ABA18 • Anesthesiology - Reportable to ABA

Table of Contents

ABA18 • Anesthesiology - Reportable to ABA

How to Receive Credit

NetCE 4 Hour Course #94342 • Sepsis: Diagnosis and Management

94342 • Sepsis: Diagnosis and Management

1. INTRODUCTION AND DEFINITIONS

2. EPIDEMIOLOGY AND BURDEN OF SEPSIS

3. RISK FACTORS AND PREVENTION

4. PATHOGENESIS OF SIRS

5. PATHOPHYSIOLOGY OF SEPSIS

6. MANIFESTATIONS OF SEPSIS

7. DIAGNOSIS AND MANAGEMENT

8. PEDIATRIC CONSIDERATIONS

9. CONCLUSION

10. CASE STUDY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #98882 • Sleep Disorders

98882 • Sleep Disorders

1. INTRODUCTION

2. THE PHYSIOLOGY OF SLEEP

3. OVERVIEW OF SLEEP DISORDERS

4. INSOMNIAS

5. SLEEP-RELATED BREATHING DISORDERS

6. CENTRAL DISORDERS OF HYPERSOMNOLENCE

7. CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS

8. PARASOMNIAS

9. SLEEP-RELATED MOVEMENT DISORDERS

10. DIAGNOSING AND TREATING SLEEP DISORDERS WITH THE HELP OF AN INTERPRETER

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #90283 • Ischemic Stroke

90283 • Ischemic Stroke

1. INTRODUCTION

2. OVERVIEW OF CEREBROVASCULAR DISEASE

3. PREVENTION

4. EARLY MANAGEMENT

5. TREATMENT

6. REHABILITATION

7. SECONDARY PREVENTION: EVIDENCE-BASED RECOMMENDATIONS

8. CASE STUDY

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

ABA18 • Anesthesiology - Reportable to ABA

Patricia Lea, RN, DNP, MSEd, CCRN

John M. Leonard, MD

Teisha Phillips, RN, BSN

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

ABA18 • Anesthesiology - Reportable to ABA

Expiration Date: 05/31/2021

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.

94342 • Sepsis: Diagnosis and Management

Patricia Lea, RN, DNP, MSEd, CCRN

John M. Leonard, MD

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Severe sepsis and septic shock present the clinician with a difficult management situation. The patients are usually unstable and may rapidly progress to ARDS, MODS, and death. There are evidence-based guidelines available to assist in the diagnosis and treatment of these disorders. This course outlines some of the current recommendations and suggestions by the Society of Critical Care Medicine and other experts experienced in treating patients with these disorders.

Table of Contents

94342 • Sepsis: Diagnosis and Management

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION AND DEFINITIONS

2. EPIDEMIOLOGY AND BURDEN OF SEPSIS

3. RISK FACTORS AND PREVENTION

4. PATHOGENESIS OF SIRS

FIRST PHASE: THE LOCAL RESPONSE

SECOND PHASE: THE EARLY SYSTEMIC RESPONSE

THIRD PHASE: PROINFLAMMATORY EXCESS

FOURTH PHASE: EXCESSIVE IMMUNOSUPPRESSIVE RESPONSE

FIFTH PHASE: TRANSITION TO MODS

5. PATHOPHYSIOLOGY OF SEPSIS

MICROBE RECOGNITION

ENDOTOXINS AND OTHER BACTERIAL TOXINS

COAGULATION SYSTEM

6. MANIFESTATIONS OF SEPSIS

CARDIOVASCULAR

PULMONARY

CENTRAL NERVOUS SYSTEM

RENAL

GASTROINTESTINAL

HEPATIC

HEMATOLOGIC

7. DIAGNOSIS AND MANAGEMENT

MANAGEMENT OF SEPSIS

SUPPORTIVE THERAPY FOR SEPSIS AND SEPTIC SHOCK

SEPSIS BUNDLE

8. PEDIATRIC CONSIDERATIONS

9. CONCLUSION

10. CASE STUDY

POST-OPERATIVE DAY 3

POST-OPERATIVE DAY 5

POST-OPERATIVE DAY 8

POST-OPERATIVE DAY 10

Works Cited

Evidence-Based Practice Recommendations Citations

94342 • Sepsis: Diagnosis and Management

Education Category. Infection Control / Internal Medicine

Release Date. 06/01/2018

Expiration Date. 05/31/2021

Course Overview

Severe sepsis and septic shock present the clinician with a difficult management situation. The patients are usually unstable and may rapidly progress to ARDS, MODS, and death. There are evidence-based guidelines available to assist in the diagnosis and treatment of these disorders. This course outlines some of the current recommendations and suggestions by the Society of Critical Care Medicine and other experts experienced in treating patients with these disorders.

Audience

This course is designed for all healthcare professionals who work with patients who present with sepsis, including nurses and physicians.

Course Objective

The purpose of this course is to provide healthcare professionals with a current review and updated, evidence-based guidance for the diagnosis and management of sepsis and septic shock. The objective is to address knowledge gaps, enhance clinical skill, and enable effective strategies of collaborative care to improve patient outcomes.

Learning Objectives

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

1. Define the various stages of sepsis, and describe the history and incidence of sepsis relative to mortality.

2. Identify risk factors associated with the development and progression of sepsis.

3. Describe the pathogenesis of SIRS, including the five phases of development, and the pathophysiology of sepsis.

4. Anticipate and assess emerging organ dysfunction associated with septic shock.

5. Recognize clinical and laboratory parameters of sepsis, and implement a strategy for antimicrobial therapy and incremental resuscitation that incorporates fluids, inotrope-vasopressors, and the selective use of corticosteroids.

6. List the diagnostic criteria of suspected SIRS in the pediatric patient.

Faculty

Patricia Lea, RN, DNP, MSEd, CCRN, received a Bachelor of Science degree in Nursing in 1973 from Houston Baptist University in Houston, Texas. She returned to graduate school to complete a Master’s degree in Education, specifically Health Education, in 1996 from Baylor University in Waco, Texas, and a Doctorate in Nursing Practice in Executive Leadership in 2014 from American Sentinel University in Aurora, Colorado. Dr. Lea specializes in critical care nursing, with an emphasis on heart failure and sepsis. She started her career at the Houston Methodist Hospital in the cardiovascular ICU and opened an acute dialysis unit at what is now Baylor St. Luke’s Medical Center in the Houston Medical Center. Dr. Lea was a Cardiovascular Clinical Coordinator and Director of the Heart Failure Clinic at Hillcrest Baptist Medical Center in Waco, Texas. In 2004, Dr. Lea returned to Houston and was employed as a Senior Research Clinical Nurse Specialist at the Texas Heart Institute coordinating stem cell and cardiac stent trials. She is currently Associate Professor and Baccalaureate Program Director at the University of Texas Medical Branch School of Nursing in Galveston, Texas.

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, Patricia Lea, RN, DNP, MSEd, CCRN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

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

Shannon E. Smith, MHSC, CST, CSFA

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 AND DEFINITIONS

Sepsis is a systemic pathophysiologic and clinical syndrome caused by infection and manifest by signs of inflammation, host immune response, and organ dysfunction. The causes of sepsis are myriad, and the scope of illness is broad. Most cases of sepsis syndrome arise from bacterial infection, but certain viral (e.g., Ebola and other hemorrhagic fevers) and fungal (e.g., candidiasis, histoplasmosis) infections induce a sepsis syndrome as well.

In simple terms, infection is the invasion of normally sterile host tissue by a microorganism; clinically, infection is recognized by the constellation of symptoms and signs that issue from the host response to the invading microorganism. Bacteremia is defined as the demonstrable presence (e.g., by culture) of viable bacteria within the general circulation.

Historically, there has been some confusion and a lack of consensus with respect to the definition of the various degrees of systemic infection and to the best way to manage the patient along the spectrum of illness and complications induced by sepsis. This lack of consensus prompted the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) to convene a conference for the purpose of agreeing on definitions for sepsis and its sequelae. The ACCP/SCCM published their definitions in 1992 [1].

A second task force, international in scope, was convened in 2001. The purpose of this conference (sponsored by the ACCP, SCCM, the European Society of Intensive Care Medicine, the American Thoracic Society, and the Surgical Infection Society) was to modify, where appropriate, the original ACCP/SCCM definitions to reflect current understanding of the pathophysiology of sepsis. Apart from recommending that the list of signs and symptoms of sepsis be expanded to reflect clinical bedside experience, the task force found insufficient evidence to support alternative definitions of sepsis [2]. This international effort has spawned the global Surviving Sepsis Campaign, comprised of 29 sponsoring clinical specialty societies that convene at regular intervals to review the clinical literature and provide evidence-based guidelines for management of severe sepsis [62,65].

According to these task forces, sepsis was defined as a systemic inflammatory response arising from known or suspected infection, leading to widespread tissue injury and manifested by two or more of the following conditions [1,2]:

- Fever (temperature greater than 38.3°C [100.6°F])

- Hypothermia (core temperature less than 36°C [96.8°F])

- Tachycardia (heart rate greater than 90 beats per minute in adults)

- Tachypnea (respiratory rate greater than 20 breaths per minute)

- Altered mental status

- Hyperventilation (partial pressure of carbon dioxide [PaCO_2] less than 32 mm Hg)

- Leukocytosis (leukocyte count greater than 12,000 cells per mm^3)

- Leukopenia (leukocyte count less than 4,000 cells per mm^3)

This emphasis on the systemic signs of inflammation as the marker for sepsis requires the recognition that other, noninfectious, pathophysiologic conditions also cause tissue injury and inflammation with systemic ramifications. Systemic inflammatory response syndrome (SIRS) includes any serious, ongoing inflammatory process resulting in end-organ damage and multisystem failure. SIRS encompasses a continuum of escalating inflammatory responses to infectious or noninfectious stimuli; end-organ dysfunction and mortality increase with each stage of the advancing inflammatory process. While sepsis is a common and important form, SIRS may also be seen in association with noninfectious insults, including trauma, burns, pancreatitis, anaphylaxis, adrenal insufficiency, pulmonary embolism, myocardial infarction, massive hemorrhage, and cardiopulmonary bypass [1,3,4].

Severe sepsis has been defined as sepsis associated with organ dysfunction and tissue hypoperfusion. Signs of tissue hypoperfusion are hypotension (systolic blood pressure <90 mm Hg or a drop in systolic pressure of >40 mm Hg), lactic acidosis, oliguria, and acute alteration in mental status. Organ dysfunction results from falling blood pressure and widespread microvascular injury caused by circulating toxic byproducts of infection and the inflammatory immune response. Common manifestations include acute lung injury, renal failure, disseminated intravascular coagulation (DIC), and laboratory signs of liver dysfunction. In clinical practice, "septic shock" (a subset of sepsis) is present when there is persistent hypotension requiring vasopressor therapy, after adequate fluid resuscitation has been administered [1,5].

In 2014, the European and American societies of critical care medicine convened a third task force (Sepsis 3) to re-examine current concepts and definitions of sepsis and septic shock in light of improved understanding of the pathobiology, epidemiology, and management of sepsis. After a synthesis of evidence, the task force determined that previous definitions (as presented by the previous task forces) are limited by an excessive focus on inflammation. The task force also concluded that the model of sepsis following a continuum through severe sepsis to shock is misleading; that the SIRS criteria have inadequate specificity and sensitivity for defining sepsis; and that the term "severe sepsis" is redundant. The Sepsis 3 report and new consensus definitions for sepsis and septic shock were published in 2016 [6]. The new Sepsis 3 definitions are intended to provide greater clarity and specificity while emphasizing the life-threatening nature of sepsis syndrome. The aim is to improve clinical recognition and achieve greater consistency in diagnosis, therapy, and clinical investigation of sepsis.

The Sepsis 3 task force emphasized that sepsis is the primary cause of death from infection and thus requires early recognition, urgent attention, and prompt treatment. Following infection, the clinical characteristics of sepsis may emerge gradually over time, shaped by the interplay of pathogen factors and host factors such as genetic determinants, age, comorbidities, and environment. Sepsis is differentiated from infection by the presence of an aberrant or dysregulated host response accompanied by organ dysfunction. Sepsis-induced organ dysfunction may be occult; therefore, its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained acute-onset organ dysfunction should thus raise the possibility of underlying infection. The clinical and biologic expression of sepsis may be modified by pre-existing illness, chronic comorbidities, medication, and interventions. Specific infections may result in organ dysfunction without generating a dysregulated systemic host response [6].

The Sepsis 3 report defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. This new definition emphasizes the loss of adaptive homeostasis in response to infection, the potential lethality of infection when any degree of organ dysfunction is present, and the importance of urgent assessment and prompt treatment. Because even modest organ dysfunction has been found to confer a mortality risk in excess of 10%, sepsis is inherently a serious condition and the term "severe sepsis" is no longer considered useful [6].

The presence and extent of organ dysfunction can be assessed with various scoring systems that rely on clinical and laboratory parameters, such as the following [6,7,62]:

- Acute lung injury: A ratio of arterial oxygen tension to fraction of inspired oxygen of 280 or less

- The presence of a metabolic acidosis (e.g., lactate >2 mmol/L)

- Oliguria: Urinary output of less than 0.5 mL/kg body weight/hour for at least two hours in a patient with a urinary catheter in place

- Coagulation abnormalities: International normalized ratio (INR) >1.5

- Thrombocytopenia: Platelet count <100,000 cells/mcL

- Elevated bilirubin: >2 mg/dL

- Acute alteration in mental status

The scoring system currently used in most critical care units is the Sequential Organ Failure Assessment (SOFA) score, which grades abnormality by organ system and accounts for clinical interventions [7]. A higher SOFA score is associated with an increased probability of mortality. Organ dysfunction can be identified by an acute change in SOFA score ≥2 points consequent to the infection [6].

Working from a model derived from a large data base, the task force was able to identify and validate a simple "bedside" clinical measure that can be used to identify which patients with suspected infection are at risk for developing sepsis, referred to as the quick SOFA (qSOFA). This measure consists of three elements:

- Respiratory rate ≥22 per minute

- Altered mentation

- Systolic blood pressure ≤100 mm Hg

Data analysis has demonstrated that patients with infection who are positive for two or more of these elements are likely to have a prolonged intensive care unit (ICU) stay (i.e., three or more days) or die in the hospital. Physicians and nurses can employ the qSOFA in the office, emergency department, or hospital ward to quickly identify which patients with an infection are on the clinical threshold of sepsis and thus at risk of further clinical deterioration. The task force suggests that positive qSOFA criteria be used to prompt clinicians to further investigate for organ dysfunction, to initiate or escalate therapy as appropriate, and to consider referral to critical care [6].

Sepsis 3 defines septic shock as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Within the clinical construct of sepsis, the patient with septic shock can be identified by the presence of the following two criteria:

- Persisting hypotension requiring vasopressors to maintain mean arterial blood pressure (MAP) ≥65 mm Hg

- Blood lactate >2 mmol/L despite adequate volume resuscitation

The hospital mortality rate for patients meeting these criteria is in excess of 40%, or four times greater than for patients with sepsis [6].

The Surviving Sepsis Campaign provides a screening tool to assist when evaluating patients in the hospital emergency department, medical/surgical/telemetry wards, or in the ICU. This may be accessed at http://www.survivingsepsis.org/Resources/Pages/Protocols-and-Checklists.aspx.

2. EPIDEMIOLOGY AND BURDEN OF SEPSIS

The first description of multiple organ failure appeared in 1973 in a discussion of three patients who died of distal organ failure that followed ruptured aortic aneurysms. Multiple organ failure was subsequently described as multiple, progressive, or sequential systems organ failure. It was noted that shock or infection alone did not cause the distal organ dysfunction. Other severe insults could set in motion an underlying reaction that would lead to widespread endothelial damage, edema resulting from increased vascular permeability, and impaired availability of oxygen [8,9,10].

Sepsis, septic shock, and multiple organ failure are major causes of morbidity and mortality in the United States, resulting in at least 800,000 hospitalizations and 250,000 deaths annually. It is estimated that 9.3% of all deaths in the United States, and nearly half of hospital deaths, are a result of sepsis, which equals the number of deaths resulting from myocardial infarction and far exceeds the mortality rates from acquired immune deficiency syndrome (AIDS) or breast cancer. The aggregate hospital cost of care for patients with septicemia totaled nearly $23.7 billion in 2013 [11,16,71].

A study of hospital emergency department visits between 1999 and 2005 found that of the 750,000 hospitalizations, more than two-thirds may have initially presented to an emergency department. Cases of suspected sepsis account for more than 570,000 emergency department visits annually. The average length of stay in the emergency department is 4.7 hours. However, more than 20% of patients with sepsis had a length of stay that exceeded six hours, resulting in a substantial burden on facilities nationwide in providing sepsis care [12,13].

The incidence of septicemia more than doubled between 1993 and 2009, increasing by an annual average of 6% [11]. Between 1993 and 2003, 8.4 million cases of sepsis and 2.4 million cases of severe sepsis were reported. The percentage of severe sepsis cases among all sepsis cases increased from 25.6% to 43.8% during the same time period [15].

The reported incidence rates of sepsis increase with advanced age. Two-thirds of all sepsis cases occur in people 65 years of age and older, with case fatality rates as high as 40% [16]. Age-adjusted rates for sepsis hospitalization and mortality increased annually by 8.2% and 5.6%, respectively, between 1993 and 2003, whereas the fatality rate decreased by 1.4% [15]. Sepsis is more common among men than women, and the fatality rate is greater in men and nonwhite populations [22].

Mortality from sepsis of gram-negative etiology is the cause of 20% to 50% of the overall total number of septic deaths. The figures are now similar for sepsis of gram-positive etiology [18]. Mortality has been reported as high as 60% in patients with underlying medical problems. Among patients who develop the complications of shock and organ failure, mortality can reach 90% [20]. Extent of organ failure contributes to the prognosis, with a greater survival rate in patients with fewer than three failing organs. The risk of death increases as each organ fails [20].

Sepsis is among the leading causes of hospitalization and ranks as the most expensive inpatient condition treated in U.S. hospitals [66]. Data from the 2008 National Hospital Discharge Survey show that the rate of hospitalization for sepsis increased from 11.8 to 24 per 10,000 population during the period 2000 through 2008 [66]. Compared with other conditions, the hospital stay for sepsis was 75% longer and the likelihood of dying during hospitalization was eight times higher. The estimated annual cost of hospitalization for sepsis and septicemia in 2008 was $14.6 billion and increasing at the rate of 11.9% each year [66].

Despite immense clinical effort and high treatment expenditures, mortality rates remain high. Those who survive often sustain permanent organ damage, some degree of physical disability, and long-term cognitive impairment [67].

3. RISK FACTORS AND PREVENTION

Evidence Based Practice Recommendation

According to the National Institute for Health and Care Excellence, risk factors for sepsis include very young (younger than 1 year) and older (older than 75 years) age; frailty; impaired immune systems and/or function; administration of chemotherapy, long-term steroids, or immunosuppressant drugs; history of surgery or other invasive procedures in the past six weeks; any breach of skin integrity; injection drug use; and indwelling lines or catheters.

https://www.nice.org.uk/guidance/ng51

Last Accessed: July 13, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Factors considered important in the development of sepsis include: inappropriate broad-spectrum antibiotic therapy; immunosuppressive treatments, such as cancer chemotherapy; invasive procedures; transplantations; fungal organisms; burns or other trauma; anatomic obstruction; intestinal ulceration; age (the very young and the very old); and progressive clinical conditions, such as malignancy, diabetes, or AIDS [24].

Healthcare-associated infections are a major cause of sepsis among severely ill patients. Increased risk of nosocomial infection is associated with the presence of underlying chronic disease, alteration in host defenses, prolonged hospital stay, and the presence of invasive catheters or monitoring devices [27]. Pulmonary, urinary tract, gastrointestinal, and wound infections predominate [28,29]. In hospitalized adult patients, the etiology of sepsis has shifted from being predominantly gram-negative nosocomial infections (Escherichia coli, Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa) to gram-positive infections (Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes). The incidence of sepsis caused by gram-positive infections has increased by 26.3% per year over the last three decades [17]. Multidrug-resistant pathogens, such as S. aureus, now account for more than half of all sepsis cases. S. aureus is singly responsible for 40% of ventilator-associated pneumonia episodes and most cases of nosocomial pneumonia [17,25]. Group B streptococcus is a leading cause of neonatal sepsis in the United States [30].

Vascular and monitoring catheters and infusion sets may become contaminated and lead to the development of nosocomial infections and sepsis. The risk of catheter-related sepsis is increased when the IV catheter is placed in a central vein, particularly if the catheter remains in place longer than three to five days or if the catheter is used for blood sampling [31]. For this reason, consideration should be given to changing the catheter and possibly the insertion site after 72 hours. The risk of contamination of arterial catheters is higher than that observed with venous catheters. Contamination can occur if the system is entered frequently for blood sampling, if the infusate remains in place for more than 48 hours, or if inflammation develops near the catheterized artery [32]. Urinary catheters left in the bladder longer than two weeks often cause infection. Therefore, increased surveillance for signs of urinary tract infections when catheters remain in place beyond a few days is necessary [33].

Central venous catheters (CVCs) are increasingly used in the pediatric population, leading to an increase in CVC-related complications. Implanted ports may be the device of choice when long indwelling times are expected, with consideration given to the patient's age and need for sedation and analgesia during the insertion procedure. Radiograph following the insertion procedure is recommended to ensure correct catheter positioning. Full sterile barrier precautions, strict protocols for catheter care, and prompt removal of the catheter when it is no longer needed are recommended to prevent infectious complications [34].

Bacterial contamination of platelet units (estimated at 1 in 1,000–3,000) results in many occurrences of transfusion-associated sepsis in the United States each year. The AABB (formerly the American Association of Blood Banks) adopted a new standard in 2004 requiring member blood banks and transfusion services to implement detection measures and limit bacterial contamination in all platelet components [35].

Patients who live with malignancy are commonly hospitalized due to infection. Immunosuppresive treatments (or the malignancy itself) can lead to severe infection, which is a frequent cause of death among cancer patients. One in six patients with sepsis has underlying disease [36].

4. PATHOGENESIS OF SIRS

The natural defense of the body to an infection, or other assault, involves a number of cellular and humoral factors. They include B and T lymphocytes, macrophages, neutrophils, platelets, tumor necrosis factor (TNF), interleukins, the coagulation factors, and probably several other products [26,37,38]. There are five rather distinct phases that describe how these biologic products work together to overcome the assault and, paradoxically, how they can interact to cause SIRS and potentially lead to critical organ failure [26,39].

FIRST PHASE: THE LOCAL RESPONSE

An infection, injury, burn, or similar process can initiate a response that causes the release of various proinflammatory mediators in the immediate area of involvement. Among others, these include the cytokines, eicosanoids, and platelet-activating factors. In an attempt to limit or ameliorate the local injury, these mediators act to remove damaged tissue, stimulate new tissue growth, and combat the spread of neoplastic cells, pathogenic organisms, and antigens. To counteract the effects of these mediators and prevent them from causing damage, the body soon produces a set of anti-inflammatory substances, such as interleukins and TNF receptors [26,39].

SECOND PHASE: THE EARLY SYSTEMIC RESPONSE

If the initial injury or insult is severe enough, the proinflammatory and anti-inflammatory mediators can appear in the systemic circulation. This may occur by direct entry into the bloodstream in the case of massive trauma, by spillover from the local site in the event of a severe infection, or by other means. The presence of these mediators in the general circulation is a sign that the local region is incapable of handling the situation and that assistance is needed. The proinflammatory response brings additional neutrophils, platelets, lymphocytes, coagulation factors, and other materials to the local site. This should eventually lead to a compensatory anti-inflammatory response that down regulates and controls the proinflammatory actions. In the typical situation, this will occur and no significant untoward effects are seen [26].

THIRD PHASE: PROINFLAMMATORY EXCESS

In some patients, control of the proinflammatory process fails to develop, resulting in a systemic reaction that produces tachycardia, abnormal body temperature, and, in time, hypotension. These are the early signs of SIRS and are thought to be due to: increased microvascular permeability with transudation into organs; platelet sludging, causing capillary blockage and ischemia; reperfusion injury; dysregulation of vasodilatory and vasoconstrictive mechanisms; and maldistribution of blood flow. Persistent hypotension and shock may supervene unless homeostasis is restored, leading to organ dysfunction or organ failure. In an acutely ill patient, altered function in more than one major organ constitutes multiple organ dysfunction syndrome (MODS). While emphasis has been placed on the role of the proinflammatory state in SIRS, an important alternative mechanism may involve an imbalance in the amount or effectiveness of proinflammatory and anti-inflammatory mediators [26].

FOURTH PHASE: EXCESSIVE IMMUNOSUPPRESSIVE RESPONSE

In some patients who survive an initial massive infection or other inflammatory process, there may be a compensatory, but excessive, anti-inflammatory response that results in immunosuppression [40]. This may explain the increased susceptibility to infection in patients with severe burns, trauma, hemorrhage, or pancreatitis. The process is thought to involve impaired monocyte function, altered T- and B-cell activity, diminished proinflammatory cytokines, and several other factors. This process can be self-limiting, and the immunosuppression can resolve without further consequences. If it does not resolve, patients may experience the final, life-threatening complication of MODS [26].

FIFTH PHASE: TRANSITION TO MODS

This phase indicates that there has been an overwhelming, dysregulated host response to the biologic insult. It can take varied forms, depending on the character and severity of critical organ failure. The progression to MODS is common in patients with late-stage SIRS and carries a high mortality risk. If the immune system cannot recover, organ failure and death may follow. In another group of patients, there may be an oscillating effect, with periods of severe inflammation, immunosuppression, and then another proinflammatory response, resulting in increased mortality rates. This has been seen in patients with severe burns, whose levels of cytokines fluctuate widely for several weeks after injury [26,38].

The nature of the insult can significantly affect the degree of local inflammation and tissue injury. The balance between the expression of pro- and anti-inflammatory mediators often determines the magnitude of early tissue injury and risk of subsequent infectious complications. High levels of the proinflammatory mediators can initiate remote organ injury as a result of organ cross talk. Organ failure and death will occur in patients in phase five unless homeostasis can be maintained and there is a balance between pro- and anti-inflammatory forces [26,41,42].

5. PATHOPHYSIOLOGY OF SEPSIS

A complex, dynamic, and bidirectional interaction occurs between pathogens and the body's immune defense mechanisms during the course of invasive infection. If the defenses are breached successfully, the result can be sepsis [20].

As noted, in the United States, the etiology of sepsis has shifted from a predominance of gram-negative bacteria to a predominance of gram-positive, drug-resistant bacteria [25]. This shift has led to a re-evaluation of basic assumptions about the pathogenesis of sepsis (e.g., there may or may not be differences in the host response to gram-negative organisms compared with the response to gram-positive organisms) [44,45]. It is important to note that discrimination between gram-negative and gram-positive organisms is based on the recovery of specific pathogens from blood or the presumed site of infection rather than from any specific immunologic criterion. In 30% to 50% of sepsis cases, the inciting organism is not identified [18,25].

MICROBE RECOGNITION

The innate immune system recognizes invading pathogens and initiates an inflammatory or septic response. Gram-positive and gram-negative bacteria activate the immune response through unique cellular constituents referred to as pattern-associated molecular patterns (PAMPs) or microbial-associated molecular patterns (because they are also common in nonpathogenic bacteria). PAMPs bind to immune system receptors called pattern recognition receptors (PRRs), which are expressed on the surface of host cells. PRRs are essential for initiating the host's immune response and regulating the adaptive immune response to infection or tissue injury, yet PRRs can also contribute to harmful systemic inflammation and tissue damage in organs [5,25].

Toll-like receptors (TLRs) are the most common class of PRRs. Each of the known TLRs has unique binding properties that allow for the differentiation between gram-negative and gram-positive bacteria. When the TLR system recognizes a pathogen, a response is generated that is both generalized (similar response to dissimilar stimuli) and specific (pathogen is recognized by multiple TLRs simultaneously). The result is an immune system response that is tailored to the pathogen [25,46]. The degree to which TLRs mediate the outcome of sepsis in individual patients is not yet fully understood [5].

TLRs can detect danger signals both inside and outside the cell [25]. TLRs induce the production of inflammasomes (multiprotein complexes) in response to the products of bacteria and damaged cells. This in turn activates caspase-1, which is important in the process of inflammation and apoptosis (a counter-regulator of the initial inflammatory response in sepsis). Caspase-1 activation is considered to be a prerequisite for an adequate immune response. Like other proinflammatory products, caspase-1 can have both positive and negative effects on the course and outcome of sepsis [5].

Nod-like receptors (NLRs) are a less well understood class of PRRs. NLRs can detect danger elements (e.g., microbial motifs, live bacteria, host-derived molecules) inside the cell [25].

ENDOTOXINS AND OTHER BACTERIAL TOXINS

Endotoxin was identified more than 100 years ago, but its potential role in the development of sepsis was not identified until 1951. Experimental studies using endotoxin reproduced some of the features of septic shock in animals, but they did not represent the features of septic shock characteristic to humans. Evidence that endotoxin might play a pathogenic role in humans was discovered accidentally in 1991, but its precise role in sepsis remains elusive. Endotoxin is often found in the blood of critically ill patients, making its measurement of limited diagnostic value. In addition, other bacterial toxins (e.g., gram-positive peptidoglycans) can induce the production of mediators associated with sepsis [18].

COAGULATION SYSTEM

The coagulation system plays an important role in the sepsis-induced inflammatory cascade. Coagulation is the inflammatory reaction to tissue injury and is activated independent of the type of microbe (e.g., gram-positive and gram-negative bacteria, viruses, fungi, or parasites). Coagulation contributes to the outcome in sepsis by down-regulating fibrinolysis and the anticoagulant systems. The collaboration between clotting and inflammation, which works to wall off damaged and infected tissues, is an important host survival strategy. Coagulation induced by inflammation can in turn contribute to further inflammation. A key to determining survival in sepsis is to limit the damage while retaining the benefits of localized clotting and controlled clearance of pathogens [5,14,47].

A continuum of coagulopathy in sepsis has been suggested, extending from the appearance of coagulation abnormalities prior to the onset of any clinical signs of sepsis to consumption of anticoagulant proteins and suppression of the fibrinolytic system. Depletion of anticoagulant and fibrinolytic factors contributes to the microvascular deposition of fibrin that is associated with organ dysfunction. Coagulation abnormalities in sepsis contribute significantly to organ dysfunction and death [5,14,48].

6. MANIFESTATIONS OF SEPSIS

Any patient with sepsis who has evidence of dysfunction in one organ in the absence of an obvious cause such as traumatic injury may have incipient dysfunction of other organs. The manifestations of sepsis may be seen in the cardiovascular, pulmonary, central nervous, renal, gastrointestinal, and hematologic systems of the body (most frequently in the lungs and circulatory system) [20].

The following signs and symptoms should not be thought of merely as the manifestations of sepsis but as clear evidence that MODS may be developing. The host response may be more important in the genesis of MODS than the specific bacterium, virus, or traumatic injury. In most patients, the extent of systemic changes corresponds to the extent of shock [19,20,49].

CARDIOVASCULAR

In addition to hypotension, a variety of other cardiovascular manifestations may be seen. Tachycardia is common. In addition, the left and right ventricles are dilated, ejection fractions are often depressed, and the Frank-Starling and diastolic pressure-volume relationships are altered [24].

Before the onset of shock, the patient's condition is usually hyperdynamic. The skin is warm and flushed, pulse volume is increased, and pulse pressure is wide. Cardiac output is typically elevated, and systemic vascular resistance (SVR) is usually decreased. Despite the increase in cardiac output, serum lactate levels are often elevated. Anaerobic metabolism occurs because of inadequate nutrient blood flow [24].

As shock sets in, SVR drops precipitously, although cardiac output continues to increase. In the later phases of shock cardiac output declines, which exacerbates the effects of hypoperfusion and allows lactate to accumulate. The decrease in cardiac output can result in a subsequent elevation of the SVR [24].

PULMONARY

Tachypnea, with a respiratory rate of more than 20 breaths per minute, is often the earliest pulmonary sign of sepsis, occurring before hypoxemia. Hypoxemia is usually present, although it may be masked by hyperventilation. The cause of hypoxemia is usually ventilation-perfusion mismatch.

As sepsis continues, marked respiratory alkalosis often ensues; PaCO_2 may be 30 mm Hg or less. The hypoxemia progresses rapidly. The result is often pulmonary edema and respiratory failure. Other pulmonary manifestations of sepsis include respiratory muscle dysfunction and bronchoconstriction. The onset of either acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension is an ominous sign [19,49,50].

CENTRAL NERVOUS SYSTEM

Altered mental status may be the most common and most overlooked manifestation of sepsis. This causes elderly patients to be at particularly high risk. Early changes include withdrawal, confusion, irritability, or agitation. In patients with severe infection, one may see disorientation, lethargy, seizures, or frank obtundation [21,50].

Eventually, symptoms and signs of encephalopathy, including nonfocal neurologic manifestations, may be seen, and some patients may become comatose. In addition, evidence of polyneuropathy, including impaired deep tendon reflexes, muscle weakness, and wasting, may be present [19,49,50].

Patients with sepsis and encephalopathy are more likely to be bacteremic and have concomitant renal and hepatic dysfunction than are patients with sepsis and normal mental status. Furthermore, the risk of death increases as the encephalopathy worsens [21].

RENAL

The renal manifestations of sepsis include oliguria and azotemia. Urinary sediment may contain red blood cells, casts, and protein. The urinary excretion of sodium may be markedly reduced (less than 20 mEq/L), and urinary osmolality may be increased (greater than 450 mOsm/kg). Protracted oliguria may reflect acute tubular necrosis, often reversible, or diffuse microvascular injury, often resulting in fixed renal failure [19,49].

GASTROINTESTINAL

Impaired motility is the most common gastrointestinal problem. Often, this manifests as abnormal gastric emptying or as a dynamic ileus. Stress ulceration is another common problem, although it may be seen less often now than in the past. There is some evidence that stress ulcers are less likely to develop when patients are given adequate fluid resuscitation, although this has not been proven conclusively [53].

HEPATIC

Large but transient elevations in serum transaminase levels may follow an episode of severe shock or hypoxemia. Less severe increases, often in association with mild-to-moderate hyperbilirubinemia, suggest focal hepatic necrosis. In the final states of sepsis, patients may have evidence of frank hepatic insufficiency, including hypoprothrombinemia, jaundice, lactic acidosis, and hypoglycemia [2,49,50].

HEMATOLOGIC

Leukocytosis, usually accompanied by a shift to the left (>10% immature cells), is the most common hematologic manifestation of sepsis. Multifactorial anemia is common in late-stage sepsis. Decreased maturity and/or survival of red blood cells may contribute to anemia. Thrombocytopenia and coagulation abnormalities (elevated prothrombin or partial thromboplastin times) are often seen in sepsis. Thrombocytopenia is more common than overt DIC in sepsis. DIC is a manifestation of advanced-stage sepsis and carries a poor prognosis [2,17,49,54,55].

7. DIAGNOSIS AND MANAGEMENT

Methods to identify critically ill patients who are likely to die as a result of sepsis have become clearer, and increased awareness that sepsis is more common and lethal than previously understood has helped to promote the development of an organized approach to care. While the early diagnosis of sepsis continues to be a challenge (primarily because a rapid, sensitive, and specific diagnostic test is lacking), research indicates that improvements in outcomes are possible when treatment protocols are applied in a timely manner [48].

As discussed, an international consortium of critical care specialty societies has worked to standardize the definition and clinical parameters of sepsis and to develop evidence-based guidelines for optimal management of sepsis and septic shock. This is an ongoing effort, the goal of which is to improve care and reduce mortality worldwide. Clinical care guidelines have been developed by the Surviving Sepsis Campaign and published by the Society of Critical Care Medicine (SCCM) in 2008, 2013, and 2016. Detailed management strategies are provided for rapid diagnostic evaluation and antimicrobial treatment, fluid resuscitation, and the use of vasopressors in septic shock [62,65,72]. Initial funding of the Surviving Sepsis Campaign was provided by the SCCM. The ongoing work and the campaign's guidelines have no direct or indirect connection to industry support. The 2016 international guideline for the management of sepsis and septic shock are available online at http://www.survivingsepsis.org/Guidelines/Pages/default.as [72].

The 2016 guideline recommendations are graded for strength ("strong" or "weak") and for quality of evidence (indicated by a letter). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system uses the letters A through D to reflect an assessment of the quality of evidence, ranging from high (A) to very low (D). As an example, it is recommended that antimicrobial therapy be initiated within three hours of the time a patient presents or as soon as possible upon recognition of sepsis (grade strong, C) and within one hour of the time there is documented hypotension (grade strong, B).

MANAGEMENT OF SEPSIS

Fluid Resuscitation and Diagnosis

The SCCM guideline emphasizes that sepsis and septic shock are medical emergencies; treatment and resuscitation should begin immediately upon recognition. Intravenous fluid resuscitation of a patient with sepsis-induced shock (defined as tissue hypoperfusion) should be initiated as soon as the hypoperfusion is recognized (i.e., not delayed pending admission to an ICU).

The principal recommendations for fluid resuscitation are [72]:

- Intravenous fluid resuscitation should be started immediately, beginning with crystalloids (grade strong, B).

- In the setting of sepsis-induced hypoperfusion, at least 30 mL/kg of intravenous crystalloid fluid should be given within the first three hours (grade strong, B),

- It is suggested that albumin be added when patients require substantial amounts of crystalloids (grade weak, C).

- Fluid resuscitation should initially target a MAP of 65 mm Hg in patients with septic shock requiring vasopressors (grade strong, B).

It is recommended that, following initial fluid resuscitation, additional fluid administration be guided by frequent reassessment of hemodynamic status. A reasonable set of treatment goals suggested for the first six hours of resuscitation are [65,72]:

- Central venous pressure of at least 8 mm Hg (12 mm Hg in mechanically ventilated patients)

- MAP of 65 mm Hg or greater

- Urine output of 0.5 mL/kg/hour or greater

- Central venous or mixed venous oxygen saturation of at least 70% or 65%, respectively

Antibiotic Therapy and Source Control

The SCCM recommends obtaining appropriate cultures before beginning antimicrobial therapy, but the process of doing so should not delay antibiotic administration. At least two sets (aerobic and anaerobic) of blood cultures should be obtained, including one drawn through any indwelling vascular catheter or device in place prior to onset of infection. Cultures from other suspected sites should be obtained as well. The guideline committee also recommends that imaging studies be performed to confirm the source of infection, assuming the patient's condition allows it [62,65,72].

Intravenous antimicrobial therapy should be started as early as possible, ideally within the first hour of recognition of sepsis or septic shock (grade strong, B). Clinical studies have shown that delay in antimicrobial therapy for serious infection and sepsis prolongs morbidity, lengthens hospital stay, and increases mortality [68]. A retrospective cohort study involving 2,731 patients with sepsis showed that initiation of antimicrobial therapy within the first hour of documented hypotension was associated with increased survival to discharge. Moreover, each hour of delay conferred an approximately 12% decreased probability of survival [69].

The initial choice of antibiotics will depend on the most likely pathogens associated with the source of infection as well as the prevalent micro-organisms in the local community and hospitals. The clinician should assess risk factors for multidrug-resistant pathogens, including prior hospitalization, health facility residence, recent antimicrobial use, and evidence of prior infection with resistant organism. The anticipated susceptibility profile of prevalent local pathogens and the ability of the antibiotic to penetrate to the source of the infection must also be considered. A combination of drugs with activity against all likely pathogens should be administered initially, but the regimen should be reassessed in light of culture results, the goal being to identify a single, narrow-spectrum antibiotic that will best control the infection [53,57]. It has been found that combining an extended-spectrum beta-lactam antibiotic (e.g., penicillins, cephalosporins) with an aminoglycoside (e.g., gentamicin) was no more effective in reducing mortality than using the beta-lactam agent alone. In addition, the combination carries an increased risk of renal damage [53,57]. A common approach is to initiate empiric therapy with a carbapenem or extended-spectrum penicillin/beta-lactamase inhibitor (e.g., ticarcillin/tazobactam) to cover gram-negative enteric bacilli and Pseudomonas, often in combination with vancomycin to cover S. aureus pending culture results.

The empirical antimicrobial regimen should be narrowed as soon as the pathogen has been identified and sensitivities are known. The duration of therapy will depend on the nature of the infection and other considerations specific to a given case. As a general rule, a 7- to 10-day course of bactericidal antimicrobial therapy is considered adequate for most serious infections associated with sepsis [72]. In the event that the syndrome is due to something other than an infectious cause, such as trauma, antibiotics should be discontinued as soon as possible.

Source control requires that a specific anatomic diagnosis of infection (e.g., skin/soft tissue infection, pyelonephritis, cholangitis, peritonitis) be identified, or excluded, as soon as possible and preferably within the first six hours after presentation. Radiographic imaging is often necessary and should be undertaken promptly as soon as the patient's condition permits and antimicrobial therapy has been administered. Source control may be achieved by percutaneous drainage of an infected cyst or abscess, debridement of infected tissue, or removal of an infected device or catheter (removal should be prompt after other vascular access has been established) [53,72]. If necessary, surgical exploration and drainage should be undertaken within 12 hours of diagnosis (grade strong, C) [65].

Vasopressors and Inotropic Therapy

If hypotension persists after intravascular volume repletion, then vasopressors may be required to restore and maintain adequate blood pressure and tissue perfusion (goal MAP ≥65 mg Hg). Such patients are considered to have the combination of vasodilation and reduced cardiac contractility, a condition best managed with a combined inotrope-vasopressor agent. In order to monitor arterial pressure accurately, it is suggested that all patients requiring vasopressors have an arterial catheter placed as soon as practical, if resources are available [72].

Historically, norepinephrine, dopamine, and epinephrine were three inotrope-vasopressor used to correct hypotension in septic shock [53]. Based on comparison studies and a meta-analysis of six randomized trials, norepinephrine is considered superior to dopamine and is now the recommended first choice for vasopressor therapy in septic shock (grade strong, B) [65,70,72]. If a second agent is needed to maintain blood pressure, epinephrine is preferred (grade 2B). Dopamine is not recommended, as there are concerns that side effects (e.g., tachyarrhythmia) may be detrimental to patients in septic shock. Low-dose dopamine should not be used for renal protection [72]. For patient safety and effectiveness, intravenous vasopressor therapy should be administered via a central venous catheter.

As an alternative second drug, or to decrease the required effective dose of norepinephrine, vasopressin (up to 0.03 units/minute) may be added to norepinephrine [62,65,72]. Vasopressin should not be administered as the initial agent in septic shock.

Phenylephrine is a pure vasopressor that may be used in very select cases of septic shock [62,65]. It reduces cardiac stroke volume, which can have deleterious effects in the patient with low cardiac output, and thus is not recommended as initial or additive therapy. Phenylephrine is reserved for the unusual case in which tachyarrhythmia limits norepinephrine use or the patient has known high cardiac output. Intravenous phenylephrine should be administered only by properly trained individuals familiar with its use [53,56,60].

Inotropic therapy may involve the use of dobutamine if the cardiac output remains low. If dobutamine is used, it should be combined with the vasopressors. All patients requiring vasopressors should have an arterial line placed for monitoring blood pressure [53,56].

Monitoring Serum Lactate

If elevated, serum lactate provides a marker of tissue hypoperfusion, and serial measurements (of lactate clearance) can be used to monitor progress in resuscitation of the patient with sepsis or early septic shock. In cases in which elevated lactate levels are used as a marker of tissue hypoperfusion, it is recommended that resuscitation efforts target serum lactate with the goal to achieve normalization as rapidly as possible (grade weak, C) [62,65,72].

Corticosteroids

Prior to the 1990s, there was evidence that the overall 28-day mortality was not impacted by the use of corticosteroids; consequently, their use was not advised. A review of studies conducted between 1992 and 2003 concluded that corticosteroids did not change the 28-day mortality in patients with sepsis and septic shock, but that the use of low-dose corticosteroids did reduce the all-cause mortality [58]. According to the 2016 guideline, corticosteroids are not recommended in adult patients with sepsis if hemodynamic stability has been achieved with fluid resuscitation and vasopressor therapy.

The patient with persistent hypotension despite fluids and vasopressors should be assessed for adrenal responsiveness and may benefit from corticosteroid therapy. If corticosteroids are to be given, the 2016 SCCM guideline suggests IV hydrocortisone at a dose of 200 mg per day, in divided doses or by continuous infusion (grade weak, D) [72]. In 2017, a multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods, all members of the SCCM and/or the European Society of Intensive Care Medicine, published a guideline for the management of corticosteroid insufficiency in critically ill patients. This group suggests using IV hydrocortisone <400 mg/day for three or more days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy. They suggest not using corticosteroids in adult patients with sepsis without shock [73].

Recombinant Human Activated Protein C

Drotrecogin alpha (activated), or recombinant human activated protein C (rhAPC), has been studied in patients with sepsis due to its antithrombotic, anti-inflammatory, and profibrinolytic properties. It was voluntarily withdrawn from the market in 2011 due to studies showing no improvement in mortality with treatment [59].

Blood Product Administration

In some cases, blood product administration may be required. The 2016 guideline recommends RBC transfusion if the hemoglobin level falls below 7.0 g/L [72]. The routine use of erythropoietin is not recommended for treatment of anemia in patients with sepsis unless other conditions are present, such as the compromise of red blood cell production induced by renal failure. Prophylactic platelet transfusion is suggested when the platelet count is <10,000/mm^3 (10 × 10^9/L) in the absence of apparent bleeding and when counts are <20,000/mm^3 (20 × 10^9/L) if the patient has a significant risk of bleeding [72].

Patients who require invasive procedures or surgery typically require a platelet count that is in excess of 50,000/mm^3[53]. The routine use of fresh frozen plasma is not recommended unless there is active bleeding or planned surgery. Direct administration of antithrombin agents for the treatment of sepsis or septic shock is not advised [53].

SUPPORTIVE THERAPY FOR SEPSIS AND SEPTIC SHOCK

Mechanical Ventilation

Patients who develop sepsis-induced acute lung injury (ALI) or ARDS may require assisted ventilation. The routine use of pulmonary artery catheters for patients with ALI/ARDS is not recommended, and it is important to remember to avoid high pressures and volumes.

The SCCM guideline committee recommends a target goal for maximum end-inspiratory plateau pressures of 30 cm H_2O and a target tidal volume of 6 mL/kg predicted body weight in adult patients with sepsis-induced ARDS (grade strong, A). In addition, the use of lower tidal volumes over higher tidal volumes is suggested for adult patients with sepsis-induced respiratory failure without ARDS [72].

