PHARM18 • Pharmacology Special Offer (Includes 28 Pharmacology Hours)

Table of Contents

PHARM18 • Pharmacology Special Offer (Includes 28 Pharmacology Hours)

How to Receive Credit

NetCE 15 Hour Course #30463 • Moderate Sedation/Analgesia

30463 • Moderate Sedation/Analgesia

1. INTRODUCTION

2. PATIENT CARE

3. PHARMACOLOGY AND DRUG ADMINISTRATION

4. DRUG CLASSES AND MEDICATIONS

5. PATIENT MONITORING DURING MODERATE SEDATION

6. DOCUMENTATION OF MODERATE SEDATION

7. COMPLICATIONS DURING MODERATE SEDATION

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

11. SEDATION OF THE CRITICALLY ILL PATIENT

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

13. CASE STUDIES

14. PRACTICE ISSUES

15. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #30873 • Epidural Analgesia Update

30873 • Epidural Analgesia Update

1. INTRODUCTION

2. HISTORICAL PERSPECTIVE

3. SPINAL ANATOMY

4. PATIENT SELECTION

5. PREPARATION OF PATIENTS

6. EPIDURAL DRUGS

7. PATIENT SAFETY CONSIDERATIONS

8. PATIENT ASSESSMENT

9. SIDE EFFECTS AND COMPLICATIONS

10. NURSING DIAGNOSES AND INTERVENTIONS

11. CASE STUDY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #95323 • Diabetes Pharmacology

95323 • Diabetes Pharmacology

1. INTRODUCTION

2. DIABETES EPIDEMIOLOGY

3. PATHOGENESIS OF DIABETES

4. DIABETES RESEARCH

5. DIAGNOSIS OF DIABETES

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

9. BIGUANIDE THERAPY

10. THIAZOLIDINEDIONE THERAPY

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

13. COMBINATION ORAL MEDICATION PREPARATIONS

14. BOLUS INSULIN THERAPY

15. BASAL INSULIN

16. COMBINATION INSULIN PREPARATIONS

17. INCRETIN MIMETICS

18. AMYLIN ANALOGS

19. PATIENT EDUCATION

20. CASE STUDIES

21. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

PHARM18 • Pharmacology Special Offer (Includes 28 Pharmacology Hours)

Susan Engman Lazear, RN, MN

Margo A. Halm, RN, PhD, NEA-BC, FAAN

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

PHARM18 • Pharmacology Special Offer (Includes 28 Pharmacology Hours)

Expiration Date: 02/28/2022

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.

30463 • Moderate Sedation/Analgesia

Susan Engman Lazear, RN, MN

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles is paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations must not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Table of Contents

30463 • Moderate Sedation/Analgesia

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. PATIENT CARE

PRESEDATION CARE

CARE DURING SEDATION

POSTSEDATION CARE

3. PHARMACOLOGY AND DRUG ADMINISTRATION

ROUTE OF ADMINISTRATION

ADMINISTRATION OF INTRAVENOUS MEDICATIONS

4. DRUG CLASSES AND MEDICATIONS

BENZODIAZEPINES

OPIOIDS

BARBITURATES

OTHER SEDATIVE HYPNOTICS

DISSOCIATIVE AGENTS

ANTAGONISTS

5. PATIENT MONITORING DURING MODERATE SEDATION

PULSE OXIMETRY

END-TIDAL CARBON DIOXIDE MONITORING

CARDIAC MONITORING

NONINVASIVE BLOOD PRESSURE MONITORING

BISPECTRAL INDEX

6. DOCUMENTATION OF MODERATE SEDATION

7. COMPLICATIONS DURING MODERATE SEDATION

OVERSEDATION AND UNDERSEDATION

RESPIRATORY INSUFFICIENCY

COMPROMISED AIRWAY

ASPIRATION

CARDIOVASCULAR COMPLICATIONS

PAIN

NAUSEA AND VOMITING

MALIGNANT HYPERTHERMIA

PARADOXICAL REACTIONS

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

PHARMACOLOGIC CONSIDERATIONS

NURSING CARE

11. SEDATION OF THE CRITICALLY ILL PATIENT

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

RADIOLOGIC INTERVENTIONS

CARDIAC CATHETERIZATIONS AND ELECTROPHYSIOLOGIC STUDIES

ENDOSCOPIC PROCEDURES

13. CASE STUDIES

PATIENT J

PATIENT D

14. PRACTICE ISSUES

ADVANCED CARDIAC LIFE SUPPORT TRAINING

MEDICAL-LEGAL CONSIDERATIONS

POLICIES AND PROCEDURES

ISSUES IN INTRAVENOUS VS. TRANSMUCOSAL ADMINISTRATION OF MODERATE SEDATION

COMPETENCY ISSUES

15. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

30463 • Moderate Sedation/Analgesia

Education Category. Medical / Surgical

Release Date. 08/01/2020

Expiration Date. 07/31/2023

Course Overview

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles is paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations must not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Audience

This course is designed for all nurses, especially those in procedural and diagnostic areas, such as radiology, endoscopy, cardiac cath, outpatient surgery, intensive care, and emergency departments.

Course Objective

The purpose of this course is to provide nurses with the knowledge required for safe drug delivery based on standardized operational guidelines. Preprocedural, intraprocedural, and postprocedural patient care are presented, as well as a thorough review of the drugs used, their advantages and disadvantages, and the safe administration of these agents.

Learning Objectives

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

1. Define moderate sedation, including the goals and objectives.

2. Detail the necessary components of the preprocedural patient care period, including patient assessment, selection, and preparation.

3. List the duties and responsibilities of those who provide care for the patient receiving moderate sedation medications.

4. Detail patient care provided during the postsedation period, including the minimal parameters that should be met by the patient prior to discharge after sedation.

5. Present the advantages and disadvantages of the various methods and routes of medication administration.

6. Review the most commonly used pharmacologic agents for moderate sedation.

7. List the advantages, disadvantages, and limitations of pulse oximetry and end-tidal carbon dioxide monitoring in the sedation setting.

8. Describe the various techniques for cardiac monitoring. Explain the advantages of each of these methods.

9. Outline the role of bispectral indexing in moderate sedation patients.

10. Develop a sedation documentation form that includes the appropriate information.

11. Discuss the most common complications occurring during or after moderate sedation.

12. Outline the anatomic and physiologic differences between children and adults and how these differences impact pediatric moderate sedation patients.

13. Describe the anatomic and physiologic differences in the elderly and the impact of these differences on the administration of sedation.

14. Explain how sedation practices should be altered in sedating the obstetric patient.

15. Review issues that impact moderate sedation administration for patients in the intensive care unit or those undergoing procedural interventions.

16. Identify practice issues for nurses administering moderate sedation.

Faculty

Susan Engman Lazear, RN, MN, received her undergraduate education at the Walter Reed Army Institute of Nursing in Washington, D.C. After completing her BSN, she served as an Army Nurse at Letterman Army Medical Center in San Francisco for four years. She then attended the University of Washington School of Nursing and received a Master’s in Nursing, specializing in Burn, Trauma and Emergency Nursing. After receiving her MN, she started Airlift Northwest, the air ambulance service based in Seattle which serves the entire Northwest region, including Alaska. Mrs. Lazear left the air ambulance service to start her own nursing education and consulting business, Specialists in Medical Education. For the past 20 years she has been teaching emergency nursing courses throughout the country. She lives in the Seattle area. Mrs. Lazear continues to teach and publish. She is both an editor and contributing author of Critical Care Nursing, published by W.B. Saunders Company, in June of 1992. She served as an author and reviewer of the Emergency Nursing Core Curriculum 6th Edition, published by W.B. Saunders Company in 2007. She has been named to the Who’s Who in American Healthcare list annually since 1992.

Faculty Disclosure

Contributing faculty, Susan Engman Lazear, RN, MN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

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

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Moderate sedation/analgesia (formerly referred to as conscious sedation) was once a task performed exclusively by anesthesiologists but is now a common nursing practice in a number of settings. The interest in and use of moderate sedation has dramatically increased as more nurses and care providers become trained in the safe delivery of patient care while administering sedative agents.

In 2001, the Joint Commission developed a new definition of moderate sedation that is now widely accepted and used. The Joint Commission identifies moderate sedation/analgesia as the second level in a continuum between minimal sedation (i.e., anxiolysis) and deep sedation (i.e., anesthesia). Thus, the Joint Commission defines moderate sedation/analgesia as "a drug-induced depression of consciousness during which individuals served respond purposefully to verbal commands either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained" [1]. The Joint Commission has mandated that an institution's sedation practices be monitored and evaluated by the department of anesthesia. In response to this mandate, the American Society of Anesthesiologists (ASA) developed practice guidelines for nonanesthesiologists who provide sedation and analgesia [2,3,4]. The practitioner should recognize that sedation is part of the continuum that progresses from minimal to moderate to deep sedation and eventually reaches the state of general anesthesia. Each individual patient should be closely and continuously monitored to prevent this progression to the deeper sedated states [5]. Practitioners of sedation should have the necessary skills to rescue a patient from a deeper level of sedation than that intended [5].

Much like the Joint Commission, the ASA has defined moderate sedation in the following manner [2]:

- Depression of consciousness is drug-induced.

- Patient responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation.

- Airway is patent without interventions, and spontaneous ventilation is adequate.

- Cardiovascular function is usually maintained.

Moderate sedation/analgesia can be used to achieve a number of objectives. Moderate sedation allows a patient to tolerate an unpleasant procedure while maintaining consciousness and cooperation. Many of the pharmacologic agents used will provide mood alteration and partial amnesia. The patient does not remember the majority of the procedure and awakens in a comfortable, composed state. The choice of medications used depends on the objectives desired; some medications will provide for an elevation in the patient's pain threshold, while others have no analgesic properties. However, it is important to note that the term moderate sedation cannot be used synonymously with pain management, as not all sedating medications will achieve the parameters of pain control. An additional goal of sedation is a rapid return of the patient to his/her presedation state with a decreased risk of resedation. It is imperative for nurses providing moderate sedation to remember that while the goals and objectives of moderate sedation are important, the most critical part of patient care delivery is providing for patient safety during the time that the patient is sedated and recovering from sedation.

Moderate sedation is delivered in a number of settings. The reasons for sedation may vary, but the Joint Commission requires that the patient receive the same level of care regardless of the practice setting. The first reports of the use of moderate sedation can be found in dental literature. Many dental and oral surgery procedures are successfully accomplished on the sedated patient. The emergency department may deliver sedation for a number of reasons, including, but not limited to, the repair of complex lacerations, reduction of fractures and casting, wound care, and abscess incision and drainage. Some patients may require lengthy, uncomfortable radiologic studies necessitating sedation in the radiology suite. Many invasive and diagnostic measures are performed using moderate sedation, such as bronchoscopy, endoscopy, cardiac studies, and pacemaker placement. The outpatient setting has seen an increased use of moderate sedation. It is not uncommon for in vitro fertilization to be performed on a sedated patient. Additionally, moderate sedation has been used as an adjunct to local anesthesia. A vast number of procedures that are uncomfortable and/or painful can be performed safely using moderate sedation [4,6,7,8,9,10,11,12,13,14,15].

As previously mentioned, the use of moderate sedation has increased tremendously. This increase in acceptance and popularity has occurred for a number of reasons. Due to healthcare reform, the financial impact of patient care is under daily scrutiny. Moderate sedation performed by trained nursing staff can greatly reduce the patient's hospital charges, as opposed to sedation performed by an anesthesiologist. A study of cardiac patients undergoing a six-hour electrophysiologic study found a reduction in costs of administering sedation ranging from $1,800 to $2,400 when a patient received moderate sedation administered by a nurse as compared to the patient receiving general anesthesia administered by an anesthesiologist [16]. This reduced cost reflected a number of factors, including shorter recovery times and a rapid return to the presedation state in the patient, thus requiring less expensive nursing care and shorter hospital stays [17,18]. One study investigated the clinical and cost outcomes associated with moderate sedation in patients undergoing transcatheter aortic valve replacement [19]. Of 231 patients initially identified, 225 were included in the study. Compared with general anesthesia, moderate sedation was associated with significantly fewer intensive care unit (ICU) hours (30 vs. 96); fewer total hospital days (4.9 vs. 10.4); a 28% decrease in direct costs; and significant decreases in all cost categories [19].

Patient acceptance and demand for moderate sedation is another reason its use has become more prevalent. The reported rates of patient satisfaction after procedures with moderate sedation have been high [20,21,22]. A knowledgeable patient recognizes that there are medications and techniques available (i.e., moderate sedation/analgesia) that allow the patient to have a procedure performed with a minimal amount of disruption in his/her daily activities. Patients no longer stay overnight after many procedures, and if given short-acting medications, they can return to their jobs and home life within a relatively short period of time.

Additionally, parents and family members do not want to see their loved ones uncomfortable or suffering and will request medications to help ease the pain. This is especially true with the pediatric patient, as many of the invasive procedures performed can be achieved with much less difficulty and pain in a moderately sedated child. The results are improved and the parent is satisfied in knowing that his/her child is not being unnecessarily restrained.

Patient satisfaction varies according to the drug used. There are a number of good, short-acting drugs available that assist in achieving the goals and objectives of moderate sedation. Prior to the 1990s, diazepam had been the drug of choice in most practice settings; however, the side effects were intolerable to many, and patients had longer recovery times. With the advent of newer benzodiazepines and opioids, patients can experience the same benefits without the disadvantages of the older drugs.

Finally, increased use of moderate sedation can be traced to the advent of new technologic innovations. With the development of pulse oximetry and noninvasive blood pressure monitoring, moderate sedation can be delivered safely and noninvasively to provide for maximum patient comfort and care.

The subsequent discussion of moderate sedation will focus on safe patient care delivery. The administration of moderate sedation can be performed using either intravenous (IV) or transmucosal (i.e., oral, intranasal, rectal, sublingual) routes. Each route has advantages and disadvantages, which will be discussed in length at a later point in this course. The issues discussed in the Patient Care section will cover both routes of administration, with special attention to IV sedation when appropriate.

2. PATIENT CARE

Care of the patient receiving sedating medications includes three phases: presedation care (i.e., care prior to the procedure); care during the procedure, and postsedation care (i.e., care after the procedure). Administering moderate sedation/analgesia requires vigilant nursing assessment during all phases to ensure safe drug administration and positive patient outcomes.

PRESEDATION CARE

Patient selection and assessment prior to drug administration is critical to safe patient care both during and after sedation. The goals of presedation selection include the recognition of risk factors that may place the patient at increased risk of complications; the recognition of patients with a high level of anxiety who may not tolerate the sedation process easily; and the recognition of pre-existing comorbidities that will complicate care delivery. For elective procedures, a preprocedure assessment may be done days or weeks in advance; early assessment is essential for allowing time to make any necessary changes, such as the discontinuation of certain medications or herbal supplements [3,4,6,23,24]. Even when an early assessment has been done, the Joint Commission requires that a presedation assessment be performed on each individual prior to beginning moderate sedation and before anesthesia induction [25]. This assessment allows the practitioner to plan and administer sedation to ensure patient safety. The components of presedation assessment include the patient's age, height, weight, and existing medical diagnosis. A physical examination with a review of the cardiac, respiratory, and neurologic systems should be completed. Astute assessment is critical as medications administered during moderate sedation will most significantly affect these body systems, and the patient who may be at risk should be identified.

The patient's past medical history should be reviewed. A history of allergies should be documented, and if necessary, therapeutic reversal agents, such as diphenhydramine and epinephrine, should be prepared. The patient's current medical history should include the reason for sedation and other current factors, including medication(s), alcohol, illicit drug, and/or tobacco use. A review of the patient's history may help to identify patients at risk for complications (Table 1) [6].

Table 1: USING HISTORY TO HELP IDENTIFY PATIENTS AT RISK FOR COMPLICATIONS

Question

Relevance to Moderate Sedation

Is there a history of cardiovascular problems?

The patient may be at increased risk for complications and may require special monitoring.

Is there a history of respiratory problems (emphysema, asthma)?

Risk of complications is greater for patients with emphysema or asthma due to potential respiratory depression.

Is there a history of seizure disorders?

If disorder is treated with benzodiazepines, a benzodiazepine antagonist cannot be used as a reversal agent.

Is there a history of liver disease?

Liver damage may prolong and/or heighten sedative effects of drugs metabolized in the liver.

Is there a history of renal disease?

Potential for problems for patients with renal insufficiency if the sedation drugs used are ones that are excreted in the urine (such as benzodiazepines and opioids).

Is there a history of thyroid disease?

Altered rates of metabolism affect the effective doses of sedation drugs.

Is there a history of substance abuse?

A back-up plan should be made with an anesthesia professional in case the patient becomes combative or uncooperative or if sedation drugs have little effect.

Are there any piercings?

Piercings may need to be removed, depending on location.

What current medications are taken?

Many prescription medications and herbal supplements may increase the risk for complications related to sedation/analgesia and/or an invasive procedure.

Source: [6]

Airway assessment should be conducted and is easily performed using the modified Mallampati scale [26,27,28]. The patient is placed in a comfortable sitting position and asked to open his/her mouth and protrude the tongue. The nurse then assesses the airway, noting the ability to visualize the fauces, anterior and posterior pillars, soft palate, and uvula. The patient with a Class 1 airway has all these structures visible. The pillars are masked by the tongue in a patient with a Class 2 airway. A patient with a Class 3 airway has only the soft palate and base of the uvula visible. A patient for whom only the hard palate is visible has a Class 4 airway [29]. The modified Mallampati scale allows the nurse to recognize which patients may be at risk for difficult airway management, including difficult intubations [28]. It has also been noted that obesity may contribute to airway difficulties [30,31]. In addition to visualization of the airway, neck circumference and body mass index should also be assessed preoperatively and considered in the overall airway assessment.

Baseline vital signs should be obtained, taking into consideration that the patient's "normal" vital signs may be masked by anxiety, pain, and fear. A baseline assessment of the patient's level of consciousness should be achieved to allow for proper assessment during sedation as well as for assessment of readiness for discharge. Additionally, baseline pulse oximetry readings should be achieved prior to initiating oxygen therapy.

An anesthesia history should be obtained, focusing on previous surgical interventions and any known complications. Appropriate laboratory studies can be obtained prior to the procedure.

It is important to accurately and fully assess the patient without performing excessive, superfluous tests. An electrocardiogram (ECG) may be indicated for patients with positive cardiac histories, but not everyone older than 40 to 50 years of age will require a presedation ECG. The performance of unnecessary tests may increase the patient's out-of-pocket costs if, for example, the patient's insurance company determines that the tests were unnecessary and declines to pay for them. Not only is this expensive, it may cause the patient to question the necessity of other important tests that may have been performed at the same time. Therefore, preprocedural tests should be weighed but by no means considered requirements for every patient.

Finally, the setting in which sedation will be administered should be considered in the selection process. The ASA Committee on Standards and Practice Parameters recommends that patients who receive moderate sedation on a scheduled basis should not drink clear fluids for at least two hours or eat solid foods (a light meal) for at least six hours prior to the procedure [32]. However, meeting the fasting requirements for emergently performed procedures is difficult, and guidelines note that when urgent or emergent procedures must be done, recent food intake is not a contraindication for administering procedural sedation/analgesia in adults or children [3,4,23,33,34]. The potential risks of sedation without fasting (e.g., aspiration) should be weighed against the benefit of performing the procedure promptly [4]. The ASA has developed a Physical Status Classification System to determine risk for complications among patients undergoing anesthesia (Table 2). This scale is frequently used in the moderate sedation setting and easily performed on all patients in all settings. Patients in Class 1 and 2 are considered good candidates for moderate sedation procedures; those in Class 3 and Class 4 carry higher risks. Nurses providing sedation should recognize that Class 3 and 4 patients may benefit from sedation and should not be excluded based upon their ASA classification. Sedation is frequently provided to ICU patients, most of whom are in Class 3 or 4, and these patients greatly benefit from the effects of the sedation.

Table 2: AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS CLASSIFICATION

Physical Status Classa

Definition

1

A normal healthy patient with no systemic disease

2

A patient with mild-to-moderate systemic disease

3

A patient with severe systemic disease

4

A patient with severe systemic disease that is a constant threat to life

5

A moribund patient who is not expected to survive without surgical intervention

6

A declared brain-dead patient whose organs are being removed for donor purposes

aThis number may be followed by an "E" if the surgery is considered an emergency

Source: [35]

A prime example of this dilemma would be a patient, 76 years of age, with a history of unstable angina who is being evaluated for sedation. His history shows that he lives alone and cares for himself. However, he is unable to walk a flight of stairs without stopping to catch his breath; thus, he would be classified as an ASA Class 3 patient. Withholding sedation because of his history may actually increase his risk of compromise if he is found to be extremely anxious about the intended intervention. His anxiety may increase his risk of developing chest pain; relieving this anxiety with sedation medications would reduce the risk of cardiac compromise.

Upon completion of the presedation assessment, a decision should be made as to the acceptability of the patient for moderate sedation. Every nurse providing sedation should recognize the patients who are at risk, and if extenuating circumstances arise, the nurse should be comfortable to say that he/she is not adequately trained in providing sedation to this particular patient. There should be no pressure on the nurse to provide sedation when suitability criteria are not met. If the criteria are met, the patient should be educated regarding the care he/she will receive during and after sedation. The patient should be told what he/she can expect during the procedure, and the nurse should inform the patient about the continuous monitoring that will occur throughout the sedation period. The techniques of noninvasive blood pressure monitoring should be explained, as this may cause momentary pain while the cuff is inflated to its highest level. The pulse oximeter probe should be explained, and the patient should be aware of its placement and use, recognizing that no pain should be experienced from its use. The vital sign assessment schedule should be explained and demonstrated, as patients will often be asked to take deep breaths. If the procedure is painful and a pain scale will be used to assess the patient's level of pain, the patient should be instructed on its use prior to beginning sedation. Finally, discharge instructions should be provided prior to the procedure; the nurse should recognize that the patient may not remember all that is told to him/her in the postsedation period. Reinforcing these instructions during the presedation period will greatly enhance patient compliance in the postsedation period.

Additional responsibilities in the presedation period include the preparation of the equipment to be used and available during the sedation period (Table 3). Patient support equipment, including oxygen and suction, should be tested to ensure proper functioning. If the nurse were to only check to make sure that the equipment is available, problems could ensue if something functioned improperly at a critical point in patient care. Monitoring equipment should be warmed up and calibrated, if necessary. Medications should be available, and determination of proper dosing should be precalculated. Reversal medications should be readily available; drawing an initial dose of the reversal agent is a wise and prudent move. These drugs can be drawn and the syringe labeled for future reference. In addition, medications used for advanced cardiac life support should be readily available.

Table 3: SUGGESTED EQUIPMENT LIST

Standard Equipment

Oxygen delivery system

Method to summon help

Cardiac monitoring system

Policy and Procedure Manual readily available

Pulse oximeter

Documentation forms

Blood pressure monitoring device

Emergency supplies (see below)

IV access equipment

Gloves

Medications appropriate to institution

Emergency Airway Supplies

Nasopharyngeal airways (appropriate sizes)

Magill forceps (adult, pediatric)

Oropharyngeal airways (appropriate sizes)

Sterile lubricant

Tongue blades

Suction equipment

Laryngoscope handle

Yankauer suction catheters

MacIntosh blades (appropriate sizes)

Suction catheters (appropriate sizes)

Miller blades (appropriate sizes)

Oxygen supply

Spare lightbulbs

Bag valve mask device (appropriate sizes)

Endotracheal tubes (appropriate sizes)

Stylets (adults, pediatric)

Emergency Support Equipment

Defibrillator

IV tubing

IV catheters (appropriate sizes)

Pediatric burette

Tourniquets

Extension tubing

Gloves

IV fluid

Alcohol wipes

3-way stopcocks

Adhesive tape

Intraosseous needles (pediatric patients)

Syringes (appropriate sizes)

Emergency Medicationsa

Glucose

Dopamine

Atropine

Sodium bicarbonate

Amiodarone

Naloxone

Epinephrine (1:1,000 and/or 1:10,000)

Flumazenil

Lidocaine

Methylprednisolone

Ammonia spirits

aChoice of medications will vary by institution policy.

Source: [6,36]

A well-stocked crash cart should also be available and within easy access in the event of an emergency. A method to summon additional help should be within arm's reach and tested to ensure accurate functioning. It is also important to ensure that all equipment is age-appropriate and size-appropriate for the patient receiving sedation. Standard adult equipment may not be appropriate for a small female; large child sizes may be more appropriate for this patient. It is imperative that this equipment is located and checked to prepare for complications, should they develop.

Many patients scheduled for moderate sedation are undergoing a planned procedure. If this is the case, the patient should have received preprocedural instructions. These instructions should include the patient's NPO status (if any), the time for arrival, the estimated time for procedure performance, and the estimated time for discharge. If the patient will be discharged to the care of a responsible adult, this person should be notified of his/her responsibilities and time for arrival (if he/she does not accompany the patient to the facility). Additionally, procedure-specific guidelines should be reviewed, including such items as bowel preparations and administration of antibiotics.

Prior to the administration of any sedating agents, the patient should sign an informed consent. Guidelines note that the risks, benefits, and limitations of moderate sedation, as well as possible alternatives (no sedation), should be discussed with patients, enabling them to make an informed decision [37]. If a patient is undergoing a scheduled procedure, this may have been accomplished at the time of preprocedural patient teaching; if the patient is undergoing an emergent procedure, this may have been accomplished during registration in the emergency department. In either case, a separate consent is not necessary [4]. However, informed consent should be present and complete prior to beginning the procedure. It is often the nurse's responsibility to ensure its placement in the patient's chart.

One immediate presedation responsibility includes establishing IV access in the patient receiving IV sedation. (This is a controversial area in the arena of transmucosal sedation and will be addressed at a later point in this course.) If the patient was not NPO, as is the case in emergent patients, medications to decrease gastric contents and stomach acid should be administered. These drugs will help reduce the risk and complications of aspiration, one of the most prevalent complications of moderate sedation. Metoclopramide will speed passage of gastric contents into the bowel, thus reducing gastric volume. The histamine antagonists cimetidine, ranitidine, and famotidine will increase gastric pH, thus reducing complications, should the patient aspirate gastric contents into his or her pulmonary tree.

The Joint Commission requires that heart rate and oxygenation be continuously monitored by pulse oximetry in all patients undergoing moderate sedation [1]. If the patient is to receive supplemental oxygen therapy, a pulse oximetry reading on room air should be documented. After oxygen therapy is initiated, another pulse oximetry reading should be obtained.

The results of all elements of the preprocedure assessment should be clearly documented before sedation is started. A final set of presedation vital signs should be obtained as baseline measures, and the patient's level of consciousness should be evaluated and documented before initiation of sedation. In addition, the patient's name, birth date, and procedure should be confirmed prior to initiating sedation [4,38].

Importance of Effective Communication

Because the history and informed consent are vital components of the preprocedure process and integral to patient safety and satisfaction, effective communication is key. Among the most important factors for effective communication are knowledge of the language preference of the patient, an awareness of the patient's health literacy level, and an understanding of and respect for the patient's and family's cultural values, beliefs, and practices (referred to as cultural competency) [39]. When the nurse and the patient speak different languages, the use of family members and/or friends as interpreters should be avoided if possible, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [40]. Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (e.g., untrained staff members, family members, friends) facilitates a broader understanding, leads to better outcomes, and is better aligned with patient preferences [41,42,43].

CARE DURING SEDATION

During sedation, the two most important responsibilities of the nurse are to ensure patient safety and monitor the patient's level of sedation. Documentation should be performed throughout the procedure as a record of patient care [44].

Throughout the sedation period, the nurse should remain with the patient at all times. There should be no other responsibilities for the nurse; assisting with the procedure should not be an expectation. It is imperative that all persons involved with moderate sedation be aware of this requirement. The nurse should never be asked to help out "just this once," thus compromising patient safety. The policy and procedure manual for moderate sedation delivery should clearly delineate the nurse's responsibilities and the right to refuse additional tasks during this period.

Evidence Based Practice Recommendation

The American Society of Anesthesiologists recommends that periodic assessment of airway patency, respiratory rate, and oxygen saturation be done during emergence and recovery, with particular attention given to monitoring oxygenation and ventilation.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

While the patient is receiving and recovering from sedation, the nurse should judiciously monitor the patient's airway [44]. It is the nurse's responsibility to ensure that during sedation, the patient's spontaneous ventilation is maintained without intervention [1]. Should the patient's level of consciousness deepen to the point that the airway is compromised, the physician should be informed and measures undertaken to reverse the effects of this untoward complication.

The patient may have supplemental oxygen supplied, although the use of prophylactic oxygen therapy is a debatable issue. Many institutions require that all patients undergoing moderate sedation have supplemental oxygen used throughout the sedation period. Other policies require that supplemental oxygen be applied if or when the patient's pulse oximetry reading drops to an unacceptable level, generally ranging from 90% to 94%. The ASA guidelines note that supplemental oxygen should be considered for moderate sedation [44].

Oxygen therapy devices are advantageous, but also disadvantageous, for a number of reasons. First and foremost, supplemental oxygen helps assure that the patient's oxygen level is adequate. However, the use of sedation medications blunts the response to falling levels of oxygen; thus, the patient may not institute compensatory measures during this period. Additionally, the application of oxygen therapy devices may be confining and can actually increase the patient's level of anxiety, which would be counterproductive to the objective of sedation. Whenever using oxygen therapy, it is imperative that the patient be educated regarding its use and purpose.

Oxygen therapy devices used in moderate sedation range from the simple (e.g., nasal cannula) to the more complex (e.g., non-rebreather and Venturi masks). The nurse caring for the patient should understand the importance of the proper application of each device used. For example, the flow rate on the simple face mask should be, at a minimum, 5 L/min. If the oxygen flow rate were less than 5 L/min, carbon dioxide (CO_2) could accumulate within the mask and the patient would rebreathe this CO_2. This would lead to a respiratory acidotic state with further compromise of the patient's ventilatory status. Table 4 summarizes the various oxygen delivery devices used in the moderate sedation setting, and notations are made about each device.

Table 4: OXYGEN THERAPY DEVICES

Type

Fraction of Inspired Oxygen (FiO_2)

Flow (L/min)

Comments

Nasal cannula

24% to 40%

3–6

Comfortable, only increases O_2 level slightly, inexpensive, high flow rate increases problems

Simple face mask

25% to 55%

5–8

Poorly tolerated if too tight

Face tent

30% to 50%

4–10

Less confining, may provide humidification during long procedures

Nonrebreather mask

40% to 100%

6–15

Mask with reservoir and one-way valves, best noninvasive device, requires tight seal to achieve high %

Venturi mask

24% to 55%

2–14

Adjustable FiO_2

Bag valve mask

up to 100%

10–15

Self-inflating, may increase gastric distention

Source: [45] Reprinted from Litwack K. Post Anesthesia Care Nursing. 2nd ed. St. Louis, MO: C.V. Mosby Co.; 1995. With permission from Elsevier.

During sedation, the patient will be monitored for his/her response to the medications used. If a patient demonstrates restlessness and agitation, the nurse should determine the cause and intervene to reverse any untoward events. Restlessness and agitation should always be considered signs of hypoxemia until proven otherwise. However, it is just as possible that these behaviors are secondary to inadequate analgesia, and further assessment should be performed. If the nurse considers hypoxemia as the primary cause and intervenes appropriately, the risk of further hypoxemia is eliminated.

