facilities emphasize the importance of strict adherence to patient isolation and barrier precautions, including the proper use of personal protective equipment (PPE).

Selected materials from the CDC website, including recommendations for travelers, interim guidance for healthcare professionals, infection control, and healthcare worker safety, are reproduced in the following sections. Please note that language and/or cultural barriers may impede assessment and education on the topic, and interpreters and translated materials are recommended, when appropriate.

COVID-19 Data Tracker

The CDC website maintains a COVID-19 Data Tracker and Weekly Review [124]. This site tracks the number of reported cases of SARS-COV-2 infection in the United States, prevalence of variant strains, rates of COVID-19 hospitalization, and vaccination status of the population. As of May 15, 2022, the seven-day moving average of daily new cases was 90,337 (2.4% increase). The CDC estimates the Omicron lineage (e.g., BA.1, BA.2) accounted for 100% of new cases. The seven-day daily average of new hospitalizations was 2,698 (8.3% increase). The seven-day moving average of daily new deaths remained stable over the prior week. Overall, about 581.8 million vaccine doses have been administered and about 221 million people (66.7% of the population) is fully vaccinated. Vaccination trends by age group show that 96.9% of people 65 or older have received at least one dose and 84.9% are fully vaccinated. About 102.3 million people (46.4% of the eligible population) have received an additional or booster dose of COVID-19 vaccine [124].

The CDC Data Tracker also monitors COVID-19 vaccine effectiveness. COVID-19 case rates and deaths among fully vaccinated and unvaccinated people are reported to the CDC from multiple jurisdictions. During the recent Omicron surge, adults who were vaccinated and boosted were 7 times less likely to be hospitalized and 21 times less likely to die from COVID-19 compared with those who were unvaccinated [124].

CDC Guidance on Travel During COVID-19

The CDC provides updated information and guidance on domestic and international travel based on SARS-CoV-2 vaccination status [13]. The CDC recommends delaying travel until fully vaccinated. Both vaccinated and unvaccinated individuals who must travel should observe the following precautions [13]:

- Avoid contact with sick people.

- Avoid touching your eyes, nose, or mouth with unwashed hands.

- Wash hands often with soap and water for at least 20 seconds or use an alcohol-based hand sanitizer that contains at least 60% to 85% alcohol.

- Avoid traveling if you are sick.

- Wear a cloth face covering in terminals and other public venues.

- Cover coughs and sneezes.

- Pick up food at drive-throughs, curbside restaurant service, or stores.

Unvaccinated persons should get a SARS-CoV-2 nasopharyngeal swab test one to three days before the trip, repeat the viral test three to five days after travel and self-quarantine for seven days after travel (or 10 days if testing is omitted). Returning travelers from any destination are encouraged to observe standard precautions, monitor health, and follow state, territorial, tribal, and local recommendations or requirements after travel [13].

As of May 2022, the CDC recommends that persons who are up to date with COVID-19 vaccination can travel with low risk to themselves and others [13]. Up-to-date COVID-19 vaccination status is defined as having received the initial primary series and an interval-appropriate booster dose. Such persons can travel safely within the United States without the need for pre-travel testing or post-travel self-quarantine if they continue to take COVID-19 precautions while traveling.

Recommended Criteria to Guide Evaluation of Patients Under Investigation for COVID-19

CDC guidance specifies who should be tested for COVID-19 and encourages clinicians to use clinical judgment in determining whether a patient with signs and symptoms compatible with COVID-19 should be tested [14]. Symptoms to be considered include fever, chills, cough, sore throat, muscle aches, shortness of breath, new loss of taste or smell, and vomiting or diarrhea. As noted, SARS-CoV-2 can cause asymptomatic, pre-symptomatic, and minimally symptomatic infection, leading to virus shedding that may result in transmission to others who are particularly vulnerable to severe disease and death. Special attention should be paid to older adults and to patients with underlying conditions or immunosuppressed states. Even mild signs and symptoms of COVID-19 should be evaluated among potentially exposed healthcare personnel because of their extensive contact with vulnerable patients in healthcare settings.