Unless contraindicated, it is recommended that mechanically ventilated patients be kept with the head of the bed elevated (30–45 degrees is suggested) to limit aspiration and prevent the development of ventilator-associated pneumonia. In hospitals with advanced experience and equipment, it may be advantageous to treat patients with ARDS in a prone position if higher pressures are required and the patient's condition allows for the positional change [53,72].

A protocol for weaning patients from the ventilator should be developed for use following a successful spontaneous breathing trial. Extubation should be considered if the breathing trial is successful. A successful breathing trial is characterized by the following criteria [53]:

- Patient is arousable.

- Patient is hemodynamically stable (without vasopressor agents).

- Patient has developed no new potentially serious conditions.

- Ventilatory and end-expiratory pressure requirements are low.

- Fraction of inspired oxygen requirements are able to be safely delivered with a face mask or nasal cannula.

The SCCM recommends a conservative fluid strategy for patients with established ARDS and no evidence of tissue hypoperfusion in order to minimize fluid retention and weight gain (which have been shown to prolong mechanical ventilation and lengthen ICU stay) [72].

Sedation, Analgesia, and Neuromuscular Blockade

Sedation, whether intermittent or by continuous infusion, may be required for patients who are mechanically ventilated. In such cases, the practice of daily interruption or lightening of the sedation, preferably by established protocol, will serve to maintain the minimum degree of necessary sedation.

Neuromuscular blockade agents are sometimes used in the ICU to improve chest compliance, reduce airway pressures, and facilitate mechanical ventilation. Neuromuscular blockade agents should be used with caution in the patient with sepsis and only for brief periods, so as to avoid the risk of prolonged blockade when the drug is discontinued. The SCCM 2016 guideline suggests using neuromuscular blockade agents for 48 hours or less in adult patients with sepsis-induced ARDS and a PaO_2/FiO_2 ratio <150 mm Hg (grade weak, B).

Glucose Control

Glucose control includes a regimen of appropriate nutrition, beginning with IV glucose and advancing early to enteral feeding for the first seven days in critically ill patients with sepsis [72]. Following initial stabilization, patients with hyperglycemia should receive IV insulin therapy to reduce blood glucose levels. SCCM guidance strongly recommends that blood glucose management in ICU patients with sepsis be done by protocol [72]:

- Insulin dosing to commence when two consecutive blood glucose levels are greater than 180 mg/dL

- Target an upper blood glucose ≤180 mg/dL rather than an upper blood glucose ≤110 mg/dL (grade strong, A)

- Monitor blood glucose every one to two hours until glucose values and insulin infusion rates are stable, then every four hours while patients are receiving insulin infusions

Note: A 2009 study demonstrated more frequent episodes of hypoglycemia and higher mortality when tight glucose control was attempted in critically ill patients [63]

Bicarbonate Therapy and Deep Vein Thrombosis Prophylaxis

Bicarbonate therapy to improve hemodynamics or reduce vasopressor requirements in patients with sepsis-induced lactic acidemia is not recommended for those patients with a pH equal to or greater than 7.15 [72]. The use of bicarbonates in SIRS requires additional study.

The use of anticoagulants to prevent deep vein thrombosis (DVT) has been well studied. For patients with sepsis, the SCCM guideline committee recommends the administration of low-dose unfractionated heparin (UFH), two to three times per day, or low-molecular-weight heparin (LMWH), once daily, unless there are contraindications, such as active bleeding, thrombocytopenia, or severe coagulopathy. LMWH has been found to be superior to UFH and is preferred in high-risk patients if there are no contraindications [53,72].

When contraindications exist, other preventive measures, such as graduated compression stockings or an intermittent compression device, are recommended. In very high-risk patients, such as those who have sepsis and a history of DVT, trauma, or orthopedic surgery, a combination of both therapies is suggested [53,56].

Stress Ulcer Prophylaxis

The SCCM guideline recommends stress ulcer prophylaxis for patients with sepsis who have risk factors for gastrointestinal bleeding, using either a proton pump inhibitor or a histamine-2 antagonist. It is recommended that stress ulcer prophylaxis not be used for patients without risk factors for gastrointestinal bleeding [72].

Communication

Also included in the supportive therapy points of care is the SCCM recommendation that advance care planning, including the communication of likely outcomes and realistic goals of treatment, be discussed with patients and families [53,72]. As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because communication with patients and families is considered an essential aspect of care, it is each practitioner's responsibility to ensure that information regarding goals and potential outcomes are explained in such a way that allows for patient understanding. 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.

SEPSIS BUNDLE

Reducing mortality due to sepsis requires an organized process that guarantees early recognition and consistent application of evidence-based practice. To this end, carefully designed protocols and measurable quality indicators should be incorporated into hospital practice. Beginning in 2005, the Surviving Sepsis Campaign converted its guideline into protocols, with sets of quality indicators that could be implemented by hospitals working to improve outcomes. The Sepsis Bundles are a series of therapies that, when implemented together, have been proven to achieve better outcomes than when implemented individually [62]. In conjunction with the 2013 guideline, two bundles (resuscitation and management) were released.

In order to reflect the changes in the 2016 guideline, in 2018 the Surviving Sepsis Campaign published the Hour-1 Bundle, taking the place of the previously separate resuscitation and management bundles [62]. This new bundle emphasizes the importance of beginning resuscitation and management immediately, then escalating care seamlessly (e.g., by adding vasopressor therapy) on the basis of ongoing clinical parameters rather than waiting or extending resuscitation measures over a longer period. The Hour-1 Bundle consists of five elements that are intended to be initiated within the first hour after the time of triage in the emergency department or, if referred from another care location, from the earliest chart annotation consistent with all elements of sepsis or septic shock. The five elements are [62]:

- Measure lactate level. Re-measure if initial lactate is >2 mmol/L.

- Obtain blood cultures prior to administration of antibiotics.

- Administer broad-spectrum antibiotics.

- Rapidly administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L.

- Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain MAP ≥65 mm Hg.

More than one hour may be required for resuscitation to be completed, but initiation of resuscitation and treatment should begin immediately [62]. The Hour-1 Bundle, based on the 2016 guideline, is evidence-based and intended for use by emergency department, hospital, and ICU staff as a tool for improving the care of patients with sepsis and septic shock.

8. PEDIATRIC CONSIDERATIONS

Sepsis is the leading cause of pediatric death worldwide. In the United States alone there are 72,000 children hospitalized for sepsis annually, with a reported mortality rate of 25% [75].

In 2002, an international panel of experts met to revise the definitions of sepsis and septic shock to include and reflect the developmental stages of children and age-specific norms of vital sign and laboratory data. The panel also modified the adult criteria for SIRS and proposed dividing the pediatric population into the following six distinct age groups to account for age-specific risks [51]:

- Newborn: 0 days to 1 week of age

- Neonate: 1 week to 1 month of age

- Infant: 1 month to 1 year of age

- Toddler and preschool: 2 to 5 years of age

- School-age child: 6 to 12 years of age

- Adolescent and young adult: 13 to 17 years of age

The panel's definition of SIRS for children includes the presence of at least two of the following criteria (one of which must be abnormal temperature or leukocyte count) [51]:

- Core temperature greater than 38.5°C or less than 36°C (measured by rectal, bladder, oral, or central catheter probe). Hypothermia may indicate serious infection (especially in infants).

- Tachycardia greater than two standard deviations above normal for the child's age in the absence of external stimulus; or unexplained persistent elevation over a four-hour time period; or, for children younger than 1 year of age, bradycardia (as defined by the panel); or unexplained persistent depression over a 30-minute time period. Bradycardia is not a sign of SIRS in older children but may be a sign in the newborn.

- Mean respiratory rate greater than two standard deviations above normal for the child's age or mechanical ventilation

- Leukocyte count that is either elevated or depressed for the child's age; or greater than 10% immature neutrophils

Because many pediatric disease processes present with symptoms of tachycardia and tachypnea, a diagnosis of SIRS should not be based solely on elevated heart and respiratory rates; abnormalities in temperature or leukocyte count must be present. Biomechanical markers of inflammation (e.g., elevated sedimentation rate, C-reactive protein, interleukin-6) have not been proven specific enough to be included in the diagnostic criteria [51].

The following definitions have also been proposed for use in the pediatric population [51]:

- Sepsis: SIRS in the presence of or as a result of suspected or proven infection

- Severe sepsis: Sepsis plus cardiovascular organ dysfunction, ARDS, or two or more other organ dysfunctions (as defined by specific criteria)

- Septic shock: Sepsis plus cardiovascular organ dysfunction

The diagnosis of sepsis and impending septic shock in neonates and children should be suspected when the usual inflammatory triad of fever, tachycardia, and vasodilation is accompanied by changes in mentation. Altered mentation may manifest as inability to be aroused, inconsolable irritability, or lack of interaction with parents. Children may present with hyper- or hypothermia, signs of decreased perfusion, and/or decreased urinary output. Because children often maintain their blood pressure until they are severely ill, hypotension is not necessary for the diagnosis (as in adults), but if present, it helps confirm a suspected case of septic shock. It is also important to note that shock in children may occur long before hypotension occurs [51].

Neonatal ICU (NICU) nurses play a key role in the early recognition and prompt treatment of infection/sepsis in the newborn. A published critical care nursing guide for understanding issues of sepsis in the NICU emphasizes the following goals [74]:

- A high index of suspicion for risk of infection

- An ability to recognize signs of infection and sepsis in infants

- A low threshold for reporting related concerns to the physician or advanced practice nurse

- Being an advocate on behalf of the infant to ensure a timely assessment and prompt therapeutic intervention

Evidence Based Practice Recommendation

If a neonate with sepsis requires intravenous fluid resuscitation, the National Institute for Health and Care Excellence recommends the use of glucose-free crystalloids that contain sodium in the range 130–154 mmol/L, with a bolus of 10–20 mL/kg over less than 10 minutes.

https://www.nice.org.uk/guidance/ng51

Last Accessed: July 13, 2018

Level of Evidence: Expert Opinion/Consensus Statement

The most widely utilized guidance for management of sepsis in the pediatric age group is the 2012 Surviving Sepsis Campaign guidelines [65,75]. When the clinical diagnosis of sepsis is made in a child, best care practice calls for prompt collection of appropriate cultures, initiation of fluid resuscitation, and administration of empiric antimicrobial therapy within one hour. If hypotension supervenes, or persists, despite completion of the initial fluid resuscitation protocol, inotropic support should be started and the patient assessed and treated for adrenal insufficiency. About 25% of children with septic shock have adrenal insufficiency and will benefit from corticosteroid therapy [75].

Clinically, pediatric septic shock takes two forms. In hyperdynamic shock, the child has rapid capillary refill and bounding pulses. In hypodynamic shock, there is prolonged capillary refill, mottled cool extremities, and diminished pulses. In both types, immediate resuscitation involves maintaining necessary circulation with fluid replacement, assuring proper ventilation, and maintaining threshold heart rates. Suggested therapeutic end points include a capillary refill of less than two seconds, warm extremities, urine output greater than 1 mL/kg/hr, normal blood pressure, normal mental status, and normal pulses with no differential between peripheral and central pulses. Frequent monitoring is required as rapid changes may occur in the status of a child with sepsis [52,53].

The international consensus panel also developed criteria for MODS in the pediatric population based on scoring systems previously described in the literature. These systems include the Pediatric Logistic Organ Dysfunction score, Pediatric-MODS score, and Multiple Organ System Failure score. The panel also considered the criteria used in the open-label rhAPC study in their development of criteria for pediatric MODS [51].

The panel's goal was to identify criteria that would optimize the enrollment of children with severe sepsis in clinical studies. To that end, they specified the following [51]:

- Cardiovascular and respiratory organ dysfunction must be present (and mechanical ventilator support for respiratory failure, if used).

- Other organ dysfunctions should be monitored during clinical studies.

- The usefulness of organ dysfunction-free days as a primary end point should be confirmed.

- Documenting organ dysfunction should be achieved with a pediatric MODS scoring system.

Experts generally agree that additional evidence-based studies are needed to understand and accurately define pediatric sepsis by accounting for the physiologic variables, age-specific norms, and risk factors of this population [23,43,75].

9. CONCLUSION

Sepsis and septic shock present the clinician with a difficult management situation. Patients are usually unstable and may rapidly progress to ARDS, MODS, and death. There are several possible causes of sepsis, including traumatic injury, infections, and burns. Gram-negative and gram-positive organisms associated with nosocomial infections account for many cases. Other bacteria, viruses, fungi, and noninfectious etiologies account for the remaining [17,19]. The mortality rate from sepsis is approximately 30%, and it was the tenth leading cause of death in the United States in 2005 [22,61].

The pathophysiology of sepsis involves multiple organ systems and is often related to an abnormal proinflammatory and/or anti-inflammatory response to a bodily insult. Management includes proper antibiotic treatment plus maintenance of hydration, ventilation, and overall homeostasis.

Evidence-based practice guidelines are available to assist in the diagnosis and treatment of these disorders. This course outlines some of the current recommendations and suggestions provided by the SCCM and other experts experienced in treating patients with these disorders.

10. CASE STUDY

Patient A is a woman, 50 years of age, who was admitted to the emergency department after a motor vehicle accident. She incurred massive abdominal injuries and was transported to the emergency department unconscious and hypotensive upon arrival. She was receiving 35% O_2 via oxygen mask. Her respiratory rate was 28 breaths per minute, and lung sounds were clear bilaterally. She had a sinus tachycardia with a heart rate of 150 beats per minute. Her blood pressure was 80/45 mm Hg. The patient had a 40 pack-year history of cigarette smoking and had been taking medications to control hypertension.

She was transported via stretcher to radiology for a computed tomography scan, which revealed bleeding in the peritoneum. She was taken immediately to surgery. Following surgery, she was taken to the ICU. Three liters of Ringer's lactate had been infused in surgery. Estimated blood loss was 2500 cc, and she received 6 units of whole blood in surgery. Despite fluid resuscitation, the patient was hypotensive during much of the surgical procedure. To assess fluid management, a pulmonary artery catheter was placed while in surgery. A variety of data was obtained upon arrival to the surgical ICU.

Vital Signs

Hemodynamic Parameters

Arterial Blood Gases (ABGs)

Laboratory Values

Ventilator Settings

BP: 100/50 mm Hg

Pulse: 120 beats per minute

Respirations: 14 breaths per minute on ventilator

Temperature: 96.5°F

CVP: 5 mm Hg

PAP: 25/15 mm Hg

PAWP: 13 mm Hg

CO: 3.2

SVR: 1,100

SvO_2: 72%

pH: 7.45

PaCO_2: 36

PO_2: 80

HCO_3: 28

SaO_2: 95%

Sodium: 130

Potassium: 4.5

Chloride: 95

Glucose: 140

Hemoglobin: 11.5

Hemocrit: 35

WBC: 11,000

Rate: 14 on assist control

FiO_2: 40%

Tidal Volume: 800

BP: blood pressure; CI: cardiac index; CO: cardiac output; CVP: central venous pressure; HCO_3: bicarbonate; FiO_2: fraction of inspired oxygen; PAP: pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; PO_2: partial pressure of oxygen; SaO_2: oxygen saturation; SvO_2: venous oxygen saturation; SVR: systemic vascular resistance; WBC: white blood cells.

Patient A was hemodynamically stable following surgery. She awakened slowly and was able to be extubated and put on a 40% O_2 mask.

POST-OPERATIVE DAY 3

Three days after surgery, the patient's level of consciousness began to deteriorate. She was obtunded and only awoke when her name was called. Her skin was warm to touch and appeared flushed, and she had 4+ bounding pulses.

Vital Signs

Hemodynamic Parameters

ABGs on 40% O_2 Mask

Laboratory Values

BP: 110/72 mm Hg

Pulse: 118 beats per minute

Respirations: 28 breaths per minute

Temperature: 104°F

CVP: 6 mm Hg

PAP: 20/12 mm Hg

PAWP: 10 mm Hg

CO: 6.0

CI: 4.2

SVR: 850

SvO_2: 85%

pH: 7.48

PaCO_2: 30

PO_2: 85

SvO_2: 85%

Hemoglobin: 9.8

Hemocrit: 28.8

WBC: 25,000

Platelets: 168,000

Urine output was 15 cc per hour for the last three hours. Cultures of sputum, urine, and blood were obtained. Antibiotic therapy was initiated.

Analysis

Identify the term that best describes Patient A's condition at the present moment.

Sepsis is caused by bacteria, viruses, or fungi in the blood. It is a clinical continuum ranging from bacteremia through septicemia to septic shock. Patient A is presently displaying signs of septicemia. Her blood pressure and cardiac output are within an acceptable range. Chemical mediators are being released and causing the physiologic changes.

POST-OPERATIVE DAY 5

On the 5th post-operative day, Patient A's blood pressure dropped to 84/58 mm Hg; her respirations were 32 breaths per minute, heart rate was 130 beats per minute, and temperature was 97°F. Despite 3000 cc fluid resuscitation, Patient A's condition continued to deteriorate. She was re-intubated and connected to a ventilator.

Hemodynamic Parameters

CVP: 3 mm Hg

PAP: 15/7 mm Hg

PAWP: 5 mm Hg

CO: 3.0

CI: 1.6

SVR: 1,597

SvO_2: 68%

Analysis

List the risk factors applicable to Patient A's case.

Trauma

Cigarette smoking

Hypertension

Abdominal injuries

Multiple invasive lines

Surgery

Patient A is in what stage of septic shock? Describe the symptoms to support your answer.

Patient A is in the hypodynamic (cold) phase of septic shock. This phase is characterized by decreased cardiac output, increased SVR, hypotension, and inadequate tissue perfusion.

What are some of the causative organisms associated with sepsis in a post-operative, hospitalized patient?

Escherichia coli

Klebsiella

Enterobacter

Pseudomonas aeruginosa

Staphylococcus aureus

POST-OPERATIVE DAY 8

On post-operative day 8, Patient A's skin was cool and cyanotic, and mottling was noted in the extremities. She responded only to painful stimuli.

Vital Signs

Hemodynamic Parameters

ABGs

Laboratory Values

BP: 38/40 mm Hg

Pulse: 170 beats per minute

Respirations: 14 breaths per minute on ventilator. She is not assisting.

Temperature: 95.6°F

CVP: 6 mm Hg

PAP: 38/20 mm Hg

PAWP: 18 mm Hg

CO: 2.0

SVR: 1746

SvO_2: 48%

pH: 7.28

PaCO_2: 48

PO_2: 40

SvO_2: 52%

SaO_2: 80%

Sodium: 160

Potassium: 6.8

BUN: 48

Creatinine: 3.0

Platelets: 72,000

PT: 21

PTT: 100.5

BUN: blood urea nitrogen; PT: prothrombin time; PTT: partial thromboplastin time.

Analysis

Patient A's temperature is 95.6°F. Is this to be expected in the hypodynamic phase and why?

Yes. Hypothermia is common during the hypodynamic phase. Metabolic and myocardial activity are greatly reduced.

What is the physiologic cause of increased SVR in the hypodynamic phase?

In the hypodynamic phase, SVR is caused by decreased cardiac output and elevated serum lactate levels.

What management would be appropriate in this phase?

Afterload reduction and myocardial support are of great importance at this point. Before the use of vasodilators, cautious fluid administration with hemodynamic monitoring is essential to provide normovolemia as the vascular capacitance increases. If fluid resuscitation proves unsuccessful, the use of vasodilators in combination with a positive inotrope may be attempted.

POST-OPERATIVE DAY 10

Patient A died on the 10th post-operative day due to the complications of septic shock: renal failure and hepatic failure complicated by DIC and ARDS.

Works Cited

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2. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference.Intensive Care Med. 2003;29:530-538.

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7. Vincent JL, de Mendonça A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26(11):1793-1800.

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14. Dhainaut JF, Shorr AF, Macias WL, et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med. 2005;33(2):341-348.

15. Dombrovskiy VY, Martin AA, Jagadeeshan S, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35(5):1244-1250.

16. BMJ Group Clinical Evidence. Sepsis. Available at http://bestpractice.bmj.com/topics/en-gb/245/epidemiology. Last accessed May 15, 2018.

17. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546-1554.

18. Vincent JL, Abraham E. The last 100 years of sepsis. Am J Resp Crit Care Med. 2006;173:256-263.

19. Bone RC. Gram-negative sepsis: a dilemma of modern medicine. Clin Microbiol Rev. 1993;6(1):57-68.

20. Al-Khafaji AH. Multiple Organ Dysfunction Syndrome in Sepsis. Available at https://emedicine.medscape.com/article/169640-overview. Last accessed May 15, 2018.

21. Lamar CD, Hurley RA, Taber KH. Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci. 2011;23(3):237-241.

22. Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data. Crit Care. 2009;13:R28.

23. Carcillo JA, Fields AI, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002;30(6):1365-1378.

24. Kali A. Septic Shock. Available at https://emedicine.medscape.com/article/168402-overview. Last accessed May 15, 2018.

25. Warner EA, Moldawer LL. Using innate immunity to characterize the host response to microbial invasion in severe sepsis. Future Microbiol. 2008;3(2):177-189.

26. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996;125(8):680-687.

27. Donowitz L, Wenzel R, Joyt J. High risk of hospital acquired infections in the ICU patient. Crit Care Med. 1982;10:355-357.

28. Brown RB, Hosmer D, Chen HC, et al. A comparison of infections in different ICUs within the same hospital. Crit Care Med. 1985;13(6):472-476.

29. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32(8):470-485.

30. Anderson-Berry AL. Neonatal Sepsis. Available at https://emedicine.medscape.com/article/978352-overview. Last accessed May 15, 2018.

31. Pinilla JC, Ross DF, Martin T, Crump H. Study of the incidence of intravascular catheter infection and associated septicemia in critically ill patients. Crit Care Med. 1983;11(1):21-25.

32. Maki DG, Botticelli JT, LeRoy ML, Thielke TS. Prospective study of replacing administration sets for intravenous therapy at 48- vs 72-hour intervals: 72 hours is safe and cost-effective. JAMA. 1987;258:1777-1781.

33. Kunin CM. Detection, Prevention and Management of Urinary Tract Infections. 4th ed. Philadelphia, PA: Lea & Febiger; 1987.

34. de Jonge RCJ, Polderman KH, Gemke RJBJ. Central venous catheter use in the pediatric patient: mechanical and infectious complications. Pediatr Crit Care Med. 2005;6(3):329-339.

35. Centers for Disease Control and Prevention. Fatal bacterial infections associated with platelet transfusions—United States, 2004. MMWR. 2005;54(7):168-170.

36. Williams MD, Braun LA, Cooper LM, et al. Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Crit Care. 2004;8(5):R291-R298.

37. Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003;9(5):517-524.

38. Rubin E, Reisner HM (eds). Essentials of Rubin's Pathology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2013.

39. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997;112:235-243.

40. Cobb JP, Buchman TG, Karl IE, Hotchkiss RS. Molecular biology of multiple organ dysfunction syndrome: injury, adaptation, and apoptosis. Surg Infect. 2000;1(3):207-213.

41. Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: from bad to worse. Immunol Res. 2001;24(3):273-287.

42. Cavaillon JM, Annane D. Compartmentalization of the inflammatory response in sepsis and SIRS. J Endotoxin Res. 2006;12(3): 151-170.

43. Proulx F, Joyal JS, Mariscalco MM, Leteurtre S, Leclerc F, Lacroix J. The pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med. 2009;10(1):12-22.

44. Opal SM, Cohen J. Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med. 1999;27(8):1608-1616.

45. Moine P, Abraham E. Immunomodulation and sepsis: impact of the pathogen. Shock. 2004;22(4):297-308.

46. Feezor RJ, Oberholzer C, Baker HV, et al. Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun. 2003;71(10):5803-5813.

47. Dettenmeier P, Swindell B, Stroud M, Arkins N, Howard A. Role of activated protein C in the pathophysiology of severe sepsis. Am J Crit Care. 2003;12(6):518-526.

48. Wheeler AP. Recent developments in the diagnosis and management of severe sepsis. Chest. 2007;132:1967-1976.

49. Cunha BA (ed). Infectious Diseases in Critical Care Medicine. 3rd ed. New York, NY: CRC Press; 2009.

50. Ely EW, Kleinpell RM, Goyette RE. Advances in the understanding of clinical manifestations and therapy of severe sepsis: an update for critical care nurses. Am J Crit Care. 2003;12:120-135.

51. Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2-8.

52. Brierly J, Carillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37(2):666-688.

53. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34(1):17-60.

54. Bone RC. Diagnosing sepsis: what we need to consider today. J Crit Illness. 1996;11:658-665.

55. Mammen EF. The haematological manifestations of sepsis. J Antimicrob Chemother. 1998;41(suppl A):17-24.

56. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004;32(9):1928-1948.

57. Silbiger PM, Grozinsky S, Soares-Weiser K. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2006;1:CD003344.

58. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock.Cochrane Database Syst Rev. 2004;1:CD002243.

59. U.S. Food and Drug Administration. FDA Drug Safety Communication: Voluntary Market Withdrawal of Xigirs [Drotrecogin Alfa (Activated)] Due to Failure to Show a Survival Benefit. Available at https://www.fda.gov/Drugs/DrugSafety/ucm277114.htm. Last accessed May 15, 2018.

60. LexiComp Online. Available at http://online.lexi.com. Last accessed May 15, 2018.

61. Institute for Healthcare Improvement. Defeating Sepsis: 25 Percent by 2009. Available at http://www.ihi.org/knowledge/Pages/ImprovementStories/DefeatingSepsis25Percentby2009.aspx. Last accessed May 15, 2018.

62. Society of Critical Care Medicine. SSC Hour-1 Bundle. Available at http://www.survivingsepsis.org/Bundles. Last accessed May 25, 2018.

63. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297.

64. Flower O, Finfer S. Glucose control in ciritcally ill patients. Int Med J. 2012;42(1):4-6.

65. Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165-228.

66. Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals. NCHS Data Brief, No. 62. Hyattsville, MD: National Center for Health Statistics; 2011.

67. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794.

68. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a multicenter severe sepsis education program. JAMA. 2008;299(19):2294-2303.

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73. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I). Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078-2088.

74. Gardner SL. Sepsis in the neonate. Crit Care Nurs Clin North Am. 2009;21:121-141.

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Evidence-Based Practice Recommendations Citations

1. National Guideline Centre. Sepsis: Recognition, Diagnosis and Early Management. London: National Institute for Health and Care Excellence; 2016. Available at https://www.nice.org.uk/guidance/ng51. Last accessed July 13, 2018.

98882 • Sleep Disorders

Teisha Phillips, RN, BSN

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Sleep is one of the most vital processes of life and serves many functions, including preservation, restoration, and memory processing. Repeated disruption of the natural sleep cycle or failure to initiate sleep (i.e., sleep disorder) can lead to a sleep deficit, which in turn causes physical, mental, and emotional fatigue. This is evidenced by the fact that many individuals with a sleep disorder express a reduction in quality of life. This course will provide information regarding the physiology of sleep; the causes, risk factors, epidemiology, and physiology of a variety of sleep disorders; diagnosis, including patient history, assessment of sleep habits, physical examination, laboratory tests, and sleep studies; and treatments to improve sleep patterns, including lifestyle/behavioral change (i.e., "sleep hygiene"), medication interventions, and other treatment options for patients.

Table of Contents

98882 • Sleep Disorders

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. THE PHYSIOLOGY OF SLEEP

CIRCADIAN RHYTHMS, HOMEOSTASIS, AND THE SLEEP-WAKE CYCLE

SLEEP STAGES

3. OVERVIEW OF SLEEP DISORDERS

DSM-5 CLASSIFICATION

SLEEP STUDY TESTS

4. INSOMNIAS

CHRONIC INSOMNIA DISORDER

SHORT-TERM INSOMNIA DISORDER

5. SLEEP-RELATED BREATHING DISORDERS

OBSTRUCTIVE SLEEP APNEA SYNDROME

6. CENTRAL DISORDERS OF HYPERSOMNOLENCE

NARCOLEPSY

IDIOPATHIC HYPERSOMNIA

OTHER HYPERSOMNIAS

7. CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS

DELAYED SLEEP-WAKE PHASE DISORDER

8. PARASOMNIAS

SLEEPWALKING

9. SLEEP-RELATED MOVEMENT DISORDERS

RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER

10. DIAGNOSING AND TREATING SLEEP DISORDERS WITH THE HELP OF AN INTERPRETER

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98882 • Sleep Disorders

Education Category. Infection Control / Internal Medicine

Release Date. 01/01/2019

Expiration Date. 12/31/2021

Course Overview

Sleep is one of the most vital processes of life and serves many functions, including preservation, restoration, and memory processing. Repeated disruption of the natural sleep cycle or failure to initiate sleep (i.e., sleep disorder) can lead to a sleep deficit, which in turn causes physical, mental, and emotional fatigue. This is evidenced by the fact that many individuals with a sleep disorder express a reduction in quality of life. This course will provide information regarding the physiology of sleep; the causes, risk factors, epidemiology, and physiology of a variety of sleep disorders; diagnosis, including patient history, assessment of sleep habits, physical examination, laboratory tests, and sleep studies; and treatments to improve sleep patterns, including lifestyle/behavioral change (i.e., "sleep hygiene"), medication interventions, and other treatment options for patients.

Audience

This course is designed for all healthcare professionals, including physicians, nurses, pharmacists, and mental health practitioners, who are involved in the care of patients experiencing a sleep-related disorder.

Course Objective

Many of the complications associated with sleep disorders are preventable, making early diagnosis and appropriate treatment vital. The purpose of this course is to provide healthcare professionals with the information necessary to identify and effectively treat sleep disorders, thereby improving patients' quality of life and preventing possible complications.

Learning Objectives

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

1. Discuss the physiology of normal sleep.

2. Describe the classification of sleep disorders.

3. Compare and contrast the types of insomnias and their associated diagnosis and treatment.

4. Evaluate the major types of sleep-related breathing disorders, particularly obstructive sleep apnea.

5. Identify the clinical signs and symptoms of narcolepsy.

6. Outline the characteristics of non-narcolepsy hypersomnias.

7. Analyze the complications and symptoms of circadian rhythm sleep disorders.

8. Describe the characteristics, diagnosis, and treatment of parasomnias.

9. Evaluate the presentation and treatment of sleep-related movement disorders.

10. Assess considerations for patients with sleep disorder who have low English literacy.

Faculty

Teisha Phillips, RN, BSN, received her Bachelor of Science in Nursing degree from Point Loma Nazarene University in 2005. She has nursing experience in a variety of clinical settings including multispecialty outpatient surgery, fertility, women's health, and cosmetic/aesthetic nursing. Her primary focus and passion is on direct patient care and patient education. She is presently employed as a perioperative nurse at an outpatient surgery center in the greater Sacramento area.

Faculty Disclosure

Contributing faculty, Teisha Phillips, RN, BSN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

James Trent, 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

Sleep is one of the most vital processes of life and serves many important functions, including preservation, restoration, and memory processing. Repeated disruption of the natural sleep cycle or failure to initiate sleep (i.e., sleep disorder) can lead to a sleep deficit, which in turn causes physical, mental, and emotional fatigue. Most individuals with a sleep disorder experience a myriad of symptoms and a reduction in quality of life [1].

The American Academy of Sleep Medicine (AASM) publication The International Classification of Sleep Disorders, Third Edition (ICSD-3) identifies more than 80 official sleep disorders [2]. Many are uncommon, but a handful (e.g., insomnias, obstructive sleep apnea, narcolepsy, restless legs syndrome) affect millions of Americans and are responsible for significant morbidity and mortality, including direct physiologic and/or psychologic complications and accidents associated with moderate or severe drowsiness.

It is estimated that 50 to 70 million adult Americans have a sleep or wakefulness disorder [1]. Some of the most serious long-term health consequences of sleep disorders (or sleep insufficiency/deficit) include glucose intolerance, increased blood pressure, increased inflammatory markers, higher evening cortisol levels, weight gain/obesity, and an increased risk of myocardial infarction, depression, and cancer [1,3,4]. Additionally, sleep apnea and narcolepsy are known to be responsible for some of the more than 800 fatalities and 44,000 nonfatal injuries caused by drowsy driving in the United States each year, adding to the considerable burden that untreated sleep disorders place on the healthcare system [5]. Other sleep disorders, including those that are transient, contribute to the remainder of the 72,000 annual crashes caused by excessive sleepiness while driving [5].

The economic cost of sleep disorders should not be underestimated. One study found that individual healthcare costs were approximately doubled for patients with undiagnosed obstructive sleep apnea [6]. Research commissioned by Congress in 1993 found that direct annual medical costs for insomnia were $15.2 billion (with the amount spent on over-the-counter products not included), and that the indirect and related annual costs (mostly costs arising from accidents) approached $56 billion [4,7,8,9]. In 2018 dollars, this translates to $26.6 billion and $98 billion, respectively, and these figures do not take into account population growth or today's increased healthcare costs.

A 2011 study found that annual workplace losses (including workplace accidents) due to insomnia and associated comorbidities totaled $91.7 billion per year [10]. The study, using extrapolated data from 7,428 U.S. workers enrolled in healthcare plans, found that presenteeism (i.e., attending work while drowsy) accounted for the majority of the losses (roughly two-thirds) and absenteeism accounted for the remainder. Comorbidity is a major factor, yet after 26 conditions were controlled for, the net annual costs of insomnia alone were $63.2 billion [10]. One limitation of the study was that only data from workers with healthcare insurance were sampled. Although the prevalence of insomnia may be similar among insured and uninsured populations, undiagnosed and untreated sleep disorders can amount to greater overall long-term cost. A 2015 study reiterated the negative impact on work performance (e.g., absenteeism, presenteeism, workplace injury, accidents driving to/from work) of one sleep disorder in particular, obstructive sleep apnea [11].

Sleep disorders have a clear impact on productivity and public health. The AASM and the Institute of Medicine emphasize that education on somnology and sleep medicine should be incorporated into continuing education programs [1]. Many of the complications associated with sleep disorders are preventable, making early diagnosis and appropriate treatment vital. Unfortunately, research indicates that sleep disorders continue to be underdiagnosed and undertreated [12,13,14,15]. One study of relatively healthy patients seeking preventive care found that 57% either reported a sleep complaint related to sleep apnea or were found to be at increased risk for the condition [13]. However, only 11% of individuals who reported sleep complaints underwent any subsequent diagnostic testing, indicating a gap in factual knowledge and appropriate clinical behaviors [13].

This course will provide information regarding the physiology of sleep; the causes, risk factors, epidemiology, and pathophysiology of various sleep disorders; diagnosis, including patient history, assessment of sleep habits, physical examination, laboratory tests, and sleep studies; and treatments to improve sleep patterns, including lifestyle/behavioral change (e.g., "sleep hygiene"), pharmacologic interventions, surgical interventions, and other treatment options for patients.

2. THE PHYSIOLOGY OF SLEEP

Sleep is an active body process marked by suspended consciousness, diminished sensory activity, relaxed musculature, reduced ability to react to stimuli, and other changes in brain activity that correspond with distinct sleep phases. Despite being necessary to humans, the basis for the need of sleep is still poorly understood. To date, the consequences of sleep deficit are the best indication of the functions sleep serves.

CIRCADIAN RHYTHMS, HOMEOSTASIS, AND THE SLEEP-WAKE CYCLE

The sleep-wake cycle consists of approximately 8 hours of sleep and 16 hours of wakefulness in healthy adults and is controlled by two internal factors: circadian rhythms and sleep homeostasis [16]. Circadian rhythms are "physical, mental, and behavioral changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism's environment" [17]. Biologic "clocks" located throughout the body manage circadian rhythms in individual body systems; these are all controlled and coordinated by the suprachiasmatic nucleus (SCN), or "master clock," located in the hypothalamus. The SCN's circadian rhythm has an endogenous component but is also driven by external cues from the environment, called zeitgebers [16]. The light-dark cycle is the overwhelmingly dominant zeitgeber for humans. Light acts on photosensitive ganglion cells in the retina that send signals directly to the SCN, providing synchronization with the particular environment. Thus, the body is able to adapt (in some cases with difficulty) and correct the sleep-wake cycle relative to differing light-dark conditions (e.g., when travelling to a different time zone).

Endogenous circadian rhythms, and therefore sleep needs, vary among individuals and age groups. Adolescents typically need 9.5 hours of sleep, and infants require 16 hours of sleep [16,18]. There are three chronotypes (identifiable using the Horne-Östberg questionnaire): morning type, an early circadian phase; evening type, a late circadian phase; and intermediate type. This is important because morning-type individuals typically sleep earlier and longer and are quicker to adjust to changes in sleep schedules than intermediate and evening types [18,19]. One study found that morning-type individuals are also less likely to deviate from their normal sleep schedule regardless of social cues (e.g., being on vacation) [18]. A 2012 study found that adolescents living in brightly lit, urban environs had a "stronger evening-type orientation than adolescents living in darker and more rural municipalities" [20]. The study also found that nighttime electronic-screen media use (i.e., a strong artificial light source) correlated with an evening-type rhythm in adolescents living in darker areas, but a morning rhythm could be established if limited and appropriate nighttime lighting (e.g., dimmer room lights, heavy curtains to block street lighting, no electronic-screen media use) was used.

Although the primary zeitgeber in humans is the light-dark cycle, there are other influential nonphotic cues, including exercise, temperature, and various social cues, that influence the regulation of various biologic processes (e.g., body temperature, hormone production) [18,21,22]. Researchers propose that sleep patterns may be influenced by other important zeitgebers, including sound, temperature, and the earth's magnetic field, that are as yet unproven or only considered weak factors [23,24]. Given that light is such a powerful influence and that humans are sensitive to very low levels of light, it is difficult to study the effects of these other possible cues. (Blind individuals typically have "free running" circadian rhythms ≥25 hours and are often the subject of zeitgeber investigations.) Some zeitgebers, such as aberrant work schedules, alarm clocks, artificial light, radio, television, and time-zone change, are known to cause disruptions to the natural sleep-wake cycle.

Homeostasis is the body process associated with maintaining a steady state of internal conditions (e.g., acid-base balance, blood pressure, body temperature). The sleep drive and amount of sleep are also under homeostatic control [16]. The neurochemistry of sleep is not fully understood, but the neurotransmitter adenosine is thought to have an important role as a homeostatic regulator of sleep [16,25]. Adenosine does not act as a classical neurotransmitter; it is neither stored nor released, but is instead thought to be formed inside or on the surface of cells [25]. The drive for sleep (and, alternately, wakefulness) has been found to be directly related to extracellular adenosine levels in the cerebral cortex and basal forebrain [25]. Concentrations of the chemical increase throughout the day and decrease during the sleep recovery period, and the feeling of intense sleepiness following prolonged wakefulness is thought to be caused by very high adenosine levels. Adenosine is a theoretical link between the humoral and neural mechanisms of sleep-wake regulation [25].

Produced in the pineal gland, melatonin is another key sleep hormone. It is regulated by darkness signals from the SCN and also provides feedback to that circadian oscillator [26]. Circulating melatonin levels increase in the hours following nightfall and drop significantly upon eye exposure to light. It is believed that this hormone supplements and reinforces the entraining effects of the light period [26]. Whereas the ganglion cells provide a light cue to the SCN, melatonin provides a darkness cue via receptors in and around the structure.

SLEEP STAGES

The sleep process consists of five stages of sleep, divided into two general categories: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep consists of four distinct phases (or stages), each of which is defined by a set of unique electrophysiologic parameters, including electroencephalogram (EEG), electromyogram (EMG), eye movements, and respiration. When awake, EEG measurements of brainwave activity show frequencies of 8 Hz or greater. When a patient is awake but relaxed with eyes closed, EEG measurements fall in the alpha range (8 to 12 Hz) when measured at posterior head regions. In children, this basic rhythm is in the theta range (4 to 8 Hz), and in infants, it is in the delta range (slower than 4 Hz). A return to wakeful levels of brain activity (greater than 12 Hz) occurs if the subject opens his or her eyes or engages in mental activity. When awake or when relaxing with eyes closed, muscle tone is normal and individuals are fully aware of their surroundings.

Stage 1

During stage 1 sleep, individuals begin to feel drowsy but can be easily aroused. Relaxation of musculature begins, as does reduced environmental awareness. Slow and rolling lateral eye movements also may occur. EEG brain activity shows interruption of the posterior dominant rhythm (i.e., alpha dropout) and the onset of a low-voltage, intermixed pattern of frequencies [27,28]. Positive occipital sharp transients of sleep (POSTS) and very brief vertex sharp waves may occur in repetitive runs. (POSTS start around 4 years of age, are common by 15 years of age, and decline after 50 years of age.) Hypnagogic hypersynchrony, or bursts of high-amplitude, diffuse, rhythmic (sinusoidal) delta activity, can arise, especially among children 3 months to 13 years of age and is considered a normal variant of drowsiness in this age group.

Stage 2

Most time is spent in stage 2 sleep during an adult's normal night's sleep. Arousal is more difficult during this phase, and the low-voltage, intermixed pattern continues. Brainwave activity slows to the theta range (4 Hz to 7 Hz). Sleep spindles (and associated K-complexes) are the defining characteristic of stage 2 sleep. Spindles are short bursts of vertex rhythmic activity between 12 and 16 Hz (typically 14 Hz) lasting about 0.5 seconds. Sleep spindles begin at 6 to 8 weeks of age and continue throughout life [27,28].

Stages 3 and 4

Muscle tone continues to decrease progressively through stages 3 and 4. Arousal is most difficult during these stages, which are marked by slow-wave sleep consisting of progressively increasing high-voltage, delta-range brain activity. During stage 3, delta activity comprises 20% to 50% of brainwave activity, and during stage 4, it is in excess of 50% [27,28]. Sleep spindles may still occur in these stages but are not a major feature. Over a lifetime, the amount of time spent in slow-wave sleep decreases. For example, men 20 to 29 years of age spend 21% of total sleep time in slow-wave sleep; this decreases to 8% by 50 years of age and to 2% by 70 years of age. In elderly individuals, almost no time is spent in stage 4 sleep and little time is spent in stage 3.

REM Sleep

As the name suggests, the major feature of REM sleep is rapid eye movement, but this stage is also characterized by muscle atonia and EEG desynchronization. Brainwave activity returns to a low-voltage intermixed pattern and becomes faster (beta and theta range), almost resembling wakefulness. Dreaming is most likely to occur in this stage. Central activity in the theta range can produce waves with a "saw tooth" appearance on a polysomnogram display.

In healthy adults, about four or five sleep cycles, each about 90 minutes, occur in one night, each one progressing through the non-REM stages, followed by REM sleep. Slow-wave sleep is lessened and REM sleep becomes more predominant with each successive sleep cycle (Figure 1) [29].

Figure 1: NORMAL SLEEP STRUCTURE IN ADULTS

Source: Reprinted with permission from Kales A, Kales JD. Sleep disorders: recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med. 1974;290(9):487-499.

Some individuals enter REM sleep before descending through non-REM phases, which is referred to as sleep-onset REM periods (SOREMPs). This is considered an indicator of a sleep disorder, usually narcolepsy, but it may also occur in patients with obstructive sleep apnea [30]. SOREMPs are uncommon in the healthy adult population but are slightly more prevalent in individuals with excessive sleepiness (e.g., adolescents and young adults, shift workers) [31]. SOREMPs are also seen with other disorders, including Prader-Willi syndrome, Kleine-Levin syndrome, Parkinson disease, and periodic limb movement disorder (PLMD) [31].

3. OVERVIEW OF SLEEP DISORDERS

As discussed, there are more than 80 official sleep disorders defined in the current AASM diagnostic and coding manual, the ICSD-3 [2]. The ICSD-3 uses a pragmatic framework for categorizing sleep disorders based primarily on pathophysiology, if known, and also phenomenology and organ system methodology [2]. Unlike in original versions, disorders are no longer grouped into three major classes: dyssomnias, parasomnias, and sleep disturbances associated with mental, neurologic, or other medical disorders. Instead, the ICSD-3 contains seven major categories of sleep disorders [2]:

- Insomnia

- Sleep-related breathing disorders

- Central disorders of hypersomnolence

- Circadian rhythm sleep-wake disorders

- Parasomnias

- Sleep-related movement disorders

- Other sleep disorders

A goal of the ICSD-3 framework was to organize sleep disorders into an International Classification of Diseases (ICD-10)-compatible format [2]. Another goal was to describe in detail all currently recognized sleep and arousal disorders, which is a missing feature of other manuals, including the widely used Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), while still maintaining a good degree of concordance with the DSM-5.

DSM-5 CLASSIFICATION

The DSM-5 contains information for making a diagnosis of a sleep disorder; however, it has less detailed descriptions of certain sleep-wake disorders than the ICSD-3. For example, the DSM-5 section on insomnia disorders does not extensively describe each of the three forms of insomnia described in the ICSD-3. The DSM-5 takes what it refers to as a "lumping versus splitting" approach to classifying sleep-wake disorders. The insomnias identified in the ICSD-3 fall under the general category of insomnia disorder in the DSM-5, lumped together due to their similar presentations and impact on clinical care for nonspecialists. While this course incorporates information from both the DSM-5 and the ICSD-3, the organization structure of the latter will be used as an outline. The following sections will discuss the more common examples of each of the seven categories, and those with the greatest incidence will be discussed in more detail.

SLEEP STUDY TESTS

Many tests are available to assess the quality of an individual's sleep, and a discussion of each is beyond the scope of this course. However, the most commonly used tests are polysomnography and the multiple sleep latency test (MSLT), both of which are used in the evaluation of many sleep disorders.

Polysomnography is preferably conducted by a certified sleep technologist at an AASM-accredited facility. This test monitors many physiologic parameters, including electrocardiogram, EEG, eye movements (electrooculogram), chin EMG, airflow, oxygen saturation, respiratory effort, and heart rate [32]. A technician will note if snoring is present and, if so, the degree (i.e., mild, moderate, or severe). Body position and leg EMG derivations are also recommended.

One full-night study is typical, but split-night studies (i.e., polysomnography followed by continuous positive airway pressure [CPAP] titration) may be used when initial monitoring shows a high apnea-hypopnea index (AHI) score. This index will be discussed in detail later in this course. The AASM Manual for the Scoring of Sleep and Associated Events is used to set up and analyze the study, and the results are reported as an AHI score (or a respiratory disturbance index) for review by a qualified sleep physician. Polysomnography can help rule out the possibility of sleep disorders, and it will also show if the patient's sleep cycle is normal or if REM sleep occurs at unusual times.

Portable monitor testing has a known likelihood of producing false-negative results; therefore, it is considered inferior to overnight sleep lab polysomnography [32]. Airflow, blood oxygenation, and respiratory effort are the minimum test parameters needed for a complete at-home study. The sensors are similar or identical to those used for polysomnography and will either be placed by a sleep technologist, other trained professional, or the patient following detailed instruction. The AHI score is calculated per the AASM Manual using the truncated portable monitor test data. Tests of patients who have a high probability of obstructive sleep apnea and a low AHI should be considered inaccurate and should be repeated (in a sleep lab whenever possible) [32].