Vital signs may be assessed as frequently as every five minutes and should also be assessed at one minute after each additional dose of IV sedative. This will ensure the recognition of developing cardiovascular and respiratory complications secondary to medication administration. It is also prudent to assess the patient's airway with each vital sign assessment and ask the patient to take a deep breath (unless contraindicated by the procedure). This will ensure safe patient care delivery throughout the procedure.

An additional concern during sedation is the accumulation of secretions in the airway. Certain medications (e.g., ketamine) are more likely to produce secretion formation, and the nurse should maintain constant vigilance of the airway to prevent airway obstruction. Suction should be done using a Yankauer-type device.

Finally, to ensure that the goals of sedation are being met, the nurse should assess the patient's level of consciousness and, again, document this throughout the procedure [4,33,44]. Although several scales and scoring systems have been developed to describe the level of consciousness, none are ideal. The sedation scale should be developed to decrease observer bias. The patient should be able to be assessed by a number of different individuals at the same time and receive the same score with each assessment. The scale should have graded changes that reflect different sedation levels, and similar changes should be noted with different sedating agents. The patient should experience no pain or discomfort, and the scoring should be noninvasive. Furthermore, the scale should be easy to use, interpret, and record.

One recommended tool is the Modified Observer's Assessment of Alertness/Sedation Scale (Table 5) [38]. The patient's response to verbal commands should be monitored routinely, except for patients who are unable to respond (e.g., young children, mentally impaired individuals) or during procedures in which the lack of patient movement is essential [18,28]. For situations in which a verbal response is not possible (e.g., upper endoscopy), the patient and the nurse who is monitoring should determine hand signals before sedation is administered.

Table 5: MODIFIED OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION SCALE

Responsiveness

Score

Agitated

6

Responds readily to name spoken in normal tone ("alert")

5

Lethargic response to name spoken in normal tone

4

Responds only after name is called loudly and/or repeatedly

3

Responds only after mild prodding or shaking

2

Does not respond to mild prodding or shaking

1

Does not respond to deep stimulus

0

Source: [38] Reprinted from Cohen L, Delegge MH, Aisenberg J, et al. AGA Institute review of endoscopic sedation. Gastroenterology. 2007;133(2):676-701. With permission from Elsevier.

Other commonly used scales include the Ramsay Sedation Scale, the Sedation-Agitation Score, the Richmond Agitation-Sedation Scale (RASS), and the Motor Activity Assessment Scale. All of these scales were developed for use in a variety of settings, including the ICU. The Ramsay Sedation Scale (Table 6) was developed for ICU patients and is one of the scoring systems most widely used during moderate sedation [46,47]. The desirable level of sedation using the Ramsay Sedation Scale is a level of 2 or 3; however, upon inspection of this scoring system, clarity is lacking between these two levels [6]. Many documentation forms use the Modified Aldrete Score for assessing the patient's level of functioning; however, this score was developed for monitoring the patient's readiness for discharge and is not recommended as a method of assessing the patient's level of sedation during the procedure. Other scoring systems exist, some of which include recommendations for frequency of drug administration [6].

Table 6: RAMSAY SEDATION SCALE

Score

Response

1

Patient anxious, agitated/restless, or both.

2

Patient is cooperative, oriented, and tranquil.

3

Patient responds to commands only.

4

Patient exhibits brisk response to light glabellar tap or loud auditory stimulus.

5

Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus.

6

Patient exhibits no response.

Source: [47]

POSTSEDATION CARE

After administration of the sedation medication is complete, patient monitoring should continue until the patient achieves his/her presedation level of consciousness and functioning. The ASA recommends that monitoring continue until the patient is near the baseline level of consciousness and is no longer at increased risk of cardiorespiratory depression [44]. If the patient is to be transferred to a separate recovery area, the nurse administering the sedatives should accompany the patient to the recovery area and give a complete, concise report to the nurse responsible for further patient care. This report should include information regarding the respiratory, circulatory, and neurologic function of the patient before and during the procedure. Measures to control the patient's pain should be shared, as well as the time and effectiveness of pain medications.

Other important items to reference in this report include the total amount of sedative drugs received and the time of reversal agent administration, if given. Information on any untoward complications should be provided, as well as measures undertaken to correct these problems. The patient's fluid status may be important to share, as knowledge of the patient's ability to take oral fluids or to void will impact the length of time for recovery. Finally, a preprocedural level of functioning should have been documented so that discharge can be based on these findings.

During the postsedation period, the patient's vital signs and pulse oximetry readings should be assessed on a regular basis. The time frame for these assessments can vary, depending on the drug, the route, the amount of drug received, and the time since the last dose. Generally, vital signs and pulse oximetry readings are obtained on a 15-minute cycle until stable and then on a regular basis until the time of discharge.

The patient may need reorientation to time and place. The amnesic effects of many of the medications administered will prevent the patient from remembering certain facts about his/her surroundings. As the medications wear off, the patient will need less reorientation.

Another measure that may be necessary in the postsedation period is limitation of stimuli to the patient. The risk of untoward reactions increases with certain medications (e.g., ketamine) and with certain forms of stimuli (e.g., loud noises). Limiting these exposures will ensure a safe, comfortable arousal for the patient.

Discharge of the patient after sedation is a critical part of postsedation care. There are a number of variables that affect discharge of the patient. Most critical is the location and type of the unit to which the patient will be transferred. Many patients are discharged to home, and care of the patient should be well-delineated so that both the patient and the caregiver are comfortable with the expectations of the remaining recovery period.

Other factors that impact discharge of the patient include the type of procedure performed, the type of monitoring used during the procedure, the type and amount of medication received, the patient's preprocedure health status, and the development of any complications. Many of the procedures performed under moderate sedation are those in which rapid recovery and discharge of the patient is an expectation. If a procedure is expected to be lengthy and requires in-depth monitoring and postsedation care, the patient may not be considered a candidate for moderate sedation provided by nursing staff. This decision is made during the presedation assessment.

Typical discharge criteria require that the patient return to his/her preprocedural status. The patient should have adequate respiratory function and stable vital signs. The preprocedural level of consciousness should be reached, without the risk of resedation and a return to a decreased level of functioning. Intact protective reflexes, including gag reflex, are imperative. The patient should have his/her pain under control, and the procedural site should be stable, without evidence of bleeding or other complications. Many facilities also delineate a time period since last receiving medications as a parameter for discharge. Finally, if a patient is to be discharged to home, a responsible adult caregiver should be present to accompany the patient [38,44]. If the patient is a child who still uses a car seat, the American Academy of Pediatrics (AAP) suggests that at least two adults be available to take the child home, so one adult can sit with the child while the other drives [33]. Parents should be told that the child is at risk for airway obstruction if his or her head falls forward while in the car seat [44].

A number of discharge scoring systems are used to assist the staff with identifying patients who are ready for discharge, but there are no established standard discharge criteria; healthcare facilities should establish their own standardized criteria [33,38,44]. The scoring system should provide objective, measurable parameters for the patient to attain (e.g., stable vital signs, alert/oriented status, patent airway, adequate pain control) and should identify the score for discharge. The patient should meet the appropriate criteria to achieve that score [38,44].

One of the most commonly used discharge scoring systems is the Modified Aldrete Score (Table 7). This scoring system is used on a daily basis by postanesthesia care nurses working with ambulatory patients. The easy-to-use, simple scoring mechanisms are very useful for patients undergoing moderate sedation. A score of 18 or higher indicates a patient's readiness for discharge [48,49].

Table 7: MODIFIED ALDRETE SCORE

Domain

Criteria

Score

Activity

Able to move four extremities voluntarily on command

2

Able to move two extremities voluntarily on command

1

Able to move no extremities voluntarily on command

0

Respiration

Able to breathe deeply and cough freely

2

Dyspnea or limited breathing

1

Apneic

0

Circulation

Blood pressure (BP) + 20 of preanesthetic level

2

BP + 22–49 of preanesthetic level

1

BP + 50 of preanesthetic level

0

Consciousness

Fully awake

2

Arousable on calling

1

Not responding

0

Oxygen saturation

Able to maintain O_2 saturation >92% on room air

2

Needs oxygen inhalation to maintain O_2 saturation >90%

1

O_2 saturation <90% even on oxygen supplement

0

Dressing

Dry

2

Wet, but stationary

1

Wet, but growing

0

Pain

Pain free

2

Mild pain

1

Pain requiring parenteral meds

0

Ambulation

Able to stand up and walk straight

2

Vertigo when erect

1

Dizziness when supine

0

Fasting/feeding

Able to drink fluids

2

Nauseated

1

Nausea and vomiting

0

Urine output

Has voided

2

Unable to void, but comfortable

1

Unable to void, but uncomfortable

0

Source: [48] Reprinted from Aldrete J. Discharge criteria. Bailliere's Clin Anaesthesiol. 1994;8(4):763-773. With permission from Elsevier.

Other similar scoring systems are the Post-Anesthesia Discharge Scoring System (PADSS) and the Modified Post-Anesthesia Discharge Scoring System (MPADSS) [50,51,52,53]. These systems have a maximum total score of 10; a patient with a score of 9 or greater is considered fit for discharge [53]. It is important to remember that whichever type of scoring system is used, individual patient requirements should be met to ensure a safe, continued recovery following discharge. Additionally, this score should be incorporated into the documentation record for the patient.

Discharge criteria are used in almost all environments in which moderate sedation is administered; however, these criteria are not without controversy. It is important for facilities to regularly review and update discharge criteria to ensure that current guidelines are being followed. The typical criteria of stable vital signs with a return to presedation values may not be attainable in all patients. Patients with a history of hypertension may not reach their "normal" systolic blood pressure due to the vasoactive effects of the sedating agents used. It may require 24 hours for the patient's vital signs to return to their presedation level. However, this should not prevent this patient from being discharged.

Although the ASA recommends that a mandatory minimum stay not be required, many facilities have a typical time requirement of 30 to 60 minutes after the last sedative dose and/or two hours after the last reversal dose as criteria for discharge [44]. Many healthy adult patients may awaken much faster than this, especially if the total sedative dose was small. On the other hand, elderly patients may need more time for monitoring, as circulation times are slower and the risk of slow release of sedative from the fatty tissue may develop.

The ability to achieve the presedation level of activity may be impossible in a small population. The patient who underwent arthroscopic surgery on a lower extremity and is now required to use crutches for ambulation will not achieve his/her presedation level of activity for a number of weeks.

The absence of nausea and vomiting is often used as a criterion for discharge; however, it should be recognized that certain procedures and medications may increase nausea (and possibly vomiting) for prolonged periods of time. For example, intravenous ketamine may cause vomiting in children for up to two hours after administration. Ensuring a good intact gag reflex so that the child can protect his/her airway is critical in this population. However, keeping the child for an extra two hours for monitoring is generally not accepted, either by parents or staff.

An additional discharge requirement may be to ensure that the patient has taken fluids orally; however, many facilities have eliminated criteria related to the ability to eat or drink before discharge, and the ASA states that this requirement may only be necessary for select patients [38,44]. The problem of using oral fluid intake as a criterion for discharge is that many patients will willingly force fluids so that they may leave the facility. This may be done even though it is not in the best interest of the patient. As an example, patients who are experiencing bouts of nausea may drink fluids just so they can go home. This intake of fluids may be all that is necessary for the patient to vomit, which may, in turn, delay the patient's discharge. The requirement that all patients drink clear fluids prior to discharge has also been eliminated for many patients [44]. Guidelines recommend that toleration of fluids should only be required for specific populations, such as diabetics [44,50]. Patients who are discharged prior to taking fluids should be advised to start drinking clear liquids when they feel ready.

Evidence Based Practice Recommendation

The American Society of Anesthesiologists states that the routine requirement for urination before discharge should not be part of a discharge protocol and may only be necessary for selected patients.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Although it continues to be included in the Modified Aldrete Score, the requirement that all patients void prior to discharge has not been supported by research, and it may lead to delays in patient discharge. As such, many facilities have eliminated this requirement [38,44,50,54]. Assessment of urine output is useful in detecting some postoperative complications, and patients who are at high risk of urinary retention are generally required to void prior to discharge [44]. This includes patients who have had pelvic or genitourinary surgery, rectal or urologic procedures, hernia repairs, perioperative urinary catheterization, a history of urinary retention, or neuraxial anesthesia [50]. However, patients without an urge and no evidence of bladder distension (as shown by ultrasound) may be exempt from the voiding criteria [50,54]. Patients who do not void prior to discharge should be given clear instructions on seeking medical attention if they remain unable to void eight hours after discharge [50].

Discharge criteria are simply measures that provide the practitioner with some parameters for discharge. Each individual patient should be evaluated based on a number of considerations, not just on meeting the outlined criteria [44]. It is the practitioner's responsibility to ensure patient safety at the time of discharge, and this should be documented in the patient's chart at the time the patient leaves the facility. If a patient is unable to meet the required discharge criteria but is discharged, these discrepancies should be noted in the patient chart at the time of discharge.

Prior to leaving, the patient and caregiver should receive postprocedural instructions (Table 8). These should be provided both verbally and in writing [38,44,55]. The instructions should be reviewed with the patient and caregiver, and a signed copy of these instructions should be included in the patient's chart. It is important to remember that not all patients go home immediately after sedation; many are returned to their nursing unit. The same type of discharge instructions provided to the patient and caregiver should also be given to the staff assuming care of the patient in a nursing unit. It cannot be assumed that the floor nursing staff fully comprehends the postsedation care required for moderate sedation recovery.

Table 8: SAMPLE DISCHARGE INSTRUCTIONS

Today you received medications to make you sleepy during your procedure. The medications you received are: _____________________________________________________________________________________________.

The following items are recommendations for your care during the next 24 hours.

1. Do not drive or operate heavy machinery for 8 to 24 hours.

2. Do not consume any alcoholic beverages for 24 hours.

3. Do not make any important decisions for 24 hours.

4. Describe pain management plan and medication use (if appropriate): You will experience pain for the next few hours (or specific time frame). Your doctor provided you with the name of medication to take every three to four hours for pain. If you did not receive pain medications, you can take... (List over-the-counter medications and instructions for use).

5. You may resume your regular diet unless instructed otherwise. If you feel sick to your stomach, you may begin with clear liquids and add items as you feel ready.

6. It is best to rest the remainder of the day.

7. Describe surgical site management (if appropriate).

8. If you are unable to reach your physician, you can call the emergency room at 555-5555.

(Note: These should be provided in written format and signed by the patient and caregiver.)

Source: [56] Reprinted from Odom J. Conscious sedation in the ambulatory setting. Crit Care Nurs Clin North Am. 1997;9(3):361-370. With permission from Elsevier.

Information to include in discharge teaching includes postprocedural diet, level of activity, postprocedural care (e.g., wound care, dressing changes), and patient follow-up for both emergency and normal care. If medications are given, the purpose, name, dosage, route, frequency, duration of use, and significant or expected side effects, if any, should be explained. It is also helpful to provide the patient with the name of the sedating agent(s) that he/she received. If the patient needs to contact someone for further information or emergency treatment, this information may be invaluable.

Discharge instructions provided to the patient should be reiterated to the responsible caregiver who is accompanying the patient from the facility. This individual should understand the importance of following instructions, whether it is to awaken the patient on a regular basis or monitor the patient's procedural site. The caregiver should be instructed how to obtain assistance in the event of an emergency.

As mentioned previously, providing discharge information during the presedation period will assist the patient with remembering and complying with the instructions provided. A patient in the postsedation period may remain slightly amnesic and many items may be forgotten. Reinforcing these instructions both prior to the procedure and in written format following the procedure will help to ensure good patient compliance.

Finally, postprocedural follow-up, in the form of a telephone call, can help improve future patient care. This telephone call should be placed within 24 hours of the patient's discharge and ascertain that the patient is safe and fully recovered from the effects of the medications administered. Information to obtain may include the incidence of complications related to the sedation and/or procedure, recovery time, adequate pain management, compliance with instructions, and patient satisfaction. This information should be recorded and evaluated on a regular basis. Compiling this information will allow for identification of trends in care and measures that can be instituted to improve care, if necessary.

3. PHARMACOLOGY AND DRUG ADMINISTRATION

Medication administration for moderate sedation incorporates a number of issues. The choice of medication(s) depends on the type of procedure being performed and the estimated length of the procedure. The route of administration should be chosen for its efficacy, patient compliance, and method of action. The method of administration depends on the agent being administered, the route of administration, and the actions desired. Unfortunately, there is no one perfect agent that will meet these criteria.

The ideal moderate sedation agent should be one that is rapid acting with limited cardiorespiratory effects. A titratable medication would allow the practitioner to administer drugs in which the length of action is equal to the length of time required for sedation. Providing both analgesia and sedation would be beneficial in many situations and for many procedures. Furthermore, this ideal agent would be eliminated expeditiously for rapid return to the presedation state. And if complications were to occur, a drug that is readily and easily reversed would be optimal.

Because this drug does not exist, the following discussion will focus on the advantages and disadvantages of the routes and methods of administration and on the classes of medications.

ROUTE OF ADMINISTRATION

Transmucosal and intravenous moderate sedation produce sedation in the patient through somewhat different pathways. Most commonly, transmucosal administration includes oral, sublingual, and rectal administration. Other forms of administration include intramuscular, inhalation, subcutaneous, and topical administration. Intravenous sedation will be addressed separately.

Oral administration of moderate sedation agents is safe, economical, and convenient. It is accepted by many patients; however, it does require patient cooperation to ensure adequate drug delivery. Absorption from the oral route generally occurs in the small intestine secondary to its thin lining and large surface area. Thus, drugs must pass through the stomach and into the small intestine. Their absorption is dependent upon blood flow to these organs, the state of the drug (i.e., liquid or solid), and the contents of the gastrointestinal tract. Drug degradation may occur secondary to digestive enzyme activity, consequently limiting the dosage reaching the central circulation. Additionally, the practitioner should consider the level of the patient's anxiety; high levels of anxiety can delay gastric emptying time, delaying onset of action.

Oral administration may precipitate emesis in some patients, especially if the agent is foul tasting and/or smelling. This increases the risk of aspiration and should always be considered when preparing the patient and resuscitation equipment. Additionally, many drugs administered orally go through what is termed "first-pass effect." Once in the vascular space, drugs that are absorbed from the stomach and/or small intestine first pass through the hepatic circulation, where hepatic metabolism occurs. Hence, the amount of the drug undergoing first-pass effect that reaches the central circulation is lower than the actual dose administered by the oral route. Many drugs exhibit this first-pass metabolism; therefore, drug dosing for the oral route is frequently larger on a milligram per kilogram basis.

Sublingual administration is a convenient and easy method of drug delivery. With the advent of oral transmucosal fentanyl, sublingual administration is becoming more commonly used in the pediatric population. The advantage of this route is that no first-pass effect occurs; the blood supply from the oral cavity drains directly into the superior vena cava. The disadvantages are that sublingual absorption requires highly lipid-soluble drugs and patient cooperation. If a patient chews a medication that is to be administered via oral mucosa (e.g., a lozenge), absorption is compromised and total drug dosing is difficult, if not impossible, to calculate.

Another route that is becoming more frequently used is intranasal administration. Some medications can be mixed in normal saline and instilled into the nasal passage. This method is most frequently used when administering midazolam to pediatric patients. The patient rapidly achieves maximum effect, and the length of action is short. The disadvantages include the limit on the volume of medication that is tolerated by this route and the risk of the patient swallowing the medication, thus converting absorption to the oral route. Additionally, the patient may sneeze with this technique, and the volume of medication received is imprecise.

Rectal administration is used in a number of situations. Many adult patients find this route distasteful; however, it is used frequently with the pediatric population. It is also a useful route for patients experiencing significant nausea and vomiting. Drug absorption through the rectal wall is somewhat dependent on where the drug is actually deposited. If the drug is deposited into the proximal rectum, first-pass effect may occur. If the drug is deposited into the distal rectum, the drug will bypass hepatic circulation, thus avoiding the first-pass effect [57]. It is difficult to assess the patient's rectal anatomy to ensure proper placement of the drug. Furthermore, if the drug is irritating to the lining of the rectum, the patient may expel the drug prior to its absorption, hindering drug dosing.

As noted, rectal administration is used most commonly in the pediatric setting. This route provides practitioners with the ability to initially sedate a scared and/or combative child prior to insertion of an IV line.

Administering medications via the intramuscular route is often rejected by patients, if given the choice. Intramuscular injections can cause pain and irritation of the tissues. Intramuscular absorption is dependent on blood flow to the muscle, and the onset of sedation can be quite rapid if blood flow is adequate. However, if blood flow is compromised, onset is slow and length of action may be prolonged as the drug stays sequestered in the muscle and is slowly released. Despite these disadvantages, certain medications, such as ketamine, are being administered more frequently by this route. One complication of intravenous ketamine use is emergence excitement, the incidence of which is greatly reduced with intramuscular or oral administration [58]. Emergence reactions also may be reduced by pretreatment with a benzodiazepine, use of ketamine at the lower end of the dosing range, and minimizing verbal and tactile stimulation of the patient during the recovery period [59].

Inhalation administration is currently limited to the use of nitrous oxide due to the fact that sedation drugs are not prepared in an appropriate form. The inhalation route is easily used, the drugs are rapidly absorbed, and the effects are rapid in onset. Improper use of the inhaler limits the ability to regulate drug dosage, but with minimal teaching, many patients, including children as young as 3 years of age, can be instructed on proper inhaler use. Even children younger than 3 years of age can receive medications by this route, with assistance of the care provider and the use of a spacer device.

Transdermal and subcutaneous administration is generally reserved for sedation and pain management in settings other than moderate sedation. Fentanyl is available for administration in a patch; however, the drug release is slow and the amount of medication is inadequate to achieve the level of sedation desired in moderate sedation settings. Transdermal absorption is dependent on the use of drugs that are lipid soluble, and the dose depends on how much medicine is exposed to the surface skin. Thus, this route is generally not used in the moderate sedation setting.

Finally, moderate sedation may be administered by the IV route. There are a number of controversies surrounding IV and transmucosal routes, and these are addressed in detail later in this course. It is important to remember that intravenous absorption and response is dependent, in part, on circulation times. Intravenous drugs achieve a rapid plasma level and do not undergo first-pass effect. However, the incidence of complications is greater, and these complications can occur immediately after IV administration. Intravenous administration requires careful monitoring to prevent untoward patient responses. The drugs can be delivered in large volumes and, if given by continuous infusion, provide continuous therapeutic drug plasma levels. All the drugs used for sedation are available in the intravenous form and administered by this route in very large numbers.

ADMINISTRATION OF INTRAVENOUS MEDICATIONS

Methods of administration of IV medications include single-dose injection, bolus technique, continuous infusion technique, and drug combination therapy. Each method has distinct advantages and disadvantages, and certain drugs can only be administered by one technique.

Single-dose injection is also known as "titration to effect." The patient is given frequent, small doses of the medication, and the effects are monitored prior to further drug administration. This method requires that the practitioner monitor the patient's vital signs and level of sedation after each drug dose and titrate subsequent doses based upon these responses. Single-dose injection provides for better control of the amount of drug delivered, although repeated doses may prolong the patient's recovery time. Additionally, this route requires more nursing time in order to prepare the drug, administer the drug, and monitor the effects. Yet, it is one of the safest methods for drug delivery. The risk of oversedation or undersedation is minimal.

The bolus technique is the administration of the entire dose, or a large percentage of the drug, all at once, causing a rapid onset of action and allowing the drug to reach a therapeutic level very quickly. Deep, rapid sedation is more common, and the risk of respiratory depression increases. The major disadvantage of this method is that the length of action of the drug may be shorter than the procedural time, causing the patient to be inadequately sedated toward the end of the procedure. Another predicament that may develop with the bolus technique is a rapid onset of complications. This is most often seen with the rapid administration of high doses of fentanyl. Chest wall rigidity develops in these patients, rendering the patient unable to breathe. Efforts to support ventilations are difficult, if not impossible, and the patient must be administered a neuromuscular blocking agent, such as succinylcholine. The patient is then paralyzed for a short period of time, and ventilatory assistance must continue until the return of ventilatory function. In addition, naloxone should be administered to reverse the effects of the narcotics. This complication can be completely avoided with proper drug dosing and drug delivery techniques.

Continuous infusions are advantageous in that they provide a constant plasma level of the drug. Recovery time is often shorter, and the individual begins to awaken as soon as the drug is discontinued. Propofol is administered by this route, as its extremely short length of action makes other methods and routes impractical. This technique does require constant vigilance of the infusion to ensure adequate drug dosing and prevent accidental overdose.

Finally, combination drug therapy may be used. Most commonly, opiates and benzodiazepines are combined to achieve an appropriate level of sedation and pain control. As to be discussed next, benzodiazepines do not provide analgesia, and for any procedure that is painful, another agent should be used. A possible disadvantage of drug combinations is the synergistic, cumulative effects of drugs, producing the risk of profound, deep sedation. The likelihood of side effects increases, and the risk of cross reactions exists. However, with drug combination therapy, the goals and objectives of moderate sedation can be achieved with proper drug dosing.

4. DRUG CLASSES AND MEDICATIONS

The medications used for moderate sedation provide a number of different actions. Medication choice should be made with consideration of a number of factors, including the actions of the drugs, their relative length of action, and the bioavailability of each drug. The two most common medications administered for moderate sedation are midazolam and fentanyl. These drugs, as well as many others, are included in the following discussion. The reader is referred to Table 9 for drug dosing.

Table 9: PHARMACOLOGY OF MODERATE SEDATION MEDICATIONS

Agent

Onset

Peak

Duration

Antagonist

Half-Life

Usual Dosea

Notes

Benzodiazepines

Midazolam (Versed)

IV: 3–5 mins

IM: 5–15 mins

Intranasal: <5 mins

PO: 10–20 mins

IV:3–5 mins

IM: 30–60 mins

Intranasal: 10 mins

PO: 2–6 hrs

IV: <2 hrs

IM: 1–6 hrs

Flumazenil

1–4 hrs

0.5–2 mg over 2 mins, Max 5 mg

(Do NOT exceed 2.5 mg as initial dose or 1.5 mg initially in elderly)

Pediatric doseb:

IV/PO: 0.25–0.5 mg/kg

IM: 0.1–0.15 mg/kg

Nasal: 0.2–0.4 mg/kg (not an approved route)

Give slowly. MR every 5 mins w/0.5 mg; can be given by infusion. Adolescent/pediatric patients may exhibit paradoxic excitement. Decrease dose by 30% (50% in the elderly) if patient is taking other narcotics or CNS depressants.

Diazepam (Valium)

IV: 1–5 mins

PO: 15–60 mins

IV: 1 min

IV: 2–4 hrs

Flumazenil

20–50 hrs

2–10 mg, Max 20 mg

Pediatric dose:

IV: 0.2–0.3 mg/kg/dose

PO: 0.2–0.3 mg/kg/day (Max 10 mg)

MR at 5–10 min intervals w/1 mg.

Increased half-life in neonates, elderly.

Lorazepam (Ativan)

IV: 2–3 mins

IM: 20–30 mins

Up to 2 hrs

6–8 hrs

Flumazenil

10–20 hrs

0.05 mg/kg, Max 2 mg IV, 4 mg IM

Pediatric dose: 0.02–0.09 mg/kg

MR at 5–10 min intervals for prolonged sedation, used in critical care setting.

Opioids (Narcotics)

Fentanyl (Sublimaze)

IV: 1–3 mins

IM: 7–8 mins

TM: 5–15 mins

IV: 5–15 mins

IM: 15–20 mins

TM: 15–30 mins

IV: 30–60 mins

IM:1–2 hrs

TM: 12 hrs

Naloxone

2–4 hrs (longer with TM route)

25–100 mcg IV

Pediatric dose: IV/IM: 0.5–2 mcg/kg/dose

TM: 5–20 mcg/kg

MR 25 mcg every 5 mins.

Give slowly to prevent chest wall rigidity.

Apnea may occur.

Morphine

IV: 5–10 mins

IM: 10–30 mins

PO: 20–40 mins

IV: 10–20 mins

IM: 30–60 mins

PO: 1–2 hrs

IV: 1–4 hrs

IM: 4–5 hrs

PO: 4–24 hrs

Naloxone

2–4 hrs

2.5–10 mg IV slowly

Pediatric dose:

IV: 0.05–0.1 mg/kg

IM: 0.15–0.3 mg/kg

MR 2–5 mg every 5 mins.

Give slowly.

Assess patient's pain level, hypotension, nausea and vomiting.

Meperidine (Demerol)

IV: 2–5mins

IM: 10–15 mins

PO: 10–15 mins

IV:5–7 mins

IM: 35–60 mins

PO: 1 hr

2–4 hrs

Naloxone

2.5–4 hrs

25–50 mg IV over 2 mins, Max 150 mg

Pediatric dose: 1–2 mg/kg/dose

MR 10–15 mg every 5–10 mins.

Use with caution in patients with liver disorders; avoid use in patients with renal impairment. Do not use in patients taking MAO inhibitors.

Remifentanil (Ultiva)

IV:1–3 mins

3–5 mins

Dose dependent,5–15 mins after discontinuing drug

Naloxone

10–20 mins

1 mcg/kg IV bolus followed by an infusion of 0.1 mcg/kg/min titrated for effect

Assess patient's pain after procedure secondary to short length of action.

Sedative Hypnotics

Propofol (Diprivan)

IV: 30–60 secs

1 min

3–10 mins

None

4–7 hrs

Initial: 2–2.5mg/kg

Maintenance: 100–200 mcg/kg/min

Pediatric dose:

Initial: 1–2 mg/kg

Maintenance: 125–300 mcg/kg/min

May cause hypotension, bradycardia, or respiratory depression.

Etomidate (Amidate)

30–60 secs

1 min

3–5 mins

None

2–3 hrs

Initial: 0.1 mg/kg over 30–60 secs

Maintenance: 5–20 mcg/kg/min

Solution may cause pain on injections. Preadministration of lidocaine may be considered.

Chloral hydrate

15–30 mins

30–60 mins

1–2 hrs

None

8–11 hrs (longer in neonates)

500–1,000 mg, Max 2 g/day.

Pediatric dose: 50–75 mg/kg/dose

Induces sleep 1–4 hrs. Monitor airway, O_2 saturations. Sedation failure increases with age. Best used in children younger than 3 years of age.

Dissociatives

Ketamine (Ketalar)

IV: 30–60 secs

IM: 3–4 mins

IV: 1 min

IM/Rectal: 12–25 mins

PO: 30 mins

Intranasal: 10–14 mins

IV:5–10 mins

IM: 12–25 mins

Intranasal: Up to 60 mins

None

10–15 mins

IV: 0.5–1 mg/kg

IM/Rectal: 2–5 mg/kg

PO: 4–6 mg/kg

Pediatric dose:

IV:1–2 mg/kg/dose

IM: 4–5 mg/kg/dose

May cause emergence reactions, including vivid dreams, hallucinations, or delirium.

Barbiturates

Methohexital (Brevital)

IV: 30 sec

Rectal: 5–15 mins

IV: 45 sec

Rectal: 5–10 mins

IV: 5–15 mins

Rectal: 45–60 mins

None

1–4 hrs

Pediatric dose:

IM: 0.5–1mg/kg of a 5% solution

Rectal: 25 mg/kg of a 1% solution

May cause paradoxical excitement in children and elderly.