The CDC has established priorities for COVID-19 diagnostic testing [14]. High priority for testing applies to hospitalized patients with compatible clinical features, healthcare facility workers and those who work in congregate living settings with symptoms, and residents in long-term care facilities (including prisons and shelters) with symptoms. Priority designation for testing applies to any person in the community with symptoms of potential COVID-19. In addition, persons without symptoms may be prioritized by health departments or clinicians for reasons such as public health monitoring, sentinel surveillance, or screening purposes.

Clinicians should work with their local and state health departments to coordinate testing through public health laboratories or work with commercial or clinical laboratories using SARS-CoV-2 diagnostic tests granted an Emergency Use Authorization by the FDA. Patients should be evaluated and discussed with public health departments on a case-by-case basis if their clinical presentation or exposure history is equivocal.

Other considerations that may guide testing include epidemiologic factors (e.g., close contact with an individual who in the past 14 days has tested positive for SARS-CoV-2) and the occurrence of local transmission or a cluster of COVID-19 within a specific community setting (e.g., nursing home, manufacturing facility) [14]. Close contact is defined as one of the following:

- Being within approximately 6 feet (2 meters), or within the room or care area, of a novel coronavirus case for a prolonged period of time while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, certified disposable N95 respirator, eye protection); close contact can include caring for, living with, visiting, or sharing a healthcare waiting area or room with a novel coronavirus case.

- Having direct contact with infectious secretions of a novel coronavirus case (e.g., being coughed on) while not wearing recommended personal protective equipment.

Any patient with fever and severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization and without alternative explanatory diagnosis (e.g., influenza) should be evaluated for COVID-19, even if no source of exposure has been identified [14].

A symptomatic patient should be provided a surgical mask and placed on respiratory isolation, preferably in an airborne isolation negative pressure room. Caregivers should observe enhanced precautions (i.e., wear gloves, gown, eye protection device [other than prescription eye glasses], and N95 respirator). For information on the management of patients with COVID-19, see https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.

Diagnostic Testing

The CDC recommends that healthcare providers should immediately notify both infection control personnel at their healthcare facility and their local or state health department in the event of a newly diagnosed or suspected case of COVID-19.

Confirmation of COVID-19 is performed using the RT-PCR assay for SARS-CoV-2 on respiratory specimens (which can include nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, or sputum) and serum. The FDA has worked to expedite the availability of tests through emergency authorization of commercial laboratories that have developed SARS-CoV-2 testing capability. Information on specimen collection, handling, and storage is available at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. After initial confirmation of COVID-19, additional testing of clinical specimens can help inform clinical management, including discharge planning. Additional guidance for collection, handling, and testing of clinical specimens is available at the CDC website [12].

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19 [15].

Interim Clinical Guidance for Management of Patients with Confirmed COVID-19

Interim clinical guidance and additional resources for clinicians caring for patients with COVID-19 is provided and updated at the CDC and NIH websites, selected aspects of which are reproduced in this section [15].

As noted, the clinical presentation of COVID-19 can range from asymptomatic to critically ill, and older patients and those with comorbidities are considered at greater risk for more severe disease. Among patients who developed severe disease, the median time to dyspnea was 5 to 8 days, the median time to ARDS was 8 to 12 days, and the median time to ICU admission was 10 to 12 days. Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, 26% to 32% of patients were admitted to the ICU [15]. Only 3% to 17% of all patients with COVID-19 develop ARDS, but this increases to 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU. Mortality among patients admitted to the ICU ranges from 39% to 72%, depending on the study [15]. The median length of hospitalization among survivors was 10 to 13 days.

Clinical management entails prompt implementation of recommended infection prevention and control measures and supportive management of complications, including advanced organ support if indicated [15]. Healthcare personnel should care for patients in an airborne infection isolation room. Isolation Precautions should be used when caring for the patient. For more detailed recommendations, see the CDC's Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. The NIH and the Infectious Diseases Society of America provide updated COVID-19 management guidelines, including specific recommendations for the use of remdesivir and dexamethasone in hospitalized patients [10,57].