The MSLT is a daytime test that can determine if REM sleep patterns occur during wakefulness and monitor the amount of time it takes for the patient to fall asleep normally during the day. For example, sleep latency periods (i.e., the time it takes to fall asleep) are typically 8 minutes or less in narcoleptic patients, but healthy individuals usually take 12 or more minutes to fall asleep during the daytime [33].

4. INSOMNIAS

The term insomnia is defined generally as difficulty with initiation, duration, consolidation, or quality of sleep. It is commonly applied when three conditions are satisfied: ample time and opportunity for sleep, persistent sleep difficulty, and daytime dysfunction associated with sleep deficit [2].

Chronic or short-term insomnia is a problem for most people at some point in their lives. Patients will experience problems going to sleep or staying asleep and are distressed by the number of hours they are awake at night or by a quality of sleep perceived as poor [2]. However, if daytime function is unaffected, the complaint does not warrant treatment other than discussion and education, because by definition they do not have an insomnia disorder. Patients with clinically significant insomnia typically become fatigued, irritable, cognitively impaired, and/or depressed and some complain of headaches, muscle tension, palpitations, work impairment, and social withdrawal [2].

There are now three formal insomnia diagnoses listed in the ICSD-3: chronic insomnia disorder, short-term insomnia disorder, and other insomnia disorder [2]. This is a significant departure from the previous version of the ICSD, which included 11 diagnoses. Many sleep disorders diagnosed in the past have a complaint of insomnia in common. These included adjustment insomnia (acute insomnia); psychophysiologic insomnia; paradoxical insomnia; idiopathic insomnia; insomnia due to mental disorder; inadequate sleep hygiene; behavioral insomnia of childhood; insomnia due to drug or substance; insomnia due to medical condition; insomnia not due to a substance or known physiologic condition, unspecified (nonorganic insomnia, not otherwise specified [NOS]); physiologic (organic) insomnia, unspecified (organic insomnia, NOS).

Insomnia is no longer regarded as either being due only to a primary sleep disorder or because of an underlying medical or psychiatric condition (i.e., as a primary disorder or as a disorder secondary to another comorbid condition). For one, the symptoms and features of primary and secondary insomnia overlap considerably, and differentiation was often difficult or impossible. Additionally, patients usually met the criteria for more than one ICSD-2 insomnia subtype. Evidence has shown that when a patient's underlying medical condition causing insomnia is treated, the insomnia often persists, or when the insomnia was treated, both the comorbid medical condition and the sleep disorder improved [2]. The first two categories of insomnia—chronic insomnia disorder and short-term insomnia disorder—now reflect an all-encompassing view of disordered sleep and are based on various levels of sleep dysfunction. The third category—other insomnia—is included in the ICSD-3 to describe individuals with difficulty initiating and maintaining sleep, but who do not meet the criteria for the other two categories. The AASM does not foresee many individuals receiving this diagnosis, and it will not be discussed in this course.

CHRONIC INSOMNIA DISORDER

According to the ICSD-3, chronic insomnia disorder is defined as "chronic sleep onset and/or sleep maintenance complaints with associated daytime impairment, and is reserved for individuals whose sleep difficulties exceed minimal frequency and duration thresholds shown to be associated with clinically significant morbidity outcomes" [2]. This diagnosis encompasses many insomnia subtypes found in other texts, including primary insomnia, comorbid insomnia, chronic insomnia, secondary insomnia, sleep-onset association disorder, behavioral insomnia of childhood, disorder of initiating and maintaining sleep, and limit-setting sleep disorder. As discussed, this consolidation is not for the sake of simplicity, but reflects the actual state of current knowledge and evidence regarding chronic insomnia. The specific primary insomnia clinical/pathologic subtypes that are now considered part of this larger, global class in the ICSD-3 are shown in Table 1[2].

Table 1: CLINICAL AND PATHOPHYSIOLOGIC SUBTYPES IN THE ICSD-3

Diagnosis

Features

Symptoms

Psychophysiologic insomnia

Elevated levels of somatic and cognitive arousal, especially when trying to sleep

Learned sleep-preventing associations

Excessive focus on sleep

Excessive worry about sleep

Difficulty sleeping in usual sleep setting (e.g., at home),but may fall asleep easily away from home or at home when not trying to sleep

Idiopathic insomnia

Early onset (i.e., infancy)

Genetic or congenital alterations in sleep-induction/arousal systems in the brain

No genetic markers are known

Gradual inability to sleep beginning at a very young age with no discernible cause

Paradoxical insomnia

Individuals underestimate the amount of sleep actually obtained

Complaint of wakefulness in spite of sleep studies showing normal amounts of sleep

Altered sleep/wake system

Extreme subjective sleep disturbance without objective corroboration

Inadequate sleep hygiene

Frequent napping/irregular sleep schedule

Regular use of caffeine, alcohol, tobacco, or other drugs close to bedtime

Regularly engaging in mentally, physically, or emotionally stressful activity before bedtime

Using the bed for activities other than sleep or sex (e.g., reading, television, video games)

Inappropriate pre-sleep and sleep environment (e.g., too hot, excessive light, too loud or quiet)

Inability to initiate sleep

Chronic sleep/wake difficulty

Behavioral insomnia of childhood (sleep-onset association type or limit-setting type)

Poor sleep training or limit setting by caretakers or parents

Some children are a mixed type

Child's dependence on specific objects, settings, or stimulation for initiating or returning to sleep (sleep-onset association type)

Bedtime stalling or refusal (limit-setting type)

Source: [2]

Although these subtypes are discussed in the ICSD-3, a diagnosis of chronic insomnia disorder should be made for all adult and pediatric patients who have a complaint of persistent and frequent insomnia, despite the absence or presence of a comorbid medical disorder, psychiatric disorder, or substance abuse [2]. Given the state of knowledge and evidence regarding insomnia, this has been deemed the most justifiable approach and is more compatible with the DSM-5.

Epidemiology

Approximately 10% of the adult population is affected by chronic insomnia disorder as defined by the ICSD-3 [2]. The disorder is more common in women than in men and affects a greater number of individuals with low socioeconomic status versus those who are economically and socially stable. Patients with medical, psychiatric, and/or substance abuse problems are disproportionately affected. Older individuals are more often diagnosed with chronic insomnia, likely due to medical conditions, medications used to treat them, and age-related sleep continuity decline [2]. Transient insomnia affects 30% to 35% of the adult population.

Prevalence of insomnia in children and adolescents is estimated at 10% to 30% and 3% to 12%, respectively, with wide variance due to definitions of insomnia used in research. It is more frequently diagnosed in adolescent girls than boys [2]. Although the specific ICSD-3 diagnosis has changed, the problems associated with childhood sleep disorders have not. Most chronic childhood insomnia cases are due to caregiver/parental behavior, bedtime interactions, and cultural influences, and the underlying difficulties are still primarily sleep-onset and/or limit-setting problems [2]. The need for and provision of nighttime contact varies among cultures, which should be taken into account. Infants do not establish a regular sleep pattern until approximately 3 to 6 months of age, and an insomnia diagnosis is typically not made before 6 months of age.

The evidence for familial occurrence of insomnia is weak, but there does appear to be some influence, particularly between mothers and daughters, monozygotic twins, and, to some extent, other first-degree relatives [2]. It is not known what the association(s) may be; theories range from learned behavior and a shared environment to genetic predisposition and the byproduct of a common psychopathology.

Diagnosis in Adults

A diagnosis of chronic insomnia disorder is based primarily on subjective reports from adult patients and objective and subjective reports for children and adolescents. The differential diagnosis of chronic insomnia may include a sleep study, if warranted, but typically is not needed for routine evaluation.

There are three features of chronic insomnia disorder [2]. The first is frequent and persistent difficulty initiating or maintaining sleep, and this is the intrinsic essential feature of chronic insomnia disorder [2]. This repetitive failure results in the patient's general dissatisfaction with sleep and quality of life. Insomnia, though chronic, does not necessarily occur every night. Some patients will have episodes of recurrent insomnia, while others constantly struggle with sleep insufficiency. It is common for individuals with persistent insomnia to have several bad nights of sleep with an occasional good sleep [2]. Other patients who are predisposed to insomnia may experience poor sleep in relation to stressful life events. An initial episode of acute insomnia related to a stressful event will typically resolve in most individuals as they adjust to their new reality; however, this episode has the potential to become a chronic problem for some patients. The remembrance and anticipation of insomnia following a stressful event, coupled with actual sleep difficulties and daytime impairment, can lead to a cycle of disordered sleep [2].

The second feature of chronic insomnia is worry about sleep difficulties and/or academic, family, social, vocational, or other functional impairment [2]. Patients with insomnia often display excessive preoccupation with sleep, which can be problematic. Worrying about not getting enough sleep and not being able to initiate sleep following an episode of insomnia can lead to a vicious cycle of becoming tense or agitated as bedtime approaches (with corresponding adrenaline release), trying too hard to sleep (e.g., lying in bed for extended periods of time), becoming increasingly distressed and agitated at the inability to sleep, and being further unable to initiate sleep [34].

Preoccupation with general health and wellness may predispose individuals to chronic insomnia, and repression and internalization of disturbing feelings may be a common trait [2]. It may appear that patients are overly anxious, and in fact, recurrent thoughts of poor sleep performance may trouble these individuals in the morning and afternoon and attain a peak at night. However, generalized anxiety is not the norm for chronic insomnia sufferers. Screening for comorbid general anxiety is recommended when symptoms seem to extend beyond an emphasis on disordered sleep [2]. Environmental and biologic sleep cues often become triggers for heightened sleep anxiety and arousal. For example, when the sun sets and darkness falls, thoughts of poor previous nights' sleep and sleep performance anxiety may begin. In healthy individuals, feelings of drowsiness lead to increased calm, but fatigue can cause panic and distress in those with chronic insomnia. Patients may think, "I feel tired, but I know that if I go to bed I will not be able to fall asleep," or, "I feel tired now, but I am going to feel even worse tomorrow morning when I am not able to sleep tonight." This may be, or become, true as the patient ruminates about sleep and stresses.

Subjective or objective deficits with daily functioning are noticed in individuals with chronic insomnia. These may manifest as depression, lethargy, or a desire to limit activities or work. Work productivity may suffer, as may academic performance.

Patients often readily express sleep anxiety and may acknowledge their ability to sleep normally in unfamiliar settings [2]. The lack of environmental triggers in unfamiliar environments can help prevent sleep performance worry.

The third essential feature of chronic insomnia disorder is inability to sleep and remain asleep despite plenty of time to sleep, no nighttime interruptions, an adequate sleep environment, and other sufficient circumstances [2]. Practicing sleep hygiene, or maintaining an ideal sleep environment and optimum mental/physical state to promote sleep, is discussed later in this course.

Diagnosis in Children

The diagnosis of chronic insomnia in children is somewhat different because of the strong influence of parental/caregiver and environmental factors on development. Parents should be questioned regarding their expectations for their child's sleep. Putting children to bed prematurely or allocating too much time in bed can cause sleep difficulties that may lead to chronic insomnia [2]. On the other hand, parents may not be implementing or enforcing regular bedtimes or may allow children to postpone bedtimes. As children develop greater language skills and seek individuality, limit setting becomes more important. Studies have also shown that parents of children who faced a life-threatening illness are less strict about enforcing bedtimes and allow their children greater leeway with sleeping (e.g., joining the adult bed upon waking) [2]. Abuse and unstable home environments are also known factors for insomnia in children and adults. Crowded homes (e.g., with extended family of many generations) are associated with poor limit setting and negative sleep-onset cues. Children should also be carefully screened for comorbid medical and psychiatric conditions that may have gone unnoticed. The diagnostic criteria for adults and children are shown in Table 2.

Table 2: THE ICSD-3 DIAGNOSTIC CRITERIA FOR CHRONIC INSOMNIA DISORDER

A. The patient reports, or the patient's parent or caregiver observes, one or more of the followinga:

1. Difficulty initiating sleep

2. Difficulty maintaining sleep

3. Waking up earlier than desired

4. Resistance to going to bed on appropriate schedule

5. Difficulty sleeping without parent or caregiver intervention

B. The patient reports, or the patient's parent or caregiver observes, one or more of the following related to the nighttime sleep difficulty:

1. Fatigue/malaise

2. Attention, concentration, or memory impairment

3. Impaired social, family, occupational, or academic performance

4. Mood disturbance/irritability

5. Daytime sleepiness

6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression)

7. Reduced motivation/energy/initiative

8. Proneness for errors/accidents

9. Concerns about or dissatisfaction with sleep

C. The reported sleep/wake complaints cannot be explained purely by inadequate opportunity (e.g., enough time is allotted for sleep) or inadequate circumstances (e.g., the environment is safe, dark, quiet, and comfortable) for sleep.

D. The sleep disturbance and associated daytime symptoms occur at least three times per week.

E. The sleep disturbance and associated daytime symptoms have been present for at least three monthsb

F. The sleep/wake difficulty is not better explained by another sleep disorder.

aReports of difficulties initiating sleep, difficulties maintaining sleep, or waking up too early can be seen in all age groups. Resistance going to bed on an appropriate schedule and difficulty sleeping without parent or caregiver intervention is seen most commonly in children and older adults who require the supervision of a caretaker due to a significant level of functional impairment (e.g., those with dementia).

bSome patients with chronic insomnia may show recurrent episodes of sleep/wake difficulties lasting several weeks at a time over several years, yet not meet the three-month duration criterion for any single such episode. Nonetheless, these patients should be assigned a diagnosis of chronic insomnia disorder, given the persistence of their intermittent sleep difficulties over time.

Source: Reprinted with permission from American Academy of Sleep Medicine. The International Classification of Sleep Disorders-[3]Diagnostic and Coding Manual. [3]rd ed. Westchester, IL: American Academy of Sleep Medicine; 2014.

Subjective assessment with a sleepiness instrument, such as the Epworth Sleepiness Scale (Table 3), may be helpful to ascertain the patient's degree of impaired sleep, but laboratory testing to measure sleepiness (e.g., the Maintenance of Wakefulness Test) usually does not show greater sleepiness in this cohort compared with healthy individuals [35]. The Epworth Sleepiness Scale has been found to be particularly effective for identifying cases of insomnia and less useful for diagnosing other sleep disorders [36]. Sleep studies are not typically needed to make a diagnosis, but polysomnography may reveal poor sleep continuity (e.g., decreased sleep efficiency, intermittent wakefulness) and more stage 1 sleep and limited stage 3 and 4 sleep [35,37]. As noted, many persons with insomnia sleep better outside their own bed, and overnight laboratory testing may not provide significant data. Polysomnographic results also vary considerably from night to night in these patients [35]. Polysomnography is recommended for elderly individuals, as they are more prone to having identifiable etiologies of insomnia.

Table 3: THE EPWORTH SLEEPINESS SCALE

Situation

Scorea

Sitting and reading

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

Watching television

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

Sitting inactive in a public place (e.g., a theater or a meeting)

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

As a passenger in a car for an hour without a break

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

Lying down to rest in the afternoon when circumstances permit

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

Sitting and talking to someone

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

Sitting quietly after a lunch without alcohol

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

In a car, while stopped for a few minutes in traffic

0 = No chance of dozing

1 = Slight chance of dozing

2 = Moderate chance of dozing

3 = High chance of dozing

aA total score of 10 or more from the eight criteria reflects above normal daytime sleepiness and need for further evaluation.

Source: [38]

Treatment

Approximately 7 of 10 individuals with persistent insomnia struggle with insomnia after one year of treatment, and half still have insomnia three years later [2]. Complications of chronic insomnia include increased risk of depression, hypertension, work disability, and protracted use of prescription or over-the-counter sleep aids. Therefore, effective professional therapies are needed to avoid dangerous comorbidities and adverse drug effects. Additionally, managing comorbid medical and psychologic conditions with sleep-disrupting effects is necessary for these patients.

Sleep Hygiene

Management of chronic insomnia centers on behavior and lifestyle modification combined with counseling and instruction in effective sleep hygiene practices. Some of the foremost behaviors patients should modify or adhere to include keeping a consistent sleep schedule (i.e., going to bed at the same time each night and waking up at the same time each morning), devoting at least seven to eight hours each night to sleep, and creating and maintaining a bedtime ritual. The optimum sleep time varies among individuals, but those with persistent excessive daytime sleepiness should sleep a minimum of six to eight hours [31].

Establishing a bedtime ritual involves deciding upon an activity or series of activities that provide conditioned sleep cues and consistently repeating those activities each night. The first part of the ritual should involve quitting challenging, engaging, or stressful tasks (e.g., paying bills, playing video games, watching television) and resolving any lingering worries (e.g., quarrels, dwelling problems). Some people find that if tasks are incomplete or issues are left unresolved, making a to-do list for the next day will help to clear their mind [31]. Next, patients should focus on relaxation for 20 or 30 minutes. During this time, they might read, listen to relaxing music, take a warm bath, or practice meditation and/or deep-breathing exercises. There are many other lifestyle modifications that can reduce the likelihood of developing a sleep disorder or can lead to a reduction of symptoms of an existing disorder. The following guidelines are all components of proper sleep hygiene and should be included as part of patient education for any sleep disorder [10,31]:

- Large, heavy meals should be avoided late in the day, as should spicy, new, or exotic foods.

- Alcohol, caffeine, and nicotine should be avoided for at least four to six hours before bedtime. Alcohol initially acts as a sedative, but as the effect wears off, it can cause individuals to wake during the night. Chocolate, coffee, tea, and many other beverages contain caffeine and should be avoided at night.

- Long naps should not be part of a normal day. Occasional, light (30-minute) naps are permissible, but regular naps interrupt the sleep-wake cycle and can make falling asleep difficult at night. Patients should be able to remain awake throughout the day, and if this is not possible, this indicates insufficient sleep and/or a sleep disorder.

- Upon waking in the morning, individuals should seek out sunlight. Exposure to bright sunlight helps regulate the sleep-wake cycle. This is especially important for older adults and those who do not leave the house regularly.

- Patients should be encouraged to engage in at least 20 minutes of moderate-intensity exercise per day, a minimum of two to three hours before bedtime. Vigorous exercise is best performed in the afternoon or earlier in the day, while relaxing exercises (e.g., deep breathing, light yoga, meditation) may be performed before bedtime. Exercise performed earlier in the day helps deepen sleep.

- The bed should be used only for sleep and sex. Patients who do not fall asleep within 15 to 20 minutes of being in bed should get out of bed and engage in an uncomplicated or relaxing activity in low-light conditions until they feel drowsy. Taking a bath, reading, or having a small snack is recommended; watching television, doing work, or engaging in other mentally engaging activities is not. One should not lie in bed trying to force sleep.

The following changes to the sleeping environment have also been shown to promote sleep [31]:

- Keep the bedroom at a cool, yet comfortable, temperature. Use blankets rather than a heater for warmth, as cooler room temperatures lead to better sleep.

- Remove the television from the bedroom. Television programs and commercials are designed to be engaging and/or provocative and can keep individuals awake for many hours. Additionally, darkness is necessary to stimulate melatonin production, and light from the television can be disruptive if left on all night.

- Keep the bedroom as dark, quiet, and relaxing as possible. Ensure that bedding is comfortable. Use an eye shade or thick curtains to block out early morning sunlight, streetlights, and headlights. Some people find earplugs useful, and others use white noise or other machines to block out aberrant sounds.

A sleep hygiene regimen is a universally applicable prevention and treatment strategy that can improve sleep quality for those with and without a specific sleep disorder. Most sleep experts recommend that sleep hygiene be used as an adjunct to treatment for sleep disorders [2]. Despite limited research supporting the role of proper sleep hygiene in patients with insomnia, many patients will find these suggestions helpful. It has been found that individuals with chronic insomnia who are highly aware of poor sleep hygiene practices may be the most indifferent toward making changes [2].

Cognitive-Behavioral Therapy and Other Modalities

Certain forms of chronic insomnia tend to be less amenable to control with simple nonpharmacologic and brief sedative-hypnotic modes of treatment. Some form of cognitive-behavioral therapy (CBT), utilizing stimulus control, relaxation training, and sleep restriction therapies, sequentially or in combination, achieves the best results [37,39]. Stimulus control therapy, which is akin to maintaining strict sleep hygiene, has been extensively studied and is the most recommended modality for initial insomnia treatment [34]. However, because sleep cues and other practices learned with sleep hygiene/stimulus control may become (or may already be) a cause of arousal, it is unlikely that all clinical subtypes will benefit significantly from this form of therapy.

The effectiveness of CBT for psychophysiologic insomnia has been demonstrated in several studies [34,39,40,41]. Patients also tend to prefer CBT over pharmacologic options and other forms of psychotherapy [41]. Relaxation techniques (e.g., biofeedback, breath counting/deep breathing, meditation, progressive relaxation) can be an effective adjunct to CBT [37,42]. Progressive relaxation can be particularly effective in patients who somatize stress into physical tension. This form of therapy involves tensing and relaxing individual muscle groups while breathing deeply, starting from the toes, working progressively through the calves, thighs, stomach, shoulders, hands, arms, and neck, and ending with the facial muscles. Deep breathing exercises use slow, controlled breaths (while counting) to "quiet" racing thoughts; if the mind wanders from counting breaths, patients should resume counting and eventually they should fall asleep [42].

Sleep restriction is also a useful form of therapy [42,43]. This technique is based on the observation of deeper, more consolidated sleep in sleep-deprived test subjects. Through this paradoxical approach, patients learn to associate time spent in bed with time spent sleeping [44]. The first step is for patients to keep a sleep log for two weeks to determine their average total sleep time (i.e., average amount of time asleep in bed); 30 minutes is added to this time to establish the time they will be allowed in bed [45]. For example, if the patient's average total sleep time is 5 hours, the allowed time in bed will be 5.5 hours. Next, a wake time is set based upon when the patient needs to start their day (e.g., 6:30 a.m.), and the bed time is set by counting backward based on the time in bed allowance (e.g., 1:00 a.m.). Regardless of how sleepy the patient feels, he or she must not nap or get into bed before the prescribed bedtime. Upon waking, the patient should expose his or her eyes to bright light (daylight whenever possible) to reinforce the sleep/wake cycle [45]. If after two weeks the patient feels tired during the day, they may add 15 minutes to the sleep allowance, and every successive week they may add an additional 15 minutes until they are able to get to sleep easily, are sleeping well throughout the night, and feel rested during the day [45]. The minimum amount of sleep needed to achieve these goals is recommended, and a consistent sleep and wake time must be maintained. This therapy should be discontinued if job performance or safety is compromised due to excessive daytime sleepiness.

Pharmacologic Options

For some patients, CBT in combination with a pharmacologic agent, administered over six to eight weeks, is an effective strategy. The primary pharmacologic option for patients with chronic insomnia disorders is the administration of sedative-hypnotic drugs at night (e.g., eszopiclone, ramelteon, triazolam, zaleplon, zolpidem). However, long-term treatment with sedative-hypnotics is associated with a high incidence of adverse effects, including cognitive impairment, constipation, dizziness, headache, heartburn, the development of parasomnias (e.g., sleepwalking, sleep driving), and reduced respiratory drive [40]. If used, the lowest effective dose is recommended to reduce the incidence of these effects [40]. Patients should be cautioned not to combine these medications with alcohol or other central nervous system (CNS) depressants, as their combination can cause increased liver toxicity and drastically reduced cognitive and psychomotor functioning [46].

Evidence Based Practice Recommendation

The American Academy of Sleep Medicine recommends the following agents be considered for the treatment of chronic sleep-onset insomnia:

- Eszopiclone

- Zaleplon

- Zolpidem

- Triazolam

- Temazepam

- Ramelteon

https://aasm.org/resources/clinicalguidelines/040515.pdf

Last Accessed: December 7, 2018

Strength of Recommendation: Weak (A lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients)

Different sedative-hypnotics are indicated for various sleep difficulties. Zaleplon is fast acting, but has a short half-life; this drug may be best for patients who experience night awakenings with difficulty returning to sleep [47]. Zolpidem has a rapid onset and short-half life as well; patients with difficulty falling asleep may benefit from this drug. A controlled-release version is also available. Eszopiclone has a slow onset and long duration of action and is indicated for patients with difficulty staying asleep and with perception of poor sleep quality.

Hypnotic drugs are best utilized when nonpharmacologic measures do not achieve symptom reduction, when insomnia causes serious impairment, or when an immediate response is desired [44]. The following are best practice guidelines regarding the prescription and use of sedative-hypnotics [44,48]:

- Avoid these agents or exercise caution if patient has a history of substance abuse, acute cerebrovascular accident, myasthenia gravis, or respiratory impairment.

- Prescribe hypnotics only for short durations (one to two weeks) and intermittently (based on symptom resolution).

- Watch for requests for escalating doses or resistance to tapering/discontinuing hypnotic.

- Hypnotics should be discontinued gradually. Be alert for adverse effects (especially rebound insomnia) and withdrawal phenomena when titrating doses.

- The lowest effective dose should be prescribed.

Herbal and Hormonal Supplements

A variety of herbal, hormonal, and dietary supplements have been marketed as sleep aides, with scant evidence of significant benefit. Melatonin, a brain hormone produced by the pineal gland, does have some function in regulating the normal sleep cycle, and melatonin supplementation may be of benefit to a subset of patients with delayed sleep phase syndrome (a disturbance of the circadian rhythm). However, it does not appear to be helpful for most people who have insomnia. It is safe when used in modest dosage (2–3 mg per night) for short periods (three months or less) [49]. Melatonin is unregulated by the U.S. Food and Drug Administration (FDA); formulations vary in strength, and higher doses can lead to adverse side effects (e.g., disrupted sleep, fatigue, headache).

Valerian is a popular herbal product commonly used to self-treat insomnia. It causes CNS sedation by inhibiting the breakdown of certain chemical mediators within the brain. Clinical trials have shown minimal effectiveness at best [50]. This product is also unregulated by the FDA. Daytime drowsiness and rare instances of liver toxicity have been observed in association with its use.

SHORT-TERM INSOMNIA DISORDER

The essential features and diagnostic criteria of short-term insomnia disorder are similar to those of chronic insomnia disorder, minus the frequency and duration criteria. Insomnia is considered short-term if lasting fewer than three months [2,37]. The differential diagnosis should exclude circadian rhythm sleep-wake disorders caused by jet lag or rotating shift work. These are caused when the established circadian rhythm is decoupled from the normal sleep-wake schedule. Individuals with short-term insomnia experience sleep difficulties within their normal sleep-wake schedule.

Approximately 15% to 20% of individuals experience short-term insomnia each year [2]. The frequency is higher in women than in men and in older age groups. Although many cases of short-term insomnia resolve over time or when the stressor is removed, a significant number of cases progress to chronic insomnia, as discussed. Treatment of short-term insomnia should focus on good sleep hygiene, but CBT and pharmacotherapy may be warranted in order to ensure non-progression to chronic insomnia [37].

5. SLEEP-RELATED BREATHING DISORDERS

As the name suggests, the ICSD-3 category of sleep-related breathing disorders includes any respiratory disorders that occur during sleep. This category is further organized into the following subgroups and disorders [2]:

- Obstructive sleep apnea syndromes (adult and pediatric) caused by upper airway obstruction.

- Central sleep apnea syndromes, which are caused by cardiac or nervous system dysfunction. The eight disorders in this group are:

- Central sleep apnea with Cheyne-Stokes breathing

- Central apnea due to medical condition without Cheyne-Stokes breathing

- Central sleep apnea due to high altitude periodic breathing

- Central sleep apnea due to a medication or substance

- Primary central sleep apnea

- Primary central sleep apnea of infancy

- Primary central sleep apnea of prematurity

- Treatment-emergent central sleep apnea

- Sleep-related hypoventilation disorders, including obesity hypoventilation syndrome, congenital central alveolar hypoventilation syndrome, late-onset central hypoventilation with hypothalamic dysfunction, idiopathic central alveolar hypoventilation, sleep-related hypoventilation due to medication or substance, and sleep-related hypoventilation due to a medical disorder

- Sleep-related hypoxemia disorder, including sleep-related hypoxemia

- Isolated symptoms and normal variants

Only obstructive sleep apnea syndrome will be discussed in detail in this section, as the other sleep-related breathing disorders are comparatively rare and/or mainly associated with other medical conditions. For example, central sleep apnea due to Cheyne-Stokes breathing is primarily associated with congestive heart failure and stroke, and primary central sleep apneas of infancy or prematurity are associated with premature birth and low birth weight, occurring in 25% of infants weighing <2,500 g and 84% of infants weighing <1,000 g [2]. Others are extremely rare. It is estimated that there are perhaps a total of 200 congenital central alveolar hypoventilation syndrome cases worldwide [2].

OBSTRUCTIVE SLEEP APNEA SYNDROME

Obstructive sleep apnea syndrome is characterized by recurrent upper airway obstruction caused by repetitive narrowing or collapse of the pharyngeal airway during sleep, resulting in reductions (hypopneas) or pauses (apneas) in breathing, in spite of abdominal and chest movements; reduced blood oxygen saturation (less than 50% in some patients); and frequent arousals (potentially hundreds per night) [2,51]. Loud snoring coupled with periods of silence lasting at least 10 seconds, but often 20 to 30 seconds, are features of the syndrome. Gasping may occur instead of snoring, especially in children and adolescents; however, most patients with obstructive sleep apnea begin loud snoring in childhood. Patients may have grown accustomed to the excessive sleepiness, mental dullness, depression, frequent night awakenings, dry mouth, and morning headaches that accompany the disorder [2]. Alcohol use can increase snoring intensity, as can excess weight gain and obesity. Patients with obstructive sleep apnea often have nasopharyngeal abnormalities [2]. Adult patients typically have a generalized narrowing of the upper airway, and enlarged adenoids and/or tonsils are commonly seen in children.

Individuals may experience bouts of acute obstructive sleep apnea as the result of an inflammation-causing illness (e.g., Epstein-Barr virus, upper respiratory infection) or as a result of the ingestion of alcohol, drugs, or medications that cause relaxed muscle tone (especially in the genioglossus and geniohyoideus muscles). Individuals with occasional symptoms do not typically seek or need extensive evaluation or care for sleep apnea other than treatment for a primary condition or cessation of the substance causing airway restriction [2]. On the other hand, patients for whom the disorder is chronic (i.e., six months or longer) require careful evaluation and prompt initiation of treatment, as even mild cases of chronic obstructive sleep apnea have been consistently and independently linked to cardiac arrhythmias, cardiovascular disease, hypertension, stroke, motor vehicle accidents, and diminished quality of life [52,53].

If a patient presents with complaints of excessive daytime sleepiness or non-restful sleep and a history of snoring, obstructive sleep apnea should be suspected. A comprehensive medical history and physical evaluation should be obtained, and various objective sleep studies (e.g., polysomnography, portable monitors, MSLT) should be completed to confirm the diagnosis. The AHI scale has been developed to quantify and standardize the degree of obstructive sleep apnea severity. The score is determined by adding the number of apnea and hypopnea events during a patient's overnight sleep study, dividing the total number of events by the minutes of sleep, and finally multiplying the result by 60. For example, if a patient sleeps 8 hours (480 minutes) and has 120 apnea events and 80 hypopnea events (200 total events), the calculation for this patient would be 200 events ÷ 480 minutes × 60, for an AHI score of 25. The AASM Task Force has defined the following cut-points for obstructive sleep apnea [54]:

- Normal: Less than 5 AHI

- Mild: 5 to 15 AHI

- Moderate: 15 to 30 AHI

- Severe: More than 30 AHI

In the example, the patient has an AHI score of 25, or moderate obstructive sleep apnea.

Epidemiology

Obstructive sleep apnea is by far the most common sleep-related breathing disorder [51]. Using the AASM criteria, it is estimated that 1 in 5 American adults has at least mild obstructive sleep apnea and 1 in 15 has at least moderate obstructive sleep apnea [52]. The incidence of the disorder increases with age, and it is two to three times more common in men than in women [51,52,55]. The estimated incidence among various age-groups is [51,55]:

- Children: 2% to 8% among both sexes

- 30 to 65 years of age: 9% of women, 24% of men

- 65 to 99 years of age (with an AHI greater than 10): 56% of women, 70% of men

Differences in incidence among racial and ethnic groups have not been extensively studied. Although race is thought to be an important risk factor for sleep disordered breathing, at this time it is not certain what role race or ethnicity plays in the development of obstructive sleep apnea. Researchers have attempted to link occurrence of the disorder to racial craniofacial differences and variations in body mass trends or fat distribution, with little replicable data to support their hypotheses [55]. Again, this may be due to a lack of research that accounts for race in the United States and other Western countries and limited research of the disorder in Africa, Asia, and the Pacific Islands.

Risk Factors

Many risk factors have been theoretically linked to obstructive sleep apnea. The most widespread factors are alcohol consumption, smoking, overweight and obesity, and hormonal changes related to pregnancy, menopause, and polycystic ovary syndrome [52]. There are conflicting studies for each of these theories, and only overweight and obesity is considered a statistically significant risk factor.

Excess body weight is the strongest risk factor for obstructive sleep apnea in the general population, and most (though not all) patients who present with the disorder are heavier than normal weight [2]. The overweight and obesity epidemic in the United States has caused a concurrent rise in the prevalence of sleep disordered breathing, but the mechanisms involved are still unclear [56]. Hypotheses for the pathophysiology of overweight and obesity in the disorder include distorted upper airway structure and function (caused by altered neck morphology), an altered relationship between respiratory drive and load compensation, and intensification of apnea/hypopnea events through obesity-related decreases in functional residual capacity and increased whole-body oxygen demand [52,57,58]. Other obesity-related conditions, including insulin resistance, generalized inflammation, hypoactive hypothalamic corticotropin-releasing hormone neurons, and visceral adiposity, have been suggested as factors in the development of obstructive sleep apnea following excessive weight gain [59]. Individuals with an "apple-shaped" body (i.e., central adiposity) or who have a greater neck circumference are thought to be more affected than those who are "pear shaped" (i.e., gynoid adiposity), but there is little concrete evidence to support this idea [56].

Obesity may also be a risk factor for obstructive sleep apnea in children and adolescents. One study found a relative risk 4.59 times higher in obese children 2 to 18 years of age compared with normal weight controls [60].

Despite the lack of consensus regarding the role of excess body weight in the pathogenesis of obstructive sleep apnea, studies have shown a strong positive correlation between body mass index (BMI) and AHI [52,57,61]. A decade-long Wisconsin study of 690 randomly selected participants (mean age: 46 years) found that a 10% weight gain yielded a six-fold increase in the odds of developing moderate-to-severe sleep disordered breathing compared with individuals who maintained a steady weight [56]. Those who lost 10% of their initial weight during the study period lowered their AHI score by an average of 26% (range: 18% to 34%). Several small-scale studies have shown improvements in obstructive sleep apnea symptoms following surgical weight-loss interventions. Body mass reduction following bariatric surgery can cause the most dramatic (though possibly short-term) decrease in AHI score [52,53,57,61].

Evaluation and Diagnosis

History and Physical Examination

The diagnosis of obstructive sleep apnea is usually made in one of three settings: a general, routine health evaluation, a screening of high-risk patients, or an evaluation suggestive of obstructive sleep apnea [32]. High-risk groups include individuals who are obese or are being evaluated for bariatric surgery; those with atrial fibrillation, congestive heart failure, treatment-refractory hypertension, nocturnal dysrhythmias, pulmonary hypertension, type 2 diabetes, and/or stroke; and high-risk driving populations (i.e., commercial truck drivers). During the initial evaluation, a history of snoring and daytime sleepiness should be taken, along with an assessment of BMI, blood pressure, maxillofacial irregularities (e.g., retrognathia), and upper airway restriction (e.g., large adenoids/tonsils).

A detailed sleep history should be obtained, including evaluation for [32]:

- Snoring

- Witnessed apneas

- Gasping/choking episodes

- Excessive sleepiness not explained by other factors, including assessment of sleepiness severity by the Epworth Sleepiness Scale

- Total sleep amount

- Nocturia

- Morning headaches

- Sleep fragmentation/sleep maintenance insomnia

- Decreased concentration and memory

Any of the previously discussed complications associated with obstructive sleep apnea (e.g., hypertension, stroke, motor vehicle accidents) should be documented. The physical examination may reveal common physical traits associated with obstructive sleep apnea, including [32]:

- Increased neck circumference (>17 inches in men, >16 inches in women)

- BMI ≥30

- Large tongue (modified Mallampati score of 3 or 4)

- Lateral peritonsillar narrowing

- Tonsillar hypertrophy

- Elongated/enlarged uvula

- High arched/narrow hard palate

- Nasal abnormalities (e.g., deviation, polyps, valve abnormalities, turbinate hypertrophy)

- Retrognathia

- Overjet (protrusion of the upper teeth)

The differential diagnosis of obstructive sleep apnea in adults includes nonpathologic snoring, panic attacks, laryngospasm related to gastroesophageal reflux, and dyspnea associated with pulmonary edema [2].

Testing

Evidence Based Practice Recommendation

The American College of Physicians recommends polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea. Portable sleep monitors are recommended for patients without serious comorbidities as an alternative to polysomnography when it is not available for diagnostic testing.

http://annals.org/aim/fullarticle/1892620

Last Accessed: December 7, 2018

Level of Evidence: Moderate-quality evidence (Randomized, controlled trials with important limitations)

Objective testing with a standardized method follows suspicion of obstructive sleep apnea to confirm the diagnosis and guide the initiation of treatment. In-laboratory polysomnography is the preferred method of objective sleep testing and is recommended for most patients [32]. At-home testing with portable monitors may be used prior to laboratory testing or to confirm the efficacy of treatments, but it should not be used for individuals with a high degree of comorbidity unless in-laboratory monitoring is not feasible due to safety or mobility issues.

Diagnostic Criteria for Adult Patients

The AASM has established diagnostic criteria for adults suspected of having obstructive sleep apnea. In all cases, the disorder must not be better explained by another current sleep disorder, medical or neurologic disorder, medication use, or substance use disorder. In addition, patients must display the following signs and symptoms [2]:

- Polysomnographic recording or out of center sleep testing showing 15 or more predominantly obstructive respiratory events (i.e., apneas, hypopneas, or respiratory effort-related arousals) per hour of sleep

OR

- Polysomnographic recording or out of center sleep testing showing five or more predominantly obstructive respiratory events per hour of sleep

- At least one of the following:

- Complaints of daytime sleepiness, unrefreshing sleep, unintentional sleep episodes during wakefulness, fatigue, or insomnia

- Waking with breath holding, choking, or gasping

- Bed partner or observer reports loud snoring, breath interruptions, or both

- Diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes

Diagnostic Criteria for Pediatric Patients

The criteria established to diagnose obstructive sleep apnea in adults have been found to be insufficient to identify children with the disorder. For these patients, parents or caretakers must report a history of labored breathing, snoring, or both, and observation of at least one of the following must be made to diagnose pediatric obstructive sleep apnea [2]:

- Snoring

- Labored, paradoxical, or obstructed breathing during sleep

- Sleepiness

- Hyperactivity

- Behavioral problems

- Learning problems

Differentiating obstructive sleep apnea from primary snoring requires the use of polysomnography. Further, one (or more) scorable event per hour must be recorded during the sleep study. For diagnosis of obstructive sleep apnea in children, polysomnographic findings must include [2]:

- One or more obstructive apneas, mixed apneas, or hypopneas, per hour of sleep

OR

- A pattern of obstructive hypoventilation, defined as at least 25% of total sleep time with hypercapnia (PaCO_2 > 50 mm Hg) in association with one or more of:

- Snoring

- Flattening of the inspiratory nasal pressure waveform

- Paradoxical thoracoabdominal motion

The disorder must also not be better explained by any other medical condition, including another sleep disorder.

Treatment

Due to the chronic nature of the disorder, obstructive sleep apnea treatment is typically long-term and includes behavioral, medical, and surgical options. Patient education regarding the clinical consequences, natural history, pathophysiology, and risk factors of the disorder, and general information, such as alcohol avoidance, risk factor modification, medication effects, weight loss, sleep position, and drowsy driving, should be given upon diagnosis. The goals of treatment are to improve breathing during sleep, to lessen or prevent the sequelae associated with excessive daytime sleepiness and the disorder itself, and patient and partner satisfaction [32].

Positive Airway Pressure Therapy

According to the American College of Physicians (ACP) the principal initial treatment for obstructive sleep apnea is positive airway pressure (PAP) therapy, which uses forced air to maintain a patent pharyngeal airway [62]. This therapy may be provided in one of three modes: continuous (CPAP), bilevel (BPAP), or autotitrating (APAP), all with or without pressure relief (i.e., partial pressure reduction during expiration) [32,60]. CPAP is the standard mode of PAP therapy; BPAP and APAP are used when CPAP cannot be tolerated. CPAP therapy is also recommended for patients with mild obstructive sleep apnea who have failed to improve with behavior modification or who are unable to enact lifestyle changes and who have symptoms that affect their ability to perform daily tasks and impact their quality of life [60].

CPAP appliances consist of a mask or other device that fits over the nose or the nose and mouth, a tube that connects to the mask, and a motor that blows air into the tube [63]. A humidifier and/or heater can be used to condition the device air and lessen or prevent complications, such as throat irritation, nasal dryness, and nasal bleeding. Many patients have difficulty adjusting to wearing the mask and may feel confined during sleep. Periodically wearing the mask during the day, trying CPAP while awake, or using relaxation exercises should be recommended to help in getting comfortable with the device [63]. Newer machines have a "ramp" feature that slowly builds to the prescribed pressure level, which can help with adjusting to the unnatural feeling that CPAP can create.

The clinical effectiveness of CPAP therapy on measures of self-reported daytime sleepiness, fatigue, cognitive function, and depression is supported by evidence. However, the effect on other measures, such as hypertension and cardiovascular events, is unclear [63]. A 2012 clinical trial summary showed that 19% of patients in the CPAP study group developed hypertension, compared with 22% in the control group (dietary and sleep hygiene counseling), and 8% of patients using CPAP had a cardiovascular event, compared with 8% in the control [64]. Although the authors stated that CPAP therapy outcomes failed to reach statistical significance in reduction of these two measures, the small study size may have had limited power to detect a significant difference. A meta-analysis that included 3,780 patients found that, compared with medical therapy alone, CPAP was not associated with a reduced risk of major adverse cardiac events. Improved cardiac outcomes were observed only in a subgroup of patients who wore the CPAP mask for more than four hours at a time [65].

Oral Appliances

Evidence Based Practice Recommendation

The American Academy of Sleep Medicine recommends sleep physicians consider prescription of oral appliances, rather than no treatment, for adult patients with obstructive sleep apnea who are intolerant of CPAP therapy or prefer alternate therapy.

http://jcsm.aasm.org/ViewAbstract.aspx?pid=30098

Last Accessed: December 7, 2018

Level of Evidence: Moderate

An oral appliance is a custom-fit, molded mouthpiece that is fitted by a dental professional to enlarge the upper airway and/or decrease upper airway collapsibility. There are two types of oral appliances: mandibular advancement devices (MADs), which advance the mandible with respect to the resting position and cover the upper and lower teeth, and tongue-retaining devices, which do not reposition the mandible but hold the tongue forward relative to the resting position. The ACP recommends MADs as an alternative for patients who cannot tolerate or would prefer not to use PAP therapy [62]. A complete dental history and dental examination for appraisal of characteristic patterns of wear from nocturnal bruxism; soft tissue, periodontal, and temporomandibular joint (TMJ) assessment; evaluation of occlusion; and resolution of dental pathology precludes the fitting of the appliance. The type employed will be based on a patient's individual anatomy, preferences, and dental assessment. MADs require satisfactory jaw range of motion, no important TMJ disorder, and enough healthy teeth upon which to seat the oral appliance.

A 2006 Cochrane Database review found that oral appliances had similar effectiveness on self-reported outcome measures (e.g., subjective sleepiness, depression) as CPAP therapy but were inferior in reducing respiratory disturbances among most patients [66]. Patients expressed a strong preference for the oral appliances. However, participants were more likely to withdraw on oral appliances than on CPAP therapy. Oral appliance therapy is recommended for patients with mild obstructive sleep apnea who fail behavioral treatments or for patients with mild-to-moderate obstructive sleep apnea who prefer the option over CPAP, who are not candidates for CPAP, or who do not respond to CPAP, or for those carefully selected patients in whom they are as effective in reducing daytime symptoms and AHI score [32,66].

Behavior Modification

There have been no large-scale clinical trials of dietary, exercise, medication, or surgical weight-loss interventions on outcomes in patients with sleep disordered breathing. However, the ACP recommends that all overweight and obese patients diagnosed with obstructive sleep apnea be encouraged to lose weight [62]. Many small-scale studies have shown that BMI reduction (by any means) is effective at reducing the number and duration of apnea and hypopnea events [53]. Other behavioral options include positional therapy and avoidance of alcohol and sedative drugs.

A 10% weight loss can considerably reduce the total number of obstructive events per night, and all patients should be strongly encouraged to achieve a BMI ≤25 through a combination of diet and exercise to improve obstructive sleep apnea symptoms and lessen the risk of comorbidities [32,56]. Subsequent to body mass reduction, AHI should be reassessed using in-lab polysomnography to determine whether PAP adjustments are needed or if PAP therapy may be discontinued altogether. Because significant and lasting weight reduction is typically not achieved by most patients, especially with a dietary component alone, other treatment strategies should be employed simultaneously [32]. Even sustained weight loss does not often fully alleviate the disorder.

A supine sleep position is most likely to affect breathing, and maintaining a non-supine position throughout sleep helps to keep the airway patent in some patients [32]. Identification of individuals who have a low AHI in a non-supine position is necessary before positional therapy is initiated. If appropriate, a device (e.g., alarm, backpack, tennis ball, pillow) may be employed to keep the patient from sleeping on his or her back.

Surgical Treatment

Before the widespread use of PAP therapy, surgery was the primary treatment for obstructive sleep apnea, and it is still indicated for certain cases. Many surgical options involving reconstruction (or bypass) of the upper airway can be used to reduce the severity of obstructive sleep apnea symptoms and increase the effectiveness of behavioral and medical treatments (Table 4); however, it is beyond the scope of this course to cover the details of each procedure. Bariatric weight-loss surgery is also considered a treatment for obstructive sleep apnea and is indicated for patients with a BMI ≥40 or BMI ≥35 with significant comorbidities and failure to achieve weight loss with diet and exercise [32].