Thiopental (Pentothal)

IV: 30–60 sec

IV: 30–40 sec

IV: 5–30 mins

None

3–11.5 hrs

Initial: 3–5 mg/kg

Maintenance: 25–100 mg/kg as needed

Pediatric dose:

Initial: 5–6 mg/kg

Maintenance: 1 mg/kg as needed

Tissue necrosis with extravasation.

Repeated dosing may cause cumulative effects.

Pentobarbital (Nembutal)

IV: 1 min

IM: 10–15 mins

IV, IM: 10–15 mins

IV: variable

None

15–50 hrs

IM: 150–200 mg

Pediatric dose: IV: 2 mg/kg

IV no faster than 50 mg/min. Allow time between IV doses for effect. Monitor for prolonged recovery.

Antagonists

Naloxone (Narcan)

IV: 1–2 mins

IM: 2–5 mins

15–30 mins

30–120 mins

N/A

60–90 mins (3–4 hrs neonates)

0.4–2 mg IV

May titrate for reversal (add 0.4 mg in 10 mL syringe: give 1 mL=0.04 mg)

Pediatric dose: 0.1–2 mg/kg

MR every 1 min to max of 10 mg. Observe for resedation. May not reverse cardiovascular effects. May cause noncardiogenic pulmonary edema.

Flumazenil (Romazicon)

1–3 mins

6–10 mins

1 hr

N/A

40–80 mins

0.2 mg IV over 15 sec, Max 3 mg/hr

MR every 1 min to max 1 mg

Pediatric dose: 0.01 mg/kg over 15 sec, MR every 1 min to max 2 mg

Observe for resedation. Use with caution in patients with a history of benzodiazepine abuse or seizures.

Nalmefene (Revex)

IV: 1 min

IM: 5–15 mins

IV: 2 mins

IM: 1.5 hrs

1–10 hrs (dose dependent)

N/A

12.5 hrs

0.25 mcg/kg, MR every 2–5 mins

Dose >1 mcg/kg has no added benefit

Give over 60 seconds to patients with renal failure.

aUsual dose is a safe dose to begin sedation. Higher doses are frequently administered. The practitioner must be aware that the higher the dose, the greater the risk of complications.

bThe pediatric dose is for children >6 months of age.

MR = may repeat, TM = transmucosal.

Source: [6,59,60,61,62,63]

BENZODIAZEPINES

Benzodiazepines are a class of drugs that is very familiar to most nurses. These drugs are used on a daily basis and have actions that are predictable and meet patients' needs. The benzodiazepines to be included in this discussion include midazolam, diazepam, and lorazepam. Other benzodiazepines used less frequently include triazolam, chlordiazepoxide, and alprazolam.

Benzodiazepines facilitate the inhibitory action of gamma-aminobutyric acid (GABA) in the brain, thus reducing excitatory impulses. The drugs are lipid soluble; however, midazolam is available in a water-soluble suspension. The water-soluble suspension reduces the pain on injection that is experienced with diazepam, which is commonly administered in a propylene glycol suspension. Benzodiazepines are classified by their half-lives as short-acting (e.g., midazolam), intermediate-acting (e.g., lorazepam), or long-acting (e.g., diazepam) [64,65].

Benzodiazepines are frequently used in moderate sedation due to their excellent amnesic properties, including antegrade amnesia. The patient's level of anxiety is reduced secondary to the anxiolytic action. Additionally, the patient may achieve some skeletal muscle relaxation [64,66].

The major effect of these drugs is on the respiratory system of the patient. The patient may develop a depressed ventilatory response to increasing carbon dioxide levels with subsequent falling levels of arterial oxygenation. Each 0.1 mg/kg of midazolam is said to reduce the body's response to rising carbon dioxide levels by 50%. In addition, there is a rise in pulmonary airway resistance. As the patient's level of consciousness decreases, the risk of respiratory insufficiency increases greatly [66,67].

Because the patient's compensatory responses are blunted, carbon dioxide levels will continue to rise and oxygen levels will continue to fall unless additional therapeutic measures are undertaken. It is imperative that the nurse administering these drugs is aware of this risk and continuously monitors the patient's respiratory effort and oxygen saturations. With the development of easy-to-use end tidal CO_2 meters, the practitioner is better prepared to monitor for this developing complication.

Benzodiazepines produce a slight decrease in cardiovascular function. The patient may experience a decrease in peripheral vascular resistance and a subsequent drop in blood pressure and cardiac output. Patients with low cardiac output require slower loading times for benzodiazepines to reduce the risk of profound respiratory and cardiovascular depression [68].

The central nervous system effects include a reduction in cerebral blood flow, a decrease in cerebral oxygen consumption, and an elevation in the seizure threshold. The hypnosis provided by this class of drugs helps achieve the relaxation and amnesia for which these drugs are known.

The benzodiazepines should be used with caution in patients with [68]:

- A history of chronic obstructive pulmonary disease or sleep apnea

- Known cardiovascular depression

- Drug and/or alcohol intoxication

- Liver and/or renal disease

- Difficult airways

Furthermore, precautions should be taken for the very young, elderly, and pregnant or lactating patient. Patients on heparin may experience prolonged bleeding times with midazolam use [69]. Certain medications, including metoprolol, propranolol, and digitalis, will have an increased effect of action. Thus, the patient with a slow heart rate secondary to the negative chronotropic effects of digitalis should be closely monitored for the development of symptomatic bradycardia while receiving any of the benzodiazepines.

All the benzodiazepines used in moderate sedation are 97% to 98% protein bound [59]. This is an important consideration in many elderly patients with decreased protein stores. The less body proteins available, the more free-circulating drug exists. Thus, the effects of action are potentiated. It is recommended that long-acting benzodiazepines not be used in elderly patients due to the increased risk for drug metabolite accumulation resulting in excessive sedation, cognitive impairment, and falls [68,70]. If possible, benzodiazepines should be avoided altogether for this population.

Benzodiazepines have the advantage of being reversible with flumazenil. However, this antagonist should be administered intravenously, which limits its use in patients sedated with benzodiazepines by transmucosal routes. (Further information on flumazenil can be found in the Antagonists section).

Midazolam is a drug that is easily administered by a number of routes (i.e., intramuscularly, orally, rectally, intranasally) [71]. Intravenous administration provides rapid onset of action (i.e., three to five minutes), with a duration of less than two hours. It is easily titrated and associated with less pain at the injection site [59,71]. Intranasal midazolam has become popular as a method of achieving moderate sedation in the pediatric population, although this is an off-label use [59,71,72]. This method may also be used to achieve initial sedation in a child prior to insertion of an IV line. Additionally, midazolam can be administered by continuous infusion. The loading dose is 0.5–2.0 mg/kg over two minutes, which may be repeated every two to three minutes, if needed, for a total dose of no more than 5 mg [59].

Because midazolam can be expensive for sedation by continuous infusion, other benzodiazepines may be preferred to reduce the medication costs. One systematic review found no high-quality evidence supporting the use of midazolam over other medications for preprocedural sedation. The authors also found moderate-quality evidence suggesting that oral midazolam produces less effective sedation than chloral hydrate for children undergoing noninvasive diagnostic procedures [73].

Diazepam

Diazepam is the benzodiazepine to which all others are compared. Its long length of action (i.e., two to four hours) may preclude its use for short-term moderate sedation. However, it has the efficacy of a single-dose injection with good outcomes in many patients. Diazepam may be given intravenously, orally, and rectally. Intramuscular injection is quite painful, and this route is avoided. The half-life of diazepam is long, varying from 20 to 50 hours in healthy adults [59]. The elderly, neonates, and those with severe hepatic disorders are more at risk for prolongation of action, and the dosage administered should be reduced in these populations.

Lorazepam

Lorazepam is an intermediate-acting benzodiazepine with a length of action ranging from six to eight hours [59]. It is a popular drug for prolonged sedation and is frequently encountered in the intensive care environment.

OPIOIDS

Opioids, also referred to as narcotics, bind with specific receptors in the central nervous system. These receptors include the mu, kappa, delta, and sigma subtypes. The actions of each receptor type varies; the mu, kappa, and delta receptors all provide some level of analgesia, while the sigma does not. Additionally, narcotics can produce sedation, and in higher doses, will produce a profound decrease in the patient's level of consciousness and a risk of respiratory arrest [57].

The cardiovascular system is significantly affected by this class of drugs. All narcotics, with the exception of meperidine, produce bradycardia. (Meperidine produces tachycardia secondary to its vagolytic effect.) Blood pressure is affected by this decrease in heart rate; the patient may experience a drop in his/her systemic pressure. Morphine and meperidine also induce the release of histamine, leading to a decrease in systemic vascular resistance [57].

The respiratory system is most affected by the narcotics that release histamine (i.e., morphine, meperidine). This histamine release can produce bronchoconstriction in the patient; thus, these drugs should be used with caution in the patient with a history of asthma. Additionally, opioids depress respiratory rate and volume. As with benzodiazepines, a similar, although not as profound, depressed response to rising carbon dioxide levels occurs. As the dose increases, the risk of respiratory depression and apnea increases [57].

Chest wall rigidity is an uncommon, but life-threatening, complication that can occur with the rapid intravenous administration of narcotics, especially fentanyl. The chest wall muscles become tight, and the patient is unable to be ventilated. To successfully resuscitate the patient, the administration of succinylcholine should be performed rapidly and the patient ventilated with a bag-valve-mask device until the respiratory drive returns. Additionally, naloxone should be administered to combat the effects of the narcotics and repeated if necessary. Obviously, with this development, the goals and objectives of moderate sedation are no longer being met and other actions should be undertaken if the procedure is to be continued [57].

Narcotics also impact the central nervous system by producing an increase in cerebral metabolic rate and blood flow. Intracranial pressure may rise, increasing the risk to the neurologically compromised patient. The vomiting center in the brain may be stimulated. Many patients complain of nausea after administration of these drugs, and some may begin to vomit.

Careful administration of narcotics should be considered in any neurologically compromised patient or any patient with a history of chronic obstructive pulmonary disease, asthma, cardiovascular depression, a difficult airway, or morbid obesity. Patients with symptomatic bradycardia should be placed on a cardiac monitor and continually monitored for the cardiovascular depressive effects of these medications [57].

Fentanyl

Fentanyl is a popular narcotic for moderate sedation due to its short length of action. The patient achieves the benefits of sedation and analgesia but is arousable within a short period of time. The drug can be administered intravenously, intramuscularly, and transmucosally. It is reversible with naloxone. The analgesic activity of 100 mcg of fentanyl is equivalent to approximately 10 mg of morphine [59].

Oral administration of fentanyl is available in lozenge, buccal film, buccal tablet, or sublingual tablet form. Fentanyl lozenges were first developed for use in pediatric oncology and have become a popular and desirable method for achieving moderate sedation in children [74]. The lozenge, film, and tablets all have a premeasured dose of fentanyl and are scored to allow administration of varying dosages. The child should be instructed to suck on the medication; if the child chews it, the medication absorption converts from sublingual absorption to gastric absorption and first-pass effect will limit the amount of drug available [59].

Morphine

Morphine is one of the least expensive and most popular of all the medications used for moderate sedation. Nurses and physicians are comfortable with the actions of morphine, the effects are well known, and untoward complications can be avoided with proper administration. The risk of hypotension is great with morphine secondary to the action of histamine upon the vascular system. Therefore, the patient should be continually assessed during administration for profound cardiovascular depression. With slow titration of the drug, these effects can be negligible.

Meperidine

Meperidine was previously used for its analgesic properties. However, the American Pain Society and the Institute for Safe Medication Practices (ISMP) do not recommend the use of meperidine for its analgesic properties, unless the patient experiences acute pain. If the patient experiences acute pain, it is recommended that treatment with meperidine be limited and used with caution in patients with liver and renal disease [59].

Remifentanil

Remifentanil has a very short length of action that is dose dependent and varies from 3 to 10 minutes [59]. It is important to remember that the length of analgesic action is also short, and the patient should be assessed for adequate pain control after the normal length of action time has been surpassed [75].

Other Opioids

There are several other opioids that may be used to induce moderate sedation. For example, hydromorphone has been found to be safe and effective, with a low risk of adverse effects, such as excessive sedation or respiratory depression [76]. The opioids are popular drugs for a number of reasons, as many practitioners feel comfortable with administering these drugs, and their actions are well defined and predictable. The analgesic properties are the best of any of the drugs used in sedation, and whenever a painful procedure is initiated, these drugs should be at the top of the consideration list.

BARBITURATES

Barbiturates have been available for a number of years, and their actions are well known. Ultra-short-acting barbiturates are used in the moderate sedation setting and include methohexital. Thiopental and thiamylal are no longer available in the United States [77]. Pentobarbital, a short-acting barbiturate, is used in young children undergoing radiologic procedures. These drugs are highly lipid soluble and can become rapidly sequestered in fatty tissues. Repeated doses can lead to accumulation of the drug and subsequent prolongation of the length of action.

The actions of the barbiturates include sedation, hypnosis, and anticonvulsant properties. There is no analgesia achieved with these medications; therefore, their use is limited to interventions that are not painful [59].

One of the most profound effects of barbiturates is the precipitous drop in systemic vascular resistance upon intravenous administration. This decreased resistance leads to a significant drop in blood pressure, compensatory tachycardia, and decreased venous return. The patient with a sensitive cardiovascular system or hypovolemia should be closely monitored during drug administration [59].

Respiratory effects include the development of a decreased ventilatory response to falling oxygen and rising carbon dioxide levels, as seen with the benzodiazepines. If the drugs are administered rapidly intravenously, there is a moment of apparent apnea in many patients [59]. This will often be followed by a large gasping respiration, and then the patient begins to breathe normally and comfortably on his/her own. However, there is a moment when the nurse administering these drugs feels uncomfortable with the ominous feeling of having significantly oversedated the patient. Fortunately, this apparent cessation of breathing is short lived, and by the time the nurse is beginning to act, the patient is breathing again. Regardless, it is one of the scariest moments in the moderate sedation setting.

Methohexital can produce bronchospasms in many patients, especially those with a history of asthma or reactive airway disease [59]. Pentobarbital is most commonly used in the radiology setting when a motionless patient (most commonly a child) is necessary to achieve a good study. Administration of this drug requires vigilant assessment, as airway compromise is a common consequence [59].

Central nervous system effects include a decrease in the cerebral metabolic rate, a decrease in cerebral blood flow, and a subsequent drop in intracranial pressure. In low doses, the barbiturates may cause disorientation or excitement, and the patient should be monitored for these effects [59]. Safety measures should be instituted to protect the patient from harm.

The practitioner should be careful in administering these drugs to patients with [59]:

- Hepatic dysfunction

- Cardiovascular depression

- Hypovolemia

- Seizure disorders

- Chronic obstructive pulmonary disease

- Difficult airways

- Alcohol intoxication

- History of sleep apnea

- Morbid obesity

The use of barbiturates is common in many situations. A barbiturate may be administered as a single-dose injection for a short-term procedure, such as cardioversion. The patient is sedated, cardioverted, and arouses within minutes. In many cases, the patient will be completely unaware that the procedure has been completed upon arousal.

Barbiturates can also be useful in combination drug therapy. A dose of 10–20 mg of methohexital may be added to benzodiazepine administration to achieve further sedation. Care should be used in this setting, as the cumulative sedative effects can be compromising to the patient, producing deep sedation [59].

Another concern with the barbiturates is the significant tissue damage that occurs if the drug extravasates into the local tissues. The pH of this class of drug is very high, leading to profound tissue necrosis at the extravasation site [59]. In this event, the affected area should be immediately infiltrated with 5–10 mg of phentolamine, diluted in 10 mL of normal saline [59]. It is imperative that if barbiturates are being used in a facility, one or two vials of phentolamine are available for this untoward complication.

Finally, it is important to remember that there is no antagonist available for the barbiturates. Any complications that develop should be managed with supportive therapies until the sedative effects are cleared.

OTHER SEDATIVE HYPNOTICS

Sedative hypnotics as a class encompass many agents, the most common being barbiturates and benzodiazepines. An additional two medications, propofol and etomidate, are also used in moderate sedation. These ultra-short-acting agents provide no analgesic effects, and pain management requires concomitant use of analgesic agents [59].

Evidence Based Practice Recommendation

According to the American College of Emergency Physicians, propofol can be safely administered to children and adults for procedural sedation and analgesia in the ED.

https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia

Last Accessed: July 14, 2020

Strength of Recommendation: A (Generally accepted principle for patient care that reflect a high degree of clinical certainty)

Propofol is a sedative hypnotic that is being used more frequently in the moderate sedation setting. It produces a cortical depression of very short action; the patient awakens very rapidly upon discontinuation of its administration. The drug also has an antiemetic effect, although there are no analgesic properties [59]. Propofol produces negative inotropic effects on the cardiovascular system, leading to a significant drop in the patient's blood pressure after administration. This hypotension is associated with a decrease in cardiac output and arrhythmia development [59]. The therapeutic index of propofol is narrow and the risk for deep sedation is high. Therefore, the ASA recommends that patients who receive propofol (by any route) should receive care that is consistent with that required for deep sedation. Additionally, clinicians who administer propofol should be qualified to rescue patients from any level of sedation, including general anesthesia [78]. Propofol has no antagonist [59].

Respiratory system effects include a dose-dependent respiratory depression, progressing to apnea in higher doses [59]. The patient may experience hiccoughs, wheezing, and coughing [59]. While these effects are not life-threatening, they may be very uncomfortable for the patient.

The patient receiving propofol may complain of a headache or appear confused and/or euphoric. There are a small number of reports from patients describing very sexually explicit dreams while sedated with propofol [79]. Some patients may verbalize these sexual fantasies, and many practitioners who have administered this drug can relate tales of patient's fantasies.

The peak effect of propofol can be achieved within one minute and lasts four to eight minutes; thus, the drug is administered by continuous infusion [59]. It is important to remember that special handling of the drug is required to prevent the risk of multi-system sepsis. Propofol is available as an oil-in-water emulsion that contains egg lecithin, glycerol, soybean oil, and very small amounts of preservative. It is recommended that the drug be used and completed within 6 hours if transferred to a syringe or other container prior to administration, and 12 hours if used directly from a vial or prefilled syringe. When preparing the drug, strict aseptic technique should be used [59]. The vial top should be disinfected with 70% alcohol, a sterile vent spike should be used to withdraw the drug, and the medication should be drawn up into a sterile syringe. Once drug administration is completed, the IV solution and IV tubing should be discarded and replaced with new solutions. If the drug is used for continuous sedation (e.g., as used in an ICU), it is recommended that the IV line and solution be changed every 12 hours [59]. Any patient who receives prolonged sedation with propofol should be monitored for developing signs of infection [59].

It should be noted that in 2010 the manufacturer of propofol, Hospira, announced a voluntary recall of the drug to all healthcare professionals [80]. This recall was related to concerns of particulate matter (i.e., subvisible inert stainless steel particles) that would not dissolve in the patient's blood, potentially blocking blood flow. The recall affected propofol that was distributed both in and outside the United States between March 2008 and April 2010. Healthcare professionals were urged to immediately discontinue use of the drug and monitor patients who may have received it [80].

Propofol has also been associated with several iatrogenic infections [81]. Researchers identified 20 propofol-related outbreaks that occurred during 1989–2014. The outbreaks affected 144 patients and resulted in 10 deaths. Contributing factors included reuse of syringes for multiple patients and prolonged exposure to the environment when vials were left open. Some countries have begun adding antimicrobial drugs to the emulsion to prevent further outbreaks, but no comprehensive information exists on the effectiveness of these measures [81,82].

Etomidate is another ultra-short-acting sedative hypnotic used to induce moderate sedation. Intravenous etomidate has a very rapid onset of action, with peak effect reached within one minute [59]. The sedating effect lasts 5 to 15 minutes. Although this rapid onset and duration of action is similar to propofol, administration of etomidate via continuous infusion has been associated with increased morbidity and mortality as a result of its adrenal suppression [59,83]. This effect on adrenal function is dose dependent and cumulative. Therefore, etomidate is only recommended for short-term sedation, and the patient should be monitored for adverse effects [59].

Etomidate has been found to have a relative lack of significant hemodynamic and respiratory effects, making it an appropriate drug for use in patients with unstable heart disease, difficult airways, or asthma [59,84]. Etomidate has been associated with an increased risk for myoclonus and nausea and vomiting upon emergence from sedation [59,85]. Pretreatment with midazolam has been shown to effectively prevent and lessen the degree of etomidate-induced myoclonus [82].

Etomidate's rapid onset and duration and favorable side effect profile make it especially desirable for procedural sedation in emergency situations, particularly for cardioversion, intubation, dislocation or fraction reduction, and abscess incision and drainage [59,85,86]. When compared to propofol in a randomized trial, etomidate showed comparable safety but a lower rate of procedural success and a very high rate of induced myoclonus in 20% of patients [87]. Intravenous etomidate administered after fentanyl has been shown to be effective for short-duration, painful emergency department procedures in children [34].

Another consideration of administration is that both propofol and etomidate are painful on injection. This can be combated by administering lidocaine. Lidocaine administration can precede the propofol or etomidate (the patient is administered 0.5 mg/kg IV) or lidocaine can be added to the IV solution [59].

Propofol and etomidate have no antagonists. However, the advantage of their use is their short length of action. Should a patient develop complications, these are generally short-lived due to the rapid metabolism. Regardless, during this time period the patient should be supported with appropriate therapeutic interventions.

DISSOCIATIVE AGENTS

Ketamine is an agent that "dissociates" the thalamus from the limbic system [59]. The drug produces a cataleptic state, and onset of sedation is noted when nystagmus and an open-eye gaze develops. During administration of ketamine, the individual remains responsive but not always appropriately so.

The drug provides both analgesia and amnesia [59]. Other than the narcotics mentioned earlier, this is one of the few drugs used for moderate sedation that provides for pain control. Another action that may be undesirable in some patient populations is the skeletal muscle movement that can occur. A patient who is required to lie completely still, like those undergoing MRI, should in most cases not receive ketamine for sedation.

Unlike other sedatives, ketamine produces a stimulation of the sympathetic nervous system, resulting in excitation of the cardiac system. This leads to an increased heart rate, cardiac output, and blood pressure. Myocardial oxygen consumption increases; therefore, patients with a history of coronary artery disease, hypertension, or congestive heart failure are not considered good candidates for its use [59].

The benefit of this drug is on the respiratory system, as it produces bronchodilation and has a minimal effect on the patient's respiratory drive. Therefore, this may be the sedative of choice (assuming there are no other contraindications) for the asthmatic patient [59]. Ketamine is commonly used for procedural sedation and analgesia in children. One systematic review of seven studies evaluated the use of intranasal ketamine in 264 children 0 to 14 years of age [88]. In four of the seven studies, intranasal ketamine provided superior sedation to comparators and resulted in adequate sedation for 85% of the participants. Vomiting was the most common adverse effect (occurring in 10% of patients) [88]. Saliva and mucus production are increased, especially in the pediatric patient. These effects are usually tolerable in the adult, but the child may require the administration of an antisialagogue or an anticholinergic agent to help dry these secretions [59]. Prophylactic anticholinergics were once recommended for adults to reduce the risk of airway-related adverse events (by preventing oral secretions), but studies showed no benefit to this prophylaxis [62].

Cerebral vasodilation occurs with ketamine use, leading to an increase in cerebral blood flow, an increase in intracranial pressure, and an increase in cerebral oxygen consumption. Therefore, ketamine use in the patient with a history of intracranial pathologies should be avoided [59].

An additional central nervous system effect is the development of emergence delirium in the patient awakening from ketamine sedation. This complication occurs in approximately 10% to 30% of adults who receive ketamine [62]. These reactions range from vivid dreams to hallucinations and delirium [62]. Because of the risk for emergence reactions, ketamine is not usually used alone in adults [89]. The concomitant use of midazolam may help reduce this risk [59,62]. Benzodiazepines were once recommended to combat emergence reactions in children, but reactions in this population are rare and prophylaxis is no longer recommended [90].

In the emergency department setting, intravenous administration of ketamine is preferred for adults because of the ease of repeated doses and reduced risk for vomiting [90]. In the event of an inadvertent overdose, no antagonist exists and the effects cannot be reversed [91].

ANTAGONISTS

Antagonists, also known as reversal agents, act on the receptors in the central nervous system to reverse the pharmacologic effects of the medications administered. They have no other pharmacologic properties. Generally, their length of action is short, usually shorter than the length of action of the drug being reversed. Thus, administration requires repeat dosing.

Opioids and benzodiazepines both have antagonists available to reverse their actions. Naloxone is the opioid antagonist, and flumazenil is the benzodiazepine antagonist [59].

The advantage of the antagonists is that they can be administered in small doses, with a goal of reversing deep sedation and respiratory depression. By administering the drugs in this manner, the patient's respiratory drive increases but the effects of the sedative are not completely reversed. In other words, the intervention can proceed and the patient can remain, by definition, moderately sedated. This is more easily achieved with naloxone. Titrating small increments of the drug can be easily accomplished by adding the naloxone to a syringe and giving 1 or 2 mL as needed. (SeeTable 9 for more specific preparation.)

To reverse sedation, flumazenil is administered in 0.2 mg increments, repeating the dose (maximum four doses) at one-minute intervals to a maximum of 1 mg [59]. Eighty percent of the response will be achieved within the first three minutes after administration [59]. If the patient remains in a deep sedated state, additional drug may be necessary [59]. After administration of flumazenil, the patient may complain of flushing, headache, and fatigue. A transient hypertensive episode may be evident [59].

Although these agents are said to have no pharmacologic effect, there is a risk associated with rapid administration, especially with higher doses. Naloxone given rapidly can produce a noncardiogenic pulmonary edema, evidenced by increasing shortness of breath, rales and rhonchi on chest auscultation, and decreasing blood oxygen levels [59]. In acute cases, ventilatory support will be required.

Flumazenil can precipitate seizure activity in the patient with a history of benzodiazepine use or abuse. Many patients under-report their drug use and may falsify their benzodiazepine intake. If flumazenil is administered to these patients, it may produce seizure activity. When administering flumazenil, seizure precautions should be considered [59].

Although the use of antagonists in moderate sedation is a debatable issue, the ASA recommends that, whenever possible, antagonists should be on hand during the use of moderate sedation [44]. Some physicians will order naloxone or flumazenil at the end of the procedure in an effort to rapidly reverse the effects of sedation. In some instances, this is warranted to allow for further evaluation of the patient's neurologic status. On the other hand, reversal for the sake of reversal is not considered by many to be acceptable. Reversal of narcotics will reverse the analgesic effects, and if reversal is abrupt, the patient is not allowed time to slowly reorient to his/her surroundings. In addition, reversal agents are not without complication (as noted previously); the risks of reversal should be considered.

As reversal has a number of detrimental effects, many institutions and practitioners now utilize antagonists as rescue medications. The antagonist is administered in small doses to "rescue" the patient from an unintended deep level of sedation. This allows the patient to return to the moderately sedated level and allows for procedure completion.

Many practitioners think that it is safer for the patient to arouse slowly and comfortably at the end of the procedure. If a drug with a length of action equal to the length of the procedure was chosen and used, arousal should not take long. Patients will appreciate the care they receive and be satisfied with the results. Additionally, many institutions have the requirement that if a patient receives a reversal agent, that patient should be monitored for two hours prior to discharge. Therefore, the patient who is not reversed can be discharged earlier, when he/she is capable of meeting the appropriately assigned discharge criteria.

The ASA guidelines note that other steps should be taken before or concomitantly with pharmacologic reversal in patients who become hypoxemic or apneic during sedation, including [44]:

- Encouragement or stimulation of deep breathing

- Supplemental oxygen

- Positive pressure ventilation if spontaneous ventilation is inadequate

The ASA also recommends that patients be closely monitored after pharmacologic reversal to ensure that sedation and cardiorespiratory depression do not recur [44].

Knowledge of the drug therapy used in moderate sedation is imperative to delivering safe patient care. Until the advent of the ideal agent, nurses should be aware of the uses, contraindications, and considerations of the moderate sedation medications in their facility's formulary.

5. PATIENT MONITORING DURING MODERATE SEDATION

PULSE OXIMETRY

Pulse oximetry monitoring has become the standard for monitoring patients undergoing moderate sedation. The ability to assess oxygen desaturation greatly improves patient care and helps to ensure patient safety. The Joint Commission requires that all patients undergoing moderate sedation be continually monitored with pulse oximetry [1].

Pulse oximeters provide a noninvasive estimation of arterial oxyhemoglobin saturation [92]. A saturation of 90% is equivalent to an arterial oxygen blood gas value of 60 torr. During moderate sedation, many patients develop respiratory insufficiency secondary to sedating medications. If this respiratory compromise continues unchecked, significant tissue hypoxia will develop. The pulse oximeter allows the practitioner to monitor the hemoglobin saturation as a method of early detection of impending hypoxia [61]. Studies have shown that monitoring pulse oximetry greatly improves the practitioner's ability to assess changes in the early stages of hypoxia and initiate interventions to reverse developing complications. It has not been shown to affect the outcome of sedation or length of hospital stay [93,94,95].

An additional advantage of pulse oximetry is the rapid response time between changes in patient status and the reading on the monitor. Monitoring is noninvasive and does not require that the patient be cannulated for a blood gas sample. Furthermore, the advantage of being able to assess the patient who is draped or in a darkened room is clearly optimal to providing safe patient care. Pulse oximeters are said to be accurate within the range of 65% to 95% saturations, with only a 1% to 2% error. A number of patient variables (e.g., hemoglobin level, patient's oxygenation ability, percentage of inspired oxygen) may impact the accuracy of saturation values [96].

Pulse oximeter probes may be placed in a number of locations, including the fingers, toes, earlobes, nose, or forehead. Repetitive research studies have evaluated pulse oximetry monitoring and the results consistently demonstrated that the probes placed on the patient's earlobe are more accurate and have faster response times than probes placed elsewhere [97]. With this in mind, the practitioner should assess the earlobe site for use in probe placement. In certain procedures, as when the patient's head is draped, this location would not be considered appropriate. Proper positioning of the oximeter probe is essential to prevent production of artifactual data (e.g., underestimation or overestimation of oxygen saturation) [5].

Prior to application of the probe, it is critical to ensure that the site is prepared properly. Fingernail polish will prevent accurate measurements and should either be removed or the fingertip ruled out for probe placement [98]. The skin may be gently cleansed to remove accumulated dirt and body oils. The area of probe placement should be checked for proper circulation with good capillary refill. Patients with poor capillary refill secondary to peripheral vascular disease will be better monitored using the earlobes, nose, or forehead locations. After good venous circulation is assured, the probe may be placed. There are a number of types of probes, both permanent and disposable. The practitioner should be able to demonstrate competency in pulse oximetry monitoring prior to using this technique.

It is important to recheck the probe location for good capillary refill, both immediately after probe placement and intermittently during patient monitoring. The probe should not be placed on the same extremity in which blood pressure will be measured. When the cuff inflates, the blood flow to the extremity may be compromised, producing an inaccurate saturation reading.