Management of COVID-19 in the Ambulatory Care Setting

Patients with a mild clinical presentation may not initially require hospitalization [15]. However, clinical signs and symptoms may worsen with progression to lower respiratory tract disease in the second week of illness; all patients should be monitored closely. As noted, possible risk factors for progressing to severe illness may include, but are not limited to, older age, obesity (body mass index >35), and underlying chronic comorbidities (e.g., lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, pregnancy).

Approximately 80% of patients with symptomatic SARS-CoV-2 infection have mild COVID-19 (having no viral pneumonia or hypoxemia) and do not require medical intervention or hospitalization [57]. Such patients can be managed in the ambulatory setting. Patients with moderate COVID-19 (having signs of viral pneumonia but without hypoxemia) or severe COVID-19 (those having dyspnea, hypoxemia, or lung infiltrates) require in-person evaluation and ongoing observation for progression of pulmonary disease. It is important to identify those patients at risk for progression to severe disease and therefore candidates for early therapeutic intervention.

Several therapeutic options are now available for nonhospitalized patients with mild COVID-19 who are at risk for disease progression, including anti-SARS-CoV-2 monoclonal antibody, parenteral remdesivir, and oral anti-SARS-CoV-2 agents. Factors to consider in selecting the best treatment option for a given patient are clinical efficacy and availability of the treatment option, feasibility of parenteral administration (for remdesivir or monoclonal antibody), potential drug-drug interactions (particularly those associated with use of nirmatrelvir-ritonavir), and the local prevalence of SARS-CoV-2 VOCs [57]. As of May 2022, Omicron is the predominant SARS-CoV-2 variant and sotrovimab is the only monoclonal antibody product with acceptable activity against this variant. Administration of remdesivir requires three consecutive days of intravenous infusion. Selection of nirmatrelvir-ritonavir necessitates reviewing the patient’s concurrent medications and supplements to evaluate potential drug-drug interaction. Molnupiravir, which has a lower efficacy than the other treatment options, should only be used when other options are not available [57].

The CDC advises that the decision to monitor a patient in the inpatient or outpatient setting should be made on a case-by-case basis. Important considerations are the patient's clinical status, reliability of clinical monitoring, and need and options for home isolation to reduce risk of secondary transmission. For more information, see the CDC's Criteria to Guide Evaluation of Patients Under Investigation (PUI) for COVID-19 at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html.

The CDC recommends that for most patients with confirmed SARS-CoV-2 infection the decision to discontinue transmission-based precautions should be made using a symptom-based strategy [88]. In general, patients with mild-to-moderate COVID-19 who are not immunocompromised may discontinue isolation once five to seven days have passed since onset of illness, respiratory symptoms have improved, and at least 24 hours have passed since resolution of fever (without the use of fever-reducing medications). For patients who were asymptomatic throughout their infection, precautions may be discontinued when at least five days have passed since the date of their first positive viral diagnostic test. Symptomatic and asymptomatic persons should continue to wear a well-fitted mask (for five additional days) when around others at home and in public. Additional considerations apply to patients who have sustained severe or critical illness and to those who are significantly immunocompromised [88].

9. OTHER AVAILABLE RESOURCES

CDC Information for Healthcare Professionals about Coronavirus (COVID-19)

https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html

CDC Information for Healthcare Professionals about COVID-19 Vaccination

https://www.cdc.gov/vaccines/covid-19/index.html

CDC Coronavirus Disease 2019 (COVID-19) Resources for Health Departments

https://www.cdc.gov/coronavirus/2019-ncov/php/index.html

World Health Organization Coronavirus Disease 2019 (COVID-19) Pandemic

https://www.who.int/emergencies/diseases/novel-coronavirus-2019

Johns Hopkins University and Medicine Coronavirus Resource Center

https://coronavirus.jhu.edu

NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

https://www.covid19treatmentguidelines.nih.gov

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management

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