Table 4: COMMON SURGICAL PROCEDURES FOR OBSTRUCTIVE SLEEP APNEA BY SITE

Site

Procedure

Upper airway

Tracheotomy

Nasal

Septoplasty

Functional rhinoplasty

Nasal valve surgery

Turbinate reduction

Nasal polypectomy

Endoscopic procedures

Oral, oropharyngeal, and nasopharyngeal

Uvulopalatopharyngoplasty and variations

Palatal advancement pharyngoplasty

Tonsillectomy and/or adenoidectomy

Excision of tori mandibularis

Palatal implants

Hypopharyngeal

Tongue reduction

Partial glossectomy

Radiofrequency ablation

Lingual tonsillectomy

Tongue advancement/stabilization

Genioglossus advancement

Hyoid suspension

Mandibular advancement

Tongue suspension

Laryngeal

Epiglottoplasty

Hyoid suspension

Global airway

Maxillomandibular advancement

Bariatric surgery

Source: [32]

After a diagnosis of obstructive sleep apnea has been established, it should be determined if patients are appropriate candidates for surgery as a primary, secondary, or adjunct treatment [67]. Candidates should also be screened for comorbidities that would affect the outcome of surgery. This and individual anatomy will dictate which option is chosen. Patients with obstructive sleep apnea who have gross anatomic abnormalities that are correctable (e.g., tonsillar and/or adenoidal hypertrophy, collapse or narrowing of the retropalatal or retrolingual areas) should be considered for primary surgical treatment regardless of the severity of the disorder [32]. Surgery as secondary treatment should be considered for patients who have failed to improve with PAP therapy or with an oral appliance or who cannot tolerate either modality. Upon examination of the upper airway, a patient with a gross obstruction that is deemed likely to interfere with the placement, effectiveness, or tolerance of either oral appliances or PAP should be considered a candidate for surgery as an adjunct treatment [32].

The goals, benefits, risks, complications, and possible side effects of the chosen procedure(s) should be discussed, and the willingness to undergo surgical therapy should also be assessed. Although certain procedures (e.g., maxillomandibular advancement, radiofrequency ablation) seem to be effective in reducing AHI score, evidence for most procedures is of low quality and long-term data regarding effectiveness and sequelae is not available [67]. Patients should be informed that most surgeries will not cure obstructive sleep apnea but may improve clinical outcomes (e.g., cardiovascular risk, daytime sleepiness, mortality) [32]. The exception is tracheotomy, which can completely eliminate obstructive sleep apnea but not improve blood oxygen saturation or resolve other symptoms of hypoventilation syndrome. Tracheotomy for obstructive sleep apnea is typically only performed when all other options have been exhausted, when clinically urgent, or in special populations (e.g., patients with Alzheimer disease, Down syndrome, or mental and physical handicaps), as it is a radical procedure that requires a high level of care and lifestyle modification [67].

Pharmacologic and Oxygen Therapies

There are no effective pharmacotherapies for obstructive sleep apnea with the exception of medications used to treat conditions (e.g., hypothyroidism, acromegaly) that can precipitate obstructive sleep apnea or that worsen symptoms of the disorder (e.g., rhinitis) [32]. Patients with persistent daytime sleepiness (despite well-documented improvement in AHI score with PAP or other treatments) may benefit from use of the analeptic modafinil. All other causes of daytime sleepiness must be ruled out and PAP therapy should not be discontinued when taking modafinil. This drug is also used for the treatment of narcolepsy and will be discussed in detail later in this course.

Oxygen therapy is not considered a useful treatment for obstructive sleep apnea, as it has been found that it can lengthen the duration of apneas [32]. However, it is sometimes used to relieve hypoxemia. Resolution of hypoxemia must be documented to justify continued use, especially in patients with comorbid respiratory disease who are at an increased risk of hypercapnia with oxygen therapy.

6. CENTRAL DISORDERS OF HYPERSOMNOLENCE

The ICSD-3 category of central disorders of hypersomnolence includes those that cause excessive daytime sleepiness as the primary complaint; circadian-rhythm shifts and disturbed nocturnal sleep must not be the cause of the primary symptom [2]. The eight disorders in this group are narcolepsy type 1 (with cataplexy); narcolepsy type 2 (without cataplexy); idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder; hypersomnia due to a medication or substance; hypersomnia associated with a psychiatric disorder, and insufficient sleep syndrome [2]. For simplification, the two types of narcolepsy will be discussed as one in the following section, as will idiopathic hypersomnia, along with a brief section on other ICSD-3 hypersomnias.

NARCOLEPSY

Narcolepsy is a primary disorder of the CNS characterized by recurring episodes (every two to three hours) of extreme sleepiness, sudden and irresistible sleep attacks, disturbed nighttime sleep, and memory problems resulting from sleep deficit [2,68]. Sleep spells (or attacks) usually occur during activities or situations in which sleepiness is common (e.g., as a passenger, in a class with no participation, during movies) and last 10 to 20 minutes, on average. However, they may also occur at times when sleeping is not normal (e.g., while driving, eating, walking, or talking). Individuals will feel rested when they awake, but this sense of refreshment does not last long. Sleepiness soon returns, and the cycle repeats. The disorder strongly features SOREMPs and is associated with several pathologic REM sleep phenomena, including cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations.

Narcolepsy occurs in two basic subtypes: with cataplexy and without. Cataplexy is defined as a loss of bilateral muscle tone triggered by intense emotions with an exciting element (e.g., anger, elation, laughter, surprise, sexual arousal) [2,68]. All skeletal muscle groups may be involved, or the effects may be localized. Typical patterns include weakening of the eyelids, mouth, neck, waist, or upper or lower limbs. Smooth, cardiac, and oculomotor muscles are unaffected. The severity of cataplexy varies between individuals and can range from mild eye droop and slurred speech to buckling of the knees and complete postural collapse with fall. The episodes typically last from seconds to minutes. Recovery is usually immediate and complete, but episodes can be repetitive in some individuals if the emotional stimulus recurs, referred to as status cataplecticus, and in rare instances, recurrent attacks have been known to last for up to one hour [2]. Some patients experience cataplexy daily, while others may experience it less than monthly [68].

Most narcoleptic patients experience sleep paralysis, or an inability to speak or move for one to several minutes (up to one hour rarely) while transitioning into and out of sleep (hypnagogic and hypnopompic, respectively) [2]. Like cataplexy, sleep paralysis is a pathologic version of REM sleep atonia and does not affect smooth, cardiac, or oculomotor muscles; however, a sensation of being unable to breathe often accompanies the episode. In cataplexy and sleep paralysis, extensor and flexor reflexes are both lost, which typically only occurs in healthy individuals during REM sleep [33]. A 2011 meta-analysis of 35 studies found that sleep paralysis is experienced by approximately 7.6% of the U.S. general population at some point in their lives, but up to 60% of patients with narcolepsy regularly experience the phenomenon [69,70,71]. Sleep paralysis is typically accompanied by hallucinations.

The hypnagogic and hypnopompic experiences (HHEs) that accompany sleep paralysis appear in three generalized categories but are overwhelmingly of the first type of hallucination, dubbed "Intruder." These hallucinations are described as a sensed evil, malevolent, or threatening presence [72,73]. The second type, the "Incubus," is less common. Described as a demonic or alien being on/near the bed or on top of the body, it is associated with chest pressure, breathing difficulties, and/or pain. Pain is experienced by some individuals while attempting to move their limbs, and another subset may think their limbs are moving when they actually remain still (e.g., while fighting off a perceived threat) [72]. An extreme sense of dread or terror is usually felt during these two types of experiences. Individuals can misconstrue sounds and visions during HHEs (e.g., an object or a shadow may be seen as demon, but later they can reason the misinterpretation) or they may have full-blown, vivid hallucinations (e.g., interaction with beings they are convinced have an external source) [73]. Interestingly, descriptions of beings are consistent throughout history and across cultures, and it is thought that many alien, ghostly, and demonic assault, visitation, and possession incidents are derived from "Incubus"-type HHEs. The third type, "unusual bodily experiences," is infrequently encountered and is described as a flying/floating, out-of-body, or blissful experience without a frightening component [72].

Epidemiology

Narcolepsy is the second most common sleep-related disorder in the United States (after obstructive sleep apnea), affecting an estimated 1 in 2,000 individuals or an estimated 135,000 to 200,000 Americans [33]. Men and women are equally affected, but prevalence varies by race/ethnicity. For example, compared with the United States, narcolepsy is more common in Japan and less common in Israel. Narcolepsy with cataplexy is less common, estimated to affect 1 in 3,000 Americans [33]. The age of onset is typically between 7 and 25 years.

Risk Factors

The causes of narcolepsy are not well known, so it is difficult to determine the influencing factors. There is a heritable component that can predispose individuals to developing the disorder. Certain gene variants of the human leukocyte antigen (HLA) complex and its receptor, T-cell receptor alpha (TCRA), are strongly associated with narcolepsy [33]. Most (though not all) narcoleptic individuals possess the HLA-DR2 or HLA-DQB1*0602 phenotype, which are risk factors for autoimmune disease. However, inflammatory markers and signs/clinical features of inflammatory processes are typically not found in narcoleptics [74,75,76]. This suggests that if the disorder does have an autoimmune origin, the pathology is confined to the nervous system.

Researchers believe that individuals with the implicated subtypes of HLA and TCRA are more prone to an immune system attack on hypocretin-producing neurons in the hypothalamus [33]. The neurotransmitter protein hypocretin regulates appetite, feeding, and sleep patterns, including keeping brain systems from unexpectedly shutting off while awake. People with narcolepsy with cataplexy (and a certain subset of individuals without cataplexy) typically have very low levels of hypocretin, which could explain why they develop narcolepsy and also the higher rate of obesity in this population [33,77].

Though a genetic predisposition does exist, it does not fully explain development of the disorder, as most individuals with the HLA/TCRA variants do not develop narcolepsy and some narcoleptics do not possess these subtypes. In certain rare instances, tumor growth or head trauma have led to narcolepsy [33]. Other factors, including environmental toxins, stress, dietary factors, changes to the sleep schedule, and hormonal changes, likely contribute to the development of the disorder. Infectious agents have been identified as triggers for narcolepsy, particularly Streptococcus spp. and the H1N1 influenza virus, but it is not yet known if the infections are direct triggers or if they indirectly increase susceptibility (e.g., due to the relaxed blood-brain barrier during fever) [33].

Diagnosis

Evidence Based Practice Recommendation

According to the European Federation of Neurological Societies, a prerequisite before implementing a potentially lifelong treatment is to establish an accurate diagnosis of narcolepsy with or without cataplexy and to check for possible comorbidity. Following a complete interview, the patient should undergo an all-night polysomnography followed immediately by a multiple sleep latency test.

https://www.eaneurology.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2011_Management_of_narcolepsy_in_adults.pdf

Last Accessed: December 7, 2018

Level of Evidence: Expert Opinion/Consensus Statement

As discussed, the most common presentation for all sleep disorders, including narcolepsy, is excessive daytime sleepiness. Cataplexy is rare without narcolepsy and is considered a positive indicator of the disorder [33]. If cataplexy is not present, all other causes of excessive sleepiness must be ruled out by collecting a thorough medical history and conducting an exhaustive clinical examination. The Epworth Sleepiness Scale can be used to identify excessive daytime sleepiness. For the diagnosis of narcolepsy to be confirmed, polysomnography and an MSLT should be performed in a sleep clinic. A polysomnographic study for narcolepsy is similar to an obstructive sleep apnea study. The MSLT will indicate shorter sleep latency periods in patients with narcolepsy compared with healthy individuals [33].

Laboratory testing may include cerebrospinal fluid (CSF) hypocretin-1 levels, but the value of this test is debated [2,33,78]. CSF hypocretin sampling is generally not recommended unless MSLTs are inconclusive or unavailable. This is because reduced or absent levels are usually only found in patients with cataplexy [33,78]. Although most narcoleptic patients without cataplexy have normal hypocretin levels, there is a subset who is deficient, including individuals with the HLA-DR2 phenotype, those at a younger age at onset, and patients with shorter mean REM latency periods [77].

Treatment

Narcolepsy is incurable, and the loss of hypocretin in patients with cataplexy is believed to be irreversible [33]. However, there are several pharmacologic and behavioral treatment options that, when combined, can greatly reduce symptoms of the disorder and help improve patients' quality of life.

Pharmacologic Therapies

Traditional drug treatment options for narcolepsy have included CNS stimulants taken during the daytime to help patients remain alert, sedatives taken at night to help patients attain more restful sleep, and tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) to help control cataplexy, sleep paralysis, and HHEs [33,79,80]. Certain drugs have been found to exert multiple effects; for example, modafinil, a stimulant drug used to treat daytime sleepiness, may also exert antidepressant effects by modulating serotonin transmission [81]. These drug classes are still recommended for prescription today, but the use of a single drug, sodium oxybate, to control all symptoms of narcolepsy (including cataplexy) is gaining favor following a series of successful clinical trials [80,82,83,84,85,86]. However, due to abuse potential, access to the drug is tightly restricted [33,46].

If a CNS stimulant is prescribed in order to combat the effects of excessive daytime sleepiness, the most common are various amphetamines and methylphenidate [33,79]. These agents can be effective in reducing daytime sleepiness and the occurrence of sleep attacks. Amphetamines (e.g., amphetamine, dextroamphetamine, methamphetamine) have been prescribed for narcolepsy since the 1930s and, at lower dosages, act primarily by causing dopamine (and noradrenaline) release [87]. They may be prescribed at 10–60 mg/day. However, amphetamine use is associated with a number of adverse effects, including headache, insomnia, irritability, nervousness, and palpitations, and less frequently, anorexia, hyperhidrosis, nausea, orofacial dyskinesia, and psychosis [79]. Abuse of prescribed amphetamines is rare among narcoleptics, but tolerance develops in one-third of patients. Due to these risks and the proven efficacy of newer drugs, amphetamines are no longer recommended as first- or second-line therapy. Methylphenidate has similar, though milder, adverse effects and a much shorter half-life [80]. It is also prescribed at 10–60 mg/day, but it is recommended only when modafinil is insufficiently active, when modafinil must be supplemented at a specific time of the day, or in situations where maximum alertness is required [33,78].

Modafinil, a stimulant, was approved for use in the United States in 1998 and is the treatment of choice for narcolepsy when the most serious symptom is excessive daytime sleepiness due to its efficacy, limited adverse effects, and easiness of manipulation [33,78]. To date, researchers have been unable to determine the exact mechanism(s) of action, but modafinil is known to increase the release of monoamines (e.g., dopamine, norepinephrine, histamine) from synapses [79,88]. Therefore, the central histaminergic and dopaminergic systems are suspected to be involved. Unlike with classic CNS stimulants, the coadministration of a dopamine antagonist only partially weakens the effectiveness of modafinil, leading researchers to describe the drug as a wakefulness promoting agent [89]. The starting dose is 200 mg, and the usual effective dose is 200–400 mg taken as a single morning dose or as a split dose (first in the morning and then around noon). However, evidence of benefit with a dose greater than 200 mg/day is lacking [46]. There is a low prevalence of common side effects, including headache (13%), nervousness (8%), nausea (5%), and rhinitis, all of which are typically mild [78,80]. More serious side effects have been noted and are mainly allergic/inflammatory reactions, including hives, rash, and swelling. Other severe dermatologic reactions have occurred, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), prompting the FDA to issue a safety labeling change in 2007 [46]. There have been very few instances of DRESS, Stevens-Johnson syndrome, and TEN (less than 10 since 1998), and modafinil is considered a safe treatment for excessive daytime sleepiness.

For patients with excessive daytime sleepiness with poor nighttime sleep and cataplexy, the first-line treatment is sodium oxybate [78]. This drug, also known as gamma hydroxybutyrate (GHB), is a powerful sedative that has been burdened by the stigma as a party or "date-rape" drug and a performance-enhancing drug [80]. Misuse of the drug can be life-threatening, and steps should be taken to ensure no other sedatives (including alcohol), muscle relaxants, or respiratory depressants are taken concurrently and that sleep disordered breathing is not present or does not develop. Sodium oxybate is restricted and can only be prescribed by those enrolled in the Xyrem Patient Success Program and dispensed by the designated centralized pharmacy [46]. The initial dose is 4.5 g/night in two equal doses [46]. The first dose is taken sitting upright in bed just before sleep; the patient should lie down immediately after dose one; the second dose is taken 2.5 to 4 hours later. (An alarm may be necessary.) The dose can be increased by 1.5 g at two-week intervals up to a maximum dose of 9 g/night [46,78]. Patients usually begin to improve after the first few nights, but the optimal response (even at the starting dose) can take up to 8 to 12 weeks. Adverse effects are common and include headache (9% to 37%), dizziness (8% to 37%), nausea (8% to 40%), vomiting (2% to 23%), pain (9% to 20%), confusion (3% to 17%), sleep disorder (6% to 14%), somnolence (1% to 14%), abdominal pain (3% to 11%), enuresis (3% to 17%), and urinary incontinence (<1% to 14%, usually nocturnal) [46].

Antidepressants are considered second-line agents for cataplexy and are also an effective treatment for sleep paralysis and HHEs [78]. The most potent anticataplectic drugs are tricyclic antidepressants, especially clomipramine (10–75 mg). However, these agents have the disadvantage of anticholinergic side effects. SSRIs have fewer side effects but are slightly less active [78]. Venlafaxine, a norepinephrine/serotonin reuptake inhibitor, is widely prescribed despite a lack of published clinical evidence to support its use. The same paucity of data exists for norepinephrine reuptake inhibitors (e.g., reboxetine, atomoxetine) [78]. Other pharmacologic agents are no longer recommended for use based on either a lack of clinical efficacy data or on their undesirable adverse effects and safety profiles [78].

Caution should be given when treating patients with comorbid psychiatric disorders. Sodium oxybate should not be used in patients with depression. Instead, antidepressants should be prescribed along with a referral to a psychiatrist or mental health provider [78].

Behavioral Therapies

There are several lifestyle and dietary changes that may help reduce the symptoms and risks of narcolepsy, although there are no accepted behavioral treatments for cataplexy [78]. Behavior modification is useful as medications cannot ensure a consistent state of alertness in individuals with the disorder. Practicing strict sleep hygiene is important, and engaging in relaxation exercises or taking a bath before bedtime may offer a benefit [33]. Daytime napping has been shown to improve alertness and shorten reaction times [33]. Regular exercise (20 minutes/day, four to five hours before bedtime) can lead to better sleep and help prevent or reduce narcolepsy-related weight gain. Alcohol and caffeine should be avoided, especially at night.

One of the major risks of narcolepsy is falling asleep while performing hazardous tasks (e.g., driving, operating machinery) or collapsing due to cataplexy at an ill-timed moment (e.g., while descending a stairway). Automobile accidents are 10 times more common in individuals with untreated narcoleptic symptoms, but when medication and behavioral therapies are being used, the accident rates are similar to healthy individuals [33]. Scheduled naps are recommended to reduce the likelihood of falling asleep unexpectedly. The Americans with Disabilities Act guarantees equal opportunity for narcoleptic students and workers, and reasonable adjustments to school and work schedules should be encouraged to accommodate periodic naps [33].

Support groups for narcolepsy are helpful for many patients. Overcoming feelings of isolation by connecting with other people with the disorder and lessening the sense of judgment by outsiders are important both for those who have just received a diagnosis and experienced patients alike. It may be difficult for individuals living in non-metropolitan areas to find a support group, and for these patients online groups can be useful. More information about narcolepsy support groups is available at https://www.narcolepsynetwork.org. The Narcolepsy Network offers meetings in several U.S. cities and hosts online support groups as well [90].

IDIOPATHIC HYPERSOMNIA

Idiopathic hypersomnia is a rare disorder, affecting approximately 50 people per million population [91]. However, there are many potential causes of daily, unrelenting hypersomnia, and the disorder is a consideration in the differential diagnosis of several other conditions and sleep disorders. Therefore, a brief discussion is warranted.

Idiopathic hypersomnia is characterized by excessive daytime sleepiness without cataplexy and is not better explained by another disorder [2]. Most hypersomniacs have extreme difficulty waking from sleep. If naps are taken, they are usually longer than those taken by individuals with narcolepsy, and many patients experience confusion or disorientation, called sleep drunkenness, upon waking [92]. Also unlike narcolepsy, most (though not all) patients wake from naps still feeling drowsy or unrefreshed. Irresistible urges to sleep (sleep attacks) are rare with this disorder, and cataplexy is not a feature [91,92]. Narcoleptics typically have disturbed nighttime sleep, whereas patients with this disorder do not. Unusual or inappropriate behaviors (e.g., staring, acting intoxicated) may occur in patients who do not take daytime naps.

Diagnosis

There are many medical conditions that can cause hypersomnia, including Kleine-Levin syndrome, Parkinson disease, dementia, and post-traumatic stress disorder, all of which should be ruled out with a complete medical history, physical examination, and diagnostic workup. Standard sleep studies are used to confirm the diagnosis of idiopathic hypersomnia, including MSLT and polysomnography. The absence of multiple SOREMPs (one or fewer) during MSLT and greater time spent in slow-wave sleep during polysomnography suggest idiopathic hypersomnia [91]. On the other hand, multiple SOREMPs (two or more) are indicative of narcolepsy.

Treatment

The same array of pharmacologic options used to treat excessive daytime sleepiness in narcolepsy may be prescribed for idiopathic hypersomnia, but the level of effectiveness is typically not replicated [91,92]. Only half of patients treated report any improvement of symptoms. Although sleep hygiene practices are usually not helpful for idiopathic hypersomnia patients, they should be discussed because there are virtually no risks or drawbacks [91]. Patients should be advised to avoid sedative drugs and alcohol.

OTHER HYPERSOMNIAS

Recurrent hypersomnia is characterized by periodic episodes of extreme somnolence accompanied by cognitive and behavioral disturbances lasting for days to weeks that punctuate an otherwise normal, healthy sleep pattern. During hypersomnia episodes, patients may sleep up to 20 hours per day (range: 10 hours to nearly 24 hours) [2,93]. The average number of episodes is 2 per year, but it can occur up to 12 times per year. The most commonly known form of this disorder is Kleine-Levin syndrome, but there are other forms of recurrent hypersomnia with incomplete features of the syndrome, which may be associated with a medical disorder, psychologic disorder, or medication/substance use [2]. Kleine-Levin syndrome is exceptionally rare in the United States, with fewer than 1 case per million population, although some believe this is an underestimate [93]. The prevalence is greater in individuals of Jewish descent compared with the overall population [94]. The onset of Kleine-Levin syndrome usually occurs in adolescence and follows an infection, such as a cold or influenza.

All patients with recurrent hypersomnia have various forms of cognitive impairment and altered perception during episodes [94]. Cognitive symptoms include impaired speech (94%), difficulty with concentration (91%), and memory impairment (66%). Altered perception symptoms include dream-like state (81%), derealization (66%), and hypnagogic hallucinations (42%). Many patients experience other psychologic symptoms, including eating behavior disorders (95%), hypersexuality and disinhibition (53%), and depressed mood (53%) [94].

Recurring excessive sleepiness can occur during the premenstrual period in adolescent girls, referred to as menstrual-related hypersomnia, and is often controlled with birth-control pills [95]. This and other disorders that cause bouts of excessive sleepiness (e.g., encephalopathy, depression) should be differentiated from hypersomnia disorders.

Treatments include various stimulants, lithium, carbamazepine, and the antiparkinsonian drug amantadine, all of which have marginal efficacy [94,95]. Hypersomnia episodes typically decrease in intensity and frequency within 8 to 12 years of onset, with eventual complete resolution common.

7. CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS

Disorders that fall into the ICSD-3 category of circadian rhythm sleep-wake disorders are caused by alterations to the internal circadian timekeeping system or by environmental, physiologic, or behavioral factors that alter timing of sleep relative to an individual's circadian rhythm, leading to insomnia and/or excessive daytime sleepiness and impaired functioning [2]. Sleep timing that does not follow circadian rhythms will typically cause nonoptimal sleep. The ICSD-3 contains seven disorders of this type [2]:

- Delayed sleep-wake phase disorder

- Advanced sleep-wake phase disorder

- Irregular sleep-wake rhythm disorder

- Non-24-hour sleep-wake rhythm disorder

- Shift work disorder

- Jet lag disorder

- Circadian sleep-wake disorder not otherwise specified NOS

Most circadian rhythm sleep disorders are uncommon or occur overwhelmingly in specific populations (e.g., the non-24-hour sleep-wake rhythm type in blind individuals). Jet lag and shift work disorders are related to very specific sets of conditions. Medical conditions that may be responsible for circadian rhythm abnormalities include dementia, Parkinson disease, and hepatic encephalopathy [2]. Delayed sleep-wake phase disorder affects a significant number of adolescents and young adults.

DELAYED SLEEP-WAKE PHASE DISORDER

Delayed sleep-wake phase disorder is characterized by a habitually delayed sleep time (relative to socially acceptable or conventional sleep times) with difficulty falling asleep when others do [2]. The offset is usually more than two hours, but sleep is normal once initiated (though a late wake time is preferred if allowed). Daytime functioning is normal when individuals are allowed to sleep later, but dictated schedules cause deteriorated well-being. Depression or suicidal ideation may be the primary reason for adolescents' clinical presentation [2]. Patients with this disorder are definite "evening types."

The incidence of this disorder is unknown in the general population, but it is more common in adolescents and young adults (7% to 16%), with a mean onset of 20 years of age [2]. About 1 in 10 sleep clinic patients with chronic insomnia have a delayed sleep phase. Roughly 40% of patients with this disorder have a family member with the disorder [2].

Staying up late, with activity and indoor bright lights, can promote the disorder, as can a corresponding reduction in bright morning light [2]. Shift work, changes in schedules, and frequent travel across time zones can also precipitate the disorder. Attempts at retraining, using sleep hygiene and bright light therapy may work, but patients usually maintain a strong desire for "eveningness" despite intervention [2].

8. PARASOMNIAS

In the ICSD-3, parasomnias are divided into three categories: non-REM-related parasomnias (i.e., disorders of arousal from non-REM sleep), REM-related parasomnias, and other parasomnias [2]. Non-REM-related parasomnias consist of disorders of arousal, confusion arousals, sleepwalking, and sleep terrors, and sleep-related eating disorder; parasomnias usually associated with REM sleep consist of REM sleep behavior disorder, recurrent isolated sleep paralysis, and nightmare disorder. Other parasomnias consist of exploding head syndrome, sleep-related hallucinations, sleep enuresis, parasomnia due to a medical disorder, parasomnia due to a medication or substance, and parasomnia, unspecified [2].

SLEEPWALKING

Sleepwalking, or somnambulism, is a non-REM arousal disorder that causes individuals to walk or perform other activities while asleep. Activities may include sitting upright in bed, walking around inside/outside the house, moving furniture, getting dressed, preparing food, trying to "escape," jumping from windows, driving a car, and many others, though dangerous activities are rare [96,97]. It is fairly common for sleepwalking children to engage in inappropriate behaviors, such as urinating in a closet or waste basket [2]. Accidents and falls may also occur, and people have even committed homicide or pseudosuicide while asleep. Patients can become violent when others attempt to awaken them from the sleepwalking episode, and most will be extremely confused if awakened and will not recall the events of the episode [96,97].

It should be noted that sleep driving associated with z-drugs (e.g., zolpidem, zopiclone) and other psychiatric medications is unrelated to sleepwalking [98]. Sleep drivers will typically have some level of cognitive function (e.g., are responsive to police questioning) but will display poor balance and walking ability. Sleepwalkers, on the other hand, are perfectly able to balance while walking but have no ability to interact.

Sleepwalking typically occurs during non-REM sleep stages 3 and 4 (slow-wave sleep), which is more common early in the night (during the first-third of sleep) [96]. Episodes last an average of 10 minutes but range from a few minutes to more than 30 minutes. Patients usually return to bed before waking, but some may fall asleep in another location or awaken while sleepwalking [2]. Sleep talking may also be exhibited by these individuals, and sleep terrors may occur at other times. Sleepwalking episodes may occur frequently (several times per night, for several nights) or only rarely or when precipitating factors are present [2].

Epidemiology

The prevalence of sleepwalking ranges from 4% in adults to 17% in children [2]. The disorder may begin as soon as a child is able to walk, but the age of onset is usually between 4 and 8 years. The disorder is most common in children 5 to 12 years of age [2,96]. A 2004 National Sleep Foundation poll found that sleepwalking a few nights per week occurs in 1% of preschoolers and 2% of school-age children [99]. Sleepwalking is more common in children with sleep enuresis (chronic bedwetting). Symptoms of sleepwalking disappear after adolescence in most patients; however, the disorder can occur at any age [2,96]. Approximately one-third of cases develop after adolescence [2]. Girls and boys are affected equally in childhood, but the gender distribution in adults is not well defined [2]. One study of an adult population of sleepwalkers in Nigeria found prevalence roughly three times higher in men than in women [100].

Sleepwalking may occur in isolated cases, but there is a known genetic susceptibility and a familial pattern [2,101]. The incidence in children is 60% when both parents have the disorder and 45% when one parent is affected. The incidence is 22% if neither parent has the disorder but when sleepwalking is familial (i.e., occurs in more distant relatives) [2]. A 2012 Stanford School of Medicine study found that the self-reported yearly incidence of sleepwalking was 3.6%, equating to about 8.5 million Americans [102]. According to the study, the lifetime prevalence of a sleepwalking episode was estimated at 29.2%, with 30.5% of participants reporting a family history of the disorder. Twin studies support the role of genetic susceptibility in at least 65% of cases [2].

Risk Factors

Although there is a strong heritable factor for sleepwalking, the pathology of sleepwalking is not known [2,96]. Individuals who are predisposed to sleepwalking may become active sleepwalkers when priming factors exist and a precipitating factor triggers an episode [2,101]. Priming factors deepen and increase slow-wave sleep and include anxiety, fatigue, fever, the premenstrual period, sleep deprivation, and physical or emotional stress. Alcohol use and certain medications may also be priming factors, but it is unclear if the many case reports of "sleepwalking" under the influence of substances are due to extreme intoxication or complex medication interactions (or medication/psychopathologic interactions) [2,96,101]. Precipitating factors, or triggers, identified in primed individuals in sleep laboratories include light, noise, periodic leg movements, sleep disordered breathing, and touch.

Certain mental disorders (e.g., obsessive-compulsive disorder) and medical conditions (e.g., organic brain syndrome, partial complex seizures) are associated with sleepwalking, as is obstructive sleep apnea [2,96,102]. Medication-related sleepwalking may occur, most commonly in individuals with a complex medical and psychiatric history associated with multiple medications [101]. The 2012 study found a higher risk of frequent sleepwalking episodes (two or more times/month) with obstructive sleep apnea syndrome (odds ratio [OR]: 3.9), obsessive-compulsive disorder (OR: 3.9), alcohol abuse/dependence (OR: 3.5), major depressive disorder (OR: 3.5), circadian rhythm sleep disorder (OR: 3.4), SSRI antidepressant use (OR: 3.0), over-the-counter sleep aid use (OR: 2.5), and insomnia disorder (OR: 2.1) [102].

Diagnosis

Steps should be taken to ensure that sleepwalking is not the result of a medication side effect or an underlying medical or psychiatric condition. Specific medications and their dosages should be reviewed. In cases of pediatric sleepwalking, parents or caretakers will have witnessed one or more behaviors associated with the disorder, including [96,97]:

- Aggressive behavior when aroused (rare)

- The appearance of being awake while still asleep

- Open eyes during sleep, with a blank look on the face

- Confusion or disorientation when roused

- Performance of detailed activities during sleep

- No memory of the sleepwalking episode

- Sleep-talking and nonsensical verbalizations

Adult patients with no history of the disorder may similarly present with no recollection of any episode of sleepwalking or associated behaviors, which may have instead been witnessed by another person. Sleep studies and other tests and procedures are typically not needed to confirm a diagnosis in patients with known good health [2,96]. However, testing to rule out other medical conditions (e.g., partial complex seizures, obstructive sleep apnea) in patients with a limited medical history is recommended.

Treatment

There is no cure or specific treatment for sleepwalking [96,99]. As a first step in the management of sleepwalking, conditions or medications that may cause somnambulism should be identified and treated or discontinued, which may eliminate or greatly reduce sleepwalking episodes. For patients with sleepwalking as the primary diagnosis, identifying the priming and precipitating factor(s) is a cornerstone of management. Patients (or parents) should be instructed to keep a journal that includes daily activities, level of daytime sleepiness, total hours of sleep, and any illnesses or triggers of stress or anxiety to help to determine possible triggers, though dedication to observation and journaling lessens and more omissions occur over time [103].

Again, there is no high-quality evidence to support any specific sleepwalking treatment [99,104]. A tailored approach to therapy, including improvements in sleep hygiene, should be made on a patient-by-patient basis. Although medication is not usually required and is not recommended as a first-line therapy, sedative-hypnotics, tricyclic antidepressants, or SSRIs may be prescribed if sleepwalking interferes significantly with the patient's or the family's quality of life (e.g., excessive daytime sleepiness, high risk of injury, unusual symptoms, inappropriate behaviors causing family distress) [96,99]. However, the usefulness of these medications is not certain [105,106]. Care must be taken when prescribing tricyclic antidepressants, as they have many serious side effects (especially in children) and can exacerbate sleepwalking [107]. Benzodiazepines (e.g., clonazepam, diazepam) were initially prescribed for sleepwalking, with only limited benefit [105,106]. One study of individuals with either isolated sleepwalking or sleepwalking related to psychiatric conditions or obstructive sleep apnea found that benzodiazepines and psychiatric medications were not effective in reducing sleepwalking episodes. Nasal CPAP therapy for participants with obstructive sleep apnea eliminated sleepwalking in all individuals who remained compliant throughout each of the follow-up periods [106].

Hypnosis has been used as a low-cost, safe therapy for various parasomnias, including sleepwalking [99]. One small-scale study (27 participants) conducted by Hurwitz and colleagues showed a 74% success rate for long-term reduction of sleepwalking and night terror episodes ("much" or "very much" improvement on self-report) following one to six office visits and continued with at-home self-hypnotic exercises [108]. A five-year follow-up study of 36 parasomnia patients (modeled on the Hurwitz study) found a 45.4% success rate after 1 month (symptom free or "much improved"), which diminished slightly to 42.2% at 18 months and 40.5% at 5 years [109]. In this study, participants underwent one or two 50-minute hypnosis sessions, described as "deep physical relaxation but with retention of an active and focused mind, so possible new thoughts could be evaluated and incorporated into the hypnotized person's thinking" [109].

One behavioral approach, anticipatory awakenings, can be effective in reducing sleepwalking episodes. This method requires parents or caretakers to wake the patient three hours into the night and 15 minutes before the usual sleepwalking time. The patient is kept awake for 30 minutes and then may return to sleep. Anecdotal reports have found this intervention to be successful; however, it requires a significant commitment on the part of those involved [107,110].

Another key to treatment is the maintenance of a safe living environment. Patient/parent education should cover precautions to be taken, including [99,107]:

- Locking windows and doors in a way that allows for safe emergency exit

- Installing door alarms on all doors that lead outside or to a basement or attic

- Securing all potentially dangerous objects or items (e.g., tripping hazards, sharp objects, chemicals, medications, knives, guns)

- Moving the patient's bedroom to the ground floor (if possible)

- Covering windows to block out light

9. SLEEP-RELATED MOVEMENT DISORDERS

The ICSD-3 includes 10 sleep-related movement disorder diagnoses: restless legs syndrome; periodic limb movement disorder (PLMD); sleep-related leg cramps; sleep-related bruxism; sleep-related rhythmic movement disorder; benign sleep myoclonus of infancy; propriospinal myoclonus at sleep onset; sleep-related movement disorder due to a medical disorder; sleep-related movement disorder due to a drug or substance; and; sleep-related movement disorder, unspecified [2].

RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER

Although restless legs syndrome and PLMD are two distinct disorders, they are often discussed together, as they have overlapping features. PLMD is also comorbid in most (85% to 90%) patients with restless legs syndrome [2,111].

Restless legs syndrome, also known as Willis-Ekbom disease, is a neurologic sleep disorder characterized by disagreeable leg sensations that worsen when individuals are at rest (e.g., when seated) and/or at night before bedtime [2]. There is an accompanying urge to move the legs to relieve the unpleasant sensations, which are described as aching, bubbling, creeping, crawling, pulling, searing, and/or tingling; walking, stretching, or shaking usually provides relief [112]. The area between the ankle and the knee is most often affected (usually bilaterally), but the thighs, feet, and to a lesser extent the arms may also be affected [2]. Pathologic changes in efficiency of central dopamine neurotransmission are thought to cause the disorder, based on the observation that restless legs syndrome symptoms are relieved by the use of dopaminergic drugs [111]. The secondary (non-idiopathic) form of restless legs syndrome can be caused by a variety of medical conditions. Iron deficiency and uremia are common causes; others include chronic kidney disease, cobalamin (vitamin B12) deficiency, folate deficiency, diabetes, fibromyalgia, Parkinson disease, peripheral neuropathy, pregnancy, radiculopathy, rheumatoid arthritis, Sjögren syndrome, use of certain drugs (e.g., caffeine, calcium channel blockers, lithium, neuroleptics), and withdrawal from sedatives [112,113].

Troubling and painful leg sensations that cause an irresistible urge to move initially keep patients from being able to sleep, and the discomfort is often so disrupting that patients awaken several hours after falling asleep. As such, restless legs syndrome is a significant cause of (secondary) insomnia. Periodic limb movements during sleep are very common in patients with restless legs syndrome, and involuntary limb movements occur in many patients with restless legs syndrome while awake [2]. Involuntary limb movements while awake are much less common among patients with PLMD alone.

PLMD is characterized by episodes of repetitive, stereotyped leg movements during stage 1 and stage 2 sleep, consisting of extension of the big toe in combination with partial flexion of the ankle, knee, and sometimes hip [2,111]. The legs typically remain still during non-REM stages 3 and 4 and during REM sleep. Episodes prevail during the first half of the night and diminish progressively [113]. Intermittent flexion at the elbow may also be seen in some patients.

Some patients may not be roused by the movement episodes and only complain of excessive daytime sleepiness. However, the typical presentation is with frequent awakenings and poor sleep quality (i.e., insomnia). Bed partners' sleep is often disturbed by the movements. As with restless legs syndrome, this disorder is also thought to be caused by altered dopamine neurotransmission (based on the efficacy data of dopaminergic drugs) but can also be caused by a medical condition [111]. Certain medications can cause periodic limb movements during sleep, including tricyclic antidepressants (e.g., amitriptyline), neuroleptics and other antidopaminergic agents (e.g., haloperidol), and dopaminergic agents (e.g., carbidopa, which may be used in the treatment of PLMD).

Epidemiology

Approximately 5% to 15% of the adult U.S. population is affected by restless legs syndrome, and women are affected twice as often as men [2,114]. The disorder is more common in certain groups, including pregnant women (11%), uremic patients (15% to 20%), and patients with rheumatoid arthritis (up to 30%). In general, restless legs syndrome is associated with advancing age; however, the age of onset is younger than 20 years in one-quarter of patients. Among children 8 to 11 years of age and adolescents 12 to 17 years of age, the prevalence is 1.9% and 2.0%, respectively [95]. Restless legs syndrome symptoms usually appear after the 20th week when associated with pregnancy [2].

The exact incidence of PLMD alone is unknown in adults [2]. However, it is very uncommon in children and is more prevalent after middle age, with approximately 44% of adults 65 years of age or older found to have symptoms of the disorder [2,113]. It is unclear if the prevalence among older adults differentiates symptoms indicative of idiopathic PLMD and limb movements related to other conditions, but some questions have been raised as to whether PLMD is a true sleep disorder based on the high prevalence in this population [113].

Risk Factors

There is a strong heritable risk factor for restless legs syndrome [112]. One study found that more than 70% of pediatric patients with restless legs syndrome had at least one parent with the disorder [95]. As noted, restless legs syndrome is more common in women, but race does not appear to be a factor [2]. Overall, prevalence and incidence have not been well defined [95,111].

Medical or psychiatric conditions and certain medications have been associated with an increased incidence of restless legs syndrome and/or PLMD. Children with attention deficit hyperactivity disorder are more likely to have both restless legs syndrome and PLMD. Uremia and other metabolic disorders are known to cause periodic limb movements during sleep [2]. Monoamine oxidase inhibitors and tricyclic antidepressants can cause or worsen the disorder, as can withdrawal from certain drugs, including anticonvulsants, benzodiazepines, barbiturates, and other hypnotic agents. PLMD may be associated with an underlying arousal disorder [111].

Diagnosis

The history and physical examination should focus on differentiating restless legs syndrome from other conditions with shared features, including akathisia, anxiety disorders, chronic myelopathy, erythromelalgia, leg compartment syndromes, muscular pain fasciculation syndromes, myokymia, and peripheral neuropathy [2]. Subclinical hypopneas can also trigger limb movements. Iron-deficiency anemia, caffeinism, and uremia should also be considered as possible causes of secondary restless legs syndrome. The use of and withdrawal from high-risk medications should also be identified from the medical history. All conditions known to cause the symptoms indicative of the disorder should be ruled out, and serology should be obtained (e.g., cobalamin, creatinine, ferritin, folate, iron, urea) [113]. Additional serology and electrodiagnostic testing may be considered if peripheral neuropathy is suspected. The presence of periodic limb movements during sleep is a strong indication of restless legs syndrome. Several instruments are available to measure restless legs syndrome severity, including the Johns Hopkins Restless Legs Syndrome Severity Scale (Table 5) and the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI) [115]. The RLS-QLI consists of 17 items that assess the patient's social function, daily function, sleep quality, and emotional well-being, while the Johns Hopkins measure focuses on timing of symptoms [116,117].

Table 5: JOHNS HOPKINS RESTLESS LEGS SYNDROME SEVERITY SCALE

Timing of Symptoms

Score

No symptoms

0 (never)

Symptoms less than daily or almost daily

0.5 (infrequent)

At bedtime and/or during the sleep period.

Symptoms may occur within 60 minutes before the usual bedtime or simply at the time of going to bed or during the night after in bed.

1 (mild)

Evening, after 6 p.m.

Symptoms may occur anytime between 6 p.m. and the usual bedtime. (The definition of evening may need to be adjusted for patients who routinely have much later bedtimes.)

2 (moderate)

Afternoon, before 6 p.m.

Symptoms may start in the afternoon and persist into the evening or night.

3 (severe)

Before noon.

Symptoms may start in the morning or they may present virtually all day. There is usually a "protected period" in the mid-morning (8–10 a.m.) with few if any symptoms.

4 (very severe)

Source: Reprinted from Allen RP, Earley CJ. Validation of the Johns Hopkins restless legs severity scale. Sleep Med. 2001;2(3):239-242, with permission from Elsevier.

Sleep studies are not typically needed for a diagnosis of restless legs syndrome to be made; however, periodic limb movements during sleep may be confirmed using polysomnography, if necessary [2]. Polysomnographic features of PLMD are recorded using bilateral anterior tibialis EMG. Patterns of movement include repetitive contractions (four or more, with a duration of 0.5 to 5 seconds)—typically a leg jerk, followed by a short interval (milliseconds) and a tonic contraction—spaced apart by 20 to 40 seconds of relaxed muscle tone [2]. Both legs are involved in the majority of patients, but there may be inconsistent and random alternation between the left and right limbs or a unilateral, predominant pattern. The periodic limb movement arousal index measures the number of limb movements associated with EEG arousals per hour. Mild PLMD is defined as 5 to 25 movements per hour, moderate as 25 to 50 per hour, and severe as more than 50 movements per hour or more than 25 movements associated with arousals per hour [113].

Treatment

Anticonvulsants, dopamine agonists, tranquilizers, and opioid narcotics are used to manage symptoms of restless legs syndrome, and iron supplements are used when indicated [111,112]. Dopamine agonists considered effective for restless legs syndrome management include pramipexole and ropinirole, but rotigotine is recommended for long-term therapy [112,118]. These and other antiparkinsonian drugs are also first-line therapies for PLMD and may improve sleep in patients with both disorders. The anticonvulsants gabapentin and pregabalin reduce movement symptoms and neuropathic pain in patients with either restless legs syndrome or PLMD and may also help to improve sleep; however, use of these medications for restless legs syndrome and PLMD is off-label [46,112]. Gabapentin enacarbil is on-label and is preferred over gabapentin for long-term treatment [46,118]. Other treatments for these sleep disorders include stress management, muscle relaxation exercises, and sleep hygiene.

The initial dosage of pramipexole (immediate-release) is 0.125 mg once daily, two to three hours before bedtime, but higher doses (up to 0.5 mg) are typically required in order to be effective [46]. The maximum recommended dose is 0.5 mg, but doses up to 2 mg daily are occasionally used. The most frequent side effects are nausea (11% to 27%), particularly early in treatment, and headache (16%) [46]. There is no evidence that doses higher than 0.5 mg/day offer benefit [119].

Evidence Based Practice Recommendation

The American Academy of Sleep Medicine has identified pramipexole and ropinirole as the agents with the highest level of evidence supporting their use in the treatment of patients with restless legs syndrome.

https://aasm.org/resources/practiceparameters/updateto.pdf

Last Accessed: December 7, 2018

Strength of Recommendation/Level of Evidence: Standard (High or moderate evidence that benefits clearly outweigh harm/burden)

The initial dose of ropinirole (immediate-release) is 0.25 mg taken one to three hours before bedtime; the dose may be increased to 0.5 mg after two days, to 1 mg after one week, and to a maximum dose of 4 mg at week 7. Common adverse effects include dizziness (6% to 40%), fatigue (8% to 11%), nausea (40% to 60%), somnolence (11% to 40%), syncope (1% to 12%), and viral infection (11%) [46].

The rotigotine (transdermal patch) initial dose is 1 mg/24 hours (one patch per day). The daily dose may be increased by 1 mg/24 hours each week, to a maximum daily dose of 3 mg/24 hours [46]. Dose-related application site reactions are common (21% to 46%), as are gastrointestinal complications such as nausea (15% to 48%) and vomiting (2% to 20%), and CNS reactions (e.g., somnolence, dizziness, headache, fatigue, orthostatic hypotension, hallucinations) [46]. Therefore, an extended low-dose trial is recommended.

Higher doses of gabapentin (2,000–2,400 mg daily) have been found to be significantly more effective than placebo in reducing moderate-to-severe restless legs syndrome symptoms, but higher doses are also associated with a high prevalence of adverse effects (e.g., dizziness, fatigue, nausea, pain, weakness) [46,120]. The recommended initial dose for restless legs syndrome treatment (off-label) is 300 mg taken two hours before bedtime; the dose may be titrated every two weeks, until desired response is achieved, to a maximum dose of 1,800 mg [46]. (Dosages of up to 3,600 mg have been tolerated in short-term studies but are not recommended.) A combination of lower-dose gabapentin (300–1,000 mg daily) and ropinirole (0.25–1.5 mg daily) is also effective for treating restless legs syndrome and is associated with a lower incidence of adverse effects than high-dose gabapentin alone [120].