Disadvantages of pulse oximetry include the fact that there is no information on the patient's ventilatory status, as measured by the partial pressure of carbon dioxide (PaCO_2). In cases when the oxygen saturation is below 65%, the monitor will overestimate the saturation, providing an inaccurate measurement. Pulse oximeters are also prone to motion artifact, which creates a high rate of false alarms. Newer models reduce motion sensitivity, which may result in an increased frequency of missed true alarms [99]. There are a number of situations in which pulse oximetry use is limited, and practitioners should be aware of these drawbacks (Table 10). However, the advantage of monitoring the patient in the moderate sedation setting is that these situations are rarely encountered. If a patient were to be severely hypothermic, for example, he or she would most likely not be considered a good candidate for moderate sedation in the first place. However, there is one consideration that is encountered relatively frequently, as there are a number of situations in the radiology setting in which the patient receives intravascular dyes for various studies. Although the impact of intravascular dyes on pulse oximetry reading is generally considered to be short-lived, it is imperative that the practitioner caring for this patient recognize the possibility of inaccurate readings and use other methods of physical assessment to ensure adequate patient oxygenation [98,100].

Table 10: LIMITATIONS OF PULSE OXIMETRY

Significant hypotension

Anemia poisoning

Vasoconstrictive drug use

Carbon monoxide

Severe hypothermia

Methemoglobinemia

Arterial compression

Intravascular dye use

Pulsating venous blood

Muscular contractions

Source: Compiled by Author

The anemic patient should always be evaluated for signs of hypoxia in addition to the oxygen saturation reading [101]. A patient with a hemoglobin of 8 that is 95% saturated will have a pulse oximetry reading of 95%. Another patient with a hemoglobin of 16 that is 95% saturated will also have a pulse oximetry reading of 95%. Monitoring these two patients will produce the same reading; however, the second patient has twice as much hemoglobin and therefore twice as much oxygen-carrying capacity. The first patient may exhibit signs of tissue hypoxia much more rapidly than the second patient, despite the same pulse oximeter readings.

The practitioner should also be aware that the oxygen-hemoglobin saturation is dependent on the oxyhemoglobin curve. In situations in which the oxyhemoglobin curve is shifted to the left (with an increase in pH, a decrease in body temperature, or a decrease in PaCO_2), the hemoglobin's affinity for oxygen increases. This translates to less oxygen available at the tissue level. Conversely, if the curve is shifted to the right (with a decrease in pH, increase in body temperature, or an increase in PaCO_2), the affinity for oxygen decreases, and more oxygen is readily available at the tissue level. This can be demonstrated in the following example: A patient with an alveolar oxygen partial pressure (PaO_2) of 45 torr has a measured pH of 7.25. This patient's oxygen saturation reading would measure 80% [101]. If this same patient were given sodium bicarbonate (as an example) to elevate the pH to 7.4, but no interventions were undertaken to correct the PaO_2 of 45, the oxygen saturation reading would increase to 88% by simply correcting the pH. A practitioner monitoring this patient would see the improved oxygen saturation and may be inappropriately comforted by this improvement. However, the patient's oxygen level did not change, meaning that the level of hypoxemia was unchanged.

Pulse oximetry has become the standard for monitoring patients undergoing moderate sedation, despite the aforementioned limitations. In the vast majority of patients receiving sedating agents, these limitations are not problematic. However, nurses should remember that even though this monitoring technology exists, physical assessment skills cannot be disregarded. Pulse oximetry is not considered a replacement for direct observation of patient ventilatory function [102].

END-TIDAL CARBON DIOXIDE MONITORING

End-tidal CO_2 monitoring measures expired carbon dioxide and provides information about the patient's ventilation. This type of monitoring is most commonly used with deep sedation and general anesthesia but is becoming commonplace in monitoring patients undergoing moderate sedation [103]. The advantage of this type of monitoring is that it allows early detection of developing hypoventilation and possible airway obstruction. Additionally, if the patient is developing the early stages of malignant hyperthermia, this can be recognized by rising CO_2 levels.

Two techniques are used for measuring expired carbon dioxide. The first uses a photo detector that calculates the CO_2 value as it passes through a transducer. The second method, capnography, actually obtains a sample of expired air and diverts it to a machine (i.e., capnograph) that directly measures the carbon dioxide level. Both techniques are easily accomplished on intubated patients. Measurement of end-tidal CO_2 levels in nonintubated patients is also possible [103]. Using microstream technology, a nasal cannula-type device can be applied to the patient's nares to allow for end-tidal CO_2 measurements. These devices are comfortable for patients and provide the practitioner with additional information regarding the patient's ventilatory status.

Evidence Based Practice Recommendation

The American College of Emergency Physicians states capnography may be used as an adjunct to pulse oximetry and clinical assessment to detect hypoventilation and apnea earlier than pulse oximetry and/or clinical assessment alone in patients undergoing procedural sedation and analgesia in the ED.

https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia

Last Accessed: July 14, 2020

Strength of Recommendation: B (Recommendation for patient care that reflects moderate clinical certainty)

Recommendations about noninvasive monitoring of end-tidal carbon dioxide with capnography have evolved. At the time of their guidelines on monitoring during moderate sedation, the ASA, the American Society for Gastrointestinal Endoscopy (ASGE), and the American Gastroenterological Association (AGA) Institute found insufficient evidence to recommend the routine use of capnography, and the American College of Emergency Physicians (ACEP) noted only that procedural monitoring "may include" capnography [4,38,44,55]. However, since the publication of those guidelines, several studies have demonstrated that capnography readings are a more sensitive measure of ventilatory function, detecting hypoventilation earlier than changes in vital signs, clinical observations, or pulse oximetry [104,105,106,107]. In a study in the emergency department setting, capnography had a sensitivity of 100% (specificity 64%) in detecting hypoxia before onset [106]. In addition, a meta-analysis (five studies) demonstrated that respiratory depression was more than 17 times more likely to be detected during procedural sedation when capnography was used than when it was not used [107]. In 2010, the ASA issued updated standards for anesthetic monitoring, stating that monitoring for the presence of exhaled carbon dioxide should be carried out during moderate (or deep) sedation [108]. Use of capnography during sedation is also recommended by the Emergency Nurses Association, and, in a joint position statement, the ASGE, the American Association for the Study of Liver Diseases (AASLD), the ACG, and the AGA Institute acknowledge that capnography reduces the occurrence of apnea and hypoxemia during gastrointestinal endoscopy with propofol sedation [109,110]. In the 2014 revision to its clinical policy on procedural sedation and analgesia in the emergency department, the ACEP states that capnography used as an adjunct to pulse oximetry and clinical assessment may detect hypoventilation and apnea earlier than pulse oximetry and/or clinical assessment alone in patients undergoing procedural sedation in the emergency department [34]. A multisociety-developed curriculum on sedation during gastrointestinal endoscopy notes that proper training should include interpretation of capnography readings [62].

Guidelines from the AAP/American Academy of Pediatric Dentistry support the use of capnography during pediatric sedation. However, it was used by less than half (45%) of practitioners in a large study of high-functioning pediatric sedation systems [33,111].

CARDIAC MONITORING

Cardiac monitoring of patients undergoing moderate sedation provides information regarding heart rate and rhythm. The Joint Commission requires continuous cardiac assessment in all patients undergoing moderate sedation [1]. Cardiac monitoring allows for the early detection of arrhythmias and the development of myocardial ischemia. In some patients, pacemaker function can also be continually assessed. Many policies and procedures recommend cardiac rhythm monitoring for all patients with an ASA Physical Status of 2 or higher [3,112]. Other policies require cardiac rhythm monitoring in all patients receiving intravenous moderate sedation, as the incidence of complications increases with this route of medication administration.

Lead placement techniques vary by institutional guidelines as well as what information is to be obtained. Modified lead II placement provides a waveform that is predominantly upright and easily recognized by most healthcare providers [113]. With modified lead II placement, the positive electrode is placed over the lowest palpable rib in the left midclavicular line. The negative electrode is placed at the first intercostal space at the right sternal border in the midclavicular line. The ground electrode is placed in the first intercostal space at the left sternal border in the midclavicular line. This allows for easy identification of P waves and the development of atrial arrhythmias. The disadvantage of modified lead II is the difficulty in visualizing bundle branch block. However, for the majority of patients who do not have a cardiac history with arrhythmia risk, modified lead II is an easy, recognizable method of cardiac monitoring.

Placement with modified chest lead using V1 (MCL1) produces a waveform that is normally negative; however, with right bundle branch block, the waveform will be upright. Many practitioners do not feel comfortable with this waveform view and therefore have difficulty in recognizing cardiac developments such as ischemia and/or arrhythmias. MCL1 placement requires that the positive electrode be placed in the fourth intercostal space to the right of the sternum. The negative electrode is placed below the left clavicle in the midclavicular line. The ground electrode may be placed in any convenient position [114].

The major advantage of monitoring the patient in MCL1 is that right and left bundle-branch block may be easily identified. Additionally, differentiation of ventricular tachycardia and supraventricular tachycardia with aberrancy is possible [114]. Premature ventricular contractions can be evaluated to determine their origin, either in the right or left ventricle. MCL1 is used frequently in intensive care units as it is equivalent to lead V1 on the 12-lead electrocardiogram. However, it has been shown to differ in QRS morphology in 40% of patients with ventricular tachycardia and is, therefore, not recommended for diagnosing wide QRS complex tachycardia [114].

Modified chest lead using V6 (MCL6) is another lead that may be used. The waveform produced is upright, and it allows identification of intraventricular conduction defects. MCL6 is equivalent to lead V6 on the 12-lead electrocardiogram [115]. With this lead, the positive electrode is placed at the fifth intercostal space in the left midaxillary line. The negative electrode is placed below the left clavicle in the midclavicular line, and the ground electrode is placed in the midclavicular line below the right clavicle.

Cardiac monitoring can be a useful adjunct to patient monitoring, particularly for high-risk patients. Detection of developing hypoxia as evidenced by arrhythmia development is beneficial to all patients, especially the patient with a positive cardiac history. Patients at risk of developing arrhythmias include the elderly, patients with abnormal electrolyte values, patients with a positive cardiac history, and patients experiencing significant hypoxic intervals. The most common arrhythmias that develop during moderate sedation include premature ventricular complexes and atrial dysrhythmias, such as atrial flutter and atrial fibrillation. Fortunately, for the vast majority of patients, these arrhythmias are readily reversed with oxygen therapy and present little danger to the patient's outcome.

Additionally, recognition of myocardial ischemia formation can allow the practitioner to determine if developing ischemia and myocardial injury is occurring. T-wave inversion is seen first with myocardial ischemia. The patient subsequently develops tall, peaked T waves, which are asymmetrical with a wide base. The ST segment becomes elevated, indicating myocardial injury. At this point, the extent of long-term myocardial damage can be reversed with oxygen and nitrate therapy. The development of Q waves can occur at any time, within a few hours or up to days after the infarct. The practitioner monitoring the patient receiving sedation can use the cardiac abnormality to determine the extent of ischemia, and consequently, a decision can be made regarding the necessity of discontinuing the procedure or correcting the ischemia (e.g., with oxygen therapy, nitrates).

The controversy regarding cardiac monitoring lies in the fact that many patients receiving moderate sedation are healthy, and continuous cardiac rhythm monitoring may be unnecessary in a large population of patients. Guidelines from the ASA, the AGA Institute, and the ASGE note that ECG monitoring is not needed for low-risk patients [38,44,55]. The ASA guidelines suggest ECG monitoring to decrease risks for patients who have significant cardiovascular disease or dysrhythmia, and the AGA Institute and the ASGE state that ECG monitoring should be considered for high-risk patients, such as patients with a history of significant cardiac or pulmonary disease [38,44,55]. The AAP recommends that an ECG monitor be readily available [33]. Each institution should develop its own policies and procedures as to which patients are candidates for monitoring and which patient populations do not require this level of care.

NONINVASIVE BLOOD PRESSURE MONITORING

Noninvasive blood pressure monitoring allows for repetitive evaluation of the patient's blood pressure with a minimal amount of nursing time. The monitor will cycle at a preset interval to obtain blood pressure readings and is accurate in a wide variety of settings.

The blood pressure cuff is placed over the brachial artery with the lower edge of the cuff one inch above the antecubital fossa. In a patient with fragile skin, a single layer of cotton padding may be placed around the arm prior to application of the blood pressure cuff. This will protect fragile tissue from repeated injury that may occur with each cuff inflation.

It is important that the practitioner place the cuff appropriately and ensure that the appropriate size cuff is used. A cuff that is too wide will provide a blood pressure reading that is inaccurately low. Conversely, a cuff that is too narrow will provide an inaccurately high reading. A proper cuff is approximately 40% of the circumference of the arm to which the cuff is applied [116]. The American Heart Association has provided recommendations for appropriate cuff sizes based on upper-arm circumference (Table 11).

Table 11: AMERICAN HEART ASSOCIATION RECOMMENDED SIZES FOR BLOOD PRESSURE CUFFS

Patient Parameter

Recommended Cuff Size

Adults (By Arm Circumference)

22–26 cm

12 x 22 cm (small adult)

27–34 cm

16 x 30 cm (adult)

35–44 cm

16 x 36 cm (large adult)

45–52 cm

16 x 42 cm (adult thigh)

Children (By Age)a

Newborns, premature infants

4 x 8 cm

Infants

6 x 12 cm

Older children

9 x 18 cm

aA standard adult cuff, large adult cuff, and thigh cuff should be available for use in measuring a child's leg blood pressure and for children with larger arms.

Source: [117]

Patients may complain of pain as the cuff inflates. Many machines now allow the practitioner to set the maximum cuff inflation pressure. This prevents overinflation of the cuff every time the cuff is used. With this ability to monitor the patient without inflicting undue pain, patient care is maximized.

Many blood pressure monitoring devices provide a digital read-out of the patient's vital signs. These are important records and should be incorporated into the patient's chart. However, it is important to remember that these attachments may become lost and separated from the chart. It is always advisable to document a set of vital signs in the chart and state that the digital read-out is attached. If legal action was to occur and no vital signs recorded and no print-out found, the nurse could face serious consequences for not obtaining vital signs. For example, if no record exists, an attorney may make the assumption that vital signs were not obtained. Additionally, the read-out may fade over time and become illegible. Also, if tape is placed over the ink when attaching the monitoring strip to the chart, the tape has the tendency to make the recording "disappear," and the readout is no longer visible.

Many blood pressure monitoring machines also allow for cardiac monitoring of the patient. Some provide a rhythm strip, and others simply monitor the heart rate. Combining these assessments ensures safe patient care without extra costs incurred for additional pieces of monitoring equipment.

BISPECTRAL INDEX

The bispectral index (BIS) has been developed as a method of objectively determining sedation status via electroencephalogram (EEG) recordings [118]. Based on the index, the sedation level can be determined mathematically based on the patient's EEG pattern. An alert adult would receive a score of 100, while a score of 0 is characterized by an isoelectric EEG pattern [118]. The bispectral index score is a relatively new tool, and research has indicated that it is a valid measure of depth of sedation, in addition to nursing evaluation [44,119,120,121]. However, some studies have found its use to be questionable among some populations, such as pediatric patients, and both the ACEP and the ASGE have found insufficient evidence to recommend routine use of BIS [4,55,62,122,123,124].

6. DOCUMENTATION OF MODERATE SEDATION

Critical to the success of moderate sedation is appropriate documentation of the procedure. Documentation provides other healthcare practitioners with information regarding the patient during the intervention. Additionally, chart reviews can be performed as a component of quality monitoring. Good documentation allows for a review of the medications, patient responses, and any adverse complications that may have developed during the procedure [125,126].

The ideal flow sheet should have three basic sections: the presedation assessment, the intrasedation record, and the postsedation record, which includes the discharge status of the patient. The format of the flow sheet should allow a reviewer to easily determine how the patient responded to therapy and sedation. Graphic flow sheets, which allow for vital sign charting next to medication administration times, allow rapid assessment of the patient and the patient's responses to medications [126].

When developing a flow sheet, input should be obtained from all users of the form. A sample form can be developed and critiqued, with changes made as appropriate. When a sample form is deemed acceptable, the form should be put into use and re-evaluated on a regular basis. It is not often that the ideal form is created during the first phase of development. Usually, it requires refinement a number of times. Unfortunately, too many individuals are resistant to change, and once a form is put into daily use, users do not want to see it changed, regardless of whether it meets their needs.

Current practice allows documentation of moderate sedation in a number of ways. The Joint Commission standards do not specify the elements required for sedation documentation but rather leave this responsibility to each individual organization, which is free to determine its documentation format [125].

The components of the presedation assessment should be easily identified to facilitate review [126]. Because the assessment of cardiac, respiratory, and neurologic components are critical in this phase of care, a section that allows for easy recording of these findings will ensure that the patient is appropriately assessed. A checked box format allows the recorder to document function and lessens the time required to complete the form.

Presedation baseline vital signs and oxygen saturations should be readily identified. If another individual is recovering the patient after sedation, he or she will need to be able to identify the patient's baseline parameters to evaluate readiness for discharge. The patient's ASA physical status and any important history, including medication use, allergies, diagnostic data (e.g., laboratory, ECG, X-ray) and last oral intake, should be included as well [3,126].

Monitoring equipment used may also be documented in a checked box format. If a patient is placed on the cardiac monitor, pulse oximeter, and noninvasive blood pressure monitor, a simple check system will expedite charting as well as act as a reminder to the care provider that these monitors should be considered.

Additional information in the presedation section could include a checklist of tasks to be accomplished during this phase of care. For example, a checklist may include such items as: informed consent obtained; emergency supplies readily available; oxygen and suction present and functional; history and physical reviewed [126]. These act as reminders and ensure that patient safety is always foremost.

The intraprocedural section should include a time-based record of patient assessment information as well as a medication section [126]. The medications should be documented according to their time of administration, the dose administered, the route of administration, and the patient's response. Vital sign assessment obtained one minute after sedative administration may be coordinated to show the effects of medications upon the patient's vital signs. All medications administered should be documented, including premedicants, sedating agents, and reversal agents, and the summary totals of their dosages should be easily identifiable [126].

If the patient is receiving intravenous solutions, these should be documented [126]. Any blood loss should be reported. A postprocedural intake and output calculation may be valuable for a number of patients.

During the procedure, the use of monitoring equipment should be documented [126]. Many noninvasive blood pressure monitors produce a paper strip with a vital sign and heart rhythm summary. These are acceptable methods of documentation. However, as discussed, the nurse should be aware that if the strip is lost or misplaced, there will be no record of vital signs on this patient, which may result in negative legal consequences. Therefore, as previously noted, it is prudent for the nurse caring for the patient to physically write in a set of vital signs and indicate that the rhythm strip is attached. Although this still does not show complete evidence of patient assessment, the nurse is able to demonstrate that he/she obtained vitals as appropriate.

Another important part of the intraprocedural form is the documentation of the patient's level of sedation. Many institutions use sedation scales as a method of documenting changes in the patient's level of responsiveness. This is a widely accepted method of documentation, and one which will stand up under legal scrutiny. The sedation scale selected should be easy to use and document. Many facilities use the Ramsay score; however, as previously discussed, this score lacks clarity in some areas [6]. Many hospitals now use the Modified Observer's Assessment of Alertness/Sedation Scale [38].

Pain assessment should also be included in the intraprocedure section. The Joint Commission requires that all patients be assessed for pain and have their pain managed appropriately. An additional box for documenting a pain score may be added to the vital sign section to ensure that the practitioner is including pain in his/her assessment. If the procedure is not painful, this too should be documented. (It is imperative to remember that if pain continues into the postsedation period, these pain assessments should be continued and documented.)

A summary of the procedure may be included in this intraprocedure section. The start and stop time of the procedure and the condition of the patient at the end of the procedure may be documented. The occurrence of any unusual events during the administration of sedation should be documented. Medication summaries should also be tallied [126].

The last section of the document is the postsedation care section. This includes assessment of the patient during the postsedation period as well as information regarding the patient at the time of discharge. Regular vital sign and pain assessments should be documented, including the patient's level of sedation. A reviewer should be able to identify the progression of the patient's arousal from the sedated state. Any complications should be described, and interventions undertaken should be documented. Pain medications, if administered, should be charted, including an assessment of the effectiveness of such medications [126].

The discharge of the patient should also be included. Depending on the location to which the patient is discharged, varying information should be documented (as previously presented). The location to which the patient is discharged should be clearly identifiable. The discharge criteria used to assess the patient's readiness for discharge should be clearly delineated. If a discharge scoring system is used, the patient's score should be noted, as well as a notation regarding the acceptable score for discharge. The condition of the patient at the time of discharge should be documented. If a patient is being discharged to home, the individual who is accompanying the patient should be identified.

Finally, discharge instructions should be charted [126]. Many facilities use standard discharge instruction worksheets that require signatures from both the patient and the nurse providing these instructions. After review, a copy of these instructions should be signed by both individuals and attached to the patient chart. The nurse(s) caring for the patient should sign the flow sheet prior to inserting the documentation record into the patient's chart.

In summary, documentation of the patient undergoing moderate sedation is an important aspect of good nursing care. The sedation assessment document should be user-friendly for the staff using the form during sedation, as well as any other individuals who may be reviewing the document at a later point. Without documentation of all aspects of the procedure, the assumption is that these activities were not completed. Therefore, it is imperative that documentation be complete, thorough, and easily legible.

7. COMPLICATIONS DURING MODERATE SEDATION

Moderate sedation is not a treatment without consequence. Although the incidence of complications is low, there are risks (Table 12). In many cases, complications are related to pre-existing comorbidities in the patient. With good presedation assessment and selection, the incidence of these problems can be kept to a minimum.

Table 12: COMPLICATIONS OF MODERATE SEDATION

Over- or undersedation

Cardiac arrest

Respiratory insufficiency

Pain

Airway obstruction

Nausea and vomiting

Aspiration

Malignant hyperthermia

Hemodynamic instability

Paradoxical reactions

Dysrhythmias

Source: Compiled by Author

OVERSEDATION AND UNDERSEDATION

Most complications occur because of sedation becoming deeper than intended (oversedation), rather than not reaching adequate sedation [44]. This is especially important for children, as studies have indicated that children often reach a level of sedation that is deeper than intended [33]. Clinicians who administer moderate sedation must be qualified to rescue patients who reach a deep level of sedation [44].

Another common complication of moderate sedation is nonoptimal sedation (undersedation) of the patient [127]. The nurse newly trained in moderate sedation administration may undersedate the patient in an effort to reduce the risk of oversedation. Although undersedation may seem beneficial as compared to oversedation, the effects of undersedation can be just as undesirable. The patient who is undersedated experiences an increased amount of stress, leading to an increased autonomic response [128]. The patient experiences an increase in heart rate and blood pressure, both of which can be detrimental in a variety of patient populations.

Certain populations are at increased risk of oversedation and undersedation, particularly the young, the old, the critically ill, and the obese [3]. Patients with liver and/or renal disease are also at increased risk, especially for oversedation [129]. Patients with high preprocedural levels of anxiety may also be at risk; the heightened anxiety state can prevent the patient from achieving the full benefits of the drug administered. As an example, a patient with a high level of anxiety is scheduled for an MRI. The patient has heard a great deal from friends and family about the claustrophobic environment of the scanner. This patient has a fear of enclosed spaces and becomes fearful that he/she will be unable to tolerate the closed-in feeling in the scanner. The nurse caring for this patient administers a low-dose benzodiazepine in an effort to relax the patient and relieve his/her anxiety. The preprocedural instructions provided to the patient explained the type of sedation and that these medications are administered to relieve the patient's heightened level of anxiety. However, the dosage administered is inadequate to achieve these goals, and the patient enters the scanner without feeling relief. The patient believes that the medication should be working but remains unable to relax. This only further increases the patient's anxiety, and the physiologic responses of an increased heart rate and blood pressure become evident.

Both oversedation and undersedation can be prevented with proper drug dosing, dosing techniques, and recognition of at-risk patients. Administering drugs in small doses on a more frequent, as-needed basis can all but eliminate these problems. Should overdosage become a problem, administration of a reversal agent (if available) may be used.

RESPIRATORY INSUFFICIENCY

Differentiating oversedation from respiratory insufficiency can be challenging. Respiratory insufficiency is a known effect of sedation agents and should also be considered a potential complication of oversedation. Clinical signs of respiratory insufficiency include decreased, shallow, or labored respirations; rocking motion of chest; weak cough; high-pitched noise during inspiration (partial obstruction); no movement of air (complete obstruction); and decreased oxygen saturation [9]. Patients with high respiratory rates, such as the pediatric patient and the obese patient, are at increased risk of respiratory insufficiency secondary to their high minute volumes. If a patient's normal respiratory rate is 30 and drops to a rate of 15/minute, there is a 50% drop in the patient's minute volume. On the other hand, if an adult whose normal respiratory rate is 20 drops to 15/minute, there is only a 25% drop in minute volume. It is clear that the patient with the higher resting respiratory rate is at increased risk for hypoxemia.

Complicating the respiratory insufficiency expected with sedative administration is the response to a developing hypoxemia. Many sedating agents blunt the patient's response to impending hypoxemia, and a vicious cycle is set in motion, the end result being a patient whose respiratory drive is insufficient to meet his/her tissue oxygen demands.

Preventing respiratory insufficiency can be accomplished by monitoring the patient's respirations and oxygen saturations every five minutes. Stimulating the patient to breathe with each vital sign assessment can also ensure adequate ventilatory effort, assuming that such behavior does not adversely interfere with the procedure being undertaken. Providing supplemental oxygen to patients at risk of decreased respiratory effort will prevent the further development of significant hypoxemia [9].

Oximetry has been shown to effectively detect oxygen desaturation and hypoxemia in patients who are administered sedatives. Early detection of hypoxemia through the use of oximetry during sedation can decrease the likelihood of adverse outcomes (e.g., cardiac arrest). Supplemental oxygen also decreases patient risk during moderate sedation [3]. In severe situations, administering a reversal agent (if available) or terminating the procedure may be necessary to reverse this problem [9].

COMPROMISED AIRWAY

Airway obstruction is another common complication that can be prevented with close monitoring. Obstruction of the airway is more common in the young child, whose tongue is larger in proportion to the size of his/her mouth. The modified Mallampati Scale is a useful tool in evaluating patients at risk for airway compromise [26,27,28,31]. This four-level pictorial tool was devised to predict difficult compromised airway and is now widely recommended as a routine screening element before procedural sedation [130]. The scale classifies the patient's airway as Class 1, 2, 3, or 4. The patient with either a Class 3 or 4 airway has an increased risk of airway obstruction in comparison to a patient with a Class 1 airway, as outlined previously. Any patient with a Mallampati Class 2 airway may also be at increased risk. While it is important to anticipate that a patient may have a difficult airway, there is no specific evidence that the Mallampati score improves the baseline clinical judgment of a standard airway evaluation. Variability in grading by independent observers makes it an unreliable assessment when used alone. It also cannot be evaluated in many young children and in patients who cannot cooperate due to an underlying psychologic or medical condition [29,130].

A prospective, observational study was undertaken to compare the rates of adverse events during pediatric procedural sedation in 575 children (median age: 6 years) with Mallampati scores of III/IV versus scores of I/II [131]. The primary reason for sedation was fracture reduction; most sedations involved the use of ketamine. Patients with scores of III/IV were more likely to require repositioning during sedation compared to those with scores of I/II, but, overall, they did not experience a higher proportion of adverse events compared with children with scores of I/II [131].

The airway also may become compromised from accumulated vomitus, blood, or oral secretions. Patients who are sedated without the benefit of gastric emptying will be at increased risk of aspiration. Controlling secretions with suction and head positioning is imperative in this group of patients.

Finally, in the event of developing deep sedation, the patient will lose submandibular muscle tone causing a slack jaw and unprotected airway. It is important to remember that sedation is a continuum; the progression to deep sedation is varied and individualized. The development of a slack jaw can occur at any time, and the patient's muscle tone and airway should be monitored at all times.

In most adult patients, the head-tilt/jaw-thrust maneuver is all that is necessary to open the airway. (Note: It is imperative to remember that in the pediatric patient, a head-tilt is NOT an appropriate airway maneuver; the child should be placed in the sniffing position with the jaw forward.) Insertion of an oral airway is generally contraindicated, as the patient's level of consciousness is not deep enough to allow placement. Placement of an oral airway may actually precipitate laryngospasm in many lightly sedated patients, necessitating intervention [9].

If the airway is compromised with accumulated particulate material, insertion of a nasal trumpet and suctioning will be required. Again, care should be taken to prevent laryngospasm that may occur with vigorous suctioning.

ASPIRATION

Aspiration is the most common cause of death secondary to intravenous moderate sedation [6]. Although the risk of death is increased, the incidence of aspiration remains lower in moderate sedation than in general anesthesia [132]. The most common cause of aspiration is the relaxed cardiac sphincter tone that develops with deeper levels of sedation. Any patient with a history of reflux is at risk, as are obese, obstetric, and elderly patients [6,24,55].

Risk of aspiration may be reduced by administering medications to decrease gastric contents or medications to increase gastric pH. Elevation of the head of the bed may decrease the patient's risk, assuming that such positioning is not contraindicated by the procedure being performed. Finally, if the patient does aspirate, suctioning and airway protection with intubation may be required. The patient may be started on antibiotic therapy and vigorous pulmonary toilet will be instituted. Postaspiration pneumonia carries a high mortality if not recognized and treated early [34,133].

CARDIOVASCULAR COMPLICATIONS

Hypotension

Hemodynamic instability is a common cardiovascular complication occurring during moderate sedation [6]. The direct cardiodepressant effect of many of the sedating drugs causes hypotension in the patient. The patient with a pre-existing compromised circulatory volume is at greatest risk for this complication [55]. Hypovolemia and hemorrhage require aggressive volume and blood replacement to prevent dangerously low circulating pressures. In acute cases, vasoactive drugs may be required to supplement hemodynamic status. Recognition of the patient at risk for hypotension will allow the practitioner to supplement the patient's volume status prior to sedation, thereby circumventing this problem. Hypotension may be an early sign of oversedation.

Other causes of hypotension include pain and the histamine release that occurs with a number of depressant agents. It is imperative that the cause of the hypotension be identified so that proper therapy can be instituted to reverse the cause and correct the problem.

Dysrhythmias

Another cardiovascular complication is the development of dysrhythmias, most commonly in the elderly individual. Most dysrhythmias occur secondary to hypoxia and can be prevented or treated with increasing oxygen percentages; other causes of dysrhythmias include fluid overload, pain, and hypovolemia [134]. The patient at risk should be placed on continuous cardiac monitoring prior to the start of the sedation and continuously monitored both throughout the sedation period and during the recovery phase [24,38,44]. Supplemental oxygen may be recommended prior to beginning the procedure. Antidysrhythmics and defibrillation are rarely required; however, access to these interventions should be readily available.

The type of agent used will affect the type of dysrhythmia that develops. Fentanyl and the barbiturates are associated with bradycardia, while dissociative agents such as ketamine are more commonly associated with tachycardia, myocardial depression, and ventricular ectopy [59,134].

Cardiac Arrest

In the event of significant cardiovascular compromise, the risk of cardiac arrest exits. With good presedation evaluation and risk assessment, the advent of cardiac arrest is rare. However, should this life-threatening event occur, the team caring for the patient should cease procedural interventions and immediately begin full resuscitation efforts. The facility's "code team" may be activated to provide expert back-up assistance in resuscitating the patient; however, the Joint Commission standards require that individuals who administer moderate sedation must also be competent to perform the rescue. A "code team" is considered an additional resource [135]. Those caring for the patient also should be well versed in the American Heart Association's cardiac arrest protocols [136]. Airway, breathing, and circulation should be managed and drug therapy instituted.

PAIN

Pain is a complication that should rarely present itself if the nurse caring for the patient is performing his/her responsibilities. It is an important preprocedural responsibility to instruct the patient regarding pain. The use of pain scales should be demonstrated so that the patient is aware of his/her responsibilities in informing the nurse of any pain. Another important teaching point to address is that there is a difference between pain and discomfort. Analgesics may be provided for pain control; however, discomfort may be a part of the procedure that cannot be eliminated. As an example, a patient undergoing a colonoscopy with moderate sedation may experience discomfort while the abdomen is assessed. This type of discomfort cannot be treated with analgesic therapy. The patient should be aware of these differences, and a path of open communication should be established. Often, nonpharmacologic interventions may be instituted to relieve discomfort, such as padding under the back (if allowed) to relieve pressure and discomfort over the sacral area.

A known painful procedure should be performed using sedating agents that have known analgesic properties. Assessing the patient's level of pain is imperative to provide safe, patient-oriented care. If a patient is experiencing a significant amount of pain, the nurse may be wary of administering further pain medications due to their synergistic effects upon sedation. This issue should be addressed with the physician, and consideration of nonsteroidal anti-inflammatory agents may be considered.

NAUSEA AND VOMITING

Evidence Based Practice Recommendation

According to the American Society of Anesthesiologists, multiple antiemetic agents may be used for the prevention or treatment of postanesthesia nausea and vomiting, when indicated.

https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686

Last Accessed: July 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Nausea and vomiting are additional complications that put the patient at risk and increase the patient's discomfort. Increased vagal tone can produce the sensation of nausea and potential vomiting. Opiate use is known to produce nausea and vomiting in some cases. Other patients at risk for experiencing these complications include those that are hypovolemic, obese, or in pain. Certain procedural interventions are known to increase the complaints of nausea and vomiting; therefore, assessment for increased risk should take place in the preprocedural period.

Administering antiemetics may be of benefit. However, these drugs can produce additional sedation, and the nurse should exercise caution when giving these drugs to the sedated patient. In the event of significant gastric distension, the use of a nasogastric tube to suction may help reduce the risks. Hypovolemia should be corrected, and pain may be treated with additional analgesics; however, the practitioner should be aware of the synergistic effects of additional analgesics already presented.

MALIGNANT HYPERTHERMIA

Malignant hyperthermia (MH) is another rare but potentially life-threatening complication [137,138]. Once again, taking good presedation history, including risk assessment for MH, can prevent this problem from developing [139]. Patients at risk for developing MH include children and those with a history of anesthetic complications [134,137]. Agents that can precipitate MH include anesthetic gases and succinylcholine [59,140]. Although the majority of these drugs are not used in the moderate sedation realm, the risk of this complication developing should not be overlooked.

The onset of symptoms of MH may begin with the development of masseter muscle spasm (also known as masseter muscle rigidity) and rising CO_2 levels. The patient can develop tachycardia and other ventricular dysrhythmias [134,139]. The patient's core temperature remains normal in the early stages; however, the skin appears flushed and may feel warm to touch. It is imperative that the care provider recognize these symptoms in this early stage. If the syndrome progresses to the state of high fever and muscle rigidity, the incidence of death and long-term sequelae increases [134].

If MH develops, the procedure should be terminated immediately and interventions undertaken to prevent its progression [140]. The patient may be administered dantrolene, and cooling measures should be instituted [134,137]. The Malignant Hyperthermia Association of the United States (MHAUS) recommends that a full supply of dantrolene be available on site to allow for initial stabilization and treatment while more vials are acquired to continue treatment, as needed [140]. Administration of dantrolene requires additional support personnel, as drawing up an adequate dose is time consuming and difficult to perform while instituting other supportive measures.

Children will respond to external cooling measures, such as ice packs to pressure points and cool cloths. The adult patient may require internal cooling, with iced lavage of the peritoneal, gastric, bladder, and rectal cavities [59]. In the event of significant hyperthermia (i.e., temperature greater than 42°C), placing the patient on the heart-lung bypass machine to institute extracorporeal cooling may be required.

Subsequent complications, such as ventricular dysrhythmias, should be treated according to standard protocols. The patient will require increased fluids to prevent the development of acute renal failure secondary to myoglobinuria. Sodium bicarbonate may be administered for severe acidosis, and diuretics may be given to prevent developing renal failure. If the patient is at increased risk of hyperkalemia, a glucose-insulin drip may be ordered to reduce the serum potassium level [59,134].

Additionally, the risk of recurrence exists. The patient should be monitored for up to 48 hours for recurring signs and symptoms. MHAUS guidelines recommend that 2.5 mg/kg of dantrolene be administered with an upper limit of 10 mg/kg [59,140]. It is also imperative that the patient and his/her family be made aware of the complication and further education instituted so that it may be prevented in the future.

PARADOXICAL REACTIONS

Finally, the risk of paradoxical reaction exists. The patient who experiences agitation, dysphoria, and/or confusion, either during sedation or upon recovery, is at risk for self-inflicted injury. These types of reactions are more common in the pediatric and elderly populations and are known side effects of certain medications (e.g., midazolam use in the elderly, benzodiazepine use in children) [141]. If a paradoxical reaction to benzodiazepines is suspected, the offending agent should be discontinued immediately. While management with observation may be sufficient, tranquilization (e.g., with low-dose ketamine, propofol, haloperidol) has been reported to be successful [142,143].

Other causes of paradoxical reactions include hypoxia and undermedication. Hypoxia should always be considered as the primary cause, and measures should be undertaken to reverse this problem. As discussed, undermedication can lead to an increased level of anxiety or provide an inadequate amount of analgesia for the patient, thus precipitating this type of reaction [141]. Treating hypoxia with oxygen administration in this combative patient may be difficult and may only increase the patient's agitation. In this case, blowing oxygen at the patient's face may help reverse the hypoxia. Administering pain medications may help ease the response, but additional sedation may develop.

Another suspected cause of paradoxical excitement is the administration of reversal agents. The rapid arousal of the patient may bring on fear, which subsequently leads to a paradoxical response. If administering a reversal agent to a patient, slow administration and reversal have been found to help decrease the risk of excitement in many patients. Titrating the reversal medications can help achieve this goal.

The risk of complications exists with any type of moderate sedation procedure but can be reduced, if not prevented, with recognition of the patient at risk and vigilant monitoring to detect early signs of patient deterioration.

8. MODERATE SEDATION OF THE PEDIATRIC PATIENT

Administering moderate sedation to the pediatric patient is a safe and effective method of controlling agitation and discomfort in the child. However, a child's ability to control his/her own behavior for purposes of cooperating for a procedure depends on the child's chronologic and developmental age. Children younger than 6 years of age and those with developmental delay often require deep levels of sedation to affect adequate behavior control. It is important to anticipate the need for deep sedation as studies have shown that children commonly pass from the intended level of sedation to a deeper, unintended level [5,144,145,146]. Also, the sedation medication used has a more profound effect on the respiratory drive, patency of the airway, and protective reflexes of a child in this age group. Administration of drug therapy and care of the patient should be modified to take into consideration the anatomic and physiologic differences in children. Institution of appropriate measures will ensure safe drug delivery with successful outcomes. The concept of rescue is particularly essential to the safe sedation of children [5].

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

The child's airway is anatomically different than the adult airway. The larynx is located more cephalad and anterior; thus, head positioning is different in the child. Airway diameter is narrow, with the narrowest section of the trachea located at the cricoid ring. Airway compromise is always a consideration secondary to the large tongue, which can relax and fall back into the airway, causing obstruction.

Children's breathing effort is different in that there is less alveolar space for gas exchange with fewer collateral ventilatory pathways. Oxygen demands are higher secondary to the child's high minute volume. Normal respiratory rates in children are faster than adults; therefore, a decrease in the child's respiratory drive secondary to drug administration can cause significant respiratory insufficiency. Additionally, the sternum and the ribs are more cartilaginous and pliable in the child, making signs of respiratory distress visually identifiable by chest wall retractions and abdominal muscle use.

Heart rate and blood pressures vary by age of the child, and the evaluation of changes should take these variables into consideration. Children's cardiac output is controlled by increasing heart rate, and drugs that slow the heart rate will cause a drop in cardiac output with a subsequent decrease in circulation times. This drop in cardiac output translates into a longer onset and a prolonged length of drug action. Additionally in children, the circulatory response to hypoxia is the development of bradycardia. Therefore, heart rate becomes an important assessment parameter.

Assessing the level of consciousness and arousal in the child should take into consideration the development age of the child. The neurologic system is not well developed until 8 to 10 years of age. Recognizing normal, age-appropriate behaviors in the child will allow the care provider to identify changes in the child's level of functioning.

The hepatic and renal function of a child is not well developed, and this will impact drug metabolism and clearance. The child may have longer length of action of drugs secondary to reduced hepatic function. On the other hand, the child may have a faster clearance time due to the higher circulating volumes. Monitoring the child for drug response is imperative due to this unpredictable medication response.

Additional considerations include fluid volume differences and differences in the distribution of these body fluids. Children have a large body surface area to body mass and are at increased risk for developing hypothermia. While circulating volume is calculated at 80–90 mL/kg, children will require additional maintenance fluids for circulatory support. Maintenance fluids are frequently required for children younger than 8 years of age, as well as children who have been NPO for a significant length of time. Table 13 outlines the formula for pediatric maintenance fluid administration. Typically, the choice of fluids includes a dextrose containing solution, such as 5% dextrose with 0.25% normal saline. This provides the child with the supplemental glucose that is required during times of stress.

Table 13: PEDIATRIC MAINTENANCE FLUID CALCULATIONS

100 mL/kg for 1st 10 kgs

(Ex: 10-kg child = 1,000 mL)

50 mL/kg for 2nd 10 kgs

(Ex: 20-kg child = 1,500 mL)

20 mL/kg for each additional kg

(Ex: 26-kg child = 1,620 mL)

Total calculated volume is divided equally over 24 hours.

Fluid of choice is generally 5% dextrose with 0.25% normal saline.

Source: [60]

PHARMACOLOGIC CONSIDERATIONS

Techniques for the pediatric patient receiving moderate sedation are different from adult patients. Internal factors (i.e., child's age, developmental level, previous experience) and external factors (i.e., parental interactions with the child, preparation, clinical skill, physical setting where procedure is performed) determine how the child will respond. Individualized dosing and titratable agents are, therefore, often necessary [71].

It is more common for children to receive transmucosal medications with excellent results. The oral route is advantageous due to its ease of administration. However, a risk of aspiration may occur, especially with foul-tasting medications. Usually, the taste of these medications is disguised in a sweet, syrupy concoction that greatly improves patient compliance. Many medications are metabolized by first-pass effect, and dosing by the oral route should be increased on a milligram per kilogram basis to achieve the same level of sedation achieved by the intravenous route.

Sublingual administration, such as fentanyl lozenges, is an easy and desirable method. The child should be able to cooperate with instructions to suck on the lozenge rather than chewing it, as chewing prevents complete absorption and compromises proper drug dosing. The advantage of sublingual administration, as previously mentioned, is the lack of first-pass effect.

Nasal administration of sedating agents is gaining popularity, especially for the pediatric population; however, not all agents are approved for this route of administration [147,148]. Midazolam can be mixed with normal saline and dripped into the nasal passages. Many children, especially younger children, tolerate this route quite well [147]. Onset of sedation is rapid, and return to a presedation state is comfortable and quick. The disadvantage of this route is that medications may produce sneezing in the child, making the volume of medication received uncertain [149]. Additionally, if the volume of saline instilled into the nasal passage is large, the child may swallow the medication, converting absorption to the oral route. A study that compared oral midazolam syrup with intranasal midazolam spray for pre-anesthetic sedation in pediatric patients found that the two routes of administration produced similar anxiolysis and sedation, but better drug acceptance and response was noted with oral midazolam [150]. A study that compared the ease of administration of oral midazolam syrup with intranasal midazolam spray as premedication administered by parents to children found that parents reported better ease of administration with the syrup than the spray and that children better accepted the syrup than the spray [151].

Rectal administration of medication is utilized frequently in the child, especially the child who is resistant to intravenous line placement. Initial doses of medications can be given rectally. Once the sedating effects occur, an intravenous line can be placed and further drug dosing accomplished by the intravenous route. The disadvantage of rectal administration in the child is the lack of retention of the drug in the rectum. Some children may bear down and dispel the medication prior to its absorption.

Intramuscular administration is the least desirable route of administration in all populations, especially with the pediatric patient. The advantage of the longer length of action should be weighed against the pain and delayed onset that occurs with this route. Furthermore, if this is the sole route for drug delivery, repeat injections may be required for further sedation, causing additional pain and discomfort in the child.

Intravenous administration has the advantage of providing the most controlled route for drug dosing. There is no question regarding the amount of drug that was administered, which may not be the case with other routes of administration. The risk of rapid onset of complications does exist but can be controlled by the titration of drugs to allow for monitoring of response to medications. Intravenous drug therapy does require intravenous line placement, which is traumatic for a large percentage of children. Thus, use of combined techniques (i.e., rectal, oral, nasal administration) for initial sedation followed by intravenous administration (for prolonged effect) is very beneficial in this population. It is important to note that the potential for adverse outcomes increases when three or more sedating agents are administered. Knowledge of the time of onset, time to peak, duration of each agent, and whether a previous dose of an agent has taken full effect is essential. An agent with a long duration of action requires a longer observation period, even if the child has achieved recovery and discharge criteria. This is especially important for infants and toddlers who are transported home in car seats. These children are at risk of resedation due to residual prolonged drug effects with the potential for airway obstruction [5]. It is essential that the nurse consider the effects of these techniques and choose the most appropriate route or methods based on each individual child's needs.

Pharmacologic effects of drug administration are affected by the higher cardiac outputs and metabolic responses in children. Drug dosing is on a higher milligram per kilogram dosage in children than in adults. The risk of this type of drug dosing is the sequestration of drugs in the fat or muscle of the child, leading to prolonged length of action and risk of resedation as the drug is slowly released from these tissues. The nurse providing sedation should always be aware that the potential for complications is higher in children and have readily available reversal agents, medications, and equipment.

Additionally, certain medications are used exclusively in the pediatric population. Thus, nurses caring for children should be aware of the pharmacology of these drugs. Fentanyl lozenges are most commonly utilized in children.

Chloral hydrate and pentobarbital are used in children undergoing radiologic procedures when a motionless patient is required, as during the MRI. These drugs have different actions in young versus older children. Chloral hydrate has a long duration of action, and residual effects (e.g., motor imbalance, agitation, restlessness) are common and may occur after the child is discharged to home. Most institutions limit the use of these two drugs to children younger than 3 years of age [152]. The nurse administering either of these drugs in the older child should carefully monitor the child for untoward effects.

NURSING CARE

Nursing care of the child receiving moderate sedation requires vigilant monitoring of the child at all times. The onset of complications may be more rapid, and the risk of untoward events is higher. However, careful assessment of the child throughout the procedure ensures that drug administration is safe and the child is comfortable.

Airway management in the child requires head positioning with consideration of anatomic variables. The child with airway compromise should be placed in the "sniffing" position, with the jaw lifted upward and forward. Placing a child in the standard head-tilt/jaw-thrust maneuver can cause inadvertent collapse of the child's airway. Signs of airway obstruction should be evaluated whenever unusual airway sounds are identified, including inspiratory stridor and/or snoring. Additional signs include restlessness secondary to developing hypoxia, intercostal muscle use, tachypnea, and bradycardia. In children 5 years of age and older, presedation assessment should include looking for loose teeth that may fall out and lead to airway obstruction. Immobilization devices (e.g., papoose boards) should be used so as to avoid airway obstruction or chest restriction. If an immobilization device is used, a hand or foot should remain exposed, and the child should never be left unattended [5]. Airway management in children with abnormal airway anatomy or airway obstruction may be accomplished with the use of devices, such as the laryngeal mask airway (LMA). The LMA device is available in a variety of sizes and may even be used in neonates [5].

The child should be administered supplemental oxygen secondary to his/her high oxygen demands. Cooperation with oxygen mask placement can be challenging in the combative and restless child. Enlisting a parent to hold an oxygen mask and blow oxygen at the child's face may be beneficial in the early stages. After the child is adequately sedated, the use of oxygen therapy devices should be continued and is usually easily accomplished. The use of capnography for sedated children is recommended, particularly when other means of assessing the adequacy of ventilation are limited. As noted, guidelines from the AAP/American Academy of Pediatric Dentistry support the use of capnography during pediatric sedation [33,111]. Several manufacturers have produced nasal cannulae that allow simultaneous delivery of oxygen and measurement of expired carbon dioxide values [5].

The child should be placed on a cardiac monitor so that signs of bradycardia are readily identified. If cardiac monitoring is not performed, frequent vital sign assessment of heart rate is imperative to recognize changes from the status quo. If anticholinergic medications, such as atropine, are given to reduce secretion formation, it is imperative that the nurse monitor for additional signs of hypoxia, as bradycardia development will be blocked by these medications.

Children may require additional fluids, especially if the child has been NPO. Generally, children receiving sedation for elective procedures should follow the same fasting guidelines as children receiving general anesthesia. The American Society of Anesthesiologists has developed guidelines for appropriate food and liquid intake for children prior to elective sedation (Table 14). For the child who undergoes sedation for an emergent procedure, the benefits and risks should be evaluated, with consideration given to the amount and type of liquids or solids ingested [32]. Routine preoperative administration of pharmacologic treatment to reduce gastric volume and increase gastric pH in patients who have no apparent increased risk for pulmonary aspiration is not recommended by the ASA [32].

Table 14: APPROPRIATE INTAKE OF FOOD/LIQUIDS BEFORE ELECTIVE SEDATION FOR CHILDREN

Ingested Material

Minimum Fasting Period

Clear liquids (i.e., water, fruit juices without pulp, carbonated beverages)

2 hours

Breast milk

4 hours

Infant formula

6 hours

Nonhuman milk: Because nonhuman milk is similar to solids in gastric emptying time, the amount ingested should be considered when determining an appropriate fasting period.

6 hours

Light meal: A light meal typically consists of toast and clear liquids. Meals that include fried or fatty foods or meat may prolong gastric emptying time. Additional fasting time (e.g., eight hours or more) may be needed in these cases. Both the amount and type of foods ingested should be considered when determining an appropriate fasting period.

6 hours

Source: [32]

Additional considerations for nursing care include keeping the child warm during the procedure. Children should also be monitored for the increased risk of paradoxical excitement and emergent reactions. Parental presence during the recovery phase commonly helps to reduce the severity of emergent excitement in children. However, prior to having a parent present in the recovery area, the nurse should evaluate the parent's level of comfort in dealing with a potentially confused and combative child. Many parents do not feel comfortable watching their child experience these types of reactions, and they should not be forced to do so under the auspices that it is helpful to the child.

Finally, discharge of the child should take into consideration the age-appropriate behaviors in children. Meeting the preprocedural level of functioning is the aim of discharge criteria in the child. A number of children undergoing sedation may not be ambulatory or able to sit without support; however, they should be able to perform those developmental tasks that they were able to accomplish in the preprocedural phase prior to discharge.

It is more common for children to vomit in the postsedation period. The caregiver should be aware of this risk and undertake measures to reduce the risk of aspiration. In addition, the caregiver should be instructed that it is not common for the child to keep vomiting. If this were to occur, the child should be returned to the institution or a follow-up telephone call should be placed.

Discharge instructions for the pediatric population should be given to both the child and the caregiver. Dependent on the age of the child, he or she may not be able to fully comprehend the need to adhere to these instructions.

The challenge in sedating the pediatric patient is achieving an appropriate level of sedation while preventing oversedation and other complications. Appropriate techniques of drug dosing and vigilant monitoring of this patient population will assure competent drug delivery.

9. MODERATE SEDATION OF THE GERIATRIC PATIENT

Sedation of the geriatric patient can provide a calm, comfortable environment for the patient who may be experiencing a high level of anxiety. However, the psychologic needs of this population are great, and the increased risk of complications is readily known to practitioners as well as patients. Allowing for adequate history taking and patient instruction is imperative to providing safe delivery of care.

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

As individuals age, there is a decrease in both laryngeal and pharyngeal reflexes; thus, the patient is at increased risk for airway compromise. The loss of dentition changes the shape of the mouth, and it may become a challenge to achieve proper placement and seal with ventilation masks. Should airway compromise develop, osteoarthritis of the neck may preclude placing the patient in the standard head-tilt/jaw-thrust maneuver. In this instance, positioning the elderly patient's head becomes a formidable task that requires the practitioner to be adaptable and able to work within the confines of the situation. If the head-tilt maneuver is not possible, placing the patient in the left lateral decubitus position may decrease the risk of inadvertent aspiration.

One of the major complications of aging and the use of moderate sedation occurs when benzodiazepines and/or opiates are used. Both of these drug classes produce enhanced depression of the patient's respiratory drive, which is a normal change that occurs with aging. With rising levels of CO_2 and falling levels of oxygenation, the younger person will increase the depth and rate of respirations to ensure adequate tissue oxygenation. This ability to respond to these changes is dampened in the elderly, putting the individual at risk for profound hypoxemia [153]. Concurrently, the blood oxygen levels decrease with age; it is not uncommon for the elderly individual to have blood oxygen levels of 80 torr with oxygen saturations of approximately 93% to 95% [153]. These compounded problems lead to a patient who is at increased risk for hypoxia and hypercapnia, which requires judicious monitoring to prevent their occurrence.

The aging process produces a decrease in cardiac output, leading to decreased renal and hepatic blood flow. By the time an individual is 80 years of age, it is said that their cardiac output is one-half that of an individual 20 years of age [154]. This drop in cardiac output requires slower loading times in the elderly, especially with barbiturates.

In addition, the cardiac conduction system deteriorates, enhancing the risk of dysrhythmia development. Combined with developing hypoxia, it is not uncommon to see dysrhythmias in this patient population [154].

Sedation drugs utilized for moderate sedation affect the central nervous system. For the elderly patient, there is an increased sensitivity to these medications. It is highly recommended that the dosage of sedating agents be decreased in the elderly person to prevent profound, deep sedation [153]. Assessing this individual may also be challenging; as individuals age there may be a decrease in cognitive abilities, memory, and data acquisition. The standard neurologic testing should be done with consideration of these changes.

It is estimated that a large percentage of the elderly population is chronically volume depleted. The frequent use of diuretic therapy presupposes these individuals to circulating volume deficits. Drugs that are water soluble have an enhanced action potential in these volume depleted patients.

Additionally, approximately 6% to 11% of older adults are heavy users of alcohol, many of whom under-report their alcohol ingestion [155]. Furthermore, an estimated 6% to 49% of older persons in hospitals or other healthcare facilities evidence either illness or other serious consequences of alcohol abuse [156]. It is these patients who can present a unique challenge when they decompensate during sedation due to combined effects of the residual alcohol in their blood stream and the sedating medication [155,156].

PHARMACOLOGIC CONSIDERATIONS

Decreases in both hepatic and renal function, which naturally occur with aging, lead to a longer half-life and longer clearance of most medications. This translates to a longer length of action; therefore, recovery from moderate sedation is longer in the elderly than it is in other adult populations [59,154]. Additionally, the elderly patient is at risk for cumulative drug effects, causing altered function of the sedating drugs. This is commonly seen when this patient population is given benzodiazepines and opiates concurrently.

Drug binding is also altered in the elderly patient. Protein-bound drugs attain an increased concentration of circulating drug secondary to the decrease in albumin that occurs with aging [154]. With more circulating drug available, the more profound the drug effects will be. Hence, any sedating drug that is protein bound will produce more profound sedation, increasing the risk of oversedation. The amount of body protein in an individual can be assessed by evaluating the patient's serum albumin level. The lower the albumin level, the lower the amount of body protein. Any patient with a decreased serum albumin would be expected to have the aforementioned risk of profound sedation.

Water-soluble drugs will have a greater amount of drug available at the target site, as the amount of total body water decreases with age [154,156]. As with protein-bound drugs, the risk of increased drug effects occurs. Coupled with the chronic volume-depleted state, the risk of oversedation occurring with water-soluble drugs is greatly increased.

Conversely, fat-soluble drugs have less drug available at the target site secondary to the increase in body fat that accumulates during aging. These drugs are sequestered in the fat and will have a slower release and, therefore, a longer length of action. Any fat-soluble drug given to an elderly individual can be expected to produce a slower, lengthier recovery period [154].

Adverse drug reactions and interactions are more common in this population due to the fact that the number of over-the-counter and prescription drugs and herbal supplements ingested is much higher [156]. Elderly patients should be monitored for adverse drug reactions, and these should be reported to the appropriate agencies. Cardiovascular medications can cause significant compounded cardiovascular instability in the elderly by producing significant bradycardia and hypotension.

Recommended drug dosing in the elderly patient should be done with the following statement in mind: Start Low and Go Slow. Adherence to this advice will greatly reduce the risk of complication development. Dosing of benzodiazepines is generally reduced by 30% to 50% from the normal adult dosage [59]. Barbiturates should be administered slowly due to decreased cardiac output and circulation times. If given too rapidly, profound hypotension and a decreased level of consciousness will occur. Sedative hypnotic doses should also be decreased, and the risk of paradoxical excitement/delirium is more common with these medications [59].

Titrating drug dosages in the elderly should be considered standard practice [59,154]. The risk of complications is high in this population, and the practitioner should undertake measures to reduce these risks.

NURSING CARE

The practitioner providing sedation to the elderly patient should adjust care during the presedation, intrasedation, and postsedation phases. Initially, thorough preprocedural assessment is imperative, including a full evaluation of the patient's airway. Recognition of comorbidities is essential to decrease the risk of complications.

Evidence Based Practice Recommendation

The American Society for Gastrointestinal Endoscopy Practice Committee recommends standard monitoring procedures in the elderly during moderate sedation with heightened awareness of this population's increased response to sedatives.

https://www.asge.org/docs/default-source/education/practice_guidelines/doc-modifications-in-endoscopic-practice-for-the-elderly.pdf?sfvrsn=60c94951_6

Last Accessed: July 14, 2020

Level of Evidence: +++O (Moderate quality)

Presedation vital signs and oxygen saturations should be attained, noting that anxiety and fear may cause these to be inaccurate. Once these parameters are attained, oxygen should be administered, with consideration of the patient with a history of pulmonary disease, which may preclude the use of high oxygen percentages. Cardiac monitoring should be instituted prior to sedation and continued throughout the sedation and recovery periods. Volume replacement may be necessary; however, it is just as important to prevent volume overload in the patient with a positive cardiac history. It is also important to remember that the elderly patient is at risk for developing hypothermia, and the patient should be kept warm during long procedures, especially those interventions with large body surface exposure.

Discharge criteria for the elderly patient may require an adjustment in the ability to meet presedation values. The normally hypertensive patient may remain slightly hypotensive secondary to prolonged cardiovascular effects of the drugs administered. This hypotension may last as long as 24 hours and should not prevent the patient from being discharged.

It is important in managing sedation in the elderly to remember these criteria to deliver safe care. With the increasing incidence of moderate sedation procedures being performed in this population, the practitioner will continue to see these patients on a regular basis.

10. MODERATE SEDATION OF THE OBSTETRIC PATIENT

Moderate sedation in the obstetric setting can be done for a variety of reasons. It is imperative that the pregnant woman be monitored for the effects of sedation on her fetus as well as herself. Many of the changes that occur with pregnancy occur over time; others can occur as soon as the woman conceives. In moderate sedation, these anatomic and physiologic responses should be addressed.

ANATOMIC AND PHYSIOLOGIC DIFFERENCES

Airway changes in the pregnant woman include engorgement of the nasal and mucous membranes leading to a narrowing of the airway. Tidal volume increases by 30% to 35%. The respiratory rate remains relatively constant or increases slightly. In order to meet her and her fetus's oxygen demands, there is a compensatory and significant increase in minute ventilation. However, the patient's vital capacity decreases as the diaphragm becomes elevated [157].

Hemodynamic changes occur during pregnancy as well. There is an increase in heart rate, which reaches a maximal value of 10% to 30% above baseline values by 32 weeks. Cardiac output increases 30% to 50% above baseline levels by 25 weeks and may be affected by position [157]. Systolic blood pressure may drop, and the patient is at risk for developing supine hypotension [157]. It is imperative that the practitioner be aware of these changes as assessment parameters are altered and the recognition of hemodynamic instability is more challenging [158].

In addition, during pregnancy there is an increase in circulating volume. The majority of this increase is in plasma volume. This blood volume increases progressively, peaking at a value of approximately 40% above baseline by the third trimester [157].

PHARMACOLOGIC CONSIDERATIONS

Sedation medications are like any other drug given during pregnancy, and considerations should be made as to the effects of the drug on both the mother and the fetus. The greatest risks occur during the first trimester, when fetal development is most adversely affected. Additional risks occur at the time of delivery, as certain medications can cross the placental barrier, leading to a sedated newborn [59].

Drug dosing in the pregnant patient is the same as for a nonpregnant female. However, the increased circulating volume will affect how water-soluble drugs are distributed and absorbed [158]. These drugs become less concentrated; therefore, onset of action is somewhat slower, although not significantly. The dosage of the drug may need to be increased, although it is safer to start at the normal recommended dosage for a nonpregnant female and increase dosage as needed.

NURSING CARE

The risk of airway compromise is increased in the pregnant patient and astute airway assessment is critical. Statistics show that 1 in 300 pregnant women will have an airway that is difficult to manage [159]. When checking for emergency support supplies, ensure that a smaller-than-anticipated endotracheal tube is available. A pregnant woman with engorged tissues may require an endotracheal tube as small as a 6.0; many of these tubes may not be cuffed, as they are usually used in the pediatric population. Therefore, it is necessary to check that the appropriate equipment is available.

Supplemental oxygen should be readily available and used early. The developing hypoxia affects not only the mother but the fetus as well [158]. Additionally, it is known that hypoxia can precipitate contractions, which should be avoided if at all possible.

Dehydration can also precipitate contractions. Therefore, ensuring adequate volume replacement for the patient who has been kept NPO is imperative. If sedation is performed emergently, assessment of the patient's food and fluid intake should be done with consideration of the fact that gastric emptying time is prolonged during pregnancy. The use of histamine blockers is recommended in this population to reduce the risk of gastric reflux and aspiration [57,158].

Positioning the patient in the left lateral decubitus position will help ensure adequate blood return to the heart. If the patient must be in the flat-lying, recumbent position for the intervention, placing a towel or blanket under the right hip to rotate the hips to the left will help achieve the same objective [59].

Fetal monitoring should be considered in all high-risk patients [158]. Instituting fetal monitoring should be performed by someone skilled in monitor use and the detection of subtle changes. Unless the nurse commonly works in the obstetric setting, an additional individual to monitor the mother and the fetus would be most helpful. When monitoring the fetus, observation of changes in heart rate and rhythm are the most sensitive indicators of fetal well-being. Decelerations in fetal heart rate that are spontaneous or in response to uterine contractions are considered signs of fetal distress [158]. In most instances, administration of oxygen and repositioning the mother may correct this untoward complication.

Although utilized infrequently in the obstetric patient, moderate sedation can be a very beneficial therapy. The mother who is comfortable and anxiety-free can provide the fetus with a safe, supportive environment. It is the nurse's responsibility to ensure that the mother is also in a safe and supportive environment throughout the intervention.