Gabapentin enacarbil is FDA-approved for the treatment of restless legs syndrome and is preferred over gabapentin due to longer duration of action and improved absorption [46,118,121]. The dosage is 600 mg once daily at approximately 5 p.m. Worsening side effects are seen at higher doses, and no benefit is reported at a dose of 1,200 mg compared with 600 mg [46]. Adverse effects (at a 600-mg daily dose) include dizziness (13% to 17%), headache (10% to 12%), and somnolence (20%), and a low rate of gastrointestinal effects are also observed (e.g., nausea, 6% to 8%) [46]. Pooled analysis of long-term use of gabapentin and other antiepileptic drugs has validated concerns regarding suicidal ideation and behavior (0.43%) compared with placebo (0.24%) [46]. Human data regarding pancreatic cancer risk have yet to be compiled, although gabapentin is associated with pancreatic adenocarcinoma in rats [46,121].

Multiple studies have shown that pregabalin is effective for managing sensory and motor symptoms of restless legs syndrome and has a low rate of mild adverse effects across a wide dosage range [122,123]. A reduction of periodic limb movements and sleep architecture improvements (e.g., increase in slow-wave sleep, decrease in waking after sleep onset and during sleep stages 1 and 2) were noted. In one study, the mean effective dose for pregabalin was approximately 350 mg/day, but in another study, a dose of 125 mg/day was shown to be effective in 90% of participants [122,123]. Pregabalin is usually taken in divided doses, either two or three times a day [46]. Dizziness (3% to 45%) and somnolence (17% to 26%) are the most frequent adverse effects [46,122].

Lifestyle Modifications and Alternative Therapies

Stress reduction, muscle relaxation techniques, and physical activity are important components of a restless legs syndrome management strategy, along with improved nutrition, proper sleep hygiene, and elimination of caffeine and alcohol intake [112,113,115]. Supplementation with specific vitamins and minerals known to support the nervous system and improve blood circulation (e.g., vitamins B12, C, D, and E; glucosamine; magnesium; zinc) may be considered for patients with inadequate nutritional intake, but little research exists apart from small studies showing some degree of symptom reduction with supplementation with vitamins B and E [115]. Other alternative therapies with little or no scientific support include acupuncture, meditation, and prayer.

Moderate aerobic exercise and lower-body resistance training are recommended to both assist in the relief of psychologic stress and lessen the severity of symptoms [112]. Endorphin release, dopamine production, and increased blood flow to leg muscles are believed to mediate symptoms [115]. Massage, warm baths, and heating pads may also be used to relieve and/or prevent restless legs syndrome symptoms, though there is a lack of strong efficacy data for these therapies. Case studies have shown a positive effect with massage (and a return of symptoms after cessation of massage therapy regimens), but the mechanisms involved are unclear [115]. Theories include improved blood circulation, dopamine release, counterstimulation of the cerebral cortex, and modulated thalamic neural activity as a response to tactile and temperature stimulus. Pulsed pneumatic compression devices have also been shown to reduce symptom severity; the proposed beneficial mechanisms are similar to those of massage [115]. Near-infrared light therapy has also successfully reduced restless legs syndrome symptom severity in small-scale studies [124].

There is a strong placebo effect in restless legs syndrome therapy [115]. A 2008 meta-analysis of 36 clinical trials found that one-third of patients had a significant improvement while receiving placebo medications [125]. In 24 of the trials, 40% of participants had a placebo response. However, this level of response was based on a reduction in the International Restless Legs Severity Scale score alone, and the placebo response was only moderate for other measures (e.g., daytime functioning, other restless legs syndrome measures). The placebo effect was found to be small for PLMD therapy [125].

In 2014, the FDA cleared the first device to improve sleep quality in patients with restless legs syndrome [126]. The device, marketed as Relaxis, consists of a vibrating pad that provides counterstimulation to a patient's legs as he or she sleeps. The manufacturer cautions that this device should not be used on patients who have had deep venous thrombosis in either leg in the six months prior to the initiation of therapy.

10. DIAGNOSING AND TREATING SLEEP DISORDERS WITH THE HELP OF AN INTERPRETER

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of the treatment and management of sleep disorders, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. 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. (In many cases, the terms "interpreting" and "translating" are used interchangeably, but interpreting is specifically associated with oral communication while translating refers to written text.) While this may be easier said than done, due to institutional and/or patient barriers, the U.S. Department of Health and Human Services Office for Civil Rights has stated that denying adequate interpreter services to patients with limited English proficiency is a form of discrimination and that insufficient use of professional interpreters and inappropriate reliance on ad hoc interpreters may compromise patient care [127].

Depending upon the patient's language, an interpreter may be difficult to locate. Or, an organization may not have the funds to bring in an interpreter. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures and assisting in promoting culturally competent communication and practice [128]. In this more active role, the interpreter's behavior also is influenced by a host of cultural variables, such as gender, class, religion, educational differences, and power/authority perceptions of the patient [128]. Consequently, an intricate, triangular relationship develops between all three parties. Another factor affecting the communication process is that many interpreters are not adequately trained in the art of interpretation in mental health and general health settings, as there are many technical and unfamiliar terms. An ideal interpreter goes beyond being merely proficient in the needed language/dialect [129]. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness [130]. They also are well-versed in interpreting both the overt and latent content of information without changing any meanings and without interjecting their own biases and opinions [130]. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital [129].

On the patients' side, they may be wary about using interpreters for a host of reasons. They may find it difficult to express themselves through an interpreter [131]. If an interpreter is from the same community as the patient, the client/patient may have concerns about sharing private information with an individual who is known in the community and the extent to which the information disclosed would remain confidential. In some cases, raising the issue of obtaining an interpreter causes the client/patient to feel insulted that their language proficiency has been questioned. Finally, if an interpreter is from a conflicting ethnic group, the patient may refuse having interpreter services. The ideal situation is to have a well-trained interpreter who is familiar with health and mental health concepts.

If an interpreter is required, the practitioner should acknowledge that he/she is more than a body serving as a vehicle to transmit information verbatim from one party to another [131]. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise [131]. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

A briefing time between the practitioner and interpreter held prior to the meeting with the client/patient is crucial. The interpreter should understand the goal of the session, issues that will be discussed, specific terminology that may be used to allow for advance preparation, preferred translation formats, and sensitive topics that might arise [129,131,132]. It is important for the client/patient, interpreter, and practitioner to be seated in such a way that the practitioner can see both the interpreter and client/patient. Some experts recommend that the interpreter sit next to the client/patient, with both parties facing the practitioner [130].

The practitioner should always address the client/patient directly. For example, the practitioner should query the client/patient, "How do you feel?" versus asking the interpreter, "How does she feel?" [130]. The practitioner should also always refer to the client/patient as "Mr./Mrs. D," rather than "he" or "she" [131]. This avoids objectifying the client/patient.

At the start of the session, the practitioner should clearly identify his/her role and the interpreter's role [131]. This will prevent the client/patient from developing a primary relationship or alliance with the interpreter, turning to the interpreter as the one who sets the intervention [129]. The practitioner also should be attuned to the age, gender, class, and/or ethnic differences between the client/patient and the interpreter [131]. For example, if the client/patient is an older Asian male immigrant, and the interpreter is a young, Asian female, the practitioner should be sensitive to whether the client/patient is uncomfortable, given the fact he may be more accustomed to patriarchal authority structures. At the conclusion of the session, it is advisable to have a debriefing time between the practitioner and the interpreter to review the session [129,131,132].

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/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 diagnostic procedures, treatment options, and medication/treatment measures are being provided, the use of an interpreter should be considered.

11. CONCLUSION

Consistent and refreshing sleep is vital to health and an overall sense of wellness. However, nearly 25% of the U.S. population is troubled by a sleep disorder, many of which remain undiagnosed or undertreated, leading to a sleep deficit that can be difficult or impossible to repay. While most forms of disordered sleep are not immediately life-threatening, they can cause considerable distress, including accidental injury, depression, fatigue, and substance abuse. Most patients with a sleep disorder initially present to their primary care provider or other non-specialist, and appropriate identification and treatment or referral are important in this setting. This is especially true for the handful of sleep disorders that cause the majority of morbidity and mortality, including obstructive sleep apnea, narcolepsy, and insomnia. Increased understanding and adherence to best practices can improve patients' quality of life and help prevent associated complications.

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Evidence-Based Practice Recommendations Citations

1. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349. Available at https://aasm.org/resources/clinicalguidelines/040515.pdf. Last accessed December 7, 2018.

2. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161(3):210-220. Available at http://annals.org/aim/fullarticle/1892620. Last accessed December 7, 2018.

3. Ramar K, Dort LC, Katz SG, et al. Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015. J Clin Sleep Med. 2015;11(7):773-827. Available at http://jcsm.aasm.org/ViewAbstract.aspx?pid=30098. Last accessed December 7, 2018.

4. Billiard M, Dauvilliers Y, Dolenc-Groselj L, Lammers GJ, Mayer G, Sonka K. Management of narcolepsy in adults. In: Gilhus NE, Barnes MP, Brainin M (eds). European Handbook of Neurological Management. 2nd ed. Vol 1. Oxford: Wiley-Blackwell; 2011. Available at https://www.eaneurology.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2011_Management_of_narcolepsy_in_adults.pdf. Last accessed December 7, 2018.

5. Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine clinical practice guideline. Sleep. 2012;35(8):1039-1062. Available at https://aasm.org/resources/practiceparameters/updateto.pdf. Last accessed December 7, 2018.

90283 • Ischemic Stroke

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

During the past decades, advances in the prevention, diagnosis, and treatment of cerebrovascular disorders have led to decreases in the prevalence of stroke (primarily ischemic stroke), but the high rates of morbidity and mortality, despite a number of modifiable risk factors, point to the need for enhanced education for both patients and physicians. Enhancing healthcare professionals' knowledge about evidence-based guidelines, as well as about advances in diagnostic tools, is crucial for improving the outcomes for individuals who are at risk for stroke or in whom a stroke has occurred. A better understanding is needed about the options for patients at risk for stroke, as well as for treatment and rehabilitation. This course explores the roles of diagnosis and screening, evaluation of individuals with suspected stroke, immediate treatment of stroke, and the elements of effective rehabilitation programs. Heightened awareness of variations in the prevalence of stroke according to age, sex, and racial/ethnic groups will help clinicians and healthcare educators target individuals in need of enhanced education about the risks of stroke, especially those that are modifiable.

Table of Contents

90283 • Ischemic Stroke

Course Overview

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. INTRODUCTION

2. OVERVIEW OF CEREBROVASCULAR DISEASE

TYPES OF CEREBROVASCULAR DISORDERS

MORBIDITY AND MORTALITY

MODIFIABLE RISK FACTORS

3. PREVENTION

PRIMARY PREVENTION

PUBLIC HEALTH CAMPAIGNS

PATIENT EDUCATION

PREDICTING RISK

4. EARLY MANAGEMENT

PREHOSPITAL EVALUATION

DIAGNOSIS IN THE ED

PHYSICAL EXAMINATION AND HISTORY

LABORATORY TESTS

CAROTID ULTRASONOGRAPHY

CEREBRAL ANGIOGRAPHY

IMAGING STUDIES

5. TREATMENT

STROKE SYSTEMS OF CARE AND COMPREHENSIVE STROKE CENTERS

EVIDENCE-BASED GUIDELINES

6. REHABILITATION

MULTIDISCIPLINARY REHABILITATION TEAM

PATIENT ASSESSMENT

EXERCISE PROGRAM

TRANSITIONS IN CARE AND REHABILITATION CONTINUITY

7. SECONDARY PREVENTION: EVIDENCE-BASED RECOMMENDATIONS

CONTROLLING RISK FACTORS

MANAGING DISEASE

8. CASE STUDY

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90283 • Ischemic Stroke

Education Category. Medical / Surgical

Release Date. 04/01/2020

Expiration Date. 03/31/2023

Course Overview

During the past decades, advances in the prevention, diagnosis, and treatment of cerebrovascular disorders have led to decreases in the prevalence of stroke (primarily ischemic stroke), but the high rates of morbidity and mortality, despite a number of modifiable risk factors, point to the need for enhanced education for both patients and physicians. Enhancing healthcare professionals' knowledge about evidence-based guidelines, as well as about advances in diagnostic tools, is crucial for improving the outcomes for individuals who are at risk for stroke or in whom a stroke has occurred. A better understanding is needed about the options for patients at risk for stroke, as well as for treatment and rehabilitation. This course explores the roles of diagnosis and screening, evaluation of individuals with suspected stroke, immediate treatment of stroke, and the elements of effective rehabilitation programs. Heightened awareness of variations in the prevalence of stroke according to age, sex, and racial/ethnic groups will help clinicians and healthcare educators target individuals in need of enhanced education about the risks of stroke, especially those that are modifiable.

Audience

This course is designed for physicians, nurses, and physician assistants in the primary care setting. Neurologists and other healthcare practitioners will also benefit from this course.

Course Objective

The early identification and management of the risk factors for ischemic stroke can lead to substantial improvement in health and reductions in cost. However, research has documented gaps between healthcare professionals' knowledge and practice with respect to prevention, with data on adherence to evidence-based or guideline-endorsed recommendations demonstrating underuse or ineffective use of all interventions for primary and secondary prevention. The purpose of this course is to provide needed information about the roles of diagnosis and screening, evaluation of individuals with suspected stroke, immediate treatment of stroke, and the elements of effective rehabilitation programs so that healthcare professionals may implement the necessary interventions appropriately.

Learning Objectives

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

1. Describe the primary types of cerebrovascular disorders and their causes.

2. Discuss differences in prevalence, morbidity, and mortality according to age, sex, and race/ ethnicity.

3. Identify the nonmodifiable and modifiable risk factors for ischemic stroke.

4. Implement primary prevention strategies according to evidence-based guidelines.

5. Discuss the need for education at the community and patient levels.

6. Apply models of predicting risk of ischemic stroke.

7. Select the appropriate tools for screening, diagnosis, and early management of ischemic stroke.

8. Describe the elements of stroke systems of care and a comprehensive stroke center.

9. Discuss evidence-based treatment options for ischemic stroke.

10. Describe the benefits and components of a specialized stroke rehabilitation team.

11. Outline the aspects of patient assessment for stroke rehabilitation.

12. Discuss evidence-based recommendations for secondary prevention of ischemic stroke.

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 M. Leonard, 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.

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

Cerebrovascular disease is associated with significant morbidity and mortality in the United States. Stroke occurs in approximately 795,000 individuals each year, of which 610,000 are first-time strokes and 185,000 are recurrent [1]. Stroke is the leading cause of long-term disability in adults; 65% of stroke survivors have some degree of impairment [1,2]. Approximately 3% of men and 2% of women reported that they were disabled because of stroke [3]. The effect of stroke on mortality is illustrated by the fact that cerebrovascular disease is the third leading cause of death in the United States, with an age-adjusted mortality rate of 37.3 per 100,000 population as of 2016 [1,3]. This represents a 16.7% decrease in the mortality rate and a 3.7% increase in actual deaths since 2006. It is a substantial healthcare issue, with one of every three deaths being attributed to stroke in 2016 [3]. In addition, the financial cost associated with cerebrovascular disease poses a substantial economic burden, with an estimated direct and indirect cost of $351.2 billion between 2014 and 2015 [3]. Despite the considerable progress being made in the areas of prevention, management, and rehabilitation, it appears that stroke will increasingly cause death and disability in the coming decades as the population ages [4]. By 2030, an additional 3.4 million U.S. adults (3.9% of the population) will have had a stroke, which is a 20.5% increase in prevalence from 2012. Additionally, the total direct medical costs of cerebrovascular disease are projected to increase to approximately $918 billion [1].

The two primary types of stroke are ischemic and hemorrhagic, and ischemic strokes account for the majority (87%) of cerebrovascular disorders [1]. There are several risk factors for ischemic stroke, and predicting risk is an important element in prevention. In predicting risk, consideration should be given not only to comorbidities but also to age, sex, and race/ethnicity, as disparities in prevalence, morbidity, and mortality have been attributed to these patient characteristics [5,6,7,8]. Evidence-based guidelines for primary and secondary prevention have been developed and should be implemented [9,10].

Among the most important risk factors for ischemic stroke is a transient ischemic attack (TIA); approximately 12% of ischemic strokes are preceded by a TIA [1]. The greatest risk for post-TIA stroke is within the first 48 hours, and the risk continues beyond 48 hours to 3 months [1,11]. Improved understanding of TIAs among both clinicians and patients is needed. A survey of 200 primary care physicians showed that 88% could not correctly identify the typical symptoms and duration of a TIA, and studies have indicated that half of individuals who have a TIA do not report the event to their primary care clinician [1,12].

The early identification and management of the risk factors for ischemic stroke can lead to substantial improvement in health and reductions in cost [13]. For example, the incidence of stroke has been reduced by 30% to 40% with the appropriate use of antihypertensive therapy [10]. Yet, research has documented gaps between physicians' knowledge and practice with respect to prevention, with data on adherence to evidence-based or guideline-endorsed recommendations demonstrating underuse or ineffective use of all interventions for primary and secondary prevention [11,14,15]. Evidence-based guidelines have also been developed for the early management of stroke and for rehabilitation after stroke and should be followed to provide optimum care [16,17,18].

The focus of this course is ischemic stroke, due to its overwhelming prevalence. Advances have been made in tools for the screening and diagnosis of ischemic stroke, and a better understanding of the options for patients at risk is needed. This course explores the role of the physical examination and history, laboratory studies, and imaging techniques in screening and diagnosis. Also discussed are evidence-based guidelines for the prevention and early management of ischemic stroke, as well as emerging treatment options. Because data have shown that outcome is improved by care provided in comprehensive stroke centers and by early rehabilitation, these topics are addressed as well [17,19,20,21]. The importance of a multidisciplinary rehabilitation team, appropriate patient assessment, and an exercise program is emphasized.

2. OVERVIEW OF CEREBROVASCULAR DISEASE

Although "cerebrovascular disease" is often used interchangeably with the term "stroke," the disease encompasses any neurovascular disorder that exists in the presence or absence of an ictus (e.g., carotid artery stenosis, arteriovenous malformations). Despite advances in understanding the pathophysiology of cerebrovascular diseases, the term "stroke" (also known as cerebrovascular accident or brain attack) is inconsistently defined. Stroke has been classically characterized as an injury to the central nervous system (CNS) by a vascular cause. Because this definition is mainly clinical and not inclusive of advances in science and technology, the American Heart Association (AHA)/American Stroke Association (ASA) convened a writing group to develop an updated definition of stroke. The AHA/ASA recommend that the term "stroke" be broadly used to include a variety of definitions (Table 1).

Table 1: AHA/ASA DEFINITION OF STROKE

Injury/Episode

Definition

CNS infarction

Brain, spinal cord, or retinal cell death attributable to ischemia, based on:

- Pathologic, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution; or

- Clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting ≥24 hours or until death, and other etiologies excluded.

Ischemic stroke

Episode of neurologic dysfunction caused by focal cerebral, spinal, or retinal infarction

Silent CNS infarction

Imaging or neuropathologic evidence of CNS infarction, without history of acute neurologic dysfunction attributable to the lesion

Intracerebral hemorrhage

Focal collection of blood within the brain parenchyma or ventricular system, not caused by trauma

Stroke caused by intracerebral hemorrhage

Rapidly developing clinical signs of neurologic dysfunction attributable to focal collection of blood within brain parenchyma or ventricular system, not caused by trauma

Silent cerebral hemorrhage

Focal collection of chronic blood products within the brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathologic examination, not caused by trauma and without history of acute neurologic dysfunction attributable to the lesion

Subarachnoid hemorrhage

Bleeding into subarachnoid space

Stroke caused by subarachnoid hemorrhage

Rapidly developing signs of neurologic dysfunction and/or headache because of bleeding into the subarachnoid space, not caused by trauma

Stroke caused by cerebral venous thrombosis

Infarction or hemorrhage in the brain, spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs caused by reversible edema without infarction or hemorrhage do not qualify as stroke.

Stroke, not otherwise specified

Episode of acute neurologic dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥24 hours or until death, but without sufficient evidence to be classified as one of the above

CNS = central nervous system.

Source: Reprinted with permission from Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064-2089.

TYPES OF CEREBROVASCULAR DISORDERS

The multiple sources, pathophysiologic mechanisms, and sequelae of stroke are reflected in the diverse types of cerebrovascular disorders. The World Health Organization classifies cerebrovascular diseases under "Diseases of the nervous system" in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), the international standard diagnostic classification for all general epidemiologic purposes and many health management purposes (Table 2) [22]. TIAs and traumatic intracranial hemorrhage are also included in the nervous system disease category in the ICD-11; vascular dementia is not. Its exclusion illustrates the heterogeneity of stroke and its sequelae. Vascular dementia, listed as dementia due to cerebrovascular disease, is categorized under "Mental, behavioral, or neurodevelopmental disorders: Neurocognitive disorders."

Table 2: SELECTED CEREBROVASCULAR DISEASES AS CLASSIFIED BY THE INTERNATIONAL STATISTICAL CLASSIFICATION OF DISEASES AND RELATED HEALTH PROBLEMS, 11TH REVISION (ICD-11)

ICD Code

Disease

8B00

Intracerebral hemorrhage

8B01

Subarachnoid hemorrhage

8B02

Nontraumatic subdural hemorrhage

8B03

Nontraumatic epidural hemorrhage

8B0Z

Intracranial hemorrhage, unspecified

8B10

Transient ischemic attack

8B11

Cerebral ischemic stroke

8B1Y

Other specified cerebral ischemia

8B1Z

Cerebral ischemia, unspecified

8B20

Stroke, not known if ischemic or hemorrhagic

Source: [22]

As noted, the two primary types of stroke are ischemic and hemorrhagic. In the United States, approximately 87% of all strokes are ischemic; 10% are hemorrhagic strokes [1]. An ischemic stroke occurs when any artery that supplies the brain with oxygen becomes stenosed or occluded, resulting in infarction [23]. In the case of hemorrhagic stroke, bleeding occurs below the arachnoid, the location of the brain's blood supply, allowing blood to directly contact and damage brain tissue. Although ischemic stroke is the focus of this course, a brief overview of hemorrhagic strokes will help to provide context and comparison of the clinical features of both types of stroke. In addition, TIAs are discussed here, as they are often a precursor to ischemic stroke.

Hemorrhagic Strokes

Hemorrhagic stroke is associated with a higher risk of fatality than ischemic stroke, and roughly one-third of patients die within 30 days after the event [1,24]. Hemorrhagic strokes are categorized by the location of the hemorrhage, either intracerebral or subarachnoid, with the former being more common.

Approximately 87% of hemorrhagic strokes are due to intracerebral hemorrhage (ICH), and because of this, the term hemorrhagic stroke often refers to ICH [25]. ICHs are characterized by bleeding directly into the brain parenchyma [25,26]. Intraventricular hemorrhage describes bleeding that extends into the ventricles [26,27]. Nontraumatic ICH is categorized as primary (unrelated to congenital or acquired lesions), secondary (caused by a congenital or acquired condition), or spontaneous (unrelated to trauma or surgery) [26].

The signs and symptoms of ICH include headache, vomiting, seizures, depressed consciousness, meningeal irritation, and blood-tainted cerebrospinal fluid. The onset of symptoms may occur within seconds to minutes after the start of an ICH. Individuals with this type of stroke often feel more ill than those with an ischemic stroke.

ICH is the least treatable type of stroke [28]. Functional independence is regained within 6 months in approximately 20% of survivors [29]. The morbidity and mortality depend on the volume and location of the hematoma. The 1-year mortality rate varies according to anatomic location, with the highest mortality rate (65%) associated with ICH in the brain stem; the rate is 57% for lobar hemorrhage, 51% for deep hemorrhage, and 42% for cerebellar hemorrhage [30]. Overall, 46% of patients with ICH survive one year and 29% survive five years [31].

As many as 80% of primary ICHs occur after small vessels are compromised by chronic hypertension [32]. Hypertension is associated with ICH originating in the periventricular deep white matter, deep subcortical structures, pons, and cerebellum [33]. In individuals older than 70 years of age, cerebral amyloid angiopathy, a condition that leads to amyloid protein infiltration into the cortical arterioles, is responsible for approximately 20% of ICHs [34]. Other causes of ICH include anticoagulant and antiplatelet use, drug use (e.g., cocaine, phenylpropanolamine), and other bleeding diathesis [28,35]. Fewer than 15% of all cases of ICH are secondary to congenital vascular abnormalities and malignant brain lesions [26].

Subarachnoid hemorrhages occur less frequently than ICHs. The hallmark of subarachnoid hemorrhage is the immediate onset of a severe headache with signs of meningeal irritation [36]. Individuals may describe this headache as their "worst ever." Nausea, vomiting, neck pain, and photophobia are also classic symptoms, although they are not always present [36]. Neurologic deficits may be acute or may manifest hours to days after the onset of bleeding.

Nontraumatic subarachnoid hemorrhages are subcategorized as aneurysmal or non-aneurysmal [37]. Aneurysmal subarachnoid hemorrhage is associated with higher rates of morbidity and mortality than non-aneurysmal hemorrhage. Among patients who live 3 months after the event, the risk of death is 8.7% within 5 years and 17.9% within 10 years [38]. In contrast, non-aneurysmal subarachnoid hemorrhages are associated with better outcomes and are less likely to cause death [39].

Most nontraumatic subarachnoid hemorrhages involve rupture of an intracranial aneurysm or cerebral arteriovenous malformation. Congenital arteriovenous anomalies are more likely to cause stroke in adolescents and young adults [40]. The incidence of perimesencephalic subarachnoid hemorrhage, a non-aneurysmal type, is increasing. Although the cause remains unknown, increased use of antithrombotic medications may be a factor [41,42].

TIAs

TIAs are sometimes referred to as "ministrokes" because, like ischemic strokes, they are caused by inadequate cerebral blood flow. TIAs are also called warning strokes, as they often precede an ischemic stroke [43]. The superseded definition of a TIA was "a sudden, focal neurologic deficit that lasts for less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain or eye perfused by a specific artery" [44]. The 24-hour time limit was an arbitrary remnant of the time interval used in prospective surveys in the early 1970s [45]. Magnetic resonance imaging (MRI) and computed tomography (CT) have demonstrated that one-third of TIAs, including those that last only minutes, cause infarcts [46].

Because TIA and ischemic stroke are less distinct from one another than once believed, a new TIA definition was proposed, revised, and endorsed in 2009. The proposed definition states that TIA is "a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than 1 hour, and without evidence of acute infarction" [44]. This definition was designed to better reflect the ischemic pathogenesis of TIA, promote its early management, and support the use of diagnostic imaging techniques to ensure that the patient does not have infarction [44]. The definition was endorsed by the 2009 AHA/ASA guideline, with the omission of "typically less than 1 hour" (as infarction is not necessarily bound by a set period of time) and reads, "Transient ischemic attack (TIA): a transient episode of neurologic dysfunction caused by focal brain, spinal-cord, or retinal ischemia, without acute infarction" [10,47].

Research shows that a TIA should be considered a dire condition that requires urgent treatment in order to prevent a more potent ischemic stroke; approximately 15% of ischemic strokes are preceded by a TIA [3]. However, there are several challenges to immediate treatment of TIAs [10]:

- A wide majority of the general population and many healthcare professionals believe that TIAs are generally benign.

- Individuals experiencing a TIA often believe they can postpone or forego professional treatment because clinical symptoms usually resolve quickly and without care.

- Due to the 24-hour arbitrary time limit in the previously accepted definition, healthcare professionals often choose to monitor a patient with a TIA rather than provide immediate treatment.

The risk of ischemic stroke is dangerously high in the period following a TIA. Research indicates that one-half of subsequent strokes occur within the first 48 hours, and a meta-analysis showed that approximately 5% of patients who have a TIA will have an ischemic stroke within seven days of that event [11,43]. The risk of stroke within three months after a TIA is approximately 10% to 20% and is 24% to 29% over the following five years [11]. Early initiation of treatment for TIA and minor stroke with existing therapies has been shown to reduce the risk of early recurrent stroke by 80% [48].

As with any stroke, the symptoms of TIA depend on the affected vascular territory. For instance, involvement of the carotid artery causes disturbances in the ipsilateral eye or brain [49]. Although the most common focal neurologic signs of TIA are sudden-onset unilateral weakness and numbness or tingling in a limb, a TIA can cause any of the following symptoms [49,50]:

- Numbness of the face, hand, or leg, with or without weakness

- Paralysis

- Slurred speech

- Dizziness

- Double vision

- Hemianopia

- Transient monocular blindness

- Imbalance

- Aphasia

- Confusion

- Head pain

Transient graying or blurring of vision is also common. Occasionally, the line of sight will be shaded. Vertebrobasilar TIAs reflect vestibulocerebellar symptoms such as ataxia, dizziness, vertigo, dysarthria, vision abnormalities (e.g., double vision, hemianopia, bilateral vision loss), and unilateral or bilateral motor and sensory dysfunctions [10].

By the time of evaluation, however, most patients appear asymptomatic because TIAs usually resolve within 5 minutes [51]. A clinician should highly suspect a TIA if the patient says, "I don't know why I'm here. Whatever it was, it is all better now" [52].

TIAs are caused by conditions similar to those leading to ischemic stroke [10]. Among the common causes are atherosclerosis of large vessels, cardioembolism, and atrial fibrillation (AF). Uncommon causes include hypercoagulable states, arterial dissection, sympathomimetic drugs (e.g., cocaine), and arteritis (caused by noninfectious necrotizing vasculitis, drugs, irradiation, or local trauma) [53].

The risk factors for TIA are also similar to those for ischemic stroke and include many modifiable factors, such as hyperhomocysteinemia, hyperlipidemia, smoking, obesity, and diabetes [10]. Risk can be reduced substantially by the treatment of vascular anomalies such as hypertension and AF, two conditions commonly associated with older age. Younger individuals (18 to 45 years of age) who have a TIA or ischemic stroke often have no detectable vascular risk factors [54].

Ischemic Strokes

Within minutes of the onset of ischemic stroke, the core of an infarct can begin to form at the least-perfused site. This site is encircled by an area partially altered metabolically and ionically by cytotoxic edema [55]. This area, the ischemic penumbra, is structurally intact and generally salvageable if reperfusion is achieved promptly. Because cerebral function deficits develop rapidly (within minutes to hours) as an ischemic stroke progresses, these brain attacks are a medical emergency. Each minute that passes results in an average loss of 1.9 million neurons and 14 billion synapses; an ischemic brain ages 3.6 years for every hour that passes after the onset of stroke [56]. For this reason, stroke specialists use the mantra, "time is brain." Although irreversible damage occurs, most individuals with stroke have recoverable penumbral tissue for at least three hours following the onset of symptoms [16].

The physical signs, symptoms, and sequelae of ischemic stroke are usually unilateral because of the circulatory anatomy of the brain (Table 3). Anterior circulation is composed of the paired internal carotid arteries and vessels that supply blood to the cerebral hemispheres [57]. Each common carotid artery bifurcates into the internal and external carotid arteries. The ophthalmic artery, posterior communicating artery, and anterior choroidal artery are supplied by the internal carotid artery (Figure 1). Most importantly, the internal carotid artery provides blood to the middle cerebral artery, the largest intracerebral vessel. The middle cerebral artery provides oxygen to the lateral, frontal, parietal, and temporal lobes and the basal ganglia. It also supplies the anterior cerebral artery, which is responsible for the medial part of the frontal and parietal lobes, most of the corpus callosum, the frontobasal cerebral cortex, deep structures, and the anterior diencephalon. The anterior choroidal artery supplies a portion of the thalamus and the posterior limb of the internal capsule.

Table 3: GENERAL REGIONS OF ISCHEMIC STROKE AND CORRESPONDING NEUROLOGIC DEFICITS

Affected Region

Common Signs and Potential Sequelae

Left anterior hemisphere

Aphasia (esp. difficulty reading, writing, calculating)

Right limb weakness and sensory loss Right field visual defect

Right anterior hemisphere

Limb motor weakness or loss

Left field visual neglect

Unable to determine two-point stimuli on left side

Left posterior cerebral artery

Aphasia (esp. difficulty reading, naming objects)

Right visual field defect

Occasionally, right-sided numbness

Right posterior cerebral artery

Left limb sensory loss

Left-sided neglect Left field visual defect

Vertebrobasilar territory (posterior circulation)

Bilateral vision disturbances and nystagmus

Dysarthria and dysphagia

Ataxia

Dizziness, vomiting, headache

No cortical deficits (e.g., aphasia, cognitive impairments)

Caudate nucleus, thalamus, frontal lobe (anterior circulation)

Sudden abnormal behavior

Thalamus (posterior circulation)

Numbness, decreased sensation on face, arm, leg on same side

Source: [57,58,59]

Figure 1: CORONAL SECTION OF THE CEREBRUM ILLUSTRATING ARTERIAL TERRITORIES

Source : [60] Reprinted from Blumenfeld H. Neuroanatomy Through Clinical Cases. 2nd ed. Boston, MA: Sinauer Associates, Inc.; 2013, with permission from Sinauer Associates, Inc.

Posterior circulation is primarily composed of the vertebrobasilar artery, the posterior cerebral artery, which it supplies, and other branching vessels [57]. The posterior cerebral artery provides blood to the occipital and medial temporal lobes, as well as regions of the midbrain, subthalamic nucleus, basal nucleus, thalamus, mesial inferior temporal lobe, and occipitoparietal cortices. The two main segments of the posterior cerebral artery (P1 and P2) are connected by the posterior communicating artery. The Circle of Willis links the anterior and posterior circulation at the base of the brain.

In general, ischemic strokes are categorized according to etiology: thrombotic and embolic [61]. In addition, they are classified into five subtypes according to a system developed by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) [62].

Thrombotic Stroke

A thrombotic stroke occurs when a thrombus impairs cerebral blood flow by further narrowing or blocking an artery, typically around an atherosclerotic plaque. The stenosed or occluded artery may be a large vessel (e.g., carotid artery systems, vertebral arteries, the Circle of Willis) or a small vessel (e.g., branches of the Circle of Willis, the posterior circulation). Approximately 21% to 27% of ischemic strokes arise from atherosclerotic disease of the large vessels [63,64]. The cerebral artery branch points, especially those of the internal carotid artery, are the most vulnerable [65]. Small-vessel disease is associated with 21% to 25% of ischemic strokes [63,64]. Thrombotic strokes caused by small-vessel disease are traditionally associated with lacunar infarcts, small, deep, subcortical lesions of 15 mm or less in diameter resulting from occlusion of a single penetrating artery [62,66]. As many as 20% of older individuals who are otherwise healthy have asymptomatic lacunar infarcts unrelated to an ictal event [67]. These silent infarctions were previously believed to be benign with a good long-term prognosis. However, they now have been linked to increased risks of stroke and death and can lead to debilitating cognitive impairments such as vascular dementia [67,68].

Independent risk factors for lacunar infarcts include hypertension, gender, age, diabetes, smoking, and a history of TIA [67]. Although hypertension is strongly associated with the development of small-vessel occlusion, lacunar infarcts also occur in individuals without hypertension. However, normotensive individuals with lacunar infarcts are typically 85 years of age or older, suggesting that hypertension accelerates the arteriopathy underpinning small-vessel disease. Diabetes is an independent risk factor for lacunar infarcts [69].

Embolic Stroke

An embolic stroke occurs when an embolus (i.e., any circulating clot or particle originating from a distal point) blocks an artery that supplies oxygen to the brain. Stroke registries indicate that 14% to 30% of ischemic strokes are embolic [70,71,72,73,74]. Emboli include blood clots, fatty deposits, atherosclerotic plaque fragments, and cancerous cells or infectious materials emanating from conditions such as atrial myxoma and endocarditis, respectively. Clinical symptoms of the resulting infarct correspond to the location of the embolus, not its type. The region of the middle cerebral artery is most frequently blocked by emboli [75].

AF is the most common cause of embolic stroke, increasing the risk of embolic stroke fivefold and doubling the risk of death [76,77]. Patients with valvular thrombi, from endocarditis or prosthetic valves, or mural thrombi from myocardial infarction (MI), AF, severe heart failure, or patent foramen ovale, are at high risk for the development of emboli [78,79]. MI is associated with a 2% to 3% incidence of embolic stroke, 70% of which occur in the first week after the event [77,79].

TOAST Classification

The subtype of ischemic stroke influences treatment decisions, prognosis, and risk of recurrent stroke. The TOAST system was designed to facilitate decision making and standardize ischemic stroke research (Table 4) [62]. Most strokes are subclassified as a large-artery atherosclerosis (caused by either a thrombus or an embolus), a cardioembolism, or an occlusion of a small vessel (lacuna) [62]. Approximately 4% of individuals with stroke have coexisting large-vessel and small-vessel disease [61,80]. Other determined causes are rare (approximately 3%), and registries have classified up to 33% of ischemic strokes as being of "undetermined etiology" [81].

Table 4: FIVE SUBTYPES OF ISCHEMIC STROKE AS CLASSIFIED BY THE TRIAL OF ORG 10172 IN ACUTE STROKE TREATMENT (TOAST)

Classification

Major Characteristics

Large-artery atherosclerosis (may be an embolus or thrombus)

Greater than 50% stenosis or occlusion of a major brain artery or branch cortical artery

Cortical, cerebellar, brain stem, or subcortical infarct

Cortical or cerebellar dysfunction

Cardioembolism (may be high or medium risk based on evidence of embolism)

Cardiac source of emboli

Cortical, cerebellar, brain stem, or subcortical infarct

Cortical or cerebellar dysfunction

Small-vessel (lacuna) occlusion

Patient presents with lacunar syndromea

Subcortical or brain stem infarcts <15 mm may be detected

Other determined cause

May be caused by conditions such as dissection, hypercoagulable states, or sickle cell anemia

May have characteristics of any of the other stroke subtypes

Undetermined etiology

May be any of the following:

Two or more causes identified

Negative evaluation

Incomplete evaluation

aThe five classic lacunar syndromes are pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and clumsy-hand dysarthria.

Source: [62,66,82,83]

MORBIDITY AND MORTALITY

Approximately 16% of men and 14% of women have a stroke by 85 years of age, and stroke is the third leading cause of death in the United States, accounting for more than 840,678 deaths in 2016 [1,3,84]. Morbidity associated with stroke is also high, with at least 65% of stroke survivors having some sort of impairment [85]. At three months after a stroke, approximately 20% of survivors depend on long-term care. Between 15% and 30% of stroke survivors are permanently disabled [86]. A six-month follow-up of ischemic stroke survivors (65 years of age and older) demonstrated that [87]:

- 50% had some degree of hemiparesis

- 35% had depressive symptoms

- 30% were unable to walk without some assistance

- 26% were dependent in activities of daily living

- 26% were in a nursing home

- 19% had aphasia

Fortunately, stroke mortality has been declining since the early 20th century. In the United States, stroke has fallen from the third to the fifth leading cause of death, representing a true mortality decline rather than a repositioning of causes of death [3,84]. This decline is a result of reduced incidence of stroke and lower case-fatality rates, concurrent with cardiovascular risk factor control interventions (e.g., hypertension control). Other efforts (e.g., diabetes control, smoking cessation programs) likely have also contributed to the decline in stroke mortality. The effects of telemedicine and stroke systems of care require additional study but appear to be significant. The decline has occurred in both women and men, for all racial/ethnic and age groups, and represents a major improvement in public health and a reduction in years of potential life lost [88].

Disparities in Prevalence and Mortality

Age, gender, and race/ethnicity play major roles in the prevalence of stroke and its associated mortality.

Age

Prolonged damage of the aging cardiovascular system by various risk factors for stroke doubles the risk of ischemic stroke for each decade of life after 55 years of age [9]. Thus, clinicians should be sensitive to their patients' modifiable risk factors, most notably hypertension, starting at an early age [1]. As many as 70% of strokes occur in individuals older than 65 years of age, and the average age at the time of ischemic stroke is 71 years in men and 75 years in women [1]. Stroke patients 85 years of age and older comprise 17% of all stroke patients [1].

Clinicians should be particularly aware of silent cerebral infarctions in older individuals, as these infarctions occur more commonly in this population [89].

Gender

Women have a higher lifetime risk of stroke than men [90,91,92]. According to estimates from the Framingham Heart Study, among people 55 to 75 years of age, the risk of stroke is 1 in 5 for women and 1 in 6 for men [93]. Age-specific stroke incidence rates are substantially lower among women than men, except in those 80 years of age and older, in which the incidence rate in women is approximately equal to or higher than the rate in men [90,91,94,95,96]. Among individuals 65 years of age and older, the median survival time after a first stroke is typically longer for women than for men. For both men and women, the median survival decreases with age (Table 5) [97]. However, the possibility of gender disparities in how health care is provided to individuals who present with stroke symptoms is also being evaluated.

Table 5: COMPARISON OF MEDIAN SURVIVAL AFTER A FIRST STROKE ACCORDING TO SEX

Age

Median Survival

Women

Men

55 to 64 years

7.8 years

13.1 years

65 to 74 years

7.7 years

6.2 years

≥75 years

2.3 years

2.1 years

Source: [97]

Studies suggest that, compared with men, women are evaluated less frequently following a stroke and that any evaluation is more likely to be delayed [98,99,100]. This pattern results from women's presentation with nontraditional symptoms or without traditional symptoms and inappropriate worry by both clinician and patient about treatment-related risks (Table 6) [98,99,101,102,103]. Although studies to evaluate differences in strokes between men and women are in early stages, preliminary results indicate that emergency medical service (EMS) personnel and clinicians need an accurate understanding of symptom presentation patterns for men and women. The prevalence of nontraditional symptoms is higher among women than men; nontraditional stroke symptoms include headache, face and limb pain, nausea, and hiccups as well as symptoms typically believed to be unrelated to neurologic deficits (e.g., chest pain, shortness of breath, palpitations) [102].

Table 6: COMPARISON OF PREVALENCE OF SELECT SYMPTOMS IN MEN AND WOMEN

Symptom on Presentation

Prevalence

Men

Women

Overall nontraditional symptoms

19%

28%

Pain

8%

12%

Altered consciousness

12%

17%

Traditional Symptoms

Imbalance

20%

15%

Hemiparesis

24%

19%

Source: [102]

Race/Ethnicity

The decline in stroke mortality has reduced, but not eliminated, the racial/ethnic gap in stroke mortality [88]. Racial/ethnic disparities in the incidence of stroke and its related mortality are substantial, and the factors contributing to the disparities are complex and poorly understood [1,5,6,7,8,104]. The risk of first-time stroke among black individuals is 1.5 times higher than that for white individuals in the United States, and the incidence of first-ever stroke is increasing among Hispanic Americans compared to whites [1]. The Northern Manhattan Study (NOMAS) showed that the age-adjusted incidence of first ischemic stroke per 100,000 individuals was 191 in the black population, 149 in the Hispanic population, and 88 in the white population [1,104]. Another study showed that the prevalence of stroke among these three groups also varied according to age [6]. In the black population, the prevalence was 4.8% for individuals 45 to 64 years of age and 10% for individuals 65 years of age and older; the corresponding prevalences were 2.3% and 10% for Hispanic individuals and 2% and 9% for white individuals [6]. Intracranial atherosclerotic strokes were the most common type of strokes among the black and Hispanic populations [1,104].

According to the AHA 2019 update on statistics for heart disease and stroke, the prevalence of stroke is highest for American Indian/Alaskan Natives and lowest for Asian/Pacific Islanders (Table 7) [1]. Data indicate variation among stroke-related mortality rates as well and show that stroke deaths have increased in minority populations while decreasing in the white population. Projections indicate a 20.5% increase in stroke by 2030, with the greatest increase (29%) in Hispanic men [1].

Table 7: RACIAL/ETHNIC VARIATIONS IN PREVALENCE OF STROKE AND HYPERTENSION

Population

Stroke Prevalence

Hypertension Prevalence

American Indian/Alaskan Native

5.3%

NA

Non-Hispanic Black

4.1%

55.4%

Non-Hispanic White

2.7%

42.8%

Hispanic or Latino

2.3%

41.1%

Asian/Pacific Islander

1.2%

NA

NA = Not available

Source: [1]

Data from 2016 demonstrated an overall rate of 37.3 deaths per 100,000, with a rate of 51.9 for the black (non-Hispanic) population, 36.1 for the white (non-Hispanic) population, 32.1 for the Hispanic population, 31.0 for the Asian/Pacific Islander population, and 30.7 for the American Indian/Alaskan Native population [1]. Risk factors, such as hypertension, diabetes, and obesity, vary among these populations as well, but increased risks alone cannot completely explain increased prevalence or mortality [9].

MODIFIABLE RISK FACTORS

Several modifiable risk factors for stroke have been well-documented in the literature, and some have been less well-documented (Table 8). The well-documented risk factors include many associated with cardiovascular disease as well, and proper management of these factors can reduce both the risk of a first-time stroke and the development of a cardiovascular condition [7,9]. Clinicians should discuss the potential for stroke associated with risk factors specific to patients and offer strategies to reduce or eliminate them [9]. Four lifestyle factors warrant brief review because of the substantial role the patient has in helping to manage risk: smoking, diet and nutrition, physical inactivity, and obesity and body fat distribution.

Table 8: MODIFIABLE RISK FACTORS FOR STROKE

Well-Documented Factorsa

Less-Documented Factorsb

Hypertension

Atrial fibrillation (AF)

Diet and nutrition

Diabetes

Cigarette smoking

Dyslipidemia

Obesity and body fat distribution

Cardiac conditions other than AF

Asymptomatic carotid stenosis

Sickle cell disease

Physical inactivity

Metabolic syndrome

Inflammation and infection

Migraine

Alcohol abuse

Hypercoagulability

Sleep-disordered breathing

Elevated lipoprotein (a)

Drug abuse

Hyperhomocysteinemia

a Listed in descending order of quality of documentation.

b Information on less-documented risks for stroke can be found in the American Heart Association (AHA) guideline "Primary Prevention of Stroke."

Source: [9]

Diet and Nutrition

Increased consumption of fruits and vegetables reduces the risk of stroke in a dose-dependent manner. Risk is reduced 6% for each serving of fruits and vegetables per day [105]. Reducing sodium intake and increasing antioxidants, potassium, and calcium also mitigates the risk of stroke [9,106,107]. The AHA/ASA recommend that individuals with stroke residing in long-term care facilities be evaluated for calcium and vitamin D supplementation [21]. The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in fruits, vegetables, and low-fat dairy products and which limits saturated and total fat intake, has been shown to lower blood pressure and likely reduce the risk of stroke [106,107].

Cigarette Smoking

Overwhelming evidence shows an undeniable association between cigarette smoking and stroke [9,108]. Smoking doubles the risk for ischemic stroke and increases the risk of hemorrhagic stroke 2 to 4 times [109]. Studies also indicate that repeated exposure to environmental ("secondhand") smoke almost doubles the risk of stroke [110]. Secondhand smoke exposure is a contributing factor in more than 8,000 stroke deaths each year [111]. Using data from the National Health Interview Survey and death certificate data for 2000 through 2004, the Centers for Disease Control and Prevention estimated that smoking resulted in an annual average of 61,616 stroke deaths among men and 97,681 stroke deaths among women [112].

Individuals who smoke should be prescribed smoking cessation medications and be informed about cessation programs, counseling, and nicotine-replacement products. Epidemiologic studies show that, following smoking cessation, stroke risk decreases over time [9]. Individuals who do not smoke should be encouraged not to start.

Obesity and Body Fat Distribution

One study has found that in the body mass index (BMI) range of 25 to 50 kg/m^2, each 5 kg/m^2 increase in BMI was associated with a 40% increased risk of stroke mortality; in the BMI range of 15 to 25 kg/m^2, there was no relationship between BMI and stroke mortality [113]. Another large epidemiologic study showed that the risk almost doubled for overweight and obese men [114]. A meta-analysis of data from 25 studies involving more than 2.2 million people showed an increased risk of ischemic stroke of 22% in overweight individuals and 64% in obese individuals [115]. Studies have not yet addressed if losing weight reduces this risk [9]. However, it is well-documented that weight loss lowers blood pressure and cholesterol and positively affects other risk factors for stroke. Clinicians should encourage overweight patients to begin a weight-loss program that includes a healthful diet and exercise and provide patients with safe weight-loss strategies, such as those recommended by the AHA [9].

Body fat distribution has proven to be a fairly reliable indicator of stroke risk [116,117]. While some studies support abdominal adiposity as a significant risk factor for stroke only in men, other research indicates that a high concentration of abdominal fat is a significant risk factor in both men and women, independent of BMI [9]. On the other hand, gynoid adiposity in women appears to be associated with a lower risk for stroke, even for women with a higher BMI [117]. A high hip-to-waist ratio may be a more important risk factor for vascular disease, including stroke, than BMI score alone [118].

Physical Inactivity

A large and generally consistent body of evidence indicates that routine physical activity prevents stroke [9]. A habitually sedentary lifestyle increases an individual's chance of stroke. Physically active men and women generally have a 25% to 30% lower risk of stroke or death than the least active people [119]. Individuals should be strongly encouraged to engage in aerobic exercise at moderate intensity for 150 minutes or more weekly, at vigorous intensity for 75 minutes or more per week, or a combination of both that fulfills these requirements [9]. It should be noted that only moderate-to-vigorous intensity exercise has been found to reduce the incidence of stroke [104].

3. PREVENTION

PRIMARY PREVENTION

To decrease the incidence of first-time stroke in the United States, primary prevention should focus on individuals at high risk with modifiable risk factors. In areas of the United Kingdom, the incidence of major stroke has been reduced 40% through a reduction in the incidence of risk factors [120]. The AHA has established evidence-based recommendations for primary prevention of stroke and has developed public campaigns and educational materials to help raise awareness of stroke.

Evidence-Based Recommendations

For most individuals with nonmodifiable stroke risks, the probability of stroke can be decreased substantially with rigorous preventive measures and the treatment of modifiable risks [9,16]. The AHA recommends addressing lifestyle risk factors, as discussed, and medically managing several risk factors, including hypertension, diabetes, AF, other cardiac conditions, dyslipidemia, and asymptomatic carotid stenosis [9].

Hypertension

Hypertension is perhaps the most significant risk factor for stroke, and risk increases as blood pressure increases [9]. Fortunately, the prevalence of hypertension has plateaued over the past decade and remained stable, at 29%, between 2008 and 2017 [121,122]. Control of hypertension (defined as blood pressure less than 140/90 mm Hg) also has improved, with rates of control increasing from 27.3% in 1988–1994 to 50.1% in 2007–2008 [9]. These improvements are likely attributable to heightened awareness and treatment, with awareness among U.S. residents increasing from 69% in 1988–1994 to 81% in 2007–2008 [9]. Still, more than two-thirds of people 65 years of age and older are hypertensive [123].

The AHA and other professional organizations recommend that all adults 18 years of age and older be screened for high blood pressure [124]. The U.S. Preventive Services Task Force (USPSTF) recommends screening for all adults 18 years of age and older and annual screening for adults 40 years of age and older who are at increased risk for high blood pressure. Increased risk is defined as [124]:

- High-normal blood pressure (130–139/85–89 mm Hg)

- Overweight or obese

- Black race

Individuals 18 to 39 years of age with normal blood pressure (<130/85 mm Hg) who do not have other risk factors should be screened every 3 to 5 years. The USPSTF additionally recommends rescreening with properly measured office blood pressure. If the blood pressure is elevated, the diagnosis should be confirmed with ambulatory blood pressure monitoring [124].

The 2017 Guideline for High Blood Pressure in Adults recommends screening every 2 years for adults with a blood pressure less than 120/80 mm Hg and screening every 3 to 6 months for people with systolic blood pressure of 120 to 129 mm Hg or with diastolic blood pressure greater than 80 mm Hg [125]. The AHA/ASA recommends that women be screened for high blood pressure before taking birth control pills, as the combination increases the risk of stroke [126].

Appropriate management of hypertension may also include dietary changes, other lifestyle modifications, and pharmacologic therapy. Studies have shown that management is possible for the majority of patients, but most will require treatment that includes two or more drugs [9].

Diabetes

The risk for stroke is 2 times higher among individuals with diabetes. In 2014, after adjusting for population age differences, hospitalization rates for stroke were more than three times higher among adults 20 years of age and older with diagnosed diabetes compared with those without diagnosed diabetes [127]. Type 2 diabetes is associated with an increased prevalence of atherogenic risk factors, such as hypertension, obesity, and dyslipidemia. The combination of hyperglycemia and hypertension is thought to increase the risk of stroke [9]. The AHA recommends that the target blood pressure for individuals with diabetes be less than 140/90 mm Hg [9]. Pharmacologic therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been shown to be safe and effective in this population [9]. In addition, lipid-lowering statins reduce the risk of first-time strokes in patients with diabetes, irrespective of the baseline lipid levels, pre-existing vascular conditions, and glycemic control [128].

Atrial Fibrillation

AF is associated with a fourfold to fivefold increased risk of ischemic stroke, and approximately 60,000 strokes occur among the 2.3 million individuals with AF annually [9]. According to the AHA/ASA, women older than 75 years of age should be screened for AF risk due to its link to greater stroke risk [126]. The AHA recommends that individuals with AF who have valvular heart disease (particularly individuals who have mechanical heart valves) should receive anticoagulant therapy [9]. Antithrombotic therapy with adjusted-dose warfarin or aspirin is approved for stroke prevention in individuals with nonvalvular AF based on their calculated risk of stroke and estimated risk of bleeding. The individual's preferences and access to high-quality anticoagulation monitoring should be considered. Warfarin therapy to maintain an international normalized ratio (INR) of 2.0 to 3.0 (target: 2.5) is strongly recommended for high-risk individuals (those with more than a 4% annual risk of stroke) with AF and no significant contraindications to oral anticoagulants [9,129]. Despite the effectiveness of such treatments, anticoagulant therapy continues to remain underprescribed due to overestimation of the associated risks of warfarin (e.g., intracranial, extracranial hemorrhage) and underestimation of stroke risk [129]. Some physicians err on the side of caution and aim for an INR greater than the recommended target, with a corresponding reduction in therapeutic effectiveness.

Other Cardiac Conditions

The management of valvular heart disease, unstable angina, chronic stable angina, acute MI, and other cardiac conditions is a critical factor in stroke prevention. Strategies to prevent postoperative neurologic injury and stroke in patients undergoing surgical revascularization for atherosclerotic heart disease can be found in the American College of Cardiology coronary artery bypass graft surgery guidelines, which are approved by the AHA [9,130]. The AHA states that it is "reasonable" to use warfarin for patients who have had ST-elevation MI and left ventricular dysfunction with extensive regional wall-motion abnormalities [9].

Dyslipidemia

The AHA recommends that statin therapy be prescribed for individuals with known coronary heart disease or high-risk hypertension (e.g., patients with diabetes), including those with normal low-density lipoprotein (LDL) cholesterol levels [9]. In addition, these individuals should be encouraged at every interaction to exercise, eat a healthful diet, and quit smoking. Niacin, bile acid sequestrants, ezetimibe, or fibric acid derivatives may also be considered for individuals with known coronary heart disease and low levels of high-density lipoprotein cholesterol, such as people in whom target cholesterol levels cannot be achieved with statins or people who cannot tolerate statin therapy; however, their effectiveness in decreasing stroke risk has not been established [9].

Asymptomatic Carotid Stenosis

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends against screening for asymptomatic carotid artery stenosis in the general adult population. The USPSTF concludes that for individuals with asymptomatic carotid artery stenosis there is moderate certainty that the benefits of screening do not outweigh the harms.

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/carotid-artery-stenosis-screening

Last Accessed: March 11, 2020

Strength of Recommendation/Level of Evidence: D (The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.)

Individuals with asymptomatic carotid artery stenosis should be screened for other modifiable risk factors, and any risk factors identified should be controlled as soon as possible. Antiplatelet therapy with aspirin is recommended, unless contraindicated [9]. Preventive carotid endarterectomy performed by a skilled surgeon is an option for patients when it is determined that the morbidity/mortality risk is less than 3% to 6%; however, the reduction in stroke risk is modest at best [9,10]. Comorbidities and life expectancy should be considered when determining if surgery is appropriate. In addition, thorough discussion with the patient and his or her family/caregivers is a necessity. Topics should include the possibility of surgery-related death, the risks and benefits associated with the procedure, and the patient's preferences. For patients with a high surgical risk, carotid angioplasty/stenting may be considered. However, the periprocedural and overall 1-year event rates in some studies have dampened the AHA's enthusiasm for the stenting option [9,10].

Depressive Symptoms

After publication of the AHA guidelines, the findings of a large study showed that depressive symptoms are an independent risk factor for stroke, especially for patients younger than 65 years of age [131]. Clinicians may consider managing depressive symptoms and mood disorders as aggressively as hypertension or diabetes, because mood disorders appear to increase risk for all types of stroke [132].

PUBLIC HEALTH CAMPAIGNS

Although public knowledge regarding the warning signs and risks of stroke has improved, the majority of the general public is still unaware that early treatment can prevent severe disability and death [133,134]. Estimates vary widely, however; the International Stroke Trial found that only 4% of patients with acute ischemic stroke arrive at the emergency department (ED) within 3 hours after the onset of symptoms, and a separate study found that 21% to 25% of individuals with acute ischemic stroke arrive at an ED within the same timeframe [135,136]. Of these individuals, 2% to 4% receive thrombolytic treatment [137,138]. It has been estimated that if all individuals called for emergency help at the onset of symptoms, as many as 29% could realistically receive treatment within 3 hours [137]. In addition, if all patients arrived at the ED within 1 hour after known symptom onset and received optimal treatment, the projected rate of thrombolysis would be 57%.

To improve the rate of early arrival in the ED, public education campaigns designed to help individuals recognize a stroke and seek early treatment often use the "five sudden warning signs" devised by the Brain Attack Coalition, or "FAST," a mnemonic device created by study investigators on the basis of the Cincinnati Prehospital Stroke Scale [139,140]. The AHA and the National Stroke Association and other organizations use FAST. Early signs and symptoms that comprise the five sudden warning signs include [140,141]:

- Numbness or weakness of the face, arm, or leg (especially on one side)

- Trouble seeing from one or both eyes

- Severe headache

- Dizziness, difficulties with walking, and loss of balance and coordination

- Confusion and trouble speaking or understanding

FAST was designed to focus on fewer common signs of stroke onset (face numbness, arm numbness, and slurred speech) and to include an action component (time) for lay persons who may have trouble recalling the warning signs and the appropriate action. A retrospective study exploring the capacity of the FAST campaign to facilitate the recognition of stroke suggests that it leads to the identification of approximately 89% of individuals who have a stroke or TIA [140]. The most common stroke symptoms were related to the face, arm, and speech/language. The same study found that a modified version of FAST (with removal of the word "numbness") decreased the number of TIAs identified and targeted ischemic stroke more readily than hemorrhagic stroke. Ultimately, it is unknown whether the general public is more likely to remember FAST or the five sudden warning signs.

In 1989, the United States Department of Health and Human Services Public Affairs launched a National Health Observance to help stimulate awareness of the risk factors, prevention, and early treatment of stroke. For more than 25 years, May has been recognized as National Stroke Awareness Month, with special campaigns to heighten awareness of stroke among the general public. Resources to aid community campaigns can be obtained from the American Stroke Association at https://www.stroke.org/en/about-the-american-stroke-association/american-stroke-month/community-resources-english.

PATIENT EDUCATION

Patient education should be presented in several forms and focus on modifiable risk factors, patients' needs, lifestyle, and life stage. Healthcare professionals can be most effective in reducing the risk of stroke when they demonstrate an interest in a patient's lifestyle and psychologic status. For instance, if a patient depends on his or her spouse or companion for meals, optimum benefits will result from educating the spouse/companion about healthy diet practices. Clinicians should also consider cultural needs when addressing prevention strategies.

When a patient/caretaker does not speak the same language as the clinician, a professional interpreter should be consulted to ensure accurate communication. A systematic review of the literature has shown that the use of professional interpreters provides better clinical care than the use of informal interpreters, with the former improving the quality of care for patients with limited English language skills to a level equal to that for patients with no language barriers [142]. Use of professional interpreters has been associated with improvements in communication (errors and comprehension), utilization, clinical outcomes, and satisfaction with care [142]. Individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [143].

Whether the education involves stroke prevention, stroke recognition, care after stroke, coping with the effects of stroke, or palliative care, written materials are as important as verbal communication. Several organizations supply general or specialized educational resources, and many also provide patients and family/caregivers with psychosocial, financial, and assisted-living information or aid (Table 9). Clinicians should attempt to obtain materials written in languages appropriate for their patient population and, if appropriate, that target patients in high-risk racial/ethnic populations, especially American Indian/Alaskan native and black individuals.

Table 9: ORGANIZATIONS PROVIDING PATIENT EDUCATION RESOURCES ON STROKE

American Heart Association

(800) AHA-USA-1 (242-8721)

https://www.heart.org

American Stroke Association (a division of the American Heart Association)

(800) AHA-USA-1 (242-8721)

https://www.stroke.org

Brain Aneurysm Foundation

(888) BRAIN02 (272-4602)

https://bafound.org

Brain Attack Coalition

(301) 496-5751

https://www.brainattackcoalition.org

Centers for Disease Control and Prevention

https://www.cdc.gov/stroke

Internet Stroke Center

(214) 648-3111

http://www.strokecenter.org

BrightFocus Foundation

(800) 437-2423

https://www.brightfocus.org

Hazel K. Goddess Fund for Stroke Research in Women

http://www.thegoddessfund.org

National Aphasia Association

https://www.aphasia.org

Source: Compiled by Author

PREDICTING RISK

When determining the appropriate degree of risk management, information regarding an individual's risk of first stroke is valuable. The goals of risk assessment tools include [9]:

- Identifying patients who are unaware of their elevated risk

- Assessing the total risk of multiple factors

- Discerning the utility of modifications and treatments

- Projecting a quantitative risk in order to select appropriate treatments or stratification in clinical trials

- Guiding appropriate use of diagnostic tests

The numerous nonmodifiable and modifiable factors that contribute to the risk of stroke have been discussed. Although many of these are independent risk factors, their interactions can affect predictions and management decisions in unexpected ways. No simple, validated stroke risk-assessment tool is currently available [9]. Although risk-assessment tools may have some utility, it is unknown if they improve primary prevention, especially when applied across subgroups according to age, gender, and race/ethnicity [9,144].

Because TIA is a substantial risk factor for a subsequent stroke, clinicians in many EDs are stratifying such patients by degree of risk with use of the ABCD or ABCD2 assessments [145,146]. The ABCD clinical tool is designed to predict 7-day risk of stroke through assessment of age (1 point for patients 60 years of age or older), blood pressure (1 point for a blood pressure greater than 140/90 mm Hg), clinical features (2 points for unilateral weakness with or without speech impairment or 1 point for speech impairment without weakness), and duration (1 point for 10 to 59 minutes, 2 points for greater than 59 minutes) [147]. The "2" designation in ABCD2 was added to represent the presence or absence of diabetes. The effectiveness of these screening tools is lessened by the fact that some individuals do not seek emergency care for a TIA or do not report a TIA to their clinician. However, the ABCD2 assessment has been shown to identify 21% of individuals with a high 2-day risk of having an ischemic stroke [145]. Individuals with high-risk TIA require the same intensity of evaluation and stroke prevention as individuals with ischemic stroke. Scores that predict future stroke risk should be used in conjunction with other diagnostic studies (e.g., imaging) and laboratory tests. The use of ED diagnostic protocols and observation units can reduce length of stay while improving patient treatment and reducing stroke rate [148,149].

4. EARLY MANAGEMENT

Because the temporal window for effective stroke treatment is short, it is imperative that evaluation and diagnosis are performed promptly and accurately. Use of EMS by persons with stroke is associated with earlier ED arrival, faster ED evaluation, more rapid treatment, and more eligible patients receiving treatment. However, only 60% of all patients with stroke use EMS. In particular, male, black, and Hispanic patients are less likely to use EMS [150].The AHA/ASA has established several evidence-based recommendations for the diagnosis and early management of adult-onset ischemic stroke [16]. These recommendations address the evaluation of the individual before he or she arrives at an ED, diagnosis in the ED, the history and physical examination, laboratory tests, carotid ultrasonography, cerebral angiography, and imaging studies.

PREHOSPITAL EVALUATION

The single most important factor influencing the treatment of stroke within 3 hours after the onset of symptoms is the rapid triage and transportation provided by EMS [151]. Public health leaders and medical professionals should design and implement education programs that emphasize the need to rapidly seek emergency care when a stroke is suspected. These programs should be racially/ethnically, age, and sex/gender diverse and should target the public, healthcare providers, and hospital and EMS personnel to increase use of the EMS system, decrease stroke onset to ED arrival times, and increase the timely use of appropriate treatment [16].

Stroke assessment should begin with the EMS dispatcher [16]. When stroke or TIA is suspected, the dispatcher should notify the appropriate EMS provider and coordinate with an appropriate acute stroke treatment facility (Table 10). Regardless of the degree of the neurologic deficits, an individual with suspected stroke or TIA should be dispatched and triaged as if he or she were a serious trauma patient [16]. If possible, the individual should be taken to a designated stroke center [16,19].

Table 10: "STROKE CHAIN OF SURVIVAL" FROM THE 2013 AMERICAN HEART ASSOCIATION GUIDELINES

Detection: Recognize stroke signs and symptoms

Dispatch: Call 911 and priority emergency medical services dispatch

Delivery: Prompt pre-hospital notification and transport to hospital

Door: Immediate emergency department triage

Data: Emergency department evaluation, prompt laboratory studies, and computed tomography

Decision: Diagnosis and decision about appropriate therapy

Drug/Device: Administration of appropriate drugs or other interventions

Disposition: Timely admission to stroke unit, intensive care unit, or transfer

Source: [152]

After the individual's airway, breathing, and circulation have been assessed and stabilized, the EMS personnel should initiate a prehospital evaluation [16,153]. If the individual exhibits common signs of stroke and/or a stroke is indicated by a validated prehospital examination tool (e.g., Los Angeles Prehospital Stroke Screen, Cincinnati Prehospital Stroke Scale), EMS providers should notify the ED that an individual with suspected stroke is in transport [16,153,154]. Any information about coexisting conditions and, most importantly, time of symptom onset should be provided in advance. A blood glucose level should also be determined, as symptoms of hypoglycemia may mimic those of a stroke [16].

Prehospital evaluation expedites the physician's evaluation of the patient on arrival in the ED. If possible, a witness (preferably a close family member or companion) should be transported with the patient to assist with patient history, symptom onset, and contact information. If no witness was present, a family member should be contacted to go to the hospital and should be informed that he or she may need to provide consent for the patient's treatment. History obtained by EMS providers should include [16]:

- Information about recent events (e.g., stroke, MI, trauma, surgery, bleeding)

- Comorbid diseases (e.g., hypertension, diabetes)

- Use of medications (e.g., anticoagulants, insulin, antihypertensives)

The patient's medication containers should be transported to the ED as well, especially if medications include anticoagulant, antiplatelet, or antihypertensive drugs. Because 60% of individuals with suspected stroke do not use EMS for initial medical care access, ED staff should be alert to signs of stroke among individuals waiting to be seen in the ED [16,150].

DIAGNOSIS IN THE ED

Organization of the ED's stroke team and assessment protocol is paramount to maximize the likelihood of early and successful management [16]. The acute stroke team should include physicians, nurses, and laboratory/radiology personnel. After the patient has been triaged and stabilized, the inaugural ED evaluation (history and physical examination), laboratory studies, and CT imaging should be performed concurrently. The multimodal approach has three goals [16]:

- Rapid and careful identification of people with stroke for treatment purposes

- Determination of the underlying cause of the stroke for secondary prevention

- Detection of stroke-mimicking conditions that may require immediate care

Within 1 hour of the patient's arrival, the evaluation (including a neurologic examination) and treatment decision should be completed. The AHA recommends that all patients receive a standardized battery of tests and procedures, with alternative tests performed only if a particular condition is suspected or the patient's history is incomplete (Table 11) [16]. Generally, diagnostic tests should be limited to save time. In addition, all diagnostic tests for stroke should be available 24 hours a day, 7 days a week.

Table 11: IMMEDIATE DIAGNOSTIC STUDIES TO EVALUATE PATIENTS WITH SUSPECTED ISCHEMIC STROKE, AS RECOMMENDED BY THE AMERICAN HEART ASSOCIATION

Population

Diagnostic Test

All patients

Cerebral computed tomography or magnetic resonance imaging (without contrast medium)

Blood glucose

Serum electrolytes/renal function tests

Markers of cardiac ischemia

Complete blood count, including platelet count

Prothrombin time/international normalized ratio (INR)

Activated partial thromboplastin time

Oxygen saturation

Electrocardiography

Selected patients

Hepatic function tests

Toxicology screen

Blood alcohol level

Pregnancy test

Arterial blood gas tests (if hypoxia is suspected)

Chest radiography (if lung disease is suspected)

Lumbar puncture (only if stroke is suspected to be secondary to an infectious disease)

Electroencephalography (if seizures are suspected)

Source: [155] Reprinted from Christensen H, Fogh Christensen A, Boysen G. Abnormalities on ECG and telemetry predict stroke outcome at 3 months. J Neurol Sci. 2005;234:99-103. With permission from Elsevier.

PHYSICAL EXAMINATION AND HISTORY

In addition to time of onset, other crucial historical data that should be obtained include [16]:

- Information about atherosclerotic and cardiac disease risk factors

- Prior and current drug abuse and history of migraine, seizure, infection, trauma, or pregnancy

- Eligibility for treatment of ischemic stroke

If a patient presents with classic signs of stroke and has one or more cardiovascular risk factors, the diagnosis of stroke can be straightforward. However, identifying more unusual cases may be a challenge. If fever and a cardiac murmur are present, the cause of the stroke may be infective endocarditis [156,157]. Giant cell arteritis may be the cause if the patient is 50 years of age or older, has a headache, and has an elevated erythrocyte sedimentation rate. The presence of ptosis and miosis contralateral to the deficit may suggest carotid artery dissection [156,157]. If the symptoms were maximal at their onset, a subarachnoid hemorrhage or embolic stroke should be suspected [158]. In up to 40% of patients with subarachnoid hemorrhage, a severe headache (sometimes called a thunderclap or sentinel headache) that may abate within minutes or hours is the only symptom [158]. Cerebral CT should be immediately performed in any patient with a suspected subarachnoid hemorrhage [36].

The general physical examination should involve assessment of the head, neck, heart, lungs, abdomen, skin, and extremities, as well as the cardiovascular, respiratory, and gastrointestinal systems [16]. Pulse oximetry and body temperature are also important evaluations. When performing the head and neck examination, the clinician should look for physical signs of trauma or seizure activity (e.g., contusions, tongue lacerations) or heart failure (jugular venous distention). Thrombolytic treatment is inadvisable for a seizure in the absence of acute ischemia detected by imaging [21].

When examining the patient's neck, carotid bruits may be heard. Although these sounds may suggest atherosclerosis, they are not sufficient for diagnosing carotid stenosis [159]. Because the prevalence of asymptomatic carotid bruits increases with advancing age, it is not a reliable clinical marker of stroke risk in individuals older than 65 years of age [160].

The cardiac examination may demonstrate contributing factors or comorbidities, such as myocardial ischemia, valvular conditions, arrhythmias, or aortic dissection (a rare cause of ischemic stroke). The diagnostic evaluation should include electrocardiography (ECG), because cardiovascular conditions such as AF and MI are prevalent among individuals with stroke [16,155]. The findings of studies have suggested that the value of chest x-ray as part of the diagnostic workup is debatable, and the 2019 AHA/ASA guideline recommends a chest x-ray only if lung disease is suspected [16]. Although cardiac monitoring in patients with stroke has not been evaluated, the AHA/ASA recommend its use in the first 24 hours to monitor for AF or MI, either of which can lead to stroke or be a dangerous coexisting condition [16].

Blood pressure sustained at or above 180/120 mm Hg may signal hypertensive encephalopathy [123,161]. Examination of the respiratory system and the abdomen may lead to the detection of additional conditions. The state of the skin and extremities may indicate systemic conditions, including coagulopathies, platelet disorders, or liver dysfunction [16]. An irregular pulse may be indicative of AF.

If only historical information and/or physical examination are relied on, up to 19% of stroke mimics are mistaken for stroke. Yet, a patient's history and examination may also identify a condition masquerading as a stroke (Table 12) [16,162]. The use of MRI or CT with laboratory studies enhances the accuracy of diagnosis, but detecting mimics with imaging techniques is a challenge if the patient has a history of stroke [16].

Table 12: COMMON NONCEREBROVASCULAR CONDITIONS THAT MIMIC STROKE

Stroke Mimic

Differential Symptoms

Brain tumor

Gradual progression of symptoms

Drug overdose

Altered mental status without focal findings

Conversion disorder

Neurologic findings in a nonvascular distribution

Inconsistent examination

Other psychiatric disorders

Hypertensive encephalopathy

Headache

Delirium

Significant hypertension

Cortical blindness

Cerebral edema

Seizure

Hypoglycemia

History of diabetes

Low blood glucose level

Decreased level of consciousness

Migraine with aura (complicated migraine)

History of similar events

Preceding aura

Headache

Hemiplegia that outlasts the headache

Seizures/postictal paresis

Paresis

History of seizures

Witnessed seizure activity

Drug toxicity

History of lithium, phenytoin, or carbamazepine use

Source: [162,163]

Another important component of the physical examination is assessment with the National Institutes of Health Stroke Scale (NIHSS). Although initially devised as a research tool to quantify neurologic deficits, this tool is now widely used to measure the severity of a stroke, devise an effective treatment plan that establishes a priority for patient safety, identify the potentially occluded vessel, and predict patient outcome [16,164]. The NIHSS is standardized, reliable, and fast and facilitates communication among healthcare professionals. Any trained healthcare professional can use the scale at the bedside in 5 to 8 minutes. In addition, results are based only on patient evaluation; a history or information from others is not necessary. It is recommended that the scale be used to assess the patient during the ED evaluation and during treatment with recombinant tissue plasminogen activator (rt-PA) or other therapies and that it be repeated often in the first 24 hours. Further information about the NIHSS and a copy of the scale can be obtained from the National Institute of Neurological Disorders and Stroke [165].

LABORATORY TESTS

For all patients with suspected stroke, the battery of diagnostic tests should be carried out concurrently with laboratory tests, including blood glucose level (to rule out hypoglycemia as a stroke mimic), complete blood count (with platelet count), serum electrolyte levels, renal function studies, and cardiac ischemia biomarkers [16]. Determination of prothrombin time and partial thromboplastin time are of particular importance when considering thrombolysis. Generally, waiting for the results of a diagnostic test should not be a reason to delay thrombolytic therapy [16]. The risk of increased neurologic damage and death caused by ischemic stroke outweighs that of a secondary hemorrhage except when a bleeding or blood disorder is suspected, the patient was given warfarin or heparin, or the patient takes anticoagulant drugs.

CAROTID ULTRASONOGRAPHY

Carotid ultrasonography is a noninvasive vascular imaging technique used to measure arterial blood flow and determine the site and degree of stenosis/occlusion of cerebral vasculature. In particular, transcranial Doppler ultrasonography, which can be performed at the bedside, serves multiple purposes in the cerebrovascular setting. Its most common uses are to assess a patient's primary and secondary stroke prevention needs and to monitor a patient's progress during the early post-acute stroke phase [10,16,166]. Additional uses of transcranial Doppler ultrasonography in patients with stroke include [16,166,167]:

- Detection of intracranial and extracranial vascular disorders

- Assessment of recurrent stroke risk (e.g., microemboli detection)

- Identification of candidates for intensive prophylactic interventions (e.g., carotid endarterectomy, angioplasty/stenting)

- Intraoperative monitoring of carotid endarterectomy

- Detection of right-to-left shunts

- Identification of subclavian steal syndrome

- Measurement of a post-subarachnoid hemorrhage vasospasm

- Assessment of recanalization (spontaneous or thrombolytically induced)

- Prognosis of patients with stroke (performed during post-acute phase)

Despite the usefulness of this technique, its performance is highly operator-dependent [166]. Considerable anatomic and physiologic knowledge of the cerebral vasculature is required, as vessel images are not produced, and skill and experience are prerequisites for data interpretation. Data acquisition and interpretation tend to be time-consuming and may delay treatment [166,168]. While these reasons suggest that vascular imaging is not practical for the diagnosis of ischemic stroke in most cases, it may be useful in some. A recommendation in the 2019 AHA/ASA guidelines states that noninvasive imaging of the cervical carotid arteries should be routinely performed within 24 hours of admission in patients with nondisabling acute ischemic stroke in the carotid territory who are candidates for carotid endarterectomy [16]. Additionally, intracranial vessel imaging is recommended to guide selection of appropriate secondary stroke prevention treatments [16].

CEREBRAL ANGIOGRAPHY

Conventional catheter angiography is invasive, uses ionic radiation, and requires a nephrotoxic contrast medium [169]. It is particularly valuable for the detection of pathologic vascular disorders that lead to cerebral hemorrhage or ischemia, including aneurysm, vasculitis, arteriovenous malformation, atherosclerosis, and arterial dissection [10,16]. Digital subtraction angiography (DSA), a type of catheter angiography, remains the standard criterion of conventional angiography for detection of many types of cerebrovascular lesions and diseases [170,171,172,173,174]. Its sensitivity and specificity equal or exceed those of noninvasive techniques; however, it can cause serious complications, such as stroke or death [16].

Unlike catheter angiography, magnetic resonance angiography (MRA) is not an x-ray. This technique creates a map of blood flow, not a true image of the vasculature anatomy. Noninvasive time-of-flight MRA is performed without contrast medium, whereas phase-contrast MRA is performed with contrast medium and is minimally invasive (catheter insertion into a blood vessel is unnecessary). Although MRA provides a high-resolution image of many vessels, it cannot reliably resolve distal or branch occlusions of the intracranial vasculature [16]. Another major disadvantage of MRA is that it overestimates the degree and length of high-grade stenosis by signaling loss of flow when blood flow is turbulent, in-plane, or slow [175]. Although MRA continues to advance technologically, in large part through the improvement of contrast media, high-grade stenosis is still overestimated using this technique when compared with DSA [176]. MRA is helpful for detecting less common causes of ischemic stroke or TIAs (e.g., arterial dissection, venous thrombosis) [172]. The 2019 AHA/ASA guideline recommends the use of MRA with diffusion-weighted MRI (DW-MRI) for selecting candidates for mechanical thrombectomy between 6 and 24 hours after last known well time [16]. DW-MRI is sensitive to acute cellular injury in cerebral ischemia and can be used to assess ischemic lesions in the first few hours [177].

Computed tomography angiography (CTA) provides a means to rapidly and noninvasively screen intracranial and extracranial vasculature for stenoses and occlusions. Preliminary data suggest that CTA effectively detects large-vessel intracranial occlusions when compared with ultrasound and DSA; however, because it provides a static image of vascular anatomy, it is inferior to DSA for demonstrating flow rates and direction [16,178]. Although CTA is fast and can be adapted to conventional CT, contrast medium is required and patients are exposed to additional radiation [16]. The 2019 AHA/ASA guideline recommends the use of CTA with computed tomographic perfusion (CTP) or MRA for selecting candidates for mechanical thrombectomy between 6 and 24 hours after last known well time [16].

Transcranial Doppler (TCD) ultrasonography has been used to detect intracranial vessel abnormalities and to evaluate occlusions and stenoses in intracranial vessels. It is less accurate than CTA or MRA for steno-occlusive disease but can detect microembolic signals that indicate extracranial or cardiac sources of embolism [152]. TCD has been shown to predict and enhance outcomes with intravenous rt-PA [179].

Because the time between the onset of stroke and treatment should be limited, catheter angiography is not recommended by the AHA for the diagnosis of a suspected stroke [152]. In the case of a stroke, the utility of the imaging tool increases after a diagnosis has been made. As with transcranial Doppler ultrasonography, cerebral angiography is particularly useful for confirming the diagnosis, monitoring the progression of thrombolytic therapy, and assisting with the prognosis, particularly during the first 72 hours after a stroke [152].

IMAGING STUDIES

High diagnostic accuracy of stroke and treatment decisions is optimized by the use of imaging tools such as CT and MRI. Collectively, these neuroimaging options provide detailed information that influences stroke treatment decisions, including infarct age, severity, and distribution; intracranial vascular status; cerebral hemodynamics; estimated reversibility of ischemic damage; and hemorrhage type and distribution [16]. For instance, a widespread distribution of early infarction or edema increases hemorrhagic transformation risk following thrombolytic therapy. CT without contrast medium is readily sensitive to these conditions [16].

For prompt and accurate diagnosis, the use of noncontrast CT or DW-MRI is recommended for suspected stroke [16]. Although noncontrast CT is less expensive, faster, and more widely available, DW-MRI more readily detects small cortical, small subcortical, and posterior fossa infarcts and distinguishes chronic ischemia from acute ischemia. MRI is also sensitive to subclinical satellite ischemic lesions that characterize the pathophysiology of the stroke [152,180]. As stated, DW-MRI can detect acute ischemic changes within minutes after the onset of stroke; CT may not detect ischemic stroke until up to 1 hour after the event [16]. However, not all patients with suspected stroke may benefit from MRI. Contraindications for MRI include claustrophobia, pacemakers, and metal implants.

If a patient is eligible for rt-PA, the AHA/ASA recommend that treatment be initiated as quickly as possible and not delayed for additional multimodal imaging (e.g., CT, MRI). Multimodal CT and MRI are not necessary when the diagnosis of ischemic stroke is very likely and their performance may delay time-sensitive administration of rt-PA. In cases of substantial diagnostic uncertainty, advanced imaging may be beneficial [16].

Although CT and MRI are increasingly available in EDs, the AHA/ASA state that noncontrast computed tomography (NCCT) is sufficient to identify contraindications to fibrinolysis and to ensure that patients with ischemic stroke receive timely intravenous fibrinolytic therapy. The AHA recommends that NCCT be obtained within 25 minutes after the patient's arrival in the ED [152].

5. TREATMENT

Because strokes are highly heterogeneous, are associated with multiple medical complications, and are time-critical, their effective management depends on organized and comprehensive care. Such treatment is optimally provided in comprehensive stroke centers and stroke systems of care. In 2007, the AHA/ASA published evidence-based guidelines to provide recommendations for treatment. These guidelines were updated in 2013 and again in 2019 [16,152].

STROKE SYSTEMS OF CARE AND COMPREHENSIVE STROKE CENTERS

Comprehensive stroke centers are designed to accommodate the needs of patients with complicated forms of stroke, intracranial hemorrhages, and subarachnoid hemorrhages, as well as patients in need of aggressive intervention measures and intensive care [19]. In general, primary and comprehensive stroke centers have been shown to be associated with better adherence to evidence-based guidelines and with an increased use of intravenous rt-PA [181]. Nationally, only 2% to 3% of individuals with stroke are treated with rt-PA, but the rate is typically greater than 10% at primary and comprehensive stroke care centers [19,138]. Overall care may also be improved at comprehensive stroke centers [181,182]. A formal certification process for comprehensive stroke centers has been established by the Joint Commission and the ASA. The Joint Commission has been certifying primary stroke centers since 2004, and it began providing certification for comprehensive stroke centers in 2014 [16]. Because patients are more likely to receive thrombolytic therapy at primary and comprehensive stroke centers, many states have enacted policies mandating the direct routing of individuals with suspected stroke (with onset of symptoms less than 3 hours previously) to either of these types of facilities. As of 2015, 1,505 of the 4,640 general hospitals and emergency rooms in the United States have been certified as primary stroke centers [183]. Seventy-four percent of the primary stroke centers have been certified by the Joint Commission and the AHA/ASA, 20% have been certified by state organizations, and 6% have been certified by other organizations. The highest proportion of primary stroke center certifications has occurred in the Northeastern United States [183]. Telemedicine for stroke (also called telestroke) and air transport are being increasingly used to serve individuals in rural areas that lack local stroke expertise [16,182].

Stroke centers are commonly part of a comprehensive support network known as a stroke system of care [16]. The system seeks ways to coordinate the highest quality of stroke prevention, community education, EMS, acute care, and post-acute care. Without a system of care, these components often operate less effectively and in isolation. Implementation of a stroke system of care in underserved regions could substantially improve treatment statistics statewide or nationwide; for example, one study showed that the additional resources at as few as six target hospitals in the western part of North Carolina would increase patient access to stroke care by 61.5% throughout the state [184].

Guidelines for establishing a stroke system of care were developed by an ASA Task Force [20]. Because of the multidisciplinary aspects of a stroke system, Task Force members were experts in areas of stroke prevention, EMS, acute stroke care, rehabilitation, and healthcare policy. Overall, the recommendations promote the communication and collaboration of patients, clinicians, facilities, and agencies. General ASA recommendations for stroke systems of care are [20]:

- Support local/regional educational initiatives designed to increase stroke awareness among the general population, with enriched targeting of populations at increased risk of stroke and poor post-stroke outcomes.

- Design/implement innovative behavioral interventions that address barriers to healthy behaviors and prevention adherence.

- Design/implement public education programs that are repetitive, designed to reach diverse populations, and focused on stroke systems and the need to urgently seek emergency care (by calling 911).

- Develop triage protocols that ensure all patients with known or suspected stroke are rapidly identified and assessed with validated stroke screening instrument.

- All stroke center certification systems should meet or exceed the standards set by nationally certified stroke centers and should work regionally in an integrated way to provide and share best practices.

- Adopt approaches to secondary prevention that address all major modifiable risk factors and are consistent with national guidelines for patients with a history or suspected history of stroke or TIA.

- Standardize postacute care and discharge. Trained stroke nurses, nurse practitioners, social workers, community health workers, and others play a critical role in this process.

- Advance the use of technology and patient-reported outcomes to facilitate improvements in stroke care transitions.

- Enact federal-level policies that standardize the organization of stroke care throughout the continuum.

EVIDENCE-BASED GUIDELINES

Thrombolytic therapy with rt-PA is the only treatment approved by the U.S. Food and Drug Administration (FDA) for ischemic stroke [16]. Anticoagulant and antiplatelet agents are also used, but their appropriateness is a source of debate and ongoing research. Intra-arterial rt-PA may be beneficial for select patients; however, the drug is not FDA approved for this use [18]. Mechanical thrombectomy is a consideration as both a primary reperfusion strategy and in conjunction with pharmacologic fibrinolysis [16].

The AHA/ASA recommendations for the treatment of ischemic stroke are based on an exhaustive review of available studies and emphasize the importance of early management [16,18]. Since publication of the 2013 guidelines, substantial new high-quality evidence on the clinical efficacy of endovascular treatments has become available. This new evidence is the basis of the AHA/ASA 2015 focused update to the 2013 guidelines and is included, where appropriate, in the recommendations that follow [18].

Recombinant Tissue Plasminogen Activator (rt-PA)

Evidence Based Practice Recommendation

With a goal to improve functional outcomes, the American College of Emergency Physicians recommends that intravenous tPA should be offered and may be given to selected patients with acute ischemic stroke within three hours after symptom onset at institutions where systems are in place to safely administer the medication. The increased risk of symptomatic intracerebral hemorrhage should be considered when deciding whether to administer tPA.

https://www.acep.org/globalassets/new-pdfs/clinical-policies/tpa-for-stroke_new.pdf

Last Accessed: March 11, 2020

Strength of Recommendation: B (Recommendation based on moderate clinical certainty)

The intravenous administration of rt-PA has been FDA-approved for the treatment of stroke since 1996. Rapid administration of rt-PA to appropriate patients remains the mainstay of early treatment of acute ischemic stroke [18]. Treatment with rt-PA is highly effective if administered within 3 hours. The earlier treatment is initiated, the higher the probability of a full recovery. Treatment within 90 minutes has been associated with a higher rate of favorable outcome at 3 months compared with treatment administered within 180 minutes [185]. For patients who meet national and international eligibility guidelines, intravenous rt-PA improves functional outcomes at 3 to 6 months when given within 4.5 hours after ischemic stroke onset and should be administered [18]. However, the therapeutic window may extend to 6 hours [186,187]. Studies to determine the threshold of rt-PA benefits are ongoing. The AHA/ASA recommend that health systems set a goal of increasing their percentage of stroke patients treated within 60 minutes of presenting to hospital (i.e., door-to-needle time of 60 minutes) to at least 80% [152].

The AHA/ASA have changed some of their recommendations regarding rt-PA treatment since their 2013 guidelines (Table 13) [16]. Administration of rt-PA is not recommended for patients who have a systolic blood pressure greater than 185 mm Hg or a diastolic blood pressure greater than 110 mm Hg [16].

Table 13: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS FOR THROMBOLYTIC THERAPY

Class I Recommendations

In patients eligible for IV rt-PA, benefit of therapy is time dependent; treatment should be initiated as quickly as possible (Class I, Level of Evidence A).

Intravenous rt-PA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class I, Level of Evidence A). Physicians should review the criteria outlined in the AHA/ASA guidelines to determine the eligibility of patients.

Intravenous rt-PA (0.9 mg/kg, maximum dose 90 mg) is recommended for administration to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke onset (Class I, Level of Evidence B). Physicians should review the criteria outlined in the AHA guidelines to determine the eligibility of patients.

Intravenous rt-PA is recommended for eligible patients with mild but disabling stroke systems who may be treated within 3 hours of onset of stroke symptoms (Class I, Level of Evidence B).

Intravenous rt-PA is reasonable in patients whose blood pressure can be lowered safely (to less than 185/110 mm Hg) with antihypertensive agents, with the physician assessing the stability of the blood pressure before starting intravenous rt-PA. Blood pressure should be maintained at <180/105 mm Hg for at least the first 24 hours (Class I, Level of Evidence B).

In addition to bleeding complications, physicians should be aware of the potential side effect of angioedema that may cause partial airway obstruction (Class I, Level of Evidence B).

Class II Recommendations

Intravenous rt-PA (0.9 mg/kg, maximum dose 90 mg) administered within 4.5 hours of stroke symptom recognition may be beneficial in patients who awake with stroke symptoms or have unclear time of onset Class II, Level of Evidence B).

Intravenous rt-PA may be beneficial for adults presenting with acute ischemic stroke with known sickle cell disease (Class IIa, Level of Evidence B).

Intravenous rt-PA may be beneficial in patients with a hyperdense MCA sign (Class IIa, Level of Evidence B).

Intravenous rt-PA administration should not be delayed while waiting for hematologic or coagulation testing, if no abnormal test results are expected (Class IIa, Level of Evidence B).

Administration of IV rt-PA is reasonable in otherwise eligible patients who have previously had a small number (1 to 10) of CMBs demonstrated on MRI (Class IIa, Level of Evidence B).

In otherwise eligible patients who have previously had a high burden of CMBs (Class IIb, Level of Evidence B).

The risk of antithrombotic therapy (other than intravenous aspirin) within the first 24 hours after treatment with IV rt-PA (with or without mechanical thrombectomy) is uncertain. Use might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV rt-PA is known to provide substantial benefit or withholding such treatment is known to cause substantial risk (Class IIb, Level of Evidence B).

It may be reasonable to choose tenecteplase (single IV bolus of 0.25 mg/kg, maximum 25 mg) over IV rt-PA in patients without contraindications for IV fibrinolysis who also are eligible to undergo mechanical thrombectomy (Class IIb, Level of Evidence B).

Tenecteplase (0.4 mg/kg single IV bolus) might be considered as an alternative to IV rt-PA in patients with minor neurologic impairment and no major intracranial occlusion (Class IIb, Level of Evidence B).

Intravenous rt-PA may be reasonable for patients who can be treated within 3 to 4.5 hours of stroke symptom of onset (Class IIb, Level of Evidence B).

The usefulness of IV administration of the glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide coadministered with intravenous rt-PA is not well established (Class IIb, Level of Evidence B).

Class III Recommendations

Intravenous rt-PA is not recommended for patients who could be treated within 3 hours of stroke symptom onset (Class III, Level of Evidence B). This applies to otherwise eligible patients with mild nondisabling stroke symptoms (NIHSS score 0–5).

Do not administer abciximab concurrently with IV rt-PA (Class III, Level of Evidence B).

Do not administer IV aspirin within 90 minutes of initiation of IV rt-PA (Class III, Level of Evidence B).

Intravenous rt-PA is not indicated for nonvascular conditions (Class III, Level of Evidence B). Clinicians should be aware that hypoglycemia and hyperglycemia may mimic acute stroke and should determine blood glucose levels prior to initiation of IV rt-PA.

Do not administer IV rt-PA to patients who have received a full treatment dose of LMWH within the previous 24 hours (Class III, Level of Evidence B).

Intravenous rt-PA is not recommended for patients who could be treated within 3 to 4.5 hours of stroke symptom onset (Class III, Level of Evidence C). Applies to otherwise eligible patients with mild nondisabling stroke symptoms (NIHSS score 0–5).

Do not delay treatment with IV rt-PA to monitor improvement (Class III, Level of Evidence C).

MCA=middle cerebral artery; CMB=cerebral microbleed; MRI=magnetic resonance imaging; sICH=symptomatic intracerebral hemorrhage.