11. SEDATION OF THE CRITICALLY ILL PATIENT

Sedation in the critically ill patient has changed dramatically over time. For many years, the patient in the ICU was deeply sedated and immobile. After years of research, it was concluded that this deep sedation was not beneficial for the patient; in fact, it produced a number of complications. The deeply sedated patient was unable to move or shift positions, leading to an increased risk of pressure sore development. Patients who were mechanically ventilated in the control mode were difficult to wean from the ventilator when the appropriate time came. In addition, family members were unable to interact with their loved ones, leading to significant emotional impact upon these individuals.

Today, the patient in the ICU is lightly sedated, and sedation is used as an adjunct to achieve therapeutic results. Patients are sedated in order to minimize patient discomfort, alleviate anxiety and agitation, attenuate the stress response, facilitate mechanical ventilation, and decrease physiologic demands. Sedation is generally for longer time frames and may be delivered by continuous infusion.

A number of interventions in the ICU are painful and/or produce discomfort. Placement of invasive monitoring lines, endotracheal tube intubation, and Foley catheter placement all increase patient discomfort. Sedatives with analgesic properties, such as narcotics, can help alleviate this pain of intrusion.

Patient's senses in the ICU are assaulted by a number of stimuli, including lights, sounds, and activities. These assaults can greatly increase the patient's level of anxiety and agitation, often leading to an increase in heart rate and blood pressure. Mild sedation can attenuate this response, decreasing the stressors upon the individual's metabolic demands. Patient comfort should be a primary concern [160].

Many modes of ventilatory support are uncomfortable to the patient and may cause the patient to fight the respirator. As an example, permissive hypercapnia is accomplished over the course of a few days, allowing the patient's CO_2 level to rise to higher than normal levels. The normal compensatory response in the healthy individual would be to increase the respiratory rate to express this excess CO_2. The patient is sedated to avoid this compensatory response.

It is well known that the stress response that occurs in an ICU patient greatly increases the patient's physiologic demands. These increased demands have a number of negative outcomes; as an example, wound healing is compromised. In an effort to reduce this stress response, the patient may be sedated to improve physiologic functioning and a return to a normal state of health.

Continuous infusion of medications is a highly popular method of ICU sedation [160]. Some patients may still be sedated on an every four-to-six-hour basis, which, if medication administration is delayed, will produce peak and trough levels of drugs. As patient and family demands are being encouraged and valued, preventing these highs and lows in sedation responses is becoming more important, making drug bolusing a less popular method of drug dosing. However, the practitioner should be aware that prolonged continual infusion of certain drugs can extend the half-life and length of action of these medications. For example, the half-life of morphine sulfate in the non-ICU patient ranges from 1.5 to 4 hours [59]. In the patient on a continuous morphine infusion in the ICU, the half-life can extend to 5.9 to 13 hours [6]. This longer length of action can delay recovery from sedation, prolonging ICU stays. Trying to meet the patient's needs without oversedation is a continual challenge in providing sedation to this population [160].

Concomitantly, sedation in the ICU may be accompanied by the use of neuromuscular blockade [161]. The level of paralysis may vary depending upon patient need and condition. However, the use of blockade may prevent full evaluation of the patient's level of response. Additionally, neuromuscular blockade will prevent using certain sedation scales as patient responses are compromised by the paralysis [161].

It has been recommended that, in addition to the necessity for evaluation in the postsedation period, ICU patients be monitored for sedation status while receiving medications [160]. One study evaluated the use of the RASS to evaluate changes in sedation and analgesia over consecutive days in the ICU. The researchers determined that the RASS was an effective tool and assisted in guiding goal-oriented sedation [160]. Other scales that have been tested for validity in ICU patients include the Ramsay Sedation Score, Sedation-Agitation Scale (SAS) Glasgow Coma Scale, Motor Activity Assessment Scale, Auditory Evoked Potentials, and the Nursing Instrument for the Communication of Sedation [162,163,164]. The use of sedation scales and protocols designed to minimize sedative use are associated with improved ICU patient outcomes, including shortened duration of mechanical ventilation, shortened ICU stay and length of hospital stay, and decreased incidences of delirium and long-term cognitive dysfunction [164].

Many institutions using sedation in the critically ill develop guidelines specifically for this patient population. The goals and objectives of ICU sedation do vary from those previously discussed. If sedation in the ICU is considered "moderate sedation," the policy and procedure for sedation should reflect this change in patient outcomes.

12. PATIENTS UNDERGOING PROCEDURAL INTERVENTIONS

Many patients receive moderate sedation when undergoing procedures in a number of settings, including, but not limited to, cardiac catheterization laboratories, endoscopy settings, gastroenterology settings, radiology settings, and other ambulatory departments. If these patients are young or elderly, the parameters previously discussed should be considered. However, in certain situations with certain procedures, there are other issues that should be addressed, and a brief discussion of these issues will be presented here.

RADIOLOGIC INTERVENTIONS

The patient undergoing radiologic procedures may be administered contrast media that has the potential to alter pulse oximeter readings [98,100]. The dye prevents the passage of the light through the tissues, thus giving inaccurate readings. These effects may last for only a brief period; however, in other situations they may last minutes to hours. Variables include the volume of dye administered, the size of the vessel in which the dye was injected, the patient's cardiac output and circulation time, and the renal function of the patient [98]. The longer the dye is on board, the longer this effect upon pulse oximetry monitoring will be experienced. The disadvantage is that the practitioner is not always able to ascertain when the dye is cleared from the body. Thus, the nurse caring for this patient should use other physical assessment tools to evaluate the oxygenation status of the patient [98].

Additionally, contrast dyes may have high sodium levels that produce a transient hypertensive period, usually followed in 15 to 20 minutes by a diuretic phase. Furthermore, during this time the patient has an increase in cardiac filling pressures. For the patient with a compromised cardiovascular system, these changes in vital signs and cardiovascular volume may not be well tolerated. It is imperative that the practitioner continually monitor these patients and intervene, should the effects be detrimental and/or lengthy in the patient.

Another complication occurring in this setting is the development of allergic or adverse reactions. Although these reactions are characterized by activation of mediators typical of allergic response, they are not antigen mediated and, therefore, are not true allergies [165]. The nurse should monitor the patient for the initial signs of developing anaphylactoid response: flushing, chills, nausea and/or vomiting, and urticaria. Epinephrine and diphenhydramine should be readily available in the setting for management of this complication [165].

For patients undergoing MRI, there are a number of important considerations. The equipment that is used should be determined to be magnetic resonance-compatible. All cables and coils should be checked to insure that there are no loops of cable or wire that can burn the patient or distort the image. Imaging is done inside a large magnet, and access to the patient is minimal. Coupled with this limited access, visibility is compromised; the room lighting is altered, and the observation window is covered with a copper mesh screen. Noise levels can reach 95 decibels and may affect the ability to hear equipment alarms. It is critical that these patients receive diligent monitoring throughout the procedure.

Medications used in children undergoing magnetic imaging require astute patient assessment, which, as noted, is challenging while the patient is in the scanner. Additionally, combination chloral hydrate and pentobarbital can produce profound sedation in the child with the risk of airway compromise and deep sedation. Nurses administering these drugs should be well versed in their actions and uses and provide vigilant monitoring during performance of the study.

Finally, many patients are anxious while undergoing studies in the radiology suite. The procedures may cause pain and discomfort, some of which can be treated with analgesics. Patients who are claustrophobic become highly anxious when an MRI is performed. Continual reassurance and support, in unison with adequate sedation, will help reduce these factors.

CARDIAC CATHETERIZATIONS AND ELECTROPHYSIOLOGIC STUDIES

Patients undergoing cardiac interventional procedures are generally cardiovascularly compromised prior to the start of the procedure. Many of these interventions are done on an elective basis to allow time for optimizing cardiovascular function. However, the patient may require emergent intervention without adequate time for stabilization. Therefore, it is imperative that presedation assessment be thorough to recognize patient risks. Patients with a history of hemodynamic instability may be at risk for significant hypotension immediately after administration of sedation agents, especially narcotics. For this reason, the sedating drug administered should be chosen with consideration of this risk.

Many cardiac studies are quite lengthy and sedation of the patient can last up to six hours or more. Obviously, with this length of procedure, nursing care and documentation is more in-depth. Providing sedation throughout the procedure can be challenging. Administering sedation with continuous infusions can ensure a therapeutic blood level that is difficult to maintain with the bolus technique of administration.

A number of sedating medications affect the cardiac conduction system, and this should be a consideration for any patient undergoing an electrophysiologic study. Also, most antidysrhythmics are discontinued prior to the start of this type of procedure to allow for drug effect evaluation. Therefore, cardiac monitoring of rate and rhythm is imperative to providing safe patient care.

ENDOSCOPIC PROCEDURES

The advantage of the majority of endoscopic procedures is their short procedural time. The use of short-acting sedatives is efficient in this population; thus, repeat drug dosing may not be required. This translates to short recovery times with early discharge [147].

During these procedures, patients may be asked to cooperate with position changes, etc. It is important that the patient's level of consciousness be appropriate to allow the patient to cooperate with these requests. As an example, during endoscopic retrograde cholangiopancreatography (ERCP) the patient is commonly placed in the prone position, which presents additional challenges in the ability to monitor the patient's airway [94,166]. Oversedation of this population is not recommended, as patient compliance and the patient's protective mechanisms are compromised [166].

Manipulation of the endoscope while in the lower esophagus may lead to cardiac dysrhythmia development. Continual cardiac rhythm monitoring should be required for all these patients. If dysrhythmias do develop, repositioning of the scope may avert their progression.

13. CASE STUDIES

The radiology department occasionally performs moderate sedation on patients who exhibit a high level of anxiety prior to a procedure. On today's schedule, there are two patients requiring MRIs. Both patients will require moderate sedation to allow the radiologist and technician to obtain an accurate study.

A nurse from the emergency department is scheduled to administer the moderate sedation agents as no registered nurse is routinely staffed in radiology. Upon arrival, the nurse begins to prepare the radiology suite for the procedure and review the patients' histories and physicals.

PATIENT J

Patient J is a young girl, 2 years of age, with a history of hydrocephalus since birth. She has been brought to the hospital with complaints of continuous vomiting, lethargy, and inappropriate behavior for her age. The pediatric neurologist orders the MRI to evaluate the current status of her cerebral spinal fluid circulation.

The neurologist orders the procedure to be performed under moderate sedation, as Patient J is not cooperative and is easily agitated. The nurse reviews her history, which is otherwise unremarkable. She is not taking any current medications at home, either prescribed or over-the-counter. She had previously been on anticonvulsant medication, which was discontinued more than a week prior to the procedure.

Upon arrival of Patient J in the radiology suite, the nurse performs a presedation assessment. Her cardiac and respiratory systems are within normal limits for her age. However, neurologic assessment of Patient J is challenging due to her decreased mental status. The nurse notes that Patient J responds to her mother, who accompanies her to the department. Although Patient J has had previous MRIs, the nurse discusses the procedure with the mother and patient. She explains what will be happening and that she will be asked to lie still for a number of minutes. Additionally, the nurse explains the use of moderate sedation to the mother and patient, ensuring the mother that Patient J will be comfortable and everything will be done to try and reduce her fear of separation from her mother. When the mother asks to stay in the room with Patient J, the nurse explains that this is neither safe nor allowed.

Additional review of Patient J's chart shows that she was admitted yesterday afternoon and received antiemetics upon admission. Upon admission, her blood pressure was low for her age. Her admission vital signs were: blood pressure, 84/68 mm Hg; pulse, 104 bpm; respiratory rate, 30 breaths/minute; and temperature, 99.7°F. Currently, her blood pressure is 92/64 mm Hg; pulse, 100; and respiratory rate, 30 breaths/minute. She has an IV line infusing 5% dextrose in 0.25% normal saline at a rate of 45 cc/hr. Her admission weight was 25 pounds (approximately 11 kgs). Upon questioning, her mother states that she has lost some weight; her normal weight is about 28 pounds. She has not taken anything by mouth since admission.

After obtaining the presedation assessment, the nurse must prepare the room, equipment, and medications for Patient J. The nurse ensures that a crash cart is located in the radiology department and checks the defibrillator for proper functioning. The oxygen set-up in the scanner is checked, as is the suction. The pulse oximeter and noninvasive blood pressure monitor are warmed up to assure that they will be ready when the sedation is to begin. Furthermore, all equipment should be determined to be MR-compatible to prevent burns during the procedure.

The medication ordered for Patient J includes midazolam 0.02 mg/kg IV or a dose of 0.5 mg/kg orally. (As Patient J has a history of vomiting, the nurse chooses to administer the midazolam via the intravenous route to ensure proper drug dosing and reduce the risk of vomiting.) Also ordered is fentanyl 0.5 mcg/kg, to be given in the event that the midazolam is inadequate in achieving the appropriate level of sedation. The nurse first calculates the correct dose based upon Patient J's weight of 11 kgs. Thus, the dose of midazolam is 0.2 mg, and the dose of fentanyl is 5 mcg. These medications are drawn into syringes and labeled. Additionally, the nurse draws 0.5 mg of naloxone (based on a dose of 0.05 mg/kg); this syringe is also labeled and placed off to the side, where it is easily accessible in the event of oversedation or other complications.

Finally, Patient J is brought into the room with the scanner and hooked up to the oxygen, pulse oximeter, and noninvasive blood pressure monitor. A presedation set of vital signs are obtained, including oxygen saturation measurements before and after oxygen therapy is initiated. The patient's IV is checked for patency and another set of vital signs is obtained. At this point, the mother is asked to leave the room, and Patient J becomes quite agitated. The radiologist orders the nurse to begin administering the sedation medications immediately in order to relax Patient J and prevent any further agitation.

The nurse administers the 0.2 mg of midazolam and monitors Patient J's response to the medication. After one minute, her blood pressure is noted to fall to a systolic pressure of 84 mm Hg. Neurologically, she is less agitated and appears to be relaxing. When asked her name she answers appropriately, but also asks again for her mother. The blood pressure decline is of concern; in response to this, the nurse increases the IV rate to 50 cc/hr. Within five minutes, her blood pressure is back up to its presedation level.

The radiologist is ready to start the scan; however, Patient J continues to move on the scanner table. The radiologist requests the nurse to administer additional medication, and the nurse administers an additional 0.2 mg of midazolam. Within two minutes, Patient J is quiet and calm and the procedure is initiated.

During the procedure, the nurse must leave the room and monitor the patient from the outside viewing area. Patient J's vital signs are continually monitored via the blood pressure monitor cycles. The nurse also observes the pulse oximeter reading as part of the patient assessment. After 10 minutes, the nurse notes that Patient J's pulse oximeter reading has fallen to a level of 91%. The radiologist is informed, and the scan is momentarily terminated to allow the nurse to enter the room and evaluate the patient. The patient's respiratory rate is now 15 breaths/minute, and the pulse oximeter reading has fallen further to 90%. The nurse immediately places Patient J's head into the sniffing position to open her airway and increase the oxygen flow rate. The patient's pulse oximeter reading increases to only 91% with this maneuver, and the nurse decides to administer a reversal agent to prevent the respiratory insufficiency from progressing further.

It is at this point that the nurse realizes that naloxone has been drawn as an antagonist. As the patient has only thus far received midazolam, the naloxone will be ineffective at reversing a benzodiazepine, as it is a narcotic antagonist. Immediately, the nurse draws up a dose of 0.1 mg of flumazenil and administers this through the IV line. Within two minutes, Patient J is breathing at a rate of 25 breaths/minute, her pulse oximeter reading has increased to 94% saturation, and her other vital signs remain within normal limits. However, she is starting to move on the table and the scan cannot be completed until she is sedated adequately to prevent body movement.

Patient J is allowed to stabilize for another five minutes, at which time the radiologist requests further sedation so the scan can be completed. The remaining time to perform the scan is approximately 10 to 12 minutes. The nurse now chooses to administer 2.5 mcg of fentanyl to Patient J and to monitor the drug effects. Although a dose of 5 mcg was ordered, the nurse is concerned that the patient will develop a second episode of respiratory insufficiency. After three minutes, Patient J remains agitated and a second dose of 2.5 mcg of fentanyl is administered.

Throughout administration of the fentanyl, Patient J's vital signs and oxygen saturations remain within normal limits. After the second dose of fentanyl (for a total of 5 mcg), the procedure can continue and is able to be completed without further complication.

Upon completion, Patient J's mother is allowed to return to her daughter's bedside and the effects of the medication are allowed to wear off. No further reversal agents are administered. Based upon the length of action of the midazolam and fentanyl, it is expected that Patient J will remain sedated for another 20 to 30 minutes. During this recovery period, the nurse continues to assess the patient's vital signs and oxygen saturations, and all parameters remain within normal limits.

Due to the fact that Patient J is an inpatient, the recovery and discharge is different than for a patient who is being discharged to home. After 30 minutes, Patient J remains sleepy but opens her eyes and recognizes her mother. When asked her name she answers appropriately. At this point, the nurse finishes documenting the procedure and Patient J is returned to her bed on the pediatric unit.

Discussion

The nurse caring for Patient J performed quite well. The presedation assessment was very thorough; it was important to consider the fact that continuous vomiting can lead to protracted volume status in children, and this could impact her response to medications. The nurse recognized that the intravenous route of medication administration is far more appropriate in this patient than the oral route. Her history of a decreased level of consciousness could hinder oral administration. Additionally, with the patient's history of vomiting, oral drug administration could precipitate a further bout of vomiting.

Preparing the medications was critical to the success of this procedure. The biggest error was in not drawing up a dose of flumazenil. The nurse chose to prepare the naloxone, without considering that the fentanyl may not have been utilized at all. It would have been to everyone's benefit had both the naloxone and flumazenil been prepared initially. However, the outcome was good; this delay did not harm the patient in any manner.

When the radiologist asked to continue the procedure, the nurse administered a dose of fentanyl that was one-half of the ordered dose, most likely based on the fact that Patient J had experienced the previous episode of respiratory insufficiency. This choice was not inappropriate, but in review of the case, it was probably inadequate due to the length of time since the initial administration of the midazolam. Had the nurse recognized that the duration of the midazolam was reached, administering the full 5 mcg of fentanyl most likely would have been safe. However, in this instance, the nurse chose to act cautiously, and no one should find fault with this action.

Finally, the recovery of this patient was uneventful. The patient reached her presedation level of functioning. As she had an altered level of functioning to begin with, this was an appropriate way to evaluate her neurologic status. However, had the nurse not performed a good presedation assessment, recognition of the patient's return to her presedation level of functioning would have been challenging.

PATIENT D

The next patient scheduled for the MRI scanner is Patient D, a man 76 years of age, who fell at home yesterday and has a history of falling. There is point tenderness at the hip joint, and the patient is unable to ambulate. The orthopedic surgeon requests an MRI of the hip and pelvic area to determine what, if any, injury could be causing this pain and dysfunction.

Patient D states that he is very claustrophobic and initially refused the MRI because of the fear of the "tube." After discussion with the surgeon, with a guarantee that he would be sedated and comfortable, Patient D agreed to the scan.

Upon review of the patient's history, it is determined that he has a history of congestive heart failure, smokes two packs of cigarettes a day, and denies alcohol ingestion. The nurse performs a presedation assessment, obtaining baseline vital signs and auscultates the patient's heart and lungs. The patient is asked to open his mouth wide, and a Mallampati score of 2 is assigned to the patient. The patient is questioned about any dentures or partials, which he denies. An anesthesia history is obtained; the patient has had two previous surgeries under general anesthesia. He denies any complications with either procedure.

Due to the patient's history of congestive heart failure, the nurse reviews the chart for a current 12-lead electrocardiogram and finds that one was obtained yesterday on admission. Additionally, Patient D's admission laboratory values are reviewed. The only abnormality is a potassium level of 3.3 mEq. The nurse determines that the patient is a Class 3 on the ASA Risk Classification score. The nurse also reviews the patient's current medication use, which includes digoxin, furosemide, and naproxen for arthritic pain control.

Although the surgeon reviewed the moderate sedation procedure with the patient, the nurse conducts patient education as well. The nurse explains that the patient will be receiving medications to help him relax and decrease his fears about the scanner. Patient D responds, "Just knock me out. I don't want to remember or feel a thing!" The nurse then proceeds to offer further information; it is imperative that the patient recognize that he will not be asleep. The patient may be asked to respond to questions throughout the procedure to adequately assess the level of sedation. Additionally, the nurse explains that the medications can help alleviate some of the patient's pain, but there is discomfort that is experienced from lying on a hard table. The patient is assured that everything will be done to make the patient as comfortable as possible, but the procedure is not discomfort-free.

At this point, Patient D reconsiders his decision to have the procedure performed. When he agreed to the procedure it was his understanding that he would be asleep, similar to what occurs with general anesthesia. It is unfortunate that the surgeon allowed the patient to develop this misunderstanding; it not only delayed the start of the procedure but backfired in that the patient's level of anxiety was heightened. It took the nurse more than 20 minutes to educate the patient and receive his permission to continue with the scan.

In preparing the room for Patient D, the nurse has only recently finished sedating the first patient and knows the equipment was functional. She places the patient on the monitor, pulse oximeter, and oxygen by face mask. Presedation vital signs are obtained and compared to the vital signs obtained on the inpatient unit. An oxygen saturation of 91% is obtained prior to initiating oxygen therapy, as is expected. With oxygen, the saturation increases to only 93%. The existing IV line is checked for patency.

The medications ordered for Patient D include midazolam 2 mg IV, fentanyl 50 mcg IV, and methohexital 10 mg IV, as needed. The nurse draws the appropriate dosages into syringes and labels each. Learning from the first patient, the nurse draws both flumazenil (0.2 mg) and naloxone (1 mg) and labels these syringes as well.

The radiologist orders the sedation to be initiated, and the nurse administers 2 mg midazolam IV over one minute. The patient demonstrates a slight drop in blood pressure; however, it is within acceptable limits. The patient remains quite agitated, asking when the medication is going to work. At this point, the nurse administers 25 mcg fentanyl IV. Patient D's blood pressure starts to fall after the dose of fentanyl, and the IV rate is increased. The patient continues to complain of discomfort and fear. His heart rate increases to a rate of 90 bpm (from a normal of 62 bpm). The radiologist requests additional sedation medication in an attempt to achieve an appropriate level of sedation in this patient.

The nurse then administers an additional 2 mg IV of midazolam. Patient D appears to relax, and he is moved into the "tube." Immediately upon entering the tube, the patient becomes severely agitated, asking to get out, and calling out, "Somebody help me." It is obvious that the patient's level of sedation is inadequate at this point, and the patient is removed from the scanner. The nurse enters the room and notes that the patient is very confused; he is unable to answer appropriately to his name, he is calling for his wife (who had died three years before), and his blood pressure, pulse, and respiratory rate are all quite high.

The radiologist orders an additional 3 mg IV of midazolam, which the nurse administers. At this point, Patient D appears more relaxed; however, when the nurse approaches the patient to listen to his heart and lungs, the patient starts thrashing about on the table. Obviously, Patient D is at risk of further injury, especially at the injured hip joint. The radiologist orders an additional 3 mg IV midazolam. However, the nurse refuses to administer this dose based upon concern of oversedation, common to the elderly individual. The nurse expresses this concern, and the order is changed to fentanyl 50 mcg IV. The nurse agrees to administer the fentanyl, and upon administration, the patient experiences a short burst of ventricular tachycardia that spontaneously converts to the patient's normal rhythm.

At this point, the radiologist decides to cancel the procedure until such time that the patient can be appropriately sedated. It is obvious that the radiologist blames the nurse for the patient's deterioration.

Despite the apparent animosity, the nurse's responsibility is to stay with Patient D and provide for his safety. The patient's oxygen flow rate is increased, after which the patient becomes quite agitated and removes the oxygen mask. While the nurse is preparing an amiodarone bolus to prevent further episodes of ventricular tachycardia, the patient becomes agitated to the point of requiring restraints. The nurse looks for assistance from other staff members but has been left alone with Patient D.

At this point, the nurse remembers the naloxone and administers 1 mg IV, hoping to see a reduction in the patient's level of agitation. However, this is not accomplished. Subsequently, flumazenil (0.2 mg IV) is administered, and the patient begins to appear more relaxed, with improving vital signs.

After three minutes, the nurse administers a second dose of flumazenil, and Patient D is able to answer questions appropriately. Throughout this time period, the nurse continues to assess Patient D's vital signs, which are slowly returning to normal.

Once the patient reaches his presedation level of functioning, the nurse transfers the patient back to the inpatient unit. Upon moving the patient into his bed, he asks, "What did they find?" Patient D is unaware that the procedure had not been completed.

Discussion

A number of mistakes were made in preparing and sedating Patient D. However, the nurse did perform a good presedation assessment. All the appropriate information was obtained from the patient, and the patient was assessed fully. One omission was putting the information to use. Elderly patients with a history of cardiac disease, especially congestive heart failure, are at increased risk of poor circulation and low cardiac outputs. These patients need special care when administering sedating agents. Additionally, the patient was on digoxin with a low potassium level, increasing the risk of dysrhythmia development. Had the nurse considered the risks involved in this patient, the incidence of ventricular tachycardia may have been avoided by further stabilization measures prior to the start of the sedation.

It was an error on the surgeon's part to assure Patient D that he would be comfortable throughout the procedure. With this false assurance, the patient was at risk for agitation when his expectations were not met. As soon as Patient D entered the scanner, this anxiety level was enhanced. Thus, the medication effects were inadequate to meet the patient's needs.

In preparing the room for this second patient, the nurse assumed that the equipment was functioning properly because it had done so during the last case. This assumption can be deadly; the equipment should always be re-tested prior to the start of a subsequent procedure. In this case, there were no apparent equipment failures, but had this occurred, the outcome could have been disastrous.

The medications ordered for Patient D were probably not the best for an elderly patient with a history of congestive heart failure. Midazolam is known to precipitate an episode of paradoxical excitement in the elderly, which became quite apparent throughout this case study. Of all the narcotics, fentanyl has the least effect upon the cardiovascular system; however, patients with a history of cardiac disease are at risk of hemodynamic instability with any of the sedating drugs. Methohexital, a barbiturate, can precipitate a profound drop in the patient's blood pressure, and although the dosage ordered was quite low, this may have been a risk for Patient D had he received this medication.

Throughout the procedure, the sedating drug of choice was midazolam. The initial dose was tolerated by the patient; however, subsequent doses caused further patient compromise. After the second dose of midazolam, Patient D was moved into the scanner, and this is when he began to exhibit signs of paradoxical excitement and confusion. Rather than treating this with flumazenil, Patient D was administered an additional 3 mg of midazolam, which caused a further decline in his level of functioning and his vital signs.

The nurse was appropriate in refusing to administer the next 3 mg dose of midazolam. However, in its place, fentanyl was administered. Prior to administering the fentanyl, the patient should have been evaluated and the cause of his agitation further investigated.

This dose of fentanyl most likely precipitated a fall in the patient's blood pressure, leading to a decreased coronary artery blood flow and precipitating the run of ventricular tachycardia. Fortunately, the dysrhythmia was self-limiting and the patient did not experience further cardiac failure, including ventricular fibrillation or asystole.

It was at this point that the radiologist canceled the procedure and left the room. Patient D was definitely not stable at this point, and additional backup should have been called. Instead, the nurse continued to support the patient alone. Fortunately, the nurse was able to handle the developments as they arose; however, had the patient developed a second bout of ventricular tachycardia or other life-threatening complications, it would have been difficult to access additional backup support.

Eventually, the nurse remembered the antagonists that were available. The dose of naloxone was appropriate to reverse the effects of the fentanyl; however, Patient D's greatest problem was the agitation secondary to the midazolam. It may have been wiser to administer the flumazenil first, followed by the naloxone, if needed.

During this difficult period, the nurse and the radiologist's relationship deteriorated to the point of becoming ineffective. Early attempts at communication and a collegial discussion of why the patient was deteriorating may have reduced the number of complications experienced by Patient D. It is imperative that the nurse and physician in charge of the procedure communicate regarding patient condition and work together to achieve a successful outcome.

When Patient D returned to his inpatient unit, he did not remember that the MRI was not performed. This is a common occurrence after the administration of benzodiazepines. The antegrade amnesia prevents the patient from remembering details. In many cases, this is a desirable effect; in this case, it may only lead to further patient mistrust. He was told that he would not remember, but at the same time, the procedure was not accomplished.

This case study demonstrates a number of the risks involved in providing moderate sedation to the elderly. This patient population is at increased risk of complications. In addition, they exhibit varying responses to the "typical" sedating medications. Prior to initiating sedation in this population, it is wise to review the risks, consider the causes, and evaluate the potential effectiveness of interventions. Then, if the patient does develop untoward complications, the cause can be more easily identified and therapies instituted earlier.

14. PRACTICE ISSUES

There are a number of issues that remain unresolved regarding the delivery of moderate sedation by nurses. Nurses are concerned about their legal status, training, competencies, and moral obligations in providing safe and competent care. With time and experience, many of these issues will resolve themselves. Others should be evaluated and policies and procedures developed to protect nurses' rights and responsibilities.

The following discussion will focus on these practice issues. At the present time, there is no right or wrong answer in solving these questions; nurses administering moderate sedation should make it their responsibility to determine what they believe to be safe care and adhere to these standards.

ADVANCED CARDIAC LIFE SUPPORT TRAINING

Many questions frequently arise when developing a moderate sedation program. Do nurses need to be Advanced Cardiac Life Support (ACLS) certified? If indeed life-threatening complications arise, should the nurse administering sedating medications be trained in the advanced management of these risks?

Many professional organizations, hospitals, and State Boards of Nursing have examined the issue of cardiac life support training. Some states and institutions have developed policies that clearly state that nurses administering moderate sedation must maintain current ACLS certification or equivalent [167,168]. The advantages of this training are far-reaching. The patient who develops a complication, such as loss of airway or dysrhythmia development, will receive immediate corrective action performed by a trained, certified nurse. It is well documented that the faster the corrective action is undertaken, the better the chance of achieving a full and complete recovery.

Additionally, the algorithms used in ACLS offer a framework for interventional guidelines. Interventions are clearly spelled out and sequenced in a step-by-step manner to alleviate the anxiety that develops when an untoward event occurs. The nurse knows immediately which actions should be performed, and there is no doubt or question as to the course of action.

Despite the apparent benefits of ACLS training, mandatory certification is not supported by a number of organizations. The ASA states that "an individual with advanced life support skills should be immediately available (within five minutes)" [3]. The Joint Commission minimally requires that the physician responsible for prescribing and ordering moderate sedation be competent in managing the patient in the event of complications; basic cardiac life support (BCLS) is required [1]. ACLS certification of the responsible physician is strongly encouraged by the Joint Commission [1]. Neither organization supports the need for ACLS certification by all members of the moderate sedation team. The "scope of practice" for certified sedation registered nurses outlined by the American Association of Moderate Sedation Nurses (AAMSN) states that ACLS training "may" be included as an additional responsibility within the expertise of the individual certified sedation registered nurse [168].

Institutions that require certification in ACLS skills should provide this type of training. The costs of producing an ACLS course are high, training the staff is expensive, and many institutions find this type of training to be unnecessary in providing safe care during moderate sedation.