Source: [16]

Between 31% and 50% of patients treated with rt-PA have a 4-point or greater improvement on the NIHSS by 3 months after the stroke [152]. These clinical improvements do not recede for at least 1 year after the stroke. In general, the best response to rt-PA has been found for patients who are younger than 75 years of age, with a baseline NIHSS score of less than 20, and no history of diabetes or pre-existing disability [152].

The most common serious medical complication of rt-PA is secondary brain hemorrhage, which occurs in 6% of patients [188]. Yet, the risk does not outweigh the benefits of rt-PA. Three months following rt-PA therapy, approximately 30% of patients are neurologically normal or near normal; 30% have mild-to-moderate neurologic deficits; 20% have moderate-to-severe deficits; and 20% have died [189]. Other dangerous complications of rt-PA, although rare, are angioedema, anaphylaxis, systemic hemorrhage, and, if rt-PA is administered soon after an acute MI, myocardial rupture [16,190].

Anticoagulants

The AHA/ASA Task Force reviewed and discussed several studies addressing the use of heparin or low-molecular-weight heparin (LMWH) as an adjunct to a thrombolytic agent in the treatment of stroke [16]. In general, the Task Force concluded that early administration of heparin or LMWH is inadvisable partly due to the increased risk of bleeding complications, especially the hemorrhagic transformation of ischemic strokes. Additionally, early administration has not been shown to prevent recurrent stroke, lessen the risk of neurologic worsening, or improve patient outcome [16].

Antiplatelets

Although no new data regarding antiplatelet treatment have emerged since the 2003 version of the AHA/ASA guideline for ischemic stroke management, the AHA/ASA recommendations for antiplatelet therapy have changed (Table 14) [16]. Data combined from two large clinical trials suggest that administration of aspirin (325 mg) within 48 hours after the onset of stroke slightly reduces mortality and morbidity by preventing early recurrent stroke in some patients [191,192]. The findings of these trials do not suggest the use of aspirin within 24 hours of thrombolytic administration or as a substitute for thrombolytic therapy. A 2014 Cochrane review confirmed the results of these trials [193]. A review that summarized the results of nine randomized controlled trials also confirmed these findings and demonstrated increased odds of complete recovery [194]. Other oral antiplatelet therapies (e.g., ticagrelor, clopidogrel, dipyridamole) are being studied in the setting of acute ischemic stroke [195].

Table 14: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS REGARDING ANTIPLATELET TREATMENT FOR ISCHEMIC STROKE

Class I Recommendations

The oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients (Class I, Level of Evidence A). For patients treated with IV rt-PA, aspirin administration is generally delayed 24 hours.

In patients presenting with minor noncardioembolic ischemic stroke (NIHSS score ≤3) who did not receive IV rt-PA, treatment with dual antiplatelet therapy (aspirin/clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset (Class I, Level of Evidence A).

Class II Recommendations

The efficacy of intravenous tirofiban and eptifibatide is not well established (Class IIb, Level of Evidence B). Further trials are necessary to clarify the safety and efficacy of this intervention.

Class III Recommendations

Ticagrelor is not recommended over aspirin for treatment of patients with minor stroke (Class III, Level of Evidence B). Ticagrelor may be a reasonable alternative in stroke patients with a contraindication to aspirin.

The administration of abciximab as medical treatment for acute ischemic stroke is potentially harmful and should not be performed (Class III, Level of Evidence B).

Aspirin is not recommended as a substitute for other acute interventions for treatment of stroke, including the intravenous administration of rt-PA (Class III, Level of Evidence B).

Source: [16]

Evidence Based Practice Recommendation

In patients with acute ischemic stroke or transient ischemic attack, the American College of Chest Physicians recommends early (within 48 hours) aspirin therapy at a dose of 160–325 mg.

https://journal.chestnet.org/issue/S0012-3692(12)X6003-3

Last Accessed: March 11, 2020

Strength of Recommendation/Level of Evidence: 1A (Strong recommendation, high-quality evidence)

Ticagrelor is a reversible, short-acting P2Y12 agonist. The Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial tested the efficacy of ticagrelor (18-mg loading dose, then 90 mg twice daily) to aspirin in 13,199 patients with acute ischemic stroke or high-risk TIA [196]. The primary outcome (i.e., time to stroke occurrence, MI, or death within 90 days) occurred in 6.7% of patients treated with ticagrelor versus 7.5% treated with aspirin. Ischemic stroke occurred in 5.8% in the ticagrelor arm versus 6.7% in the aspirin arm. There were no differences in major bleeding, intracranial hemorrhage, or fatal bleeding. A subgroup analysis of the SOCRATES trial found that ticagrelor was effective at preventing the primary outcome in patients with a background history of aspirin use [197]. Ticagrelor versus placebo was the subject of the THALES (Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death) trial, which was completed in December 2019. As of 2020, the results have not yet been published [198].

Several trials have examined the efficacy of clopidogrel plus low-dose aspirin [199,200,201,202,203,204]. While the data from two of these trials suggest a benefit from dual antiplatelet therapy (i.e., clopidogrel/aspirin), the results of the other trials suggest a lack of benefit and possibly harm in the longer term. The combination dipyridamole plus aspirin for ischemic stroke management has been studied in several trials involving more than 17,000 patients [205,206,207,208,209,210]. The combination was found to be an acceptable antiplatelet therapy for patients with ischemic stroke or TIA and probably superior to aspirin alone. However, twice-daily dosing and headache cause many patients to discontinue the regimen [207,208,209,210].

The efficacy of intravenous glycoprotein IIb/IIIa receptor blockers (GP IIb/IIIa inhibitors), such as abciximab, in combination with other interventions or alone is under investigation. Preliminary results from the Abciximab in Emergent Stroke Treatment Trial (AbESTT) indicate that intravenous GP IIb/IIIa inhibitors may accelerate spontaneous recanalization, improve microvascular patency, and offer an adequate safety profile [211,212]. However, a systematic review of GP IIb/IIIa inhibitors as well as results of the AbESTT-II (a phase III trial of abciximab) did not demonstrate either safety or efficacy of the drug for treatment of acute ischemic stroke and found an increased rate of symptomatic or fatal intracranial hemorrhage, with no reduction in death or disability in survivors [213,214]. The 2019 AHA/ASA guideline contains both revised and new recommendations regarding the use of IV GP IIb/IIIa inhibitors, including abciximab (Table 14) [16].

Angioplasty and Stenting

Although emergent angioplasty and stenting are high-risk procedures, progressing strokes, which occur when patients' moderate neurologic deficits deteriorate significantly within 72 hours after onset, are associated with very poor outcomes and high mortality rates [215]. Therefore, some case studies suggest that emergency angioplasty followed by immediate or delayed stenting is appropriate for patients with a progressing stroke caused by carotid artery occlusion or stenosis, respectively [216,217]. However, the safety and efficacy of emergency carotid artery stenting are not established, and the procedure remains controversial [218,219].

Angioplasty and stenting may be appropriate for patients with acute stroke secondary to carotid artery dissection [220,221]. In one study, emergency angioplasty and stenting of the internal carotid artery performed in conjunction with intra-arterial thrombolysis was associated with more favorable outcomes than pharmacologic treatment alone in patients with acute carotid artery occlusion and secondary artery-to-artery embolism to the middle cerebral artery [222]. In a larger study by the same group of investigators, treatment with urokinase followed by angioplasty and stenting increased recanalization [223]. Another study found that angioplasty and stenting of the proximal occlusion and stent-based thrombectomy of the intracranial occlusion may be feasible, effective, and safe in selected patients with acute internal carotid artery occlusion and concomitant major vessel embolic stroke [221].

The AHA/ASA assert that the use of angioplasty and intra-arterial thrombolytics in the emergency management of stroke should be limited to comprehensive stroke centers, which have the resources and physician expertise to perform them safely, and in the setting of clinical trials [18].

In addition to use in emergent angioplasty and stenting, mechanical thrombectomy is both a primary reperfusion strategy and an adjunct to pharmacologic fibrinolysis for achieving recanalization in patients with acute ischemic stroke [16]. Mechanical treatments include the use of catheters during angiography to directly deliver either a clot-disrupting or retrieval device to an artery-occluding thromboembolus [224].

The primary advantage of mechanical devices is their ability to remove a clot in a matter of minutes, compared with pharmacologic thrombolytics (even those delivered intra-arterially) that may take as long as two hours to dissolve the clot [225,226]. A second advantage is that newer devices (e.g., retrievable stents) have shown higher recanalization rates and better outcomes than those seen with older devices (e.g., the Merci Retriever) [224]. The primary disadvantage of endovascular therapy is the delay in initiation of treatment because of the time required to mobilize the interventional team and, in many cases, the need to transfer the patient to another hospital [227,228]. In the absence of sufficient trial data, it had been uncertain whether endovascular therapy, with or without the previous use of intravenous rt-PA, would be more effective than intravenous rt-PA alone [229]. However, newer trials (i.e., MR CLEAN, EXTEND-IA, ESCAPE, and SWIFT-PRIME) have demonstrated the efficacy of endovascular therapy using the newer, retrievable stents [230,231,232].

In addition to reviewing the results of these four trials, the AHA/ASA also reviewed the results of the REVASCAT trial [18,233]. Of the five stent retriever trials, MR CLEAN, ESCAPE, and SWIFT-PRIME permitted use of salvage intra-arterial fibrinolytic drugs, whereas EXTEND-IA and REVASCAT did not [18]. Every or nearly every patient in the trials first received intravenous rt-PA. All five studies enrolled participants 18 years of age and older. Four of the trials used NIHSS scores (>2, >5, and 8–29) as eligibility criteria, and the fifth trial enrolled patients with a similar distribution of NIHSS scores. Four of the five trials used a prestroke function eligibility criterion. All five trials required baseline nonenhanced CT or MRI and used different strategies of an imaging-based selection criterion in addition to nonenhanced CT or MRI. The overwhelming majority of patients in the trials had ICA or proximal MCA (M1) occlusion. All five trials allowed the inclusion of patients with proximal cervical carotid stenosis, and all but one trial (SWIFT-PRIME) allowed the inclusion of patients with complete atherosclerotic cervical carotid occlusion. General anesthesia and conscious sedation were the two most frequently used anesthetic approaches for patients with acute ischemic stroke receiving endovascular therapy. None of the trials established the usefulness of mechanical thrombectomy devices other than stent retrievers [18].

The AHA/ASA analysis of and conclusions about these five stent retriever trials form the basis of their 2015 focused update to the guidelines on the management of patients with acute ischemic stroke (Table 15) [18].

Table 15: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS REGARDING ENDOVASCULAR INTERVENTIONS FOR ISCHEMIC STROKE

Class I Recommendations

Eligible patients should receive intravenous rt-PA even if endovascular treatments are being considered (Class I, Level of Evidence A).

Patients should receive endovascular therapy with a stent receiver if they meet all the following criteria (Class I, Level of Evidence A):

- Prestroke mRS score 0 to 1

- Acute ischemic stroke receiving intravenous rt-PA within 4.5 hours of onset according to guidelines from medical societies

- Causative occlusion of the internal carotid artery or proximal MCA (M1)

- Age ≥18 years

- NIHSS score of ≥6

- ASPECTS of ≥6

- Treatment can be initiated (groin puncture) within 6 hours of symptom onset

As with intravenous rt-PA, reduced time from symptom onset to reperfusion with endovascular therapies is highly associated with better clinical outcomes. To ensure benefit, reperfusion to TICI grade 2b/3 should be achieved as early as possible and within 6 hours of stroke onset (Class I, Level of Evidence B).

Use of stent retrievers is indicated in preference to the MERCI device (Class I, Level of Evidence A).

The technical goal of the thrombectomy procedure should be a TICI 2b/3 angiographic result to maximize the probability of a good functional clinical outcome (Class I, Level of Evidence A).

Initial treatment with intra-arterial fibrinolysis is beneficial for carefully selected patients with major ischemic strokes of less than 6 hours' duration caused by occlusions of the MCA (Class I, Level of Evidence B). However, these data derive from clinical trials that no longer reflect current practice, including use of fibrinolytic drugs that are not available. A clinically beneficial dose of intra-arterial rt-PA is not established, and rt-PA does not have FDA approval for intra-arterial use. As a consequence, endovascular therapy with stent retrievers is recommended over intra-arterial fibrinolysis of first-line therapy (Class I, Level of Evidence E).

Class II Recommendations

When treatment is initiated beyond 6 hours from symptom onset, the effectiveness of endovascular therapy is uncertain for patients with acute ischemic stroke who have causative occlusion of the internal carotid artery or proximal MCA (Class IIb, Level of Evidence C). Additional randomized trial data are needed.

In carefully selected patients with anterior circulation occlusion who have contraindications to intravenous rt-PA, endovascular therapy with stent retrievers completed within 6 hours of stroke onset is reasonable (Class IIa, Level of Evidence C). There are inadequate data at this time to determine the clinical efficacy of endovascular therapy with stent retrievers for patients whose contraindications are time-based or nontime based (e.g., prior stroke, serious head trauma, hemorrhagic coagulopathy, or receiving anticoagulant medications).

Although the benefits are uncertain, use of endovascular therapy with stent retrievers may be reasonable for carefully selected patients with acute ischemic stroke in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the M2 or M3 portion of the MCAs, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries (Class IIb, Level of Evidence C).

Although the benefits are not established in this age group, endovascular therapy with stent retrievers may be reasonable for some patients <18 years of age with acute ischemic stroke who have demonstrated large vessel occlusion in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset (Class IIb, Level of Evidence C).

Although the benefits are uncertain, use of endovascular therapy with stent retrievers may be reasonable for patients with acute ischemic stroke in whom treatment can be initiated within 6 hours of symptom onset and who have prestrike mRS score of Class IIb, Level of Evidence B).

The use of mechanical thrombectomy devices other than stent retrievers may be reasonable in some circumstances (Class IIb, Level of Evidence B).

The use of a proximal balloon guide catheter or a large bore distal access catheter rather than a cervical guide catheter alone in conjunction with stent retrievers may be beneficial (Class IIa, Level of Evidence C). Future studies should examine which systems provide the highest recanalization rates with the lowest risk for nontarget embolization.

Use of salvage technical adjuncts, including intra-arterial fibrinolysis, may be reasonable to achieve these angiographic results, if completed within 6 hours of symptom onset (Class IIb, Level of Evidence B).

Angioplasty and stenting of proximal cervical atherosclerotic stenosis or complete occlusion at the time of thrombectomy may be considered, but the usefulness is unknown (Class IIb, Level of Evidence C). Future randomized studies are needed.

Intra-arterial fibrinolysis initiated within 6 hours of stroke onset in carefully selected patients who have contraindications to the use of intravenous rt-PA might be considered, but the consequences are unknown (Class IIb, Level of Evidence C).

It might be reasonable to favor conscious sedation over general anesthesia during endovascular therapy for acute ischemic stroke. However, the ultimate selection of anesthetic technique during endovascular therapy for acute ischemic stroke should be individualized based on patient risk factors, tolerance of the procedure, and other clinical characteristics. Randomized trial data are needed (Class IIb, Level of Evidence C).

Class III Recommendations

Observing patients after intravenous rt-PA to assess for clinical response before pursuing endovascular therapy is not required to achieve beneficial outcomes and is not recommended (Class III, Level of Evidence B).

Source: [18]

Table 15: RECOMMENDATIONS RATING SCHEME

Class/Level

Definition

Classification of Interventions

I

Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful, effective, and beneficial

IIa

Conditions for which there is evidence for and/or general agreement that the procedure or treatment may be useful, effective, and beneficial

IIb

Usefulness/efficacy is less well established by evidence or opinion

III

Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful

Level of Evidence

A

Data derived from high-quality multiple randomized clinical trials or meta-analyses of high-quality randomized clinical trials

B

Data derived from a single randomized trial or nonrandomized studies

C

Randomized or nonrandomized observational or registry studies of limited design or execution or meta-analyses of such studies

E

Consensus opinion of experts

Carotid Endarterectomy

In the setting of acute ischemic stroke, justification for emergent (within the first 24 hours) or early revascularization with carotid endarterectomy (CEA) is based on reports of increased risk of recurrent stroke in patients undergoing medical therapy while awaiting revascularization. Some studies have found that CEA is most beneficial when performed within 2 weeks of the last cerebrovascular symptom and that the benefits decline rapidly after 3 weeks [194,234]. However, the risk associated with emergency CEA is believed to be high, for several reasons, particularly in patients with an unstable neurologic status [235]. First, embolic and hemodynamic injuries can occur [236]. Second, detection of an arterial lesion and mobilization of an operating room staff is time-intensive. Lastly, hyperperfusion, which occurs in 0.3% to 1.2% of patients who have CEA, can lead to brain edema and hemorrhagic transformation [236]. Other complications may also develop.

For some patients, however, the benefit of CEA may outweigh the risk. For instance, patients with acute ischemic stroke who have already had previous CEA may be successfully treated with surgical revascularization. Some studies indicate that early CEA may also be appropriate for patients with small, nondisabling stroke in whom the goal is to reduce ongoing thromboembolism or flow-limiting ischemia [235,237,238,239,240,241]. Results of other small studies have suggested that administration of an anticoagulant and delaying surgery until after the patient is stabilized is a better option [242]. Due to the limited and conflicting data, high perceived risk, and unestablished usefulness, the AHA/ASA have a Class II, Level of Evidence B recommendation regarding the use of carotid endarterectomy for treatment of acute ischemic stroke [16].

6. REHABILITATION

More than two-thirds of stroke survivors receive rehabilitation services after hospitalization, yet only a minority receive thrombolytic therapy and many have residual functional deficits, despite the development of designated stroke centers and improvements in stroke recognition and care delivery [21]. Effective stroke rehabilitation is likely to continue to be an essential component of the continuum of stroke care for the foreseeable future. Thus, in 2016 the AHA/ASA published a guideline for stroke rehabilitation and recovery [21]. This guideline spans the entire course of rehabilitation, from the early actions taken in the acute care hospital through the patient's reintegration into the community. The guideline uses the framework (rating scheme) established by the AHA concerning classes and levels of evidence [21].

The likelihood of functional independence and survival is enhanced by organized multidisciplinary rehabilitation; five more patients for every 100 treated are able to live independently with such rehabilitation [243]. Early initiation of rehabilitation is a particularly strong predictor of improved outcome [21,244].

Rehabilitation in an inpatient stroke unit has been associated with better outcomes than rehabilitation in a general healthcare facility, with improved quality of life, survival, and functional status at 5 years [17,21,245,246,247,248,249]. Yet the decision to refer a stroke patient to a particular setting after discharge is dictated by a complex set of demographic, clinical, and nonclinical factors that are also inevitably related to patient outcomes [21]. Variations in outcomes for inpatient stroke rehabilitation have been found among racial/ethnic populations [21,250,251,252,253,254]. Black individuals have less functional improvement at discharge compared with white individuals and are more likely to be discharged to home despite worse functional independence measure (FIM) scores [255]. Asian individuals have functional improvements similar to those for white individuals but have less improvement at 3 months after discharge [255]. These disparities point to the need for focused attention on appropriate rehabilitation services for minority populations.

MULTIDISCIPLINARY REHABILITATION TEAM

Because the effects of stroke are multifaceted and unique to each patient, multidisciplinary and organized services play an important role in patient recovery [21,246]. Post-acute stroke care settings include specialized inpatient rehabilitation hospitals, stroke rehabilitation units in acute care hospitals, outpatient therapy clinics, long-term care facilities, and patients' homes. The findings of a systematic review showed that, of these settings, an inpatient specialized stroke unit is best for providing care due to the presence of skilled nursing services, physician care, and variety of therapies [256]. However, the rehabilitation needs of some patients with mild or no disabilities may be addressed effectively in an outpatient facility (e.g., all-day care at a hospital) or in their homes [21,257]. For select patients, early discharge to a community setting for ongoing rehabilitation may provide outcomes similar to those achieved in an inpatient rehabilitation unit. This "early supported discharge" model links inpatient care with community-based rehabilitation services and allows some patients to return home sooner [21]. In some cases, recovery may occur without the need for rehabilitation services.

For inpatient and outpatient rehabilitative intervention, the multidisciplinary teams typically consist of several or all of the following: physicians, physical therapists, occupational therapists, kinesiotherapists, speech and language pathologists, social workers, recreational therapists, and nurses [21]. Nursing care for patients in the post-acute phase is particularly intensive. Patients who are triaged to inpatient facilities receive great benefit from 24-hour care by nurses who specialize in stroke care [257,258].

Depending on the patient's and family's/caregivers' specific needs, a clinical psychologist, psychiatrist, dietitian, and other healthcare professionals may join a patient's stroke rehabilitation team [21,258]. However, a team's exact composition is less important in maximizing a patient's outcome than is early intervention and the use of a coordinated, interdisciplinary approach. Without communication and coordination, isolated efforts to rehabilitate the stroke survivor are unlikely to achieve their full potential [21].

The AHA/ASA recommendations for the organization of post-stroke rehabilitation care and interventions specific to the inpatient hospital setting are summarized in Table 16 and Table 17[21].

Table 16: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS FOR THE ORGANIZATION OF POST-STROKE REHABILITATION CARE (LEVELS OF CARE)

Class I Recommendations

Organized, coordinated, interprofessional care is recommended for stroke patients who are candidates for postacute rehabilitation (Class I, Level of Evidence A).

Stroke survivors who qualify for and have access to inpatient rehabilitation facility (IRF) care should receive treatment in an IRF in preference to a skilled nursing facility (SNF) (Class I, Level of Evidence B).

Organized community-based and coordinated interprofessional rehabilitation care is recommended in the outpatient or home-based settings (Class I, Level of Evidence C).

Class II Recommendations

Early supported discharge services may be reasonable for people with mild-to-moderate disability (Class IIb, Level of Evidence B).

Source: [21]

Table 17: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS FOR REHABILITATION IN THE INPATIENT HOSPITAL SETTING

Class I Recommendations

Early rehabilitation for hospitalized stroke patients should be provided in environments with organized, interprofessional stroke care (Class I, Level of Evidence A).

Stroke survivors should receive rehabilitation at an intensity commensurate with anticipated benefit and tolerance (Class I, Level of Evidence B).

Class III Recommendations

High-dose, very early mobilization within 24 hours of stroke onset can reduce the odds of a favorable outcome at 3 months and is not recommended (Class III, Level of Evidence A).

Source: [21]

Stroke is an acute and harrowing event, and the emotions and deficits that follow are usually overwhelming to the patient and the patient's family. The multidisciplinary rehabilitation team should therefore develop a treatment strategy to help individual patients based on a consensus model that incorporates family members and caregivers. Securing the family's/caregivers' active involvement early in the rehabilitation process optimizes the patient's chances for recovery and community reintegration [21,259]. After the rehabilitation team has formulated a plan of action for the patient, a team liaison should present its recommendations to the patient and family/caregivers through open discussions [260]. Providing patients and families/caregivers with both interactive and written materials is equally important [260]. Information to be presented should include:

- Preferred setting and environment based on the patient's projected recovery

- Treatment options, including suggested rehabilitation programs, estimated length of stay, frequency of therapy, and discharge criteria

- Information regarding the patient's prognosis and the anticipated recovery process

Once rehabilitation has commenced, involving the patient's family/caregivers in the rehabilitation sessions and training them to assist the patient with functional activities may aid patient recuperation [21,261]. During rehabilitation, at least one or two informal meetings per week should be held with family/caregivers to reassess their concerns about the process [262].

Social and Family Caregiver Support

As stated, the stroke survivor's family members and caregivers are integral to the post-stroke treatment plan [21]. However, 12% to 55% of caregivers suffer from emotional distress, most commonly depression [21,263,264]. Untreated depression is associated with a lower quality of life for both the caregiver and the stroke survivor [21,265]. A growing body of research is focused on treatment strategies to benefit both the caregiver and the stroke survivor and on educational programs that target issues such as supportive problem solving, physical care needs, financial and domestic assistance, respite, reassurance, and counseling [21,266,267,268,269,270].

PATIENT ASSESSMENT

For individuals who have had a stroke and are medically stable, rehabilitation assessment, prevention of medical complications, and secondary prevention become the focal points [10,16,21]. To begin, the rehabilitation team's systematic evaluation of the patient addresses various issues, including the need for rehabilitation services; the risk of complications; physical functioning, cognition, and communication; and psychosocial conditions [21]. Next, the team works with the patient and family to implement a rehabilitation plan that includes a detailed exercise program and general as well as tailored strategies for secondary prevention [10]. Throughout, the team should strive to foster a climate of familial support [21].

Need for Rehabilitation Services

When a patient is medically stabilized, a rehabilitation physician is consulted to assess the patient's rehabilitative needs and recommend the proper rehabilitation setting (Table 18) [17]. Additionally, the patient's complete medical history is provided to the rehabilitation physician. If indicated, other rehabilitation specialists may perform specialized or more intensive assessments. Overall, rehabilitation assessments should be [21]:

- Multidisciplinary, to account for the heterogeneous effects of stroke.

- Well-coordinated and prompt, so patients can begin a rehabilitation program as soon as possible.

- Well-documented, to provide the patient's rehabilitation team with accurate and detailed information.

- Conducted using formal standardized, validated measures.

Table 18: AREAS OF SPECIAL INTEREST FOR PURPOSES OF REHABILITATION ASSESSMENT

Risk factors for stroke recurrence

Medical comorbidities

Swallowing

Skin assessment and risk for pressure ulcers

Bowel and bladder function

Risk of deep vein thrombosis

Pain

Mobility, with respect to the patient's needs for assistance in movement

Safety awareness

Motor function

Cognition and communication status

Psychologic status

History of previous antiplatelet or anticoagulation use, especially at the time of the stroke

Psychosocial status

Source: [17]

The NIHSS is a strong prognosticator of functional outcome, rendering it a valuable tool for determining rehabilitation needs [271,272]. It is the most widely used global assessment of impairment in the United States. It is a good predictor of short- and long-term morbidity and mortality and has been found to be sensitive to change in numerous studies [21]. Multiple assessments with the scale provide the rehabilitation team with a sense of the patient's recovery trajectory as he or she enters the rehabilitation stage.

The NIHSS provides detailed information in addition to an overall stroke severity score. A score of less than 5 indicates minor or no functional disability, whereas a score of more than 16 suggests severe disability and an increased probability of death [273]. With the advent of stroke treatment, patients with a score of 5 to 15 are likely to benefit from rehabilitation without the need for a nursing facility [274]. Patients with a score of more than 15 may improve with rehabilitation; however, these patients will likely require long-term care. More than one-half of survivors with a baseline score greater than 20 are initially sent to some form of rehabilitation facility rather than directly discharged to a nursing facility or home [274].

Because the type of stroke affects the usefulness of the NIHSS, its results should be qualified by medical history, examination, and brain imaging data [275]. Specifically, the scale is better suited for predicting functional outcomes at 3 and 6 months after stroke for patients with subcortical lesions than for patients with cortical lesions [21,276,277]. Additionally, the reliability of the scale in predicting depressive symptoms and cognitive dysfunctions depends on the hemisphere affected [21,277]. Because the NIHSS does not include evaluation of weakness of the distal part of the upper extremity, which is common in patients with stroke, a finger extension evaluation should be conducted in addition to the scale [278,279]. The presence of finger extension or partial shoulder abduction within 72 hours after stroke onset can help predict the patient's functional recovery at six months [280,281].

Although new measurement tools are being developed, they are difficult to evaluate with the traditional criteria (e.g., validity, reliability) normally used in evidence-based reviews [21]. The AHA/ASA recommendations for the assessment of rehabilitation needs (Table 19) are based on traditional measurement models, such as the FIM [21].

Table 19: AMERICAN HEART ASSOCIATION/AMERICAN STROKE ASSOCIATION RECOMMENDATIONS FOR DISABILITY ASSESSMENT AND REHABILITATION NEEDS

Class I Recommendations

It is recommended that all individuals with stroke be provided a formal assessment of their ADLs and IADLs, communication abilities, and functional mobility before discharge from acute care hospitalization and the findings be incorporated into the care transition and the discharge planning process (Class I, Level of Evidence B).

It is recommended that all individuals with stroke discharged to independent community living from postacute rehabilitation or SNFs receive ADL and IADL assessment directly related to their discharge living setting (Class I, Level of Evidence B).

A functional assessment by a clinician with expertise in rehabilitation is recommended for patients with an acute stroke with residual functional deficits (Class I, Level of Evidence C).

Determination of postacute rehabilitation needs should be based on assessments of residual neurologic deficits; activity limitations; cognitive, communicative, and psychologic status; swallowing ability; determination of previous functional ability and medical comorbidities; level of family/caregiver support; capacity of family/caregiver to meet the care needs of the stroke survivor; likelihood of returning to community living; and ability to participate in rehabilitation (Class I, Level of Evidence C).

Class II Recommendations

It is reasonable that individuals with stroke discharged from acute and postacute hospitals/centers receive formal follow-up on their ADL and IADL status, communication abilities, and functional mobility within 30 days of discharge (Class IIa, Level of Evidence B).

The routine administration of standardized measures can be useful to document the severity of stroke and resulting disability, starting in the acute phase and progressing over the course of recovery and rehabilitation (Class IIa, Level of Evidence C).

A standardized measure of balance and gait speed (for those who can walk) may be considered for planning postacute rehabilitation care and for safety counseling with the patient and family (Class IIb, Level of Evidence B).

ADLs = activities of daily living, IADLs = instrumental activities of daily living (tasks involving more complex domestic, community, and leisure activities), SNF = skilled nursing facility.

Source: [21]

Soon after patient assessment, family/caregivers should be educated about and referred to community resources [21,282]. If it is recommended that the patient be discharged from an acute care facility to a nursing facility or the patient's home, relevant contact and background information for nursing home facilities, assisted-living services, social support groups, and stroke-related organizations should be provided to facilitate familial decision-making. Viable options should be presented to the family, especially information about long-term care placement if a severely disabled patient is not a candidate for rehabilitation [21]. If the family/caregivers will be taking care of the patient at a private residence (with or without professional assistance), it is essential to foster discussions about the needs of the patient, challenges the patient and family/caregivers may face, and the benefits of social support programs for the patient and family/caregivers. Whenever possible, written materials should be provided, and they should be in the primary language of the family. Among the important topics to discuss and provide education about include [21]:

- Secondary prevention and medication administration specifics

- Nutrition and hydration

- Symptoms of complications

- Specifics regarding assistance with activities of daily living (e.g., transfers, positioning, bathing, toileting, dressing, and grooming)

- Swallowing difficulties

- Feeding tube use

- Bladder catheter care

- Signs of mood disorders

- Strategies to improve cognitive skills and communication

- Exercises (range of motion)

Education about and referral to appropriate community resources can help to support the needs and priorities of the patient and the family or caregiver [21]. A systematic review and meta-analysis demonstrated that functional outcomes (i.e., motor, cognitive, and psychosocial function) can be improved or, at a minimum, maintained in stroke survivors when community interventions are available [21,283,284].

The patient's psychosocial status will influence his or her willingness and approach to participating in a rehabilitation program. A psychosocial assessment enables the rehabilitation team to incorporate family/caregivers more effectively into the rehabilitation process [285]. In addition, how the team manages the patient's care may be contingent on the patient's life circumstances and personality profile. Some patients and their caregivers fail to discuss psychosocial issues with their providers [21,264]. Cultural differences may also play a part in a patient's willingness to discuss these issues [21]. Areas of emphasis for the psychosocial assessment should include:

- Medical history

- Coping style

- Therapeutic style and recovery expectations

- Demographic information

- Response to treatment

- Substance use and abuse

- Psychiatric/psychologic evaluation

- Emotional and mental status and history

- Education and employment

- Spiritual and cultural beliefs

- Family/caregiver relationship

- Preferred activities

When designing and implementing the patient's treatment plan, the rehabilitation team should also take into account the residual effects of any difficulties the patient may have had before the stroke, such as drug or alcohol addiction; stress from recent life events, such as divorce, a loved one's death, or retirement; or clinical depression [21]. Individual patients will vary in how well they respond to challenging and demanding therapeutic approaches. After a patient's unique needs and circumstances are determined, relevant specialists will be incorporated into the team. All members of the rehabilitation team should be sensitive to the patient's psychosocial needs.

Risk of Complications

Medical complications related to illness, being bedridden, or lack of proper care/attention can prolong hospitalization, impede rehabilitation, increase disability, or result in death. Living in an inappropriate post-stroke environment also substantially increases a patient's risk for complications. Complications may develop in as many as 85% of hospitalized patients who have had a stroke [286]. Thus, medical examinations before and during a patient's rehabilitation program should assess the most common risks of complications: skin breakdown, deep vein thrombosis (DVT), swallowing dysfunction, bowel and bladder incontinence, falls, and pain [21].

Skin Breakdown and Contractures

Pressure ulcers are a commonly encountered complication in hospital and long-term care facilities, occurring in approximately 10% and 25% of patients in those settings, respectively [286]. According to the National Pressure Ulcer Advisory Panel, a pressure ulcer is a "localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in combination with shear" [287,288]. Although ulcers typically occur proximal to osseous prominences (e.g., the sacrum, hips, ankles), skin breakdown at the ears is also common in certain settings [289,290]. Most pressure ulcers are associated with deep tissue injury [291]. Regular assessment of skin and the use of objective risk scales (e.g., the Braden scale) may help prevent skin injury and should be followed by regular skin inspection with documentation [21,292]. Risk factors for pressure ulcers include [286]:

- Immobility

- Poor hygiene

- Urinary incontinence and other sources of moisture

- Diabetes and other causes of poor circulation

- Peripheral vascular disease

- Lower body mass index

- Localized infection or trauma

- Edema

- Poor hydration and/or nutrition

Conditions secondary to pressure ulcers include pain, localized infection, cellulitis, osteomyelitis, sepsis, and even death [293,294]. However, not all pressure ulcers, even those that are severe, will elicit a pain sensation [295].

Ulcers can be prevented or minimized with several measures, including proper positioning, turning, and transferring techniques; good hygiene; proper nutrition and hydration; and the use of barrier sprays, special mattresses, and protective dressings [21,292]. Good pain management may be necessary to perform correct positioning and frequent turning. Patients should be monitored daily for skin breakdown [21]. Any sign of a pressure ulcer warrants daily treatment [21].

Following stroke with hemiparesis, contracture on the affected side will develop in approximately 60% of patients within the first year, with wrist contractures occurring most commonly in patients who do not recover functional hand use [21,296,297]. Contractures are painful and can make self-care difficult. Many clinicians recommend daily stretching of the affected limb(s); families and patients should be taught proper stretching technique [21]. The effectiveness of resting hand splints is not well established [21]. Contractures of the ankle/foot can affect gait quality and patient safety. Ankle-foot orthosis and the nighttime use of a resting ankle splint may be beneficial in preventing ankle contracture [21].

Deep Vein Thrombosis

DVT affects only 2% of patients with stroke; yet, its prevention is critical [286]. The American Academy of Family Physicians recommends that DVT risk be calculated with use of the Well's DVT prediction model, and the results of this model will dictate subsequent DVT testing (Table 20) [298,299]. For patients with symptoms in both legs, the more symptomatic leg should be tested. A score of 3 or more on the Well's test indicates a high clinical probability of DVT; the probability is intermediate for a score of 1 or 2.

Table 20: WELL'S PREDICTION RULE FOR DIAGNOSING DEEP VENOUS THROMBOSIS: CLINICAL EVALUATION TABLE FOR PREDICTING PRETEST PROBABILITY OF DEEP VEIN THROMBOSIS

Clinical Characteristic

Score

Active cancer (treatment ongoing, within previous 6 months, or palliative)

1

Paralysis, paresis, or recent plaster immobilization of the lower extremities

1

Recently bedridden >3 days or major surgery in previous 12 weeks requiring general or regional anesthesia

1

Localized tenderness along the distribution of the deep venous system

1

Entire leg swollen

1

Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity)

1

Pitting edema confined to the symptomatic leg

1

Collateral superficial veins (nonvaricose)

1

Alternative diagnosis at least as likely as venous thrombosis

-2

Source: [299]

The D-dimer test alone is not recommended to rule out DVT in patients who have had a stroke. Patients with intermediate-to-high risk for DVT should be screened with use of ultrasonography. This imaging modality may not detect DVT in the calf, however, and repeat ultrasonography or venography should be used when DVT in the calf is suspected. Contrast venography was previously the most definitive test for the diagnosis of DVT, but today, Doppler ultrasound is the diagnostic study of choice [299].

Measures such as early mobilization and anticoagulation therapy are recommended to decrease the incidence of DVT after stroke. A patient's risk can be substantially reduced by 50-foot walks daily (with assistance, if necessary), administration of subcutaneous, low-dose unfractionated heparin (5,000 units twice a day, unless contraindicated), and the use of graduated compression stockings (GCS) as an adjunct to medication [300]. GCS and intermittent pneumatic compression may be considered for prevention of post-stroke DVT, but their routine prophylactic use requires further study. The benefit of treatment should be weighed against the increased risk of skin complications [21,301,302].

Swallowing Dysfunction

Based on instrumental testing results, dysphagia may develop in 42% to 78% of patients within three days after stroke [21,303]. This disorder is strongly linked to the development of malnutrition and pneumonia if not identified early and managed properly [21,303,304]. The AHA/ASA guidelines include a Class I recommendation for early dysphagia screening in patients with acute stroke [21]. Patients with dysphagia often have problems with aspiration, which can cause serious consequences if the stroke has suppressed cough sensations [21]. Although cerebral and cortical strokes can cause dysphagia, swallowing is most severely compromised by brain stem strokes [303].

The speech and language pathologist on the rehabilitation team should perform a brief swallow assessment on all patients with stroke before oral intake of food and fluids [21,305]. A dysfunctional swallow should be further examined using a complete bedside swallow examination. If bedside swallow screenings indicate an affected swallow, or if the patient has a high risk for aspiration and/or dysphagia, performing a videofluoroscopy swallowing study or fiberoptic endoscopic examination is recommended [21,305,306]. The grade of dysphagia correlates with dysarthria, aphasia, low functional independence, and level of cognitive functioning [306]. The speech and language pathologist may best identify the specific physiologic problem and recommend the necessary management and interventions for treatment. A Cochrane review assessing the effectiveness of a variety of interventions (e.g., acupuncture, neuromuscular electrical stimulation, physical stimulation) on functional outcome found that behavioral interventions and acupuncture reduced dysphagia, and pharyngeal electrical stimulation reduced pharyngeal transit time. However, the authors concluded that data are insufficient to determine the effect of these and other interventions (e.g., nutritional/fluid supplementation) on functional outcome and death. [304]. Authors of another review found that acupuncture may be effective for treatment of post-stroke dysphagia, but concluded that the reported benefits should be verified with further studies [307].

Bladder and Bowel Dysfunction

Upon admission to community-based facilities, approximately 50% of stroke survivors have urinary incontinence and 30% have fecal incontinence [308,309]. Almost all patients with fecal incontinence (98%) also suffer from urinary incontinence. Urinary and fecal incontinence can lead to patient discomfort, skin breakdown, and sepsis. Fecal incontinence, in particular, reduces patient and family morale.

Large infarcts, aphasia, cognitive impairment, functional disability, lesions in the frontal cortex or frontoparietal lobes, and advanced age are associated with post-stroke urinary dysfunction [310]. Medications such as diuretics, alpha-adrenoreceptor blockers, and anticholinergic drugs can cause or exacerbate this complication [311,312]. Hyper-reflexia and hyporeflexia are the most common mechanisms of urinary incontinence in stroke survivors [313]. Detrusor sphincter dyssynergia, a cause of incomplete bladder voiding, is uncommon because its pathogenesis involves lesions between the brain stem and spine [312]. When assessing bladder function in patients with acute stroke, it is important to evaluate urinary retention with use of a bladder scanner or an in-and-out catheterization; urinary frequency, volume, and control; and the presence of dysuria. Patients who have urinary incontinence may benefit from bladder-training regimens and scheduled voiding [311,314].

Fecal incontinence can be due to neurogenic impairments or leakage around a fecal impaction (overflow incontinence) [315]. If the underlying cause of fecal incontinence is neurogenic, the signs and symptoms would likely include reduced rectal sensation and tone, inability to voluntarily contract the rectal sphincter, and stool in the rectal vault [315]. A diagnosis of constipation with overflow incontinence is more likely if the patient has rectal sensation and tone.

Risk factors for impaction and constipation include immobility, inactivity, dehydration, some medications, mood disorders, and cognitive deficits [316,317]. Multivariate analysis has shown that advanced age and diabetes are risk factors for fecal incontinence [317]. Patients with persistent constipation or fecal incontinence may benefit from bowel-management programs and psychosocial support [318]. Because of the risk of skin breakdown, the social stigma, and the burden of care associated with bowel and bladder incontinence, management is an essential component of the rehabilitation process [21].

Falls

Within 12 weeks after a stroke, approximately 25% of patients will fall [286]. Up to 70% of individuals with a stroke fall during the first six months after discharge from the hospital or rehabilitation facility [21,319]. Individuals with stroke are also at risk of repeated falls that include injury [21,320]. One study found that most falls occur at home in the first 3 months following post-stroke risk assessment [320]. Falls are a common complication for several reasons, including [315,321,322]:

- Unfamiliar environment and physical state

- Pain, fatigue, poor balance, and muscle weakness

- Incontinence

- Frequent positioning, turning, and transferring, especially in rehabilitative settings

- Cognitive impairments, mood disorders (including depressive symptoms), visual impairments, spatial neglect, and any other condition that can decrease a patient's safety awareness

The Berg Balance Scale may be the most appropriate screen for patients who are likely to fall [21,323,324]. This scale tests 14 specific functional movements of daily living of increasing difficulty [325]. The 56-point maximum score indicates adequate balance and low risk of a fall. A score of less than 45 is associated with a proclivity for falling [323,325]. The score at 2 months post-stroke is useful for informing a patient's risk of falls, but it does not account for the multifactorial nature of the problem and should not preclude risk management provided in conjunction with exercise interventions, such as rehabilitation that targets gait coordination, to improve mobility [320,326]. If the patient is able to walk, the Stops Walking When Talking test may further help to identify the risk for a fall [323]. With this test, the examiner initiates a conversation with the patient while walking; if the patient stops walking to respond, the risk of a fall is increased [327]. St. Thomas' Risk Assessment Tool in Falling Elderly Inpatients (known as STRATIFY), a tool used commonly in the rehabilitation setting, has been shown to be a poor predictor of the risk for fall when screening patients with stroke [328].

In addition to the physical consequences associated with falls, there are also psychologic and social consequences. Impairments in balance, gait, motor control, perception, and vision contribute to a heightened fear of falling in the stroke survivor, with 30% to 80% reporting various levels of fear associated with falling and mobility [21]. This fear can cascade into reduced levels of physical activity and deconditioning, resulting in greater physical decline, loss of ability to perform activities of daily living, loss of independence, social isolation, and depression. Education in fall prevention, including balance training, is an essential component of the rehabilitation process [21].

Pain

Pain is one of the most frequently experienced complications. Almost one-half of all stroke survivors experience chronic pain, 65% of whom have shoulder pain [286]. Whether chronic or periodic, pain can delay functional recovery by masking motor function improvement, diminishing a patient's motivation or willingness to perform rehabilitative tasks, or limiting the patient's movement or requiring the use of a cane or wheelchair for ambulation [17]. Pain most often results from joint immobilization and the fixation of tendons and ligaments in one position [85]. In some patients, however, stroke-induced sensorimotor pathway damage leads to the sensation of pain in an affected extremity or side of the body. The most common pain syndrome of this type is central post-stroke pain, which affects 8% of patients, or at least 56,000 stroke patients in the United States each year [21,329,330]. Four percent of patients with central post-stroke pain experience it as shoulder pain. Central post-stroke pain can be difficult to manage, even with medications. Only amitriptyline and lamotrigine have been shown to be effective in placebo-controlled studies [331].

Evidence Based Practice Recommendation

The evidence from randomized controlled trials so far does not confirm or refute that electrical stimulation around the shoulder after stroke influences reports of pain, but there do appear to be benefits for passive humeral lateral rotation.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001698/full

Last Accessed: March 11, 2020

Level of Evidence: Meta-Analysis

The AHA/ASA recommend patient and family education (i.e., range of motion, positioning) about shoulder pain and care following stroke [21]. A clinical assessment of the pain that includes musculoskeletal evaluation, evaluation of spasticity, identification of any subluxation, and testing for regional sensory changes is also recommended. Ultrasound may be considered for diagnosis of shoulder soft tissue injury [21]. Botulinum toxin injection or a trial or neuromodulating pain medications may be useful to reduce severe hypertonicity in hemiplegic shoulder muscles. Positioning and the use of supportive devices may help reduce pain [21].

Use of diagnostic criteria for central post-stroke pain can be helpful [21]. Additionally, initial medical examinations should thoroughly document suspected etiology of any pain, its location and characteristics (e.g., burning, tingling, stabbing, dull), its duration and intensity, and what aggravates or relieves the pain. Any pain that interferes with the rehabilitation process should be identified and treated accordingly. There is limited evidence on the efficacy of proposed treatments for central post-stroke pain. Combined pharmacotherapy (e.g., amitriptyline, lamotrigine) and therapeutic exercise may be reasonable. Few nonpharmacologic options exist [21].

Functional Outcome

Approximately 45% of stroke survivors have residual neurologic deficits that impair mobility, which is one of the most devastating sequelae of stroke [21,87]. At 6 months, about half of ischemic stroke survivors who are 65 years of age or older have hemiparesis, nearly one-third require assistance with walking, and more than one-quarter need assistance with activities of daily living [87]. Although functional outcome primarily depends on the patient's post-stroke neurologic damage and compensatory capacity, the multidisciplinary rehabilitation team plays a major role in recovery [246]. The team's coordinated and customized efforts can help many stroke survivors adopt an active and social lifestyle. To tailor services to a patient's needs, the team should assess his or her functional abilities during the immediate post-acute stroke phase before hospital discharge. Assessment relies on a physical examination and a systematic battery of tests that measure a patient's ability to complete activities of daily living and that screens for cognitive/communication skills as well as visual/spatial neglect disorders [21]. Knowledge of the patient's preferred activities is also helpful.