In response to those who desire ACLS training, an ACLS equivalent training program can be instituted. This course would provide similar information that could be attained in an ACLS course but without providing the certification from the American Heart Association. This ACLS equivalent course would require the individual to demonstrate competency in the following areas: advanced airway management, identification of dysrhythmias, pharmacologic therapy for life-threatening dysrhythmias, and the use of a defibrillator to defibrillate, cardiovert, and institute external pacing, if appropriate. Such a course could be tailored to the institution providing the training to ensure safe care throughout the facility.

The advantage of equivalency training is that, in order to successfully pass the course, the individual must demonstrate competency in the defined areas. ACLS training also requires a demonstration of learned behaviors; however, as those who have previously attained ACLS certification know, the quality of ACLS courses can vary greatly. Learning to intubate a mannequin is nothing like intubating an individual with a compromised airway. Therefore, this equivalency training can be even more favorable to successful outcomes if it is presented appropriately.

These issues will most likely continue to be a source of debate. Those who strongly believe that ACLS certification is beneficial are not inappropriate in striving for certification. On the other hand, equivalency training may be adequate for the vast majority of moderate sedation providers. Regardless of the type of training, the important issue that should always be considered prior to the start of any sedating procedure is the immediate availability of backup assistance.

MEDICAL-LEGAL CONSIDERATIONS

In determining the nurse's scope of practice in regards to sedation administration, a number of resources should be accessed. The State Board of Nursing should be consulted as to nurses' legal scope of practice [169]. The State Boards of Nursing in all 50 states address the administration of moderate sedation, and it is imperative that the nurse be aware of these legal limitations. Some Boards of Nursing have developed fairly stringent guidelines for sedation administration. Others have more loose definitions of nurses' responsibilities that allow the nurse and the institution to develop their own policies regarding drug delivery.

Another organization that should be consulted prior to developing a moderate sedation policy is the Joint Commission. Historically, in each subsequent yearly manual, more rules and regulations regarding the delivery of moderate sedation are delineated. The Joint Commission states that the same standards of care should be met throughout the healthcare facility [1]. In other words, moderate sedation delivery in the operating room should meet the same standards as moderate sedation delivery in the radiology suite. The need to maintain current practice is critical to maintaining accreditation.

Additionally, a number of professional organizations have developed position statements regarding nursing delivery of sedation medications. The American Nurses Association first published their position statement in September 1991, and this position statement has been endorsed by twenty-three other nurses' organizations [170]. The AAMSN was founded in 2008 to foster patient safety through education for nonanesthetist RNs and to promote adherence to ANA, AANA, and ASA standards and guidelines for RNs who practice moderate sedation [171]. A number of medical organizations have also developed position statements. The American Academy of Pediatrics (AAP) has published guidelines for pediatric sedation [5]. Many, including the Joint Commission, consider these AAP guidelines as the standard for pediatric sedation delivery.

Determining the scope of practice for sedation delivery is not an easy task. Variations in practice settings, procedural interventions, and clinical situations can all present challenges to developing one set of guidelines. However, it is critical that these guidelines be well thought out and detailed in order to protect the legal practice of the nurses delivering moderate sedation.

POLICIES AND PROCEDURES

The scope of practice should be spelled out in the facility's policies and procedures for moderate sedation. These policies and procedures should be developed by a multidisciplinary team. They should identify the methods of authority, responsibility, and accountability for safe sedation care. Areas to be addressed include nursing care, patient care, and administrative concerns. The policies and procedures should be readily available in the unit where the sedation is being administered in the event that questions concerning responsibilities of care arise.

The policy should begin with a definition of the scope of practice. The intent of sedation should be detailed, including a definition of moderate sedation. The purpose of the policy should be clearly outlined.

Sample Moderate Sedation Policy

Policy

University Medical Center provides moderate sedation to patients in multiple settings, including but not limited to: the operating room, the endoscopy laboratory, the cardiac catheterization laboratory, cardioversion, the emergency department, the diagnostic imaging department, and the obstetric department. In all of these locations, a patient with the same health status can expect a comparable level of preprocedure, intraprocedure, and postprocedure care provided by equivalently trained personnel.

Purpose

1. To provide patient safety and early detection of problems that may arise during and after the administration of moderate sedation.

2. To outline responsibilities for monitoring and caring for the patient receiving moderate sedation.

3. To provide that only professionals who have demonstrated competency in moderate sedation may administer medications, including IV, and monitor patients receiving said medications.

Definitions

1. Moderate sedation/analgesia: a drug-induced depression of consciousness during which the individual responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

2. Loss of protective reflexes: the inability to handle secretions without aspiration or to maintain a patent airway independently.

3. Deep sedation: loss of protective reflexes induced by sedation medications.

Guidelines

These guidelines are designed to provide specific recommendations for the safe care of patients during the delivery of medications for sedation and analgesia by nonanesthesiologists during medical procedures.

These guidelines are NOT intended to apply to the routine administration of narcotics or sedative medications for pain or anxiety relief in an ICU, post-anesthesia care unit, or emergency department.

The policies and procedures should then continue with sections regarding patient care, including but not limited to: patient selection; patient assessment criteria; patient care preprocedure, intraprocedure, and postprocedure; patient monitoring; and criteria for discharge. Classification systems, if used, can be presented as either part of the policy or as attachments. Additionally, documentation of the procedure should be outlined, specifically addressing the minimum time between vital sign and level of sedation assessment. These minimally delineated times should be strictly adhered to; however, it is always acceptable to assess and document on a more frequent, as-needed basis.

The medication section of the policies and procedures should include a listing of the medications that are considered acceptable at the institution. As discussed previously, there is a great deal of debate regarding the use of specific medications (i.e., ketamine, propofol). Drug dosing should be clearly delineated for those medications approved for moderate sedation use. A drug table can be developed and attached to the policy. It is important to remember that this drug table will be used throughout the facility and parameters of drug dosages should be acceptable in all settings.

Some of the best sedation policies include not only the drugs and appropriate dosing, but the maximum dose allowed within a set time frame. One of the more common conflicts that develop during sedation is that the physician will ask for additional sedation medication to be administered prior to the time in which the nurse administering the drug thinks it is safe to do so. For example, a patient has received 100 mcg of fentanyl for a bronchoscopy. The nurse is assessing the patient's vital signs and level of sedation and notes a quiescent patient with a blood pressure that has dropped greater than 20 points below baseline. The nurse continues to monitor the patient for loss of protective reflexes to ensure that a deeper level of sedation is not developing. However, during the procedure, the patient moves during manipulation of the scope and the physician requests that an additional 50 mcg of fentanyl be administered. The nurse is uncomfortable with administering this additional sedative at the present time. If the policy outlines that no more than 100 mcg of fentanyl may be administered within a 10-minute time frame, the nurse can refuse to administer the sedation until that time window has passed. However, if the policy has no such time frame, the nurse should either choose to administer the drug or refuse to do so and accept the consequences for refusal. In the best of all worlds, the physician will accept this limitation on drug delivery and wait until the patient is appropriately and safely sedated. Unfortunately, what often occurs is that the physician will order the medication, the nurse will refuse to administer, and the physician will then pre-empt the nurse and take the syringe in hand and administer the additional sedation. The nurse should then continue to monitor the patient and prepare for the development of oversedation, loss of airway, or any other potential complication that can develop secondary to administration of large doses of narcotics in a short time frame. Regardless of who administered the drug, the nurse caring for the patient is responsible for continuing to provide safe care. With a detailed drug chart developed by physicians, nurses, and anesthesiologists together, these problems can be diminished.

Administrative concerns should also be presented in the policies and procedures. The standards of care should be clearly outlined, ensuring that both state and Joint Commission standards are maintained. Personnel requirements can be addressed, as well as training and competencies of the personnel administering moderate sedation.

One standard of care that is critical to safe drug delivery is that the physician be physically present in the room prior to drug administration. Many institutions neglect to spell out this requirement, and the nurse is asked to administer sedation without appropriate backup personnel. As an example, a physician telephones the endoscopy suite and orders the nurse to administer 5 mg IV midazolam, informing the nurse that he/she would like the patient sedated and ready to begin the procedure when he/she arrives in three to four minutes. The nurse may administer the drug as ordered; however, the physician may be inadvertently delayed by a telephone call, a stuck elevator, or for any number of reasons. The nurse is now caring for a sedated patient without sufficient backup. If the policy states that the medications will only be administered once the physician is present, this risk will be avoided. The Joint Commission requires that, in addition to the individual performing the sedation procedure, sufficient numbers of qualified staff be present to evaluate, monitor, administer medication, assist with the procedure, and recover the patient, if needed [125].

Finally, the policy should finish with a section concerning continuous quality improvement measures. Each department's responsibilities in record keeping and evaluation of care delivery should be clearly stated. Any adverse patient outcomes should be documented, addressed, and subsequently reviewed at a quarterly review of moderate sedation patient care.

The more comprehensive the policies and procedures, the better protected the facility and nursing staff is from legal action, should a problem arise. The policies will allow the nurses to deliver safe care before, during, and after the procedure. The policies and procedures should be updated on an annual basis to ensure compliance with changing standards of care and standards outlined by changing Nurse Practice Acts and Joint Commission requirements.

ISSUES IN INTRAVENOUS VS. TRANSMUCOSAL ADMINISTRATION OF MODERATE SEDATION

There are many issues that arise in considering the method of drug delivery, either by intravenous or transmucosal administration. It would seem to be a straightforward issue; however, on a daily basis there are a number of questions that arise. The Joint Commission moderate sedation standards state that the care standards apply "in any setting, for any purpose, and by any route" [1]. This may help to resolve some of the previous dilemmas. However, a well-developed policy and procedure manual can help resolve other specific issues, a few of which will be discussed here.

If a patient receives medications by the transmucosal route, does that patient require a patent IV line or heparin lock? Or, should the patient be cared for by someone with IV skills? Flumazenil, the benzodiazepine antagonist, should be administered intravenously. If a patient receives transmucosal midazolam, as an example, and requires an antagonist and no line has been placed, the administration of this drug is delayed while IV access is secured. Therefore, any patient receiving moderate sedation should have a patent IV line, regardless of the method of original administration.

Is the length of observation time shorter (or longer) for patients receiving transmucosal medications? Many individuals inappropriately believe that if a patient receives transmucosal medications, their recovery time is shorter. In fact, the length of action of the drug may be longer due to slower absorption.

Can individuals who receive transmucosal medications go home earlier than patients receiving intravenous medications? Can they drive themselves home and go home alone? Do they need the same type of discharge instructions as does the patient receiving intravenous medications? The answers to these questions are well accepted if the patient receives intravenous medications. There are well-developed standards of practice for intravenous drug delivery. The nurse administering sedation by the transmucosal route should answer these questions prior to drug delivery.

One of the most important things to remember is: What are the goals and objectives of moderate sedation? If the goals and objectives are the same whether the patient is receiving the sedation by the intravenous or the transmucosal route, is there a difference in care? It is definitely a point to ponder and one that should be answered by the individual and the institution and delineated in the policy and procedure for moderate sedation.

COMPETENCY ISSUES

Competency verification is a critical part in the delivery of safe patient care. A mechanism for the evaluation of the nurse's skills and knowledge should be an integral part of the moderate sedation program. Areas for moderate sedation competency evaluation include [6,168]:

- Scope of practice

- Presedation assessment

- Pharmacology of moderate sedation medications

- Intraprocedural and postsedation care

- Monitoring skills

- Complication recognition

- Complication management

- Documentation

- Discharge criteria

- Patient education

- Emergency resuscitation techniques

- Special considerations for specific populations

This is by no means considered to be a comprehensive listing; additional items can be added to it as facility policy dictates.

Ensuring competency should be done on a regular basis. Knowledge performance measures usually require that the individual meets the criteria 90% of the time, at a minimum. All nurses should strive to meet these criteria 100% of the time; however, there are times when perfection is a goal and not an achievable endpoint.

Achieving competency varies with the frequency of moderate sedation administration. Some larger institutions have a moderate sedation team whose sole responsibility is to provide sedation in various settings throughout the institution. The individuals who work on this team are able to perform a number of sedation procedures on a regular basis. Their level of competency is commonly high. However, just because an individual performs sedation frequently does not guarantee competency. On the other hand, the staff of the emergency department may be trained in moderate sedation but only perform the procedure on an as-needed basis, with the possibility of long time periods between procedures. Regardless of the frequency of sedation administration, the same standards should be met by all individuals performing sedation.

Annual or biannual evaluations should be undertaken for all individuals administering sedation, including nurses and physicians. Commonly, physicians are verified by the Department of Anesthesiology. The same stringent guidelines met by the nurses should also be met by the physicians.

Ensuring safe care delivery during sedation is paramount to a successful moderate sedation program in any facility. All the issues discussed here should be addressed and can provide an opportunity for expansion in policy development. The answers may not be readily apparent at the present time; with more experience and practice, many of these issues may become moot points as moderate sedation practice becomes more sophisticated.

15. SUMMARY

Moderate sedation is an exciting field for nurses. As newer, safer sedation medications become available, nurses will be asked to provide moderate sedation on an increasingly frequent basis. Recognition of the goals and objectives of moderate sedation is the first step in providing safe care. Medication administration and knowledge of pharmacologic principles are paramount prior to drug delivery. Providing for patient safety should be the most important aspect of nursing care delivery. Recognition of the nuances of care delivery to specific patient populations should not be overlooked. If these aspects are adhered to throughout moderate sedation, the patient will be provided with safe care before, during, and after sedation.

Works Cited

1. The Joint Commission. Comprehensive Accreditation Manual for Hospitals (CAMH). Oakbrook Terrace, IL: Joint Commission Resources; 2020.

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161. Inoue S, Kawaguchi M, Sasaoka N, Hirai K, Furuya H. Effects of neuromuscular block on systemic and cerebral hemodynamics and bispectral index during moderate or deep sedation in critically ill patients. Intensive Care Med. 2006;32(3):391-397.

162. Watson BD, Kane-Gill SL. Sedation assessment in critically ill adults: 2001–2004 update. Ann Pharmacother. 2004;38(11):1898-1906.

163. Mirski MA, LeDroux SN, Lewin JJ 3rd, Thompson CB, Mirski KT, Griswold M. Validity and reliability of an intuitive conscious sedation scoring tool: the nursing instrument for the communication of sedation. Crit Care Med. 2010;38(8):1674-1684.

164. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.

165. Maddox TG. Adverse reactions to contrast material: recognition, prevention, and treatment. Am Fam Physician. 2002;66(7):1229-1235.

166. Pannu HK, Fishman EK. Complications of endoscopic retrograde cholangiopancreatography: spectrum of abnormalities demonstrated with CT. Radiographics. 2001;21(6):1441-1453.

167. North Dakota Board of Nursing. Practice Statements: Role of Registered Nurse (RN) in the Management of Patients Receiving Moderate Sedation/Analgesia for Therapeutic, Diagnostic, or Surgical Procedures. Available at https://www.ndbon.org/RegulationsPractice/PracticeStatements/Mgmt-ModerateSedation.asp. Last accessed July 6, 2020.

168. American Association of Moderate Sedation Nurses. Certified Sedation Registered Nurse (CSRN) Scope of Practice. Available at https://aamsn.org/resources/pdfs/sedation-related-pdfs/registered-nurse-csrn-scope-of-practice. Last accessed July 6, 2020.

169. State of California Department of Consumer Affairs. Board of Registered Nursing. Conscious Sedation. Available at https://www.rn.ca.gov/pdfs/regulations/npr-b-06.pdf. Last accessed July 6, 2020.

170. Odom-Forren J. The evolution of nurse-monitored sedation. J Perianesth Nurs. 2005;20(6):385-398.

171. American Association of Moderate Sedation Nurses. About Us. Available at https://aamsn.org/about. Last accessed July 6, 2020.

Evidence-Based Practice Recommendations Citations

1. Apfelbaum JL, Task Force on Postanesthetic Care. Practice guidelines for postanesthetic care: an updated report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. Anesthesiology. 2013;118(2):291-307. Available at https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918686. Last accessed July 14, 2020.

2. Godwin SA, Burton JH, Gerardo CJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014;63(2):247-258. Available at https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia. Last accessed July 14, 2020.

3. ASGE Standards of Practice Committee, Early DS, Acosta RD, et al. Modifications in endoscopic practice for the elderly. Gastrointest Endosc. 2013;78(1):1-7. Available at https://www.asge.org/docs/default-source/education/practice_guidelines/doc-modifications-in-endoscopic-practice-for-the-elderly.pdf?sfvrsn=60c94951_6. Last accessed July 14, 2020.

30873 • Epidural Analgesia Update

Margo A. Halm, RN, PhD, NEA-BC, FAAN

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Evidence has shown that epidural analgesia is more effective than systemic narcotics in the management of acute pain for a variety of postoperative populations, including trauma procedures, thoracotomy, upper abdominal surgery, and orthopedic procedures. Benefits of the epidural route for the administration of pain management medications include improved analgesia with longer lasting pain relief using fewer doses and less sedation, resulting in earlier restoration and improvement in pulmonary function, decreased metabolic-stress response, and earlier ambulation. The purpose of this continuing education activity is to educate acute care nurses and surgical staff about the use of epidural analgesia as a method of pain control.

Table of Contents

30873 • Epidural Analgesia Update

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. HISTORICAL PERSPECTIVE

3. SPINAL ANATOMY

4. PATIENT SELECTION

TYPES OF PAIN

INDICATIONS

CONTRAINDICATIONS

5. PREPARATION OF PATIENTS

SITES FOR CATHETER PLACEMENT

PLACEMENT TECHNIQUES

CATHETER CARE

6. EPIDURAL DRUGS

ACTION

CLINICAL BENEFITS

EPIDURAL NARCOTICS

EPIDURAL ANESTHETICS

ADMINISTRATION METHODS

7. PATIENT SAFETY CONSIDERATIONS

8. PATIENT ASSESSMENT

PAIN ASSESSMENT

VITAL SIGN ASSESSMENT

NEUROLOGIC ASSESSMENT

CATHETER ASSESSMENT

9. SIDE EFFECTS AND COMPLICATIONS

NARCOTIC-RELATED SIDE EFFECTS

CATHETER-RELATED COMPLICATIONS

POSTPROCEDURE EVALUATION

PHYSICAL ASPECTS

EMOTIONAL ASPECTS

10. NURSING DIAGNOSES AND INTERVENTIONS

11. CASE STUDY

Works Cited

Evidence-Based Practice Recommendations Citations

30873 • Epidural Analgesia Update

Education Category. Medical / Surgical

Release Date. 04/01/2021

Expiration Date. 03/31/2024

Course Overview

Evidence has shown that epidural analgesia is more effective than systemic narcotics in the management of acute pain for a variety of postoperative populations, including trauma procedures, thoracotomy, upper abdominal surgery, and orthopedic procedures. Benefits of the epidural route for the administration of pain management medications include improved analgesia with longer lasting pain relief using fewer doses and less sedation, resulting in earlier restoration and improvement in pulmonary function, decreased metabolic-stress response, and earlier ambulation. The purpose of this continuing education activity is to educate acute care nurses and surgical staff about the use of epidural analgesia as a method of pain control.

Audience

This course is designed for nurses and allied surgical staff in postoperative areas including recovery, critical care, oncology, neurology, orthopedics, and obstetrics.

Course Objective

The purpose of this course is to educate acute care nurses and allied surgical staff about the use of epidural analgesia as a method of pain control in a variety of settings.

Learning Objectives

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

1. Describe the historical evolution that preceded the use of epidural analgesia as a method of pain management.

2. Review spinal anatomy, including differences between the epidural and subarachnoid spaces.

3. Identify key points in patient selection and preparation for epidural analgesia.

4. Discuss the action of epidural narcotics.

5. Compare the advantages and disadvantages of the various epidural administration methods.

6. Outline patient safety considerations applicable to the administration of epidural analgesia.

7. Discuss physiologic parameters to assess in a patient receiving epidural analgesia.

8. Describe narcotic- and catheter-related side effects/complications of epidural analgesia and appropriate nursing interventions.

9. Discuss common nursing diagnoses and interventions for the patient receiving epidural analgesia.

Faculty

Margo A. Halm, RN, PhD, NEA-BC, FAAN, received an Associate Degree of Nursing in 1981 from Iowa Central Community College, a BSN and Master of Arts in Nursing from the University of Iowa, in 1985 and 1987 respectively, and a PhD from the University of Minnesota in 2005. She is a member of the American Association of Critical Care Nurse's, and Sigma Theta Tau International. Dr. Halm has presented nationally and internationally, coauthored articles, and conducted nursing research studies on topics such as epidural analgesia, complementary therapies, women and heart disease, family presence during resuscitation and other family-centered interventions. Currently, Dr. Halm practices as the Associate Chief Nurse Executive of Nursing Research and Evidence-Based Practice at the VA Portland Health Care System in Portland, OR.

Faculty Disclosure

Contributing faculty, Margo A. Halm, RN, PhD, NEA-BC, FAAN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

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

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

The purpose of this course is to educate healthcare professionals about the use of epidural analgesia as a method of pain control. Evidence has shown that epidural analgesia is more effective than systemic narcotics in the management of acute pain for a variety of postoperative populations, including trauma procedures, thoracotomy, upper abdominal surgery, and orthopedic procedures.

By diffusing across the dura and subarachnoid space, epidural narcotics alter pain transmission by binding to mu receptors in the spinal cord. Benefits of the epidural route include improved analgesia with longer lasting pain relief using fewer doses and less sedation. This results in earlier restoration and improvement in pulmonary function, decreased metabolic-stress response, and earlier ambulation.

Preservative-free morphine and fentanyl are the most commonly administered narcotics via intermittent or continuous epidural routes [1]. Onset of analgesia ranges from 15 to 60 minutes, with a duration of 4 to 24 hours. Local anesthetics (e.g., bupivacaine) may also be used, especially in patients who have developed opioid tolerance.

Nursing responsibilities in caring for the patient receiving epidural analgesia include [1]:

- Monitoring administration of the narcotic and effectiveness of pain control

- Assessing pulmonary, neurologic, and catheter status

- Monitoring for and managing narcotic-related side effects and catheter-related complications, such as respiratory depression, nausea/vomiting, pruritus, postdural headache, epidural abscess/hematoma, and catheter migration/shearing/occlusion

- Assisting with catheter removal

- Evaluating physical and emotional aspects postprocedure

2. HISTORICAL PERSPECTIVE

The ancient Greeks were the first to describe the use of narcotics. However, not until the turn of the 20th century did reports of the first epidural anesthetics appear. In the mid-1970s an understanding of the mode of action of narcotics was developed. When discovered, endorphins (endogenous opioid-like compounds) were thought to modulate the transmission of pain by acting on spinal cord opioid receptors. The substantia gelatinosa, an area of the spinal cord found to be rich in opioid receptors, was recognized as a key feature in pain transmission. Then, in the 1980s, intrathecal opioids were initially used in the treatment of intractable cancer pain, an event that led to the eventual widespread postoperative use of spinal opioids [2]. Today, epidural analgesia is an alternative to traditional pain management methods in a variety of clinical settings.

3. SPINAL ANATOMY

The spinal cord extends from the foramen magnum at the base of the skull to the superior border of L2. It is composed of both white and gray matter. Pain receptors are located within the gray matter of the cord. The spinal cord is covered with meninges, or layers of connective tissue. The innermost layer, the pia mater, is closest to the spinal cord. As a smooth and vascular membrane, the pia mater contains many blood vessels that nourish the cells of the spinal cord.

The arachnoid mater, the middle layer, is a thin and transparent covering. Located between the arachnoid and pia mater is the subarachnoid or intrathecal space. The subarachnoid space extends from the cranium to the sacrum and contains cerebrospinal fluid (CSF) and nerve roots. The dura mater is the outermost meningeal layer. Between the dura mater and the vertebrae is a ligament called the ligamentum flavum, which lines the vertebral canal. Between the dura mater and the ligamentum flavum is the epidural space. As a potential space, it also extends from the base of the skull to the coccyx. It contains fatty and connective tissue, lymph and blood vessels, and spinal nerve roots. The epidural space functions as a fatty pad that surrounds the spinal cord and is a potential depot for lipid-soluble narcotics [2,3].

In contrast, the intrathecal space is usually accessed for a one-time administration of a narcotic bolus. The intrathecal route is used most often in anesthesia practice and for patients who require pain relief for a short duration. The main advantages of this route are its speed and reliability; however, additional doses cannot be given. Because intrathecal narcotic doses are approximately one-tenth of those used with the epidural route, the catheter is removed after administration to prevent infection or accidental overdose. Therefore, a larger volume and higher dose of narcotic is needed when utilizing the epidural route for pain management [2,4].

4. PATIENT SELECTION

Patient selection for epidural analgesia is determined by two major factors: the type of pain experienced and the patient's surgical procedure and/or medical condition.

TYPES OF PAIN

Pain can be classified in various ways. For instance, there are somatic, visceral, and neuropathic types of pain, each of which is associated with different etiologies. Somatic pain results from activation of nociceptors by thermal, mechanical, or chemical stimuli in the superficial or deep tissues. As peripheral receptors are activated, the pain perception is transmitted to the spinal cord and higher cerebral cortex, where pain is perceived. Usually constant and well-localized, somatic pain is often described as sharp, aching, or throbbing. By contrast, visceral pain results from some type of organ damage or dysfunction. Depending upon the exact etiology, visceral pain may have many different descriptions, such as deep, dull, aching, boring, or pressure-like. Lastly, neuropathic pain, originating in the nervous system, is often described as a burning, tingling, or numbing sensation.

Pain sensations traveling from the periphery to the spinal cord are mediated by three types of specialized fibers: large myelinated A fibers (A-beta); small myelinated A fibers (A-delta); and unmyelinated C fibers. Each type of nerve fiber carries a different type of sensation. Stimulation of A-beta fibers can block pain signals, essentially closing the pain "gate." A-delta fibers transmit fast-traveling pain that is pricking in sensation and highly discriminated, such as acute surgical pain. These types of pain sensations are poorly relieved by epidural analgesia [2,5]. However, the majority of pain stimuli (approximately 60% to 70%) are carried more slowly by unmyelinated C fibers. These pain sensations are characterized as dull and aching [5]. While continuous dull pain from deep structures responds the best to epidural analgesia, intermittent dull pain is poorly relieved. Central pain does not respond at all to epidural narcotics [2].

INDICATIONS

Evidence Based Practice Recommendation

The American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons conclude that thoracic epidural analgesia is recommended for open colorectal surgery, but not for routine use in laparoscopic colorectal surgery.

https://fascrs.org/ascrs/media/files/downloads/Clinical%20Practice%20Guidelines/clinical_practice_guidelines_for_enhanced_recovery-3.pdf

Last Accessed: March 4, 2021

Strength of Recommendation/Level of Evidence: 1B (Strong recommendation based on moderate-quality evidence)

Epidural analgesia is indicated in the management of both acute and chronic pain. Acute postoperative populations that may benefit from epidural analgesia include [2,4,6,7,8,9]:

- Thoracic procedures (e.g., thoracotomy, bilateral lung volume reduction, lung transplant)

- Upper abdominal procedures (e.g., esophagogastrectomy, abdominal aortic aneurysm resections, liver resection)

- Orthopedic procedures (e.g., laminectomy, hip replacement)

- Peripheral vascular procedures

- Gynecologic/urologic procedures (e.g., vaginal deliveries, cesarean section)

Trauma patients, such as those with rib fractures or other orthopedic/multiple injuries, also obtain relief with this pain management method. Patients who are predisposed to pulmonary complications due to pre-existing medical conditions, such as chronic obstructive pulmonary disease or decreased mobility, or who have a need for pulmonary hygiene, are considered the best candidates [2,6,7]. Patients undergoing procedures such as amputation have also been studied in relation to epidural analgesia. Studies of the use of pre-emptive analgesia preoperatively to decrease phantom pain sensations in patients who have undergone amputation have yielded mixed results [8,10,11,12,13,14,15].

Evidence Based Practice Recommendation

In adult patients with blunt thoracic trauma, the Eastern Association for the Surgery of Trauma and the Trauma Anesthesiology Society conditionally recommend epidural analgesia over nonregional modalities of pain control for the treatment of pain.

https://www.east.org/education-career-development/practice-management-guidelines/details/thoracic-trauma-blunt-pain-management-of

Last Accessed: March 4, 2021

Level of Evidence: This recommendation is based on very low-quality evidence but places a high value on patient preferences for analgesia.

Patients with chronic pain are also candidates for receiving epidural analgesia. The epidural route appears to be successful in relieving pain associated with gynecologic and colorectal tumors [16]. Cancer patients, especially those with regionalized pain below T1 that has been poorly controlled by systemic narcotics due to dose-limiting side effects, such as sedation and respiratory depression, are likely candidates [17,18,19]. Perioperative epidural use may also be associated with improved colon cancer survival in patients without metastases [16,20]. Tumor infiltration of bone seems to be more likely to respond to the epidural route than tumors that infiltrate nerve.

Epidural analgesia may also be indicated in patients with chronic nonmalignant pain, such as low back conditions, multiple sclerosis, and severe osteoporosis, as it may alleviate the chronic drowsiness associated with systemic narcotics [7,17,21]. However, the rapid development of tolerance may be a major limiting factor to more widespread use of epidural analgesia in patients with chronic pain [22]. Although not clearly understood, there appears to be cross-tolerance between narcotics administered epidurally and those given systemically. As a result, patients who require high doses of systemic narcotics will eventually require high epidural doses for optimal pain relief [6].

While numerous reports in the literature document the effectiveness of epidural analgesia for acute and chronic pain, criteria for specific patients most likely to benefit have not been clearly identified. More research is needed to investigate the effectiveness of epidural narcotics with different patient populations [6].

CONTRAINDICATIONS

Just as there are several indications for epidural analgesia in the acute care setting, several contraindications also exist. The first absolute contraindications for epidural analgesia are patient refusal and a history of true allergic reaction to a narcotic class. In the case of allergy, which is very rare, another opioid class may be utilized in place of the original drug. Patients who have abnormal hemostasis (e.g., thrombocytopenia, abnormal prothrombin time/partial thromboplastin time values) or who are receiving anticoagulants such as heparin, warfarin, aspirin, or enoxaparin are also contraindicated due to the increased risk of developing an epidural hematoma at the catheter insertion site. Patients who have a systemic infection or a localized infection at the puncture site are contraindicated due to the increased risk of developing an epidural abscess or meningitis [7,23].

The last two contraindications for epidural analgesia are related to neurologic status. Patients who have undergone a recent laminectomy with opening of the dura are contraindicated due to the risk of catheter migration into the subarachnoid space and accidental overdose. Increased intracranial pressure also poses considerable risk. In the event that the dura is inadvertently nicked during catheter placement, the loss of CSF could cause cerebellar or tentorial herniation [7].

5. PREPARATION OF PATIENTS

Regardless of the indication for epidural analgesia, patients and their family members must be adequately informed about this type of pain control. Prior to placement of the catheter, patients/families should be allowed to voice any concerns. Explanations should be given in layperson's terms about how epidural analgesia works and any adverse effects that may be experienced. Emphasize that side effects are temporary and can be treated. Patients may also require reassurance that epidurals do not cause sleep but that the drugs will control their perception of pain. Lastly, patients should know how long the epidural is intended to be utilized, what analgesic regime will be followed, and that the epidural drugs will not be stopped without provision for alternative pain control.

SITES FOR CATHETER PLACEMENT

With the advent of epidural analgesia, many catheters were placed in the lower lumbar region, between L4–L5. In this location, catheter placement is technically easier to perform as the spinal cord terminates above this area [2]. However, with increased utilization of epidural analgesia, it has been shown that pain may be best relieved by placing the catheter at different sites depending on the location of the patient's pain and/or surgical incision [8].

The actual site for catheter placement is determined by the dermatome innervating the area of pain. With thoracic procedures, the catheter is placed between T2–T8, depending upon whether the upper or lower lobes of the lung are affected. Mund et al. reported that the majority of epidural catheters in lung transplant patients were inserted at the level of T9 (with a range from T4–L4) [18]. Similarly, with upper abdominal, orthopedic and peripheral vascular procedures, catheters are placed between T4–L1, T10–L3, and L4–L5, respectively. In the case of trauma, the epidural catheter is placed directly at the site of injury [8]. Selecting the proper dermatome level is even more important when the patient will receive epidural local anesthetics (compared to opioids) as these agents block both afferent and efferent nerve fibers [5,24].

PLACEMENT TECHNIQUES

Insertion of an epidural catheter is done by an anesthesiology professional (anesthesiologist or certified nurse anesthetist) or physician in another specialty who has been granted clinical privileges by the institution. Epidural catheters may be placed in the operating room or as a sterile procedure at the patient's bedside. Strict aseptic technique must be used during the insertion, as well as with any contact with the solution, infusion, dressing, or site, to prevent contamination. Nursing responsibilities center on ensuring proper positioning and assisting with the procedure. The lateral position is used for catheter insertion, with the patient's hips and head flexed. This position allows for maximal separation between the intervertebral spaces. The site is then prepared using topical antiseptic and sterile drapes [2,4,7,25].

A local anesthetic, such as lidocaine, is injected into the insertion site. A sterile syringe with air or preservative-free, sterile normal saline is attached to a blunt spinal needle, inserted into the selected interspace, and advanced using gentle pressure. This technique, known as loss of resistance, is the commonly used, and currently most reliable, placement technique as the three tough ligaments that surround the spinal cord do not permit injection unless the needle has entered the epidural space. After the needle has entered the epidural space, normal saline or air may then be easily injected. The potential of intrathecal placement or nicking the dura is decreased by the fact that the flow from the needle pushes the dural layer away. The hanging drop technique is another method for catheter placement; however, it is less reliable. With this technique, it is believed that as the spinal needle enters the epidural space, negative pressure draws a drop of normal saline inward [2,7,26]. As an additional measure, some centers place epidural catheters under fluoroscopy or ultrasound guidance in patients with difficult or unclear anatomy [25,26].

With either technique, a flexible catheter is threaded through the spinal needle and advanced 2–3 cm into the epidural space. The spinal needle is then carefully removed and a slide-lock adapter is attached to the end of the catheter. This adapter permits attachment of the catheter to an injection port or infusion tubing [25]. A filter is also attached to the infusion tubing to ensure the injectate remains sterile and to prevent introduction of microparticles or bacteria into the epidural space. The filter may also be used with intermittent administration setups [7,27].

Catheter placement must be verified to avoid injection of the narcotic into the intrathecal space. The two techniques used to verify catheter placement are aspiration and the use of a test dose [25]. However, the inability to aspirate or the presence of a negative test dose does not guarantee correct catheter placement [7].

The aspiration method involves attaching a 3-cc syringe filled with 2 mL of preservative-free sterile normal saline to the end of the catheter and aspirating gently for 30 seconds. If no aspirate is obtained, the catheter should be in the epidural space. If more than 1 mL of clear fluid that tests positive for glucose is obtained, the catheter is most likely in the subarachnoid space. Bloody aspirate indicates that the catheter has punctured an epidural vein [2,4,7].

Additional verification of catheter placement may be performed by administering a test dose of a local anesthetic, such as bupivacaine or 1.5% lidocaine with 1:200,000 epinephrine. An increase in heart rate or blood pressure indicates that the tip of the catheter is in an epidural vein. Loss of sensory or motor function in the lower extremities or lower abdomen with a decrease in blood pressure over one to five minutes indicates that the catheter tip is in the intrathecal space. In the presence of these findings, the narcotic should be withheld until catheter placement can be fully assessed [2,7].

New technology is being explored for effectiveness in guiding the needle, identifying entry, and confirming the catheter location within the epidural space, including ultrasound techniques, fluoroscopy, bioimpedence, and epidurography [26]. However, further studies are required.

CATHETER CARE

After the catheter is inserted and placement verified, the final step involves dressing the site and securing the catheter. A sterile transparent occlusive dressing is applied to permit easy inspection of the site. In addition, the catheter should be taped securely up the patient's back and positioned at the head for easy access during administration [25]. To prevent catheter dislodgement, in most cases the dressing and/or tape should never be changed, only reinforced as needed [4,7,28]. In some cases, if the epidural catheter will continue to be used after 96 hours, the dressing may need to be changed. Please consult hospital policies and procedures and proceed accordingly [28].

Epidural catheters should be marked clearly to prevent accidental injection of medications. Administration sets without additional injectate ports should be used (if possible) or the ports should be taped. System connections should be assessed to ensure they are tight, dry, and intact. The infusion tubing and pumps should then be clearly labeled with a fluorescent sticker, and a sign should be placed above the bed to clearly identify that the patient has an epidural catheter [5,29]. As noted, strict aseptic technique should be utilized whenever assisting with epidural catheter insertion, or handling the epidural catheter, infusion tubing and connections, and solutions [27,28].

6. EPIDURAL DRUGS

ACTION

Epidural analgesia is a form of localized pain control. By the process of diffusion, narcotics travel across the dura and subarachnoid space and bind to mu receptors located in the substantia gelatinosa of the dorsal horn of the spinal cord. After these narcotics bind to opioid receptors, they block the release of substance P, a neurotransmitter. When substance P is decreased or absent, nociceptive impulses (pain sensations) do not travel the ascending fibers to the higher brain centers. As a result, the patient does not perceive pain [5].

The rate of narcotic diffusion across the epidural space is affected by lipid solubility. In other words, the more lipid-soluble the drug, the more rapidly it diffuses across the epidural space to the opioid receptors in the spinal cord. With rapid diffusion, less drug is available to migrate to higher brain centers via the CSF or systemic circulation. Even though small amounts of epidural narcotics do reach the supraspinal levels, analgesia is provided with fewer side effects than seen with the systemic route [6,7].

Epidural narcotics also have a selective action on opioid receptors within the spinal cord. The narcotic remains at the segmental level of the spinal cord where injected and, consequently, does not block sensory, motor, or sympathetic nerve fibers. As a result, patients experience little motor, sensory, cardiovascular, or central nervous system (CNS) effects, such as adverse changes in heart rate/blood pressure or other negative side effects associated with the use of systemic narcotics, including sedation [2,4].

CLINICAL BENEFITS

Epidural analgesia is associated with several clinical benefits. These advantages include:

- Drug benefits: Longer duration and lower total doses

- Response benefits: Improved analgesia, less sedation, earlier ambulation, and reduced morbidity from lessened complications, such as pulmonary problems or effects from the metabolic stress response

- Outcome benefits: Improved pulmonary and gastrointestinal function and shortened length of hospital stay

Drug Benefits

In the category of drug advantages, the first benefit is the longer duration of analgesic effect. When administered into the epidural space, 5 mg of morphine has a duration of 6 to 24 hours, compared to three to four hours when given systemically [7]. As a result, patients receiving epidural analgesia require an overall lower total dosage of narcotic than those who receive systemic narcotics via intramuscular (IM) injection, intravenous (IV) injection, or patient-controlled analgesia (PCA) [2,30]. In a study of epidural analgesia in lung transplant patients, patients who received medication via the epidural route had a duration of analgesia of 3.76 days versus 6.0 days in the IV PCA group before oral medications were started [18]. In cancer patients, longer-lasting analgesia without sedation means that patients are more alert, less depressed, more able to resume daily activities when possible, and more likely to be cared for at home [6].

Patient Benefits

In terms of patient response benefits, improved analgesia has been documented. Epidural narcotics provide more constant pain relief, without the peaks and valleys of serum drug levels associated with parenteral administration [29]. In one comparative analysis, three different epidural drug dosages or combinations were evaluated in patients undergoing thoracic, abdominal, orthopedic, or cardiac surgery for impact on pain intensity scores. Visual analog scale (VAS) pain scores were significantly lower in those receiving epidural fentanyl 5 mg/mL and bupivacaine 1 mg/mL, compared to ropivacaine 2 mg/mL or fentanyl 10 mg/mL and bupivacaine 1 mg/mL [31]. In another study, the probability of a VAS >40 mm was significantly lower in elective postoperative patients receiving epidural (20% probability) versus systemic narcotics (40% probability) [32]. The probability of having moderate-to-severe pain in the first 24-hour period was also significantly less in the epidural group.

The benefit of less sedation is directly related to the smaller narcotic dose required due to the longer duration associated with the epidural route. By remaining at the level of the spinal cord where they are injected, many epidural narcotics do not migrate to higher brain centers via the CSF or systemic circulation. This phenomenon, known as rostral spread, is responsible for the sedation and disorientation commonly associated with systemic narcotics [7]. Lipophilic drugs (e.g., fentanyl) are less likely to result in rostral spread than hydrophilic drugs (e.g., morphine).

Epidural analgesia leads to other clinical improvements and prevention of complications. Improvement in pulmonary function is yet another benefit of epidural analgesia. Patients receiving epidural narcotics experience an earlier improvement in pulmonary function tests (PFTs) when compared to those receiving systemic narcotics [7,33]. In one study of gastroplasty and thoracotomy patients, researchers identified that all patients had decreased PFTs [30]. However, the epidural patients had a less marked decrease in PFTs and returned to their preoperative values two days earlier than the systemic group.

In addition to an earlier restoration of pulmonary function, epidural patients experience fewer pulmonary complications. The incidence of atelectasis and pneumonia may be decreased because patients with more consistent pain control may have an increased ability to participate in pulmonary toilet activities, such as coughing and deep breathing [2,7,33,34]. Secondly, many patients receiving epidural narcotics spend less time on the ventilator and/or have less need for tracheostomy [35]. In one study, lung transplant patients who received epidural analgesia were extubated at an average of 1.46 days after surgery (range: 0.4 to 4.75 days) [23]. Reintubation rates have also been reported to be lower in lung transplant patients who received epidural analgesia (29%) versus IV PCA narcotics (55%) [18]. The reduction of these pulmonary comorbidities is especially significant for the critically ill patient in that gram-negative pneumonias may be associated with a mortality rate ranging from 33% to 70% [34,36].

Epidural narcotics may also decrease the metabolic-stress response associated with surgery and trauma. This response is characterized by an increased release of cortisol, catecholamines, and antidiuretic hormone causing hyperglycemia, sodium and water retention, potassium wasting, and muscle protein breakdown. Epidural narcotics reduce fluid mobilization and retention, the presence of which may further compromise the patient's pulmonary status and lead to respiratory distress and pulmonary edema. This clinical benefit is especially significant for congestive heart failure patients who have undergone upper abdominal surgery [7,34].

Additional studies have investigated the effects of epidural anesthesia on other patient outcomes. In one study on major vascular surgery, researchers found patients who had combined general and epidural anesthesia with postoperative epidural analgesia had significantly lower cardiac morbidity than those patients who only received general anesthesia with postoperative systemic opioid analgesia [37]. Epidural analgesia in high-risk cardiac surgical patients is associated with hemodynamic stability, decreased catecholamine response, good pulmonary function, and early extubation and discharge from intensive care [38]. Evidence of epidural anesthesia's impact on reducing thromboembolic, pulmonary, and gastrointestinal postoperative complications is also encouraging, and it is suggested that epidural anesthesia may be a significant factor in reducing gastrointestinal complications, such as postoperative ileus, in major abdominal surgery patients [39].

Earlier ambulation is the second patient response benefit of the epidural route. In one study of obese patients after upper abdominal surgery, epidural patients ambulated without assistance earlier than IM patients (23 hours versus 30 hours) [30]. Early mobilization may be a significant factor in reducing thromboembolic complications. In combination, improved pulmonary function and earlier mobilization are two of the most significant factors responsible for decreased morbidity and mortality and length of stay (LOS) in patients receiving epidural analgesia. While these findings are encouraging, more research is needed in various populations to compare the impact of epidural versus systemic narcotics on pulmonary complications and ambulation status, as well as on level of alertness and patients' ability to participate in their own care. For instance, in one study, more rapid rehabilitation was not found to be a benefit in elderly total knee replacement surgery patients who received epidural analgesia (compared to PCA) [40]. Additionally, epidural analgesia was not associated with better pain relief or higher patient satisfaction than PCA in this population.

Outcome Benefits

Mixed findings have been reported in relation to LOS. In some studies, epidural analgesia has been associated with shorter hospital stays. In a study of rib fracture patients, those receiving epidural narcotics had a shorter intensive care unit (ICU) stay (6 days versus 18 days) and overall hospital stay (15 days versus 47 days) compared to patients receiving systemic narcotics [35]. In another study of patients undergoing spinal fusion with instrumentation, epidural analgesia with bupivacaine resulted in patients tolerating a full diet earlier and being discharged an average of 0.5 days sooner than the PCA group [41]. On the other hand, McBeath and colleagues found no difference in LOS in total knee or hip replacement patients receiving either continuous epidural morphine or bupivacaine or PCA opioids (morphine or meperidine) [42]. Additionally, a retrospective analysis of more than 1,500 thoracotomy patients showed no difference between LOS in patients receiving epidural analgesia versus systemic opioid-based therapy [43]. Other outcome benefits have been reported. A study of patients with multiple rib fractures found that epidural analgesia was associated with decreased rates of nosocomial pneumonia and shorter durations of mechanical ventilation [44,45]. More studies are warranted to address the impact that epidural analgesia has on the postoperative course, including the ICU and total hospital LOS [7].

EPIDURAL NARCOTICS

Only preservative-free drugs are administered into the epidural space, as preservatives are neurotoxic and may cause injury to the spinal cord. The two most commonly used narcotics are morphine and fentanyl [2]. Common dosing, as well as the peak and duration of these drugs, are listed in Table 1. However, it is important to note that the epidural dose depends on the patient's height, age, and type of surgery (e.g., lower abdominal versus thoracic procedures) [7]. With any of these agents, the larger the volume of drug infused, the greater the chance for rostral spread to the brainstem, which is responsible for central side effects.

Table 1: EPIDURAL NARCOTICS

Drug

Initial Dose

Infusion

Peak

Duration

Morphine

1–10 mg

0.1–1.0 mg/hr

30 to 60 minutes

6 to 24 hours

Fentanyl

25–100 mcg/dose in 10 cc normal saline

25–100 mcg/hr

10 to 15 minutes

4 to 8 hours

Source: [2,5,7,46,47]

Morphine has a longer duration and is used when the patient requires analgesia over several days. As a result, monitoring for respiratory depression is required for at least 24 hours following administration of the first dose [47]. In addition, this medication is highly water-soluble and is prone to retention in the CSF and systemic circulation. Because more of the drug is available to migrate toward higher brain centers, patients receiving morphine are prone to more frequent side effects than those receiving fentanyl [7]. The maximum dose is 10 mg/day for opioid-naïve patients and 20 mg/day for opioid-tolerant patients [47]. Morphine preparations specifically indicated for epidural use are preferred over generic preparations due to sterility and quality control concerns [48].

In contrast, fentanyl is a synthetic narcotic that is 100 times more potent than morphine. As a highly lipid-soluble drug, it diffuses quickly to opioid receptors, with an onset of 10 to 15 minutes. Another main advantage of fentanyl's lipophilicity is that it leaves less drug available for rostral spread, which results in fewer narcotic-related side effects. Fentanyl has a relatively short duration (one hour or less) and is used when analgesia is needed for a short time. Respiratory depression occurs in more than 10% of patients but is more common in elderly patients [47]. Therefore, monitoring for respiratory depression periodically throughout the duration of the initial dose is necessary.

Other drugs that may be administered via the epidural route include alfentanil, ketamine, meperidine, methadone, clonidine, hydromorphone, and sufentanil, though most of these are off-label uses [47]. Of these, meperidine and methadone are both highly lipid soluble. Therefore, each drug has a quick analgesic onset but a short duration when given by bolus. However, these epidural drugs do not offer advantages over either morphine or fentanyl [6,7].

After epidural administration begins, it is important to taper systemic narcotics. The length of time required to taper systemic narcotics varies from patient to patient and depends on how long the patient has been receiving narcotics. Gradual tapering is essential to prevent narcotic withdrawal syndrome, which can occur whenever narcotics are abruptly stopped by any previous administration route (IM, SL, IV, PO, rectal, or buccal). In addition to the variables previously discussed, dosage of the epidural narcotic will also vary from patient to patient, depending upon whether they are narcotic naïve or if they have received a long-term course of narcotics. Patients with acute pain can be expected to require a lower total daily dose of epidural narcotic compared to a chronic pain patient [6].

EPIDURAL ANESTHETICS

Local anesthetics may also be administered via the epidural route. Bupivacaine, a long-acting local anesthetic, is the most often used agent. It may be administered either alone or in combination with epidural opioids, such as morphine or fentanyl, for a synergistic effect and reduction of side effects. Local anesthetics are especially useful for patients who have developed a tolerance to opioids because analgesic action is not dependent only on opioids [5].

The level of blockade achieved with local anesthetics is dependent upon both the concentration or dose and the volume of the infusion. For instance, with bupivacaine, effective analgesia is often achieved with concentrations of 1.25 mg/mL or less. If combined with opioids, the concentration of the opioid generally ranges from 0.05–0.1 mg/mL morphine or 2–5 mcg/mL fentanyl. Volumes of continuous infusions vary between 8–20 mL/hour depending upon the surgical site, catheter location, and individual patient needs [5].

In a study by Scott and colleagues, various concentrations of epidural ropivacaine were evaluated in patients after major lower abdominal surgery to determine their attenuation of IV opioids analgesia and minimization of motor block [49]. Total PCA morphine over 21 hours was significantly less in the 0.2% ropivacaine group (mean: 7.5 mg) compared to control (mean: 43.3 mg) and other ropivacaine concentrations (0.1% mean: 18.7 mg; 0.3% mean: 19 mg). Additionally, VAS scores for pain associated with coughing were significantly lower for all ropivacaine groups after four hours of epidural infusion compared to the control group. In terms of intensity of motor block, the 0.2% ropivacaine concentration provided the best analgesia with minimal motor block compared to the other concentrations. In another study, 61 high-risk patients were randomized to receive either 15 mL of 0.75% ropivacaine or 0.5% bupivacaine [50]. Analgesia effects were assessed using VAS scores, motor block, volume of local anesthetic used, and patient satisfaction. Adverse effects were noted, and patients were monitored for changes in heart rate and mean arterial blood pressure. Patients initially achieved a greater intensity of motor block with bupivacaine, but no significant differences were noted between the two drugs at 30 minutes. Similar durations of motor block, motor block profiles, and VAS scores were noted in both patient groups and no major side effects were noted in either group [50].

ADMINISTRATION METHODS

Epidural narcotics may be administered by a number of techniques. These administration routes include intermittent bolus injection, continuous infusion, PCA, or implantable ports and infusion pumps for long-term use. A position statement from the American Society for Pain Management Nursing (ASPMN) (supported by the American Society of Anesthesiologists) states that RNs may manage analgesia, including reinjection of medication following establishment of appropriate therapeutic range and adjustment of the drug infusion rate in compliance with the anesthesia provider's or physician's patient-specific written orders [51,52]. As of 2021, this statement was under revision [51].

Intermittent Administration

Intermittent administration involves injecting a narcotic bolus at a timed interval and may be used with either acute or chronic pain conditions. The major advantage of intermittent injections is that dosing is based on each individual patient's need. Primary disadvantages include inconsistent analgesia and narcotic-related side effects due to redosing intervals and fluctuating narcotic blood levels; changes in respiratory rate and end-tidal carbon dioxide (CO_2) consistent with respiratory depression; and the need for a healthcare provider to administer the dose. The major nursing consideration associated with this route is that iodine-based topical antiseptic solutions should be used to prep the injection port prior to administration. The injection port should not be cleansed with alcohol or other antiseptics as these agents may cause neurotoxicity if they enter the epidural space [7,27].

Continuous Infusion

Continuous infusions deliver epidural drugs at a constant rate by means of an infusion pump, avoiding the peaks and valleys associated with the intermittent technique. This method of administration provides more consistent analgesia due to a constant blood level of the prescribed opioid and also allows a lower total volume of drug to be infused at one time. As a result, fewer side effects, such as respiratory depression, occur with continuous infusions. In addition, the rate of the infusion may be titrated to the patient's response, providing the optimal level of analgesia. The major disadvantage of this route is reliance on an infusion pump and the potential for equipment malfunction [7].

Patient-Controlled Analgesia

PCA is another option for delivering a fixed rate of epidural narcotics. The major advantage of the PCA route is that the patient may administer additional bolus doses above and beyond the basal rate on an as needed basis. Therefore, this route gives the patient some control to alleviate their pain, especially when sudden increases in pain are experienced [6,7]. PCA has been shown to be both safe and efficacious in appropriately chosen adults, adolescents, and children, and many studies have shown that patients prefer this method of analgesia over intermittent injections [50,53,54].

Implantable Port or Infusion Pump

Implantable ports or infusion pumps are the last option for delivering epidural narcotics. Implantable devices are used for patients requiring long-term pain management, such as oncology populations. With implantable ports, the epidural catheter is surgically placed at the indicated interspace and then tunneled subcutaneously around the patient's trunk. The catheter exits on an accessible location of the abdomen so the injection port can be accessed for either intermittent or continuous infusions [6]. Nonprogrammable fixed-rate infusion pumps deliver a predetermined constant rate of infusion and allow for a change in the dose by changing the drug concentration in the reservoir. Programmable pumps (i.e., variable delivery rate pumps) allow for alterations to the dose, single doses, timed-specific doses, or changes in the continuous infusion rate [8].

Implantable ports consist of an implantable silicone catheter (sized from 4–12 F), and an implantable titanium or silicone port with a self-sealing rubber septum. This port contains an internal reservoir that can be repeatedly accessed by injection with a 90-degree non-coring needle. These needles vary from ½ to ¾ inches, and the appropriate needle length should be chosen based on the patient's size and the depth of the port. The needle should first be connected to extension tubing and flushed with 5 cc of normal saline. Using sterile technique, the site should be cleansed from the center of the port outward 2–3 inches in a circular motion first using alcohol, then followed with an iodine-based antiseptic. Accessing the port is done by stabilizing it between the thumb and index finger of the non-dominant hand. Using the other hand, the needle is inserted perpendicular to the center of the port. The needle should be pushed firmly through the patient's skin and portal septum until it hits the bottom of the platform. Once in the portal body, aspirate for blood; if positive, flush with 10 cc of normal saline. When ready for epidural analgesia, connect the infusion to the extension set and stabilize the needle in the port by covering with an occlusive dressing. To discontinue the infusion, keep the port stabilized between the thumb and index finger, hold needle firmly, and withdraw using even pressure [55,56,57].

It has been a customary nursing practice to cleanse the portal body with povidone-iodine-based solutions prior to accessing the port. This practice is done to disinfect the port and minimize the patient's risk of infection. One study investigated this practice and questioned whether or not a trace amount of povidone-iodine solution could pose some risk for toxicity, especially if the solution were systemically absorbed. In this study, three different techniques were compared: commercially available 10% povidone-iodine swabsticks, commercially available 10% povidone-iodine pledgets, and 4-inch square gauze pads saturated with 10% povidone-iodine solution. A significant difference was found with the three cleansing techniques, and the 10% povidone-iodine pledget introduced the least iodine contamination. The findings of this study are considered preliminary, and more research is needed before nurses routinely abandon the practice of using povidone-iodine for disinfection [19,58,59].

Infusion pumps may also be implanted into a subcutaneous pocket of the abdomen to administer continuous epidural infusions [7]. Both options require surgery and carry a potential for infection. Patients who are likely candidates for implantable ports or infusion pumps include those whose life expectancy is greater than a few months with pain below the mid-cervical dermatome that has been unsuccessfully treated with aggressive analgesics and is inappropriate for neurosurgical procedures [6]. Patient/family teaching for these patients should include an explanation of the procedure in terms the patient can understand, expectations for postoperative pain or discomfort and self-care responsibilities, medication preparation, the procedure for injection, assessing the exit site and tunnel area for signs and symptoms of infection, catheter care and dressing changes, refill schedules and procedures, obtaining supplies and narcotics, and follow-up care [9,27].

7. PATIENT SAFETY CONSIDERATIONS

The Institute of Medicine's 1999 report Crossing the Quality Chasm revealed that 44,000 to 98,000 patient deaths in the United States each year are due to preventable medical errors [60]. One decade later, a HealthGrades study showed that from 2007 to 2009 there were 79,670 in-hospital deaths attributable to "patient safety events" among Medicare recipients alone [61]. Although this number should be balanced against the more than 40 million Medicare hospitalizations each year, these events occur all too often and cost the U.S. healthcare system approximately $7.3 billion annually [61].

It has been identified that about 80% of all deaths from medication errors are caused by 20 drugs, including opioids and anesthetics that are commonly infused via epidural catheters [62]. Furthermore, about 60% of all life-threatening errors occur with IV therapy. These high-alert medications have a heightened risk of causing significant patient harm when used in error. These drugs contribute to large numbers of medication errors and, when improperly administered, result in poor patient outcomes.

The Joint Commission has created patient safety goals, many of which revolve around safe medication usage and administration [63]. Several patient safety goals are relevant for patients receiving epidural analgesia. First, it is necessary to verify the patient's name and date of birth (two identifiers) when administering epidural medications, including dosage changes. Another patient safety goal focuses on eliminating wrong-site, wrong-patient, and wrong-procedure surgery by conducting a "surgical pause" or "time-out" [64]. During the surgical pause, make sure the team conducts a verification process prior to insertion of the epidural catheter to confirm the correct patient, procedure, and site prior to proceeding [64]. If any concerns arise, assertively speak up on behalf of the patient's safety. Follow the institution's protocol for marking the procedure site and documenting the pause in the patient's health record.

Other national patient safety goals are also important in relation to epidural analgesia. These goals include ensuring that unacceptable abbreviations are eliminated to improve the effectiveness of communication among caregivers, IV and PCA pumps have free-flow protection, medications are standardized and the number of drug concentrations are limited to tighten the safety net for high-alert medications, and staff comply with the current Centers for Disease Control and Prevention (CDC) hand hygiene guidelines to reduce the risk of healthcare-acquired infections [65]. The CDC's guidelines include the use of non-antimicrobial soap when hands are visibly dirty or contaminated and alcohol-based waterless handrub for routine hand cleansing.

Another intervention to improve safety with administration of epidural medications is the use of dual verification. Dual verification, the independent verification by a person competent to administer the medication, is necessary with medications like epidural narcotic infusions because of their high risk of adverse patient outcomes should an error occur. Consider dual verifications on all initial epidural pump set-ups and programming changes (i.e., dose or concentration changes). A well-conducted dual verification includes:

- Order detail (drug, dose, concentration, and route)

- Medication label

- Protocol, if applicable

- Programming and any calculations (weight, body surface area, age if applicable, and dilution and syringe volume)

To be effective, this dual verification should be separately conducted. Check your institution's policy regarding use of dual verification and documentation process.

As these patient safety goals portray, patient safety has become tightly woven into the fabric of healthcare organizations. Ideally, all staff members will feel responsible for safety and pursue it on a daily basis. All members of the healthcare team should appropriately identify unsafe conditions and behaviors and intervene to correct them. Healthcare professionals actively care about safety by recognizing safe work practices and coaching peers and colleagues to eliminate unsafe behaviors. In summary, when administering high-alert medications, such as epidural narcotics, utilize these 13 evidence-based strategies for infusion safety [62]:

- Follow policies, procedures, and protocols.

- Ask for a pharmacist's review.

- Confirm the order.

- Use standard equipment and drug concentrations.

- Control the environment.

- Know and use the right equipment.

- Identify the patient in at least two ways.

- Use a labeling system.

- Obtain an independent double-check.

- Decide if you should give the drug.

- Titrate the dosage.

- Check for adverse reactions.

- Report significant changes.

8. PATIENT ASSESSMENT

The goals of nursing management for a patient receiving epidural analgesia for pain control focus on optimizing comfort and minimizing side effects related to the narcotics and/or catheter placement. In order to accomplish these goals, the assessment phase must include an ongoing evaluation of the patient's pain level, vital signs, neurologic status, and catheter site.

PAIN ASSESSMENT

The first parameter to assess is the patient's level of pain. While several tools for pain assessment are available, the most commonly used tool in clinical practice is a VAS (Figure 1) [5]. Various scales may be used, including 0–5, 0–10, or 0–100. The patient is asked what number they would assign to their level of pain, with 0 representing no pain and the largest number equaling the worst pain. These numerical ratings can then be utilized to compare subsequent pain ratings and provide an evaluation of ongoing analgesia. However, pain is a subjective experience, and a rating of 7 for one patient may not be the same in another patient. Therefore, the following assessment questions will further guide evaluating the effectiveness of the epidural route:

Figure 1: PAIN SCALES FOR USE IN CLINICAL PRACTICE

Source: Compiled by Author

- What number on a 0–10 scale would you give your pain when it is the worst that it gets?

- When is it the least painful?

- At what number is the pain at an acceptable level for you?

These questions help assess each individual patient's tolerance of pain. The pain rating that is acceptable to the patient then becomes the goal that is worked toward [6].

Some patients may have difficulty assigning a number to their level of pain. In these cases, the choice of descriptive words (e.g., no pain, a little pain, a lot of pain, too much pain) may be helpful for assessment purposes. These words can then be converted to 0–3 scale for documentation and trending. Another method for pain assessment involves the use of a vertical 10-point VAS. With this technique, the patient is asked to mark their level of pain directly on the scale [66]. Behavioral pain scales are also necessary for those patients who may be cognitively impaired or unable to respond, such as vented and paralyzed or sedated patients. With these scales, a pain intensity score can be obtained by scoring the patient's verbal response, body movement, facial cue, and tactile responses. In addition, as most nurses today practice in ethnically diverse regions, incorporation of multilingual pain scales to allow adequate pain assessment of patients is necessary.

Other important pain assessment parameters, beyond pain intensity, include the location, onset/duration, and aggravating and alleviating factors. With the emphasis by the Joint Commission on pain assessment and pain management, documentation of what has always constituted a thorough and comprehensive pain assessment has become more critical for patient care.

Regardless of the scale used, pain ratings should initially be obtained every hour until the onset of analgesia and then every two to four hours throughout duration of the analgesic effect. Objective physiologic indicators of pain should also be noted, including dilated pupils, pallor, perspiration, nausea and vomiting, and increased heart rate, blood pressure, and respiratory rate [5]. Documentation of pain ratings and other objective pain indicators and the amount of drug infused each hour should be noted on a flowsheet to assist trending and evaluation of ongoing analgesia.

Reassessment of pain and the patient's response to the epidural intervention completes the comprehensive pain assessment. Reassessment is generally recommended at 60 minutes, but with the faster onset of the epidural route, an earlier reassessment interval after dose changes may be warranted. The goal for