Several functions/activities are typically measured to assess comprehensive functional status initially and during the rehabilitation process (Table 21). Although many measurement tools can be used to objectively record a patient's comprehensive functional acuity, the most widely used and trusted instrument in the stroke rehabilitation setting is the FIM [332,333]. Throughout the rehabilitation process, FIM-supported systematic screening can help the rehabilitation team to [21,332]:

- Identify functional, cognitive, and visual/spatial deficits not previously detected

- Set realistic functional goals and document progression toward these goals

- Deduce discharge or extended care plans

- Ensure patients' safety as they perform functional tasks and teach proper mechanics to reduce their risk of injury with continued performance

Table 21: ACTIVITIES MEASURED TO ASSESS COMPREHENSIVE FUNCTIONAL STATUS INITIALLY AND DURING THE REHABILITATION PROCESS

Activities of daily living

Aerobic capacity and endurance

Balance

Bladder and bowel management

Circulatory response to position changes and other functional tasks

Communication and social cognition

Gait

Joint integrity and mobility

Locomotion

Mobility

Motor function (agility, coordination, dexterity)

Muscle performance (activation, endurance, power, strength)

Pain response to functional tasks

Posture

Range of motion

Reflex integrity

Self-care ability

Sexual activity

Upper extremity activity/function

Use of assistive and adaptive devices

Visual and spatial neglect

Source: [21,332]

As stated, loss of mobility is a devastating post-stroke outcome and restoration of gait-related activities (e.g., rising to stand, sitting down, climbing stairs) is often one of the primary goals of rehabilitation. Additionally, many patients will require assistive devices, adaptive equipment, and other items to maximize independent functioning after stroke [21].

In general, major rehabilitation goals are for patients to regain safe ambulation in their homes and community and to regain the ability to perform activities of daily living with minimal or no assistance. Thus, patients should be reassessed for daily tasks that are appropriate to their expected level of dependency [21]. If a return to independent community or home living is possible, domestic functioning should be evaluated [17,334]. Skills needed to stay home alone include preparing a meal, using safety precautions, properly taking medications, and obtaining emergency services. Patients who may resume driving should be assessed thoroughly for driving-related physical, cognitive, and behavioral functions [21]. Driving is an instrumental activity of daily living for many individuals due to its impact on their ability to participate in activities outside the home. Between one- and two-thirds of post-stroke survivors resume driving after one year, but because it is a highly complex activity requiring skills in cognition, perception, and emotional and motor control, the ability to drive is often affected by stroke. The AHA/ASA recommend that [21]:

- Individuals who appear to be ready to return to driving, as demonstrated by successful performance on fitness-to-drive tests, should have an on-the-road test administered by an authorized person and should be referred to a driver rehabilitation program for training if the test is failed.

- It is reasonable to assess individuals for cognitive, perception, physical, and motor abilities to determine readiness to return to driving. This may be achieved with a driving simulation.

Cognition and Communication

Healthy cognition and communication are considered to be essential parts of an individual's well-being. However, stroke frequently has an adverse effect on cognitive and communicative abilities.

Cognition

Calculation, executive functioning (the integration of multiple and complex processes), and visual perception/construction are the cognitive arenas most often affected during the first several weeks after a stroke [335,336]. Up to 88% of patients with a cerebellar stroke have cognitive deficits, such as impairments in abstract thought, attention, control, memory, planning, and speech [337]. In many cases, patients with stroke-associated right brain damage have anosognosia, a condition in which patients are rendered unaware of their contralateral sensory and motor neurologic deficits (hemiplegia, hemianesthesia, and hemianopia) [338]. Although many survivors regain some or all cognitive skills soon following a stroke, up to 38% remain cognitively impaired at 3 months [339]. Recovery rates may be as high as 80% within 6 months for stroke survivors, with visual perception and visual memory showing the most improvement and language and abstract reasoning showing the least [340,341]. At 1 and 3 years after a stroke, cognitive impairment is one of the factors most strongly linked with poor physical and mental health status [342]. Cognitive status is an important determinant of post-stroke success. The AHA/ASA recommend that all stroke patients be screened for cognitive deficits before being discharged to home [21].

Stroke-induced damage to the brain's cognition centers is second only to Alzheimer disease as the leading cause of dementia. Stroke-associated dementia manifests with the following symptoms [343]:

- Memory loss, especially short-term memory

- Attention deficits and difficulty following instructions

- Difficulty planning/organizing tasks or solving problems

- Confusion

- Poor judgment

- Behavioral changes, including inappropriate emotions and extreme mood fluctuations

- Mood disturbances and depression

Evidence Based Practice Recommendation

The National Guideline Centre recommends that patients should be screened for cognitive deficits after stroke. Where a cognitive deficit is identified, carry out a detailed assessment using valid, reliable, and responsive tools before designing a treatment program.

https://www.nice.org.uk/guidance/CG162

Last Accessed: March 11, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Areas of cognitive and arousal ability that should be assessed before and during rehabilitation are learning and memory, attention, visual/spatial neglect and impairments, executive functioning, and apraxia (loss of the ability to execute skilled movements despite having the desire and the physical ability to perform them) [21]. In addition to its use in assessing functional ability, the FIM is effective as an initial screen of cognitive and functional communication deficits [344]. Because stroke-related cognition deficits are independently associated with left hemispheric stroke, visual field defect, and urinary incontinence, the presence of any of these conditions should heighten awareness of the possibility of the presence of the others [339].

Visual and spatial dysfunctions may be particularly difficult to identify during the initial post-stroke examination because multiple neuroanatomic systems can be affected to varying degrees. When a standard medical examination does not include the brief, systematic screening for visual and spatial neglects, more than 60% of these dysfunctions remain undiagnosed. However, the use of the FIM may increase their early identification [344]. Patients with neglect deficits are unknowingly inattentive to specific body parts and/or spaces in the external environment. For instance, patients may brush half of their teeth or only eat food on half of their tray. Unilateral neglect is present in almost 50% of patients with right hemispheric stroke [345]. Patients with unilateral neglect are also unaware of limbs contralateral to the site of the brain lesion(s). Neglect disorders are strongly associated with poor functional outcomes and safety issues. Patients with neglect are prone to falls and injuries as well as burns to the affected limbs [322]. Addressing visual and spatial deficits as early as possible in the rehabilitation process using multiple functional adaptation techniques (e.g., visual scanning, external cues) and patient/caregiver education may decrease a patient's risk for injury [21].

Communication

As with cognitive difficulties, communication problems strain relationships between stroke survivors and their social system, impede rehabilitation, and lead to poor quality of life. Common communication-related stroke sequelae are aphasia, dysarthria, and apraxia of speech (motor speech disorder in which the muscles required for speech are less coordinated). Patients with communication disorders may also have dysphagia. How these disorders are manifested as well as their severity depends on the location and degree of the stroke. Interventions for apraxia of speech should be individually tailored and may include behavioral techniques and strategies that target [21]:

- Physiologic support for speech, including respiration, phonation, articulation, and resonance

- Global aspects of speech production (e.g., loudness, rate, prosody)

Augmentative and alternative communication devices and modalities should be used to supplement speech [21].

Aphasia affects one-third of stroke survivors and is one of the most common stroke-associated communication deficits [21,346].

The three types of aphasia are expressive, receptive, and global (Table 22) [347]. Patients with expressive aphasia have difficulties using words and sentences, whereas patients with receptive aphasia struggle to understand what others are communicating to them. Global aphasia is a combination of these two types. Aphasia is typically related to lesions on the left side of the brain, as the language center is located within this hemisphere in most individuals [348]. In many cases, aphasia (mild aphasia in particular) can be an elusive diagnosis because patients may [347]:

- Be able to carry on normal conversations in many settings

- Have trouble understanding only when sentences are long or complex

- Have trouble finding the words to express an idea or may say, "the word is right on the tip of my tongue"

Table 22: CHARACTERISTICS OF EXPRESSIVE AND RECEPTIVE APHASIA

Patients with expressive aphasia may:

- Use single words or short phrases

- Omit smaller words like "the," "of," or "and" (the patient's message may sound like a telegram)

- Say words out of sequence

- Switch sounds or first letters of words (e.g., dishwasher becomes a "wish dasher")

- Invent words

- Create meaningless sentences by fluently stringing nonsense words and real words together

Patients with receptive aphasia may:

- Require a significant amount of extra time to understand verbal communication, especially if the speech is fast

- Have difficulty following radio or television news

- Interpret figurative speech (e.g., "It's raining cats and dogs.") literally

Patients frequently have global aphasia, with various combinations of expressive and receptive difficulties.

Source: [347]

A variety of treatment approaches for aphasia have been developed, but no conclusions can yet be made about the effectiveness of one treatment over another [21].

An additional challenge in assessment is that members of the rehabilitation team typically do not have a clear sense of the patient's communication skills before the stroke. Lastly, reading and writing skills are usually more affected than oral communication.

Well-trained and organized rehabilitation teams can use alternative methods of communicating to mitigate the effects of cognitive and communication disorders. Ideally, these problems should be recognized and managed early. However, arriving at a diagnosis can be challenging. The speech and language pathologist on the rehabilitation team is best suited to evaluate the patient for cognitive/communication disorders. In some cases, problems are initially undetected or develop after the evaluation. Training the rehabilitation team to recognize symptoms of cognitive and communication deficits early (especially those that are subtle) and report findings to the speech and language pathologist can serve as a "safety net" for patients [21]. For proper diagnosis, the speech and language pathologist should also seek the help of the patient's family to gain an understanding of the patient's cognition and communication history.

Through interviews, conversation, structured observations and other formal tests, the speech and language pathologist comprehensively evaluates the individual's cognition and communication skills in the areas of speech, expression, social communication, and reading/writing (Table 23) [21,349].

Table 23: MEASURES EVALUATED TO ASSESS COGNITION AND COMMUNICATION SKILLS

Category

Skills to Evaluate

Speech

Fluency, vocal quality, clarity, loudness

Strength and coordination of muscles needed for speaking

Understanding

Use of semantics and syntax

Understanding and answering of different types of questions

Understanding facts and inferences within extended speech

Ability to follow instructions that increase progressively in length and complexity

Language sample of an extended story, written and spoken

Expression

Chaining a sequence of events together

Describe the "plot" in an action picture

Message coherency

Word recall

Use of complete sentences, telegraphic sentences or phrases, or single words

Social communication

Ability to interpret jokes and sarcasm, as well as absurdities in stories or pictures

Ability to initiate conversation, take turns speaking and listening during a discussion, and express thoughts clearly

Ability to clarify or restate a message that is initially misunderstood by a conversation partner

Reading and writing

Reading and writing of letters, words, phrases, sentences, and paragraphs

Other

Swallowing (as needed)

Ability to use an augmentative or alternative communication aid, if necessary

Source: [349]

If necessary, the speech and language pathologist formulates remediation strategies to accelerate the patient's recovery of affected communication skills, development of compensatory techniques, or use of residual skills [21,349]. In many cases, patients with stroke-induced attention deficits, visual neglect, memory deficits, executive function deficits, and problem-solving difficulties can be retrained or taught compensation techniques [350]. Strategies to enhance communication with the patient should be taught to the rehabilitation team as well as the family/caregivers [21]. Any interventions should be individually tailored and designed to target the overt communication deficit as well as any deficits that accompany or underlie the communication deficit, including attention, memory, and executive functions. The use of drugs to improve cognitive impairments is not well established [21].

Psychologic Status

Following a stroke, it is understandable that patients and their families experience intense emotions. In many cases, the staff's kindness and helpfulness, familial support, and the passage of time allow patients and their families to deal with the grief and other feelings precipitated by the stroke without medication or psychologic therapy. However, approximately 33% of patients experience post-stroke depression, and other mood disorders also manifest in stroke survivors [1,351,352]. In general, psychologic conditions can have a significant impact on the success of rehabilitation. Thus, all patients should be thoroughly evaluated for psychologic disorders as early as possible and on an ongoing basis [21].

Detecting post-stroke depression can be particularly challenging, as symptoms often appear to be typical post-stroke symptoms or are subtle. Patients may experience fatigue, sleeping difficulties, loss of appetite, tearfulness, and feelings of hopelessness. They may refuse to participate in therapy [21]. Additionally, cognitive deficits may prevent the patient from recognizing or having the ability to communicate depressive symptoms. Patients with an acquired flat affect may "sound sad" or indifferent to their situation without having post-stroke depression. Although several screening tools for depression in the older population are available (Table 24), a single, universally accepted evaluation tool for post-stroke depression has not been developed. Because little research in this area is available and the condition is underdiagnosed by nonpsychiatric physicians, the diagnosis of post-stroke depression should be based on information from multiple sources, including medical evaluation, patient self-report, observation of patient behavior, patient history, and staff reports of changes in behavior and motivation.

Table 24: SCREENING TOOLS FOR DEPRESSION

Evaluation Instrument

Time Required

Benefits

Disadvantages

Beck Depression Inventory (BDI)

10 minutes

Widely used

Easily administered

Norms available

Good for somatic symptoms

Less useful in elderly and in patients with aphasia or neglect

High rate of false-positive results

Somatic items may not be due to depression

Center for Epidemiologic Studies Depression (CES-D) Scale

<15 minutes

Easily administered

Useful in older individuals

Effective for screening in stroke population

Not appropriate for patients with aphasia

Geriatric Depression Scale (GDS)

10 minutes

Easy to use with older or cognitively impaired individuals, as well as with individuals with visual or physical problems or low motivation

High rates of false-negative results in minor depression

Hamilton Depression Scale

<30 minutes

Observer rated

Frequently used for patients who have had a stroke

Multiple versions compromise interobserver reliability

Folstein Mini-Mental State Examination

10 minutes

Widely used for screening

Several functions with summed score

May misclassify patients with aphasia

Patient Health Questionnaire-2 (PHQ-2)

15 minutes

Widely used for screening

Easily administered

Poor specificity in detecting major depression

Source: [353,354,355]

The accompaniment of post-stroke depression with other psychologic disorders is not uncommon [21]. Therefore, the medical evaluation should also screen for other categories of psychiatric symptoms [21]. Generalized anxiety disorder, which affects 20% of survivors, often coexists with post-stroke depression [356]. Generalized anxiety disorder delays the recovery of the ability to carry out activities of daily living and negatively affects social functioning [21]. Additionally, up to 15% of stroke survivors have pseudobulbar affect, characterized by uncontrollable laughing/crying [21].

Both post-stroke depression and pseudobulbar affect respond well to selective serotonin reuptake inhibitors [357]. Although these drugs carry some risk, they are safe in most patients who have had a stroke. However, these medications should not be administered prophylactically [358,359]. Although studies are limited, the use of cognitive-behavioral therapy techniques and brief supportive therapy in conjunction with medication may be beneficial to those with post-stroke depression and other neuropsychiatric sequelae of stroke [21].

EXERCISE PROGRAM

Physical inactivity that typically occurs following a stroke can exacerbate muscle weakness (through atrophy and changes in muscle fibers), fatigue, cardiovascular and metabolic deconditioning, and poor balance [360,361]. These complications have been shown to slow physical and social recovery and hinder brain activation over time [362]. Comprehensive fitness training may offset these effects (Table 25) [360,363,364]. Moreover, exercise programs can benefit a stroke survivor by reducing recurrent stroke and cardiovascular risks; reducing the risk and severity of post-stroke osteoporosis, preventing injuries and falls; increasing fitness, strength, flexibility, and functional activities; and promoting socialization [21,360,365]. However, exercise is not without risks. Training programs should be tailored to the patient's capabilities and conditions to promote safety and reduce musculoskeletal injuries [366,367]. For some patients, stroke severity and coexisting conditions may render exercise inadvisable. For instance, silent coronary artery disease, especially in sedentary patients, increases the chance of exercise-induced cardiac death. Because up to 75% of stroke survivors have cardiac comorbidities, the AHA suggests that the medical evaluation for an exercise program should include a graded exercise test with ECG monitoring [360]. Thorough screening, customized exercise program design, monitoring, and patient education should be performed during rehabilitation to maximize benefits and safety.

Table 25: SUMMARY OF EXERCISE PROGRAM RECOMMENDATIONS FOR STROKE SURVIVORS

Mode of Exercise

Major Goals

Intensity, Frequency, Durationa

Hospitalization and early convalescence

Low-level walking, self-care activities

Intermittent sitting, standing

Seated activities

Range of motion activities and motor challenges

Increase independence in activities of daily living

Increase walking speed/efficiency

Improve tolerance for prolonged physical activity

Reduce risk of cardiovascular disease

Reduce motor impairment; improve cognition

Prevent deconditioning, pneumonia, orthostatic intolerance, and depression

Approximately 10 to 20 beats per minute increases in resting heart rate; rating of perceived exertion (RPE) ≤11 (6–20 scale)

Frequency, duration as tolerated, using interval or work-rest approach

Inpatient/outpatient exercise therapy or "rehabilitation"

Large-muscle activities (e.g., walking, graded walking, stationary cycle/arm ergometry, functional activities seated exercises), if appropriate

Increase walking speed, efficiency

Improve functional capacity and independence in activities of daily living

Reduce motor impairment

Improve cognition

Improve vascular health and induce other cardioprotective benefits

40% to 70% peak oxygen uptake; 40% to 70% heart rate reserve; 55% to 80% maximal heart rate; RPE 11–14 (6–20 scale)

3 to 5 days/week 20 to 60 min/session (or multiple 10-min sessions)

Complement with pedometers to increase lifestyle physical activity

Strength/endurance (e.g., circuit training, weight machines, free weights, isometric exercise)

Increase independence in activities of daily living

Increase muscle strength and endurance

Reduce cardiac demands during lifting/carrying objects by increasing muscular strength

1–3 sets of 10–15 repetitions of 8–10 exercises involving the major muscle groups

2 to 3 days/week, with resistance gradually increased over time as tolerance permits

Flexibility/stretching

Increase range of motion (ROM) of involved extremities

Prevent contractures

Decrease risk of injury

Increase activities of daily living

2 to 3 days/week (Before or after aerobic or strength training) Hold each stretch for 10 to 30 seconds

Neuromuscular (coordination and balance activities)

Improve level of safety during activities of daily living

Improve balance, skill reacquisition, quality of life, mobility

Decrease fear of falling

Use as complement to aerobic, muscular strength/endurance training, and stretching activities

2 to 3 days/week (Consider performing on same day as strength activities)

aRecommended intensity, frequency, and duration of exercise depend on each individual patient's level of fitness.

Intermittent training sessions may be indicated during the initial weeks of rehabilitation.

Source: [360] Reprinted from Billinger SA, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(8):2532-2553. With permission from Lippincott Williams & Wilkins.©American Heart Association.

As with any rehabilitation program, the degree of a patient's cognitive and communicative deficits can affect an exercise program's success. The Neurobehavioral Cognitive Status Examination is a brief screening tool that provides a rapid and sensitive measure of the patient's cognitive function. However, it, and other brief mental status scales, cannot adequately assess executive skills and other higher-level cognitive functions [21]. Personalized, tailored counseling interventions have demonstrated mixed results in improving adherence to an exercise program, whereas physical activity counseling has resulted in greater physical activity at 9 and 52 weeks post-stroke [360]. The crucial elements of a successful physical activity counseling intervention have not been identified definitively [360]. Barriers that may need to be addressed include lack of familial support, depression, fatigue, social integration, and cultural issues [360].

The consequences of inactivity may be most noticeable in patients with hemiparesis or other gait deficits. More than 50% of stroke survivors require rehabilitation to regain a functional level of ambulation [368]. Effects of neural damage underlying gait impairment, spasticity, and poor muscle performance are significantly compounded by muscle weakness, a lack of fatigue resistance, and the increased energy demands of rehabilitation [360]. Patients with mild-to-moderate conditions can benefit from treadmill training with partial body weight support [360]. As the patient walks on a treadmill, his or her body weight is supported by harnesses to facilitate walking at a comfortable speed. This training augments conventional gait rehabilitation therapies by increasing gait speed, muscle performance, and fatigue resistance; however, its effect on long-term walking outcomes requires further study [368,369].

Incorporation of progressive resistance training increases the generalizability of the fitness program and may improve the ability to carry out activities of daily living [370]. Although there are no accepted guidelines, the AHA suggests more repetitions with reduced loads (10 to 15 repetitions rather than 8 to 12), similar to programs recommended for patients recovering from MI [360]. Additionally, at least one set of at least 8 to 10 exercises should involve the major muscle groups (arms, shoulders, chest, abdomen, back, hips, and legs).

As technology continues to advance, rehabilitation programs may become enhanced with new ways to engage stroke survivors in exercise [21]. A study of virtual reality training sessions was shown to improve arm and hand movement skills in two patients with chronic hemiparesis [371]. The approach was also able to provide individualized, progressive practice based on the patient's level of movement ability and rate of improvement [371]. Other studies have found virtual reality rehabilitation to be an equally effective and potentially motivating alternative and/or supplement to conventional training in post-stroke care [372,373].

Nerve stimulation therapy has also been proposed as a means to improve motor deficits and physical activity capacity. In 2021, the FDA approved a vagus nerve stimulation system intended to treat moderate-to-severe upper extremity motor deficits associated with chronic ischemic stroke [397]. The device may be incorporated into a comprehensive rehabilitation program for these patients.

TRANSITIONS IN CARE AND REHABILITATION CONTINUITY

The transition from inpatient care to home after a stroke can be difficult for both patients and caregivers. Ongoing rehabilitation, profound or permanent disability, or discharge to a long-term care facility affects not only the transition in care but also the continuity of that care. To ensure medical and rehabilitation continuity for the patient through the rehabilitation process and into the home or community, the AHA/ASA recommend individualized discharge planning in the transition from hospital to home that includes comprehensive assessment of activities of daily living, instrumental activities of daily living, and mobility assessments and discussion of sexual issues (e.g., safety, changes in libido), recreational and leisure activities, and return to work ability and timeline, where appropriate [21]. Patients for whom the discharge living setting is evaluated should be considered candidates for community- or home-based rehabilitation when feasible. Providers should consider alternative methods of communication and support (e.g., telephone, visits, telehealth, online support), particularly for patients who reside in rural settings [21].

Rehabilitation services provided in the community can improve cardiovascular health, decrease the risk of cardiovascular events, and increase short-term survival rates for stroke survivors [21]. Among the benefits associated with community- and home-based rehabilitation programs are reduced costs, decreased length of stay in hospitals or institutional settings, increased opportunities for involvement by patient and family/caregiver, and less stress for family/caregiver. Patient satisfaction also is generally higher.

7. SECONDARY PREVENTION: EVIDENCE-BASED RECOMMENDATIONS

In the United States, approximately 23% of stroke incidences are recurrent [1]. Due to the high risk of recurrent stroke and its consequences, secondary ischemic stroke prevention tends to follow a risk-stratified model of disease management [374]. Treatment of at-risk patients' conditions is typically aggressive, as inadequate management can have serious implications.

A patient's risk for a recurrent stroke is highest during the first year; 14% of survivors have a recurrent stroke within 1 year after the initial cerebrovascular event, suggesting that secondary prevention is time-critical and should be initiated during the rehabilitation process [375]. After the first year, the chance of recurrent stroke decreases to 4% per year [374]. Because TIA is an important determinant of stroke, the AHA secondary prevention guidelines for patients with TIA tend to be as aggressive as those established for ischemic stroke [10]. The guidelines focus on controlling several important modifiable risk factors.

CONTROLLING RISK FACTORS

A major component of secondary prevention is the treatment of modifiable risk factors and the underlying cause of the stroke. For patients who have had an ischemic event, the results of large studies have suggested that addressing hypertension, diabetes, smoking, alcohol consumption, and physical activity can reduce the risk of recurrent stroke [109].

Hypertension

The results of meta-analyses have indicated that lowering blood pressure reduces the risk of stroke 30% to 40% [376,377]. The findings of longitudinal studies suggest that treatment with antihypertensive medications in hypertensive and normotensive patients reduces the incidence of recurrent strokes, MI, and other vascular events [378]. In particular, diuretics or diuretics combined with ACE inhibitors (e.g., ramipril, perindopril) most significantly reduce the risk of recurrent ischemic stroke [10,378]. However, lifestyle modifications that include weight loss; increased intake of fruits, vegetables, and low-fat dairy products; habitual aerobic physical activity; and limited alcohol consumption are crucial components of controlling blood pressure [123]. Although most studies address the prevention of additional ischemic strokes, hypertension management has also been shown to reduce the risk of recurrent hemorrhagic stroke and is included in guideline recommendations published by the AHA/ASA [10,378].

AHA Recommendations

- Initiation of blood pressure therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established blood pressure ≥140/90 mm Hg. Initiation of therapy for patients with blood pressure <140/90 mm Hg is of uncertain benefit.

- Resumption of blood pressure therapy is indicated for previously treated patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events in those who have had an ischemic stroke or TIA and are beyond the first several days.

- Goals for target blood pressure level or reduction from pretreatment baseline are uncertain and should be individualized, but it is reasonable to achieve a systolic pressure <140 mm Hg. For patients with a recent lacunar stroke, it might be reasonable to target an systolic pressure of <130 mm Hg.

- The choice of specific drugs and targets should be individualized on the basis of pharmacologic properties, mechanism of action, and consideration of specific patient characteristics for which specific agents are probably indicated (e.g., extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, diabetes).

- The optimal drug regimen to achieve the recommended level of reductions is uncertain because direct comparisons between regimens are limited.

- Lifestyle modifications are an integral part of a patient's antihypertensive therapy.

Diabetes

Diabetes is a well-documented independent risk factor for recurrent stroke [379,380]. Aggressive control of hypertension in diabetic patients, with a lower target of 130/80 mm Hg, has been shown to reduce the risk of stroke as well as other cardiovascular events [123]. Including ACE inhibitors in the treatment regimen of patients with diabetes effectively lowers blood pressure, slows the progression of renal disease, and reduces albuminuria [10,381].

AHA Recommendations

- After a TIA or ischemic stroke, all patients should probably be screened for diabetes with testing of fasting plasma glucose, glycated hemoglobin (HbA1c), or an oral glucose tolerance test. Choice of test and timing should be guided by clinical judgment and recognition that acute illness may temporarily perturb measures of plasma glucose. In general, HbA1c may be more accurate than other screening tests in the immediate postevent period.

- Use of existing guidelines for glycemic control and blood pressure targets for patients with diabetes is recommended for patients who have had a stroke or TIA.

Cigarette Smoking

Smoking doubles the risk of stroke [382]. Its cessation eliminates the elevated risk after 5 years and reduces the overall risk of stroke-related hospitalization [10,382,383]. Exposure to secondhand smoke also appears to increase the risk of stroke [10,384]. The most effective combination of therapies for smoking cessation is nicotine replacement, social support, and counseling [10,385].

AHA Recommendations

- All patients with TIA or stroke who smoke should be strongly urged to quit and to avoid passive smoke. The use of smoking cessation programs and nicotine-replacement therapy should be considered.

- It is reasonable to advise patients after ischemic stroke or TIA to avoid environmental (passive) tobacco smoke.

Alcohol Consumption

The results of a meta-analysis suggest that the risk of stroke is increased 69% for individuals who have more than five drinks (with one drink defined as 12 ounces of beer, 4 ounces of wine, or 1.5 ounces of liquor) per day compared with nondrinkers [386].

AHA Recommendations

- Patients with ischemic stroke or TIA who drink heavily should be strongly encouraged to reduce or eliminate their alcohol consumption to lessen risk factors that increase the likelihood of recurrent stroke.

- Light-to-moderate amounts of alcohol consumption (up to 2 drinks per day for men; up to 1 drink per day for nonpregnant women) may be reasonable; however, nondrinkers should not be counseled to start drinking.

Physical Activity

Habitual exercise clearly prevents stroke [365]. In addition, a sedentary lifestyle impedes functional recovery and places patients at a higher risk for stroke recurrence.

AHA Recommendations

- After successful screening and completion of formal stroke rehabilitation, an individually tailored exercise program is indicated to enhance cardiorespiratory fitness and reduce risk of stroke recurrence.

- At least three to four sessions per week, 40 minutes per session, of moderate-to-vigorous-intensity aerobic physical exercise is reasonable to reduce stroke risk factors in eligible patients. Moderate-intensity exercise is sufficient to break a sweat or noticeably raise heart rate (e.g., walking briskly); vigorous-intensity exercise includes activities such as jogging.

- Patients who are able and willing to initiate increased physical activity should be referred to a comprehensive, behaviorally oriented program.

- Consider supervision by a healthcare professional (e.g., physical therapist) on initiation of an exercise regimen for individuals with disability after ischemic stroke.

MANAGING DISEASE

For patients who have large-artery atherosclerosis, the specific underlying condition should be managed. Similarly, identification and treatment of cardioembolic stroke sources (e.g., AF, cardiomyopathy, acute MI and left ventricular thrombus, valvular heart diseases) is recommended. Patients with ischemic stroke and a high-risk source of cardioembolism generally benefit from anticoagulant therapy.

Extracranial Carotid Artery Disease

Carotid artery revascularization is recommended by the AHA for certain patients with stenosis greater than 50% [10]. However, surgery is not beneficial for patients with stenosis of less than 50%.

AHA Recommendations

- Carotid endarterectomy (CEA) is recommended for all patients who had a recent TIA or an ischemic stroke within the past 6 months and ipsilateral severe (70% to 99%) carotid artery stenosis if the morbidity/mortality risk is less than 6%.

- CEA is recommended for certain patients (based on age, gender, and comorbidities) who had a recent TIA or an ischemic stroke within the past 6 months and ipsilateral severe (50% to 69%) carotid artery stenosis if the morbidity/mortality risk is less than 6%. CEA is not recommended when the degree of stenosis is <50%.

- When CEA is indicated for patients with TIA or stroke, surgery within 2 weeks is reasonable rather than delaying surgery if there are no contraindications to early revascularization.

- Carotid artery stenting (CAS) is indicated as an alternative to CEA for symptomatic patients at average or low risk of complications associated with endovascular intervention when the diameter of the lumen of the internal carotid artery is found to be reduced by more than 70% on noninvasive imaging or more than 50% on catheter angiography or noninvasive imaging with corroboration and the anticipated rate of periprocedural stroke or death is less than 6%.

- It is reasonable to consider patient age in choosing between CAS and CEA. For patients older than 70 years of age, CEA may be associated with improved outcome compared with CAS, particularly when arterial anatomy is unfavorable for endovascular intervention. For younger patients, CAS is equivalent to CEA in terms of risk for periprocedural complications (e.g., stroke, MI, death) and long-term risk for ipsilateral stroke.

- CAS may be considered for patients with symptomatic severe stenosis (greater than 70%) if the stenosis is difficult to access surgically, medical conditions are present that greatly increase the risk for surgery, or other specific circumstances exist (such as radiation-induced stenosis or restenosis after CEA). In this setting, CAS is reasonable when performed by operators with established periprocedural stroke and mortality rates of less than 6%, similar to those observed in trials of CEA and CAS.

- For patients with recurrent or progressive ischemic symptoms ipsilateral to a stenosis or occlusion of a distal carotid artery, or occlusion of a midcervical carotid artery after institution of optimal medical therapy, the usefulness of extracranial to intracranial bypass is considered investigational.

- Optimal medical therapy, which should include antiplatelet therapy, statin therapy, and risk factor modification, is recommended for all patients with carotid artery stenosis and a TIA or stroke.

Intracranial Atherosclerosis

The rate of stroke recurrence for patients with symptomatic intracranial atherosclerosis is approximately 9% [10]. The findings of retrospective studies have suggested that the greatest rate of recurrence is found among patients with this condition who do not have a response to antithrombotic therapy [387]. Although the results of some studies have indicated that angioplasty or stenting should be considered for such patients, the usefulness of these surgical interventions is unknown and considered investigational [10].

AHA Recommendations

With regard to patients with stroke or TIA due to 50% to 99% stenosis of a major intracranial artery:

- Aspirin 325 mg per day is recommended in preference to warfarin.

- The data are insufficient to make a recommendation regarding the usefulness of clopidogrel alone, the combination of aspirin and dipyridamole, or cilostazol alone.

- Long-term maintenance of blood pressure <140/90 mm Hg and high-intensity statin therapy are recommended.

- Angioplasty and/or stent placement is not recommended, given the low rate of stroke with medical management and the inherent periprocedural risk of endovascular treatment.

- Extracranial-intracranial bypass surgery is not recommended.

With regard to patients with stroke or TIA due to 70% to 99% stenosis of a major intracranial artery, the addition of clopidogrel 75 mg/d to aspirin for 90 days might be reasonable.

Atrial Fibrillation

The anticoagulant warfarin has a narrow therapeutic margin and numerous food and drug interactions, and these factors (which necessitate frequent INR testing and dose adjustment), combined with the associated significant bleeding risks, have led to the underutilization of this drug despite having been shown to prevent recurrent stroke substantially in patients with ischemic stroke or TIA and AF and despite the adoption of performance measures and guidelines advocating its use in these patients [10,388,389]. Easy-to-use alternative therapies are required and include dabigatran, rivaroxaban, and apixaban [390,391,392]. Significant adverse effects (i.e., serious, sometimes fatal bleeding, acute coronary events) have been associated with some of these agents, making their use inappropriate for some patients [393,394]. However, a 2011 focused update on dabigatran published by the American College of Cardiology, the AHA, and the Heart Rhythm Society recommends this agent as a useful alternative to warfarin for select patients [395].

Between 35% to 45% of patients with stroke and AF have coexisting conditions that may have caused the stroke [396]. In many cases, both the AF and the other condition (usually stenosis) will require treatment [10].

AHA Recommendations

- For patients who have experienced an acute ischemic stroke or TIA with no other apparent cause, prolonged rhythm monitoring (for approximately 30 days) for AF is reasonable within 6 months of the index event.

- For patients with ischemic stroke or TIA with paroxysmal (intermittent), persistent, or permanent AF, anticoagulation with a vitamin K antagonist (VKA) (target INR: 2.5; range: 2.0 to 3.0) is recommended.

- VKA therapy, apixaban, and dabigatran are all indicated for the prevention of recurrent stroke in patients with nonvalvular AF, whether paroxysmal or permanent. The selection of an antithrombotic agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including renal function and time in INR therapeutic range if the patient has been taking VKA therapy.

- Rivoroxaban is reasonable for the prevention of recurrent stroke in patients with nonvalvular AF.

- The combination of oral anticoagulation (i.e., warfarin or one of the newer agents) with antiplatelet therapy is not recommended for all patients after ischemic stroke or TIA but is reasonable in patients with clinically apparent CAD, particularly an acute coronary syndrome or stent placement.

- For patients unable to take oral anticoagulants, aspirin alone (75 mg to 100 mg per day) is recommended. The combination of clopidogrel plus aspirin, compared with aspirin therapy alone, might be reasonable.

- For most patients with a stroke or TIA in the setting of AF, it is reasonable to initiate oral anticoagulation within 14 days after the onset of neurologic symptoms. In the presence of high risk for hemorrhagic conversion (i.e., large infarct, hemorrhagic transformation, uncontrolled hypertension, hemorrhage tendency), it is reasonable to delay initiation of oral anticoagulation beyond 14 days.

- For patients with AF at high risk for stroke (i.e., stroke or TIA within 3 months; Cardiac failure, Hypertension, Age, Diabetes, Stroke system [CHADS2] score of 5 or 6; mechanical or rheumatic valve disease) who require temporary interruption of oral anticoagulation, bridging therapy with a LMWH administered subcutaneously is reasonable.

Noncardioembolic Strokes and TIA

The use of certain antiplatelet therapies rather than oral anticoagulation for noncardioembolic ischemic strokes and TIAs has been shown to reduce the overall risk of recurrent stroke and decrease the incidence of fatal recurrent strokes [10]. Clopidogrel is appropriate for patients who are allergic to aspirin or for patients in whom dipyridamole-associated headaches occur.

AHA Recommendation

Aspirin (50 mg to 325 mg per day) monotherapy, the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily, or clopidogrel 75 mg monotherapy are all acceptable options for initial therapy. The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, and other clinical characteristics.

8. CASE STUDY

Patient M is an active woman, 70 years of age, who lost consciousness and collapsed at home. Her daughter, who was visiting her at the time, did not witness the collapse but found her mother on the floor, awake, confused, and slightly short of breath. The daughter estimated that she called EMS within 5 minutes after the collapse, and EMS responded within 10 minutes. EMS evaluated Patient M, drew blood for a glucose level, and determined that she may have had a stroke. They notified the nearest designated comprehensive stroke center that they would be arriving with the patient within 15 minutes. Patient M's daughter accompanied her.

The triage and transportation of an individual with suspected stroke should be similar to that for an individual with serious trauma, and treatment is recommended within 3 hours after the onset of stroke. Because of the limited time available for assessment and diagnosis before optimal treatment, the EMS dispatcher should notify EMS personnel immediately and coordinate transport of the individual to the closest emergency facility, preferably one that is a designated primary (or comprehensive) stroke care center.

On presentation in the emergency department, Patient M is immediately triaged. Because Patient M is still somewhat confused, her daughter is asked to provide information on the patient's history. The daughter reports that her mother had had an episode of sudden-onset numbness and tingling in the right limb, with slight confusion and slurred speech, 3 days previously. The episode lasted only 5 minutes, and Patient M had not called her primary care physician. Additional information provided by the daughter indicates that Patient M has been treated for hypertension for 10 years but notes that she is often not compliant with her antihypertensive medicine, a diuretic. The patient has never smoked, drinks occasionally, and is of normal weight.

Patient M has two significant risk factors for stroke; one is a long history of hypertension. More than two-thirds of individuals older than 65 years of age are hypertensive, and it is important for individuals with hypertension to have regular blood pressure screening and to maintain a blood pressure of less than 140/90 mm Hg. Antihypertension therapy has been found to reduce the incidence of stroke by 30% to 40%. Patient M's noncompliance with her antihypertension medicine likely includes her among the 65% of known hypertensive individuals in whom blood pressure is not controlled.

Patient M's previous episode of numbness, confusion, and slurred speech appears to be evidence of a TIA, another substantial risk factor for stroke. Research has shown that approximately 5% of patients will have an ischemic stroke within 7 days after a TIA. In addition, the risk of stroke within 7 days is doubled for patients with TIAs who did not seek treatment. As is the case for many individuals who have a TIA, Patient M did not seek medical attention because the clinical symptoms resolved quickly. However, research findings indicate that urgent treatment should be provided for TIAs, as early treatment for TIA and minor stroke has been shown to reduce the risk of early recurrent stroke by 80%.

On physical examination, Patient M's blood pressure is 150/95 mm Hg. She has pain in her left arm and a slight headache. There are slight carotid bruits on the right. She is assessed with use of the NIHSS and found to have left hemiparesis and left visual/spatial neglect. The results of laboratory tests, including a complete blood count, prothrombin time, serum electrolyte levels, cardiac biomarkers, and renal function studies, are all within normal limits. CT of the brain indicates a thrombus in a branch of the right internal carotid artery, with approximately 50% occlusion due to atherosclerosis. There is an area of infarction in the right anterior hemisphere. There is no evidence of a subarachnoid hemorrhage. The diagnosis is made 2 hours after Patient M's arrival in the emergency department. She is treated with intravenous rt-PA at a dose of 0.9 mg/kg, and aspirin antiplatelet therapy is started at an initial dose of 325 mg, 24 hours after thrombolytic therapy, and a maintenance dose of 75 mg per day.

Many of the patient's symptoms, including her loss of consciousness, shortness of breath, pain, and headache, are nontraditional symptoms of stroke. Studies have demonstrated that nontraditional symptoms are more prevalent among women, often leading to a delay in the evaluation for stroke. EMS personnel and clinicians should be aware of the potential for nontraditional symptoms in women and carry out a diagnostic evaluation addressing a suspicion of stroke.

Patient M is eligible for thrombolytic therapy with rt-PA according to evidence-based guidelines developed by the AHA/ASA: her blood pressure is lower than 185/110 mm Hg, the onset of symptoms is less than 3 hours prior to the start of treatment, and the laboratory values are within normal limits. Antiplatelet therapy with aspirin 325 mg daily (versus anticoagulant therapy with warfarin) is recommended for treatment of patients with stroke or TIA due to intracranial atherosclerosis with 50% to 99% occlusion. Antiplatelet therapy is not recommended as an adjunctive therapy within 24 hours of thrombolytic therapy.

When Patient M's condition is stabilized, her primary care physician and consultant neurologist provide a referral for stroke rehabilitation, and a multidisciplinary rehabilitation team is formed to assess her rehabilitative needs, recommend the proper rehabilitation setting, and develop a treatment strategy tailored to her specific needs that includes daily antiplatelet therapy. Patient M is again assessed with the NIHSS, and the score is 12. The patient's cognitive and communication skills are intact on evaluation with the FIM, with the exception of the previously documented left visual/spatial neglect. The assessment also includes evaluation of the patient's risk for complications. Because of her spatial neglect, she is screened with the Berg Balance Scale and the Stops Walking When Talking test. The score on the Berg Balance Scale is 43, and Patient M does stop walking to engage in conversation. Psychosocial assessment includes screening with the Center for Epidemiologic Studies Depression (CES-D) Scale, as well as review of the medical history and conversations with the patient and her children; no signs of depression are present.

Patient M's score of 12 on the NIHSS falls within the range (6 to 15) that indicates she is likely to benefit from rehabilitation. Evaluating a stroke survivor's risk of complications is an important component of the overall assessment, and among the most common complications are falls, deep vein thrombosis, pressure ulcers, swallowing dysfunction, bladder and bowel dysfunction, and depressive symptoms. In assessing the risk of complications, the Berg Balance Scale appears to be the most appropriate screen for patients who are likely to fall, and a score of less than 45 is associated with a likelihood of falling. The risk of a fall is also increased when a patient stops walking to talk, as Patient M did, during the Stops Talking When Walking test.

Screening for signs of depression is also essential, as depression affects approximately 33% of stroke survivors. Signs of depression are subtle and may be vague. Several screening tools are available, but there is no universally accepted tool for use in the post-stroke setting. The CES-D was chosen in this case because it is easy to administer, is useful in older individuals, and has been found to be effective for screening in the stroke population, except for individuals who have aphasia. The diagnosis of depression in stroke survivors should be based on sources in addition to a formal screening tool, such as a medical evaluation, patient self-report, observation of patient behavior, patient history, and staff reports of changes in behavior and motivation.

The rehabilitation team discusses the results of the assessment with Patient M's daughter and son, both of whom live about 45 minutes away from the patient. Together, the team and the family members explore options to determine the best approach to rehabilitation. A decision is made for Patient M to be discharged to an inpatient stroke unit, and a rehabilitation program is developed. The nurse on the team discusses the program with Patient M and her children and explains the course of rehabilitation and the expectations. Rehabilitation will focus on an exercise program consisting of aerobic exercise, strength training, stretching, and coordination and balance activities.

Early initiation of rehabilitation is a particularly strong predictor of improved outcome, and rehabilitation in a stroke unit has been associated with improved quality of life, survival, and functional status at 5 years compared with a general healthcare facility. No studies have demonstrated the superiority of one rehabilitation setting over another, and the inpatient setting was chosen primarily to ensure consistent care, given how far away Patient M's children live, and the limited support she otherwise has for healthcare needs. Decisions about the setting and program for rehabilitation should be shared with family members, and family and other caregivers should be provided with educational resources about the rehabilitation process.

The exercise program developed for Patient M is designed to help her regain the ability to independently carry out activities of daily living safely and to regain a functional level of ambulation. The benefits of an exercise program include increasing fitness, strength, and flexibility; improving function; preventing injuries and falls; and reducing the risk of recurrent stroke.

Patient M gradually resumes the ability to function independently, and after more than 2 weeks in the stroke rehabilitation unit, the score on the NIHSS has improved to 5. Before she is discharged to her home, the rehabilitation team provides instructions for exercises to continue at home and recommends moderate physical activity as a secondary prevention measure. The team also educates Patient M about the importance of maintaining a normal blood pressure through use of her antihypertension medication and lifestyle modifications. At a follow-up visit with her primary care clinician at 3 months, Patient M's blood pressure is 135/80 mm Hg, and she reports that she has been compliant with her antihypertension medicine and antiplatelet therapy and is functioning well at home.

9. CONCLUSION

Ischemic stroke remains a significant contributor to morbidity and mortality in the United States. Stroke is associated with several modifiable risk factors, such as smoking, diet, physical inactivity, and obesity, and clinicians should encourage their patients to adopt healthy lifestyle habits, especially patients who are at highest risk. In addition, primary prevention of stroke involves the appropriate management of many medical conditions, such as hypertension, diabetes, dyslipidemia, and AF.

Early diagnosis and appropriate immediate treatment are key to recovery of neurologic function and survival after stroke, making it imperative for both healthcare professionals and the general public to recognize the symptoms of stroke and TIAs, a substantial risk factor for stroke. Clinicians, as well as EMS staff and ED staff, should be skilled in identifying possible stroke-related symptoms, especially noting that women are more apt to have nontraditional symptoms of both TIAs and stroke. Efforts to educate the public about the importance of seeking medical care for TIAs and about the warning signs of stroke are also essential.

Several evidence-based guidelines are available for the primary and secondary prevention of ischemic stroke, as well as for early management and rehabilitation. Adherence to these guidelines will help to reduce the prevalence of stroke and to decrease the morbidity and mortality for individuals who have stroke. Thrombolytic therapy with rt-PA is the cornerstone of treatment for ischemic stroke, and the AHA now recommends beginning antiplatelet therapy with aspirin 24 to 48 hours after the onset of stroke. Other antiplatelet agents, as well as anticoagulant therapy, are not recommended on the basis of the evidence to date.

Outcomes after stroke are improved when care is provided in a comprehensive stroke center and when rehabilitative care is provided by a multidisciplinary team. Effective rehabilitation begins with a systematic evaluation of the patient to determine the need for specific rehabilitation services, the risk of complications, the patient's physical functioning and level of cognition and communication, and the patient's psychosocial status. This evaluation allows for the development of a rehabilitation program that addresses an individual patient's specific needs, with tailored strategies for secondary prevention. When all available resources are utilized, prevention and appropriate treatment of stroke will result.

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Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Carotid Artery Stenosis: Screening. Available at https://www.uspreventiveservicestaskforce.org/ Page/Document/UpdateSummaryFinal/carotid-artery-stenosis-screening. Last accessed March 11, 2020.

2. Brown MD, Burton JH, Nazarian DJ, Promes SB, American College of Emergency Physicians. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015;66(3):322-333. Available at https://www.acep.org/globalassets/new-pdfs/clinical-policies/tpa-for-stroke_new.pdf. Last accessed March 11, 2020.

3. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2012;141(2 Suppl):e601S-e636S. Available at https://journal.chestnet.org/issue/S0012-3692(12)X6003-3. Last accessed March 11, 2020.

4. Price CIM, Pandyan AD. Electrical stimulation for preventing and treating post-stroke shoulder pain. Cochrane Database Syst Rev. 2000;(4):CD001698. Available at https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001698/full. Last accessed March 11, 2020.

5. National Clinical Guideline Centre. Long-Term Rehabilitation After Stroke. London: National Institute for Health and Care Excellence; 2013. Available at https://www.nice.org.uk/guidance/CG162. Last accessed March 11, 2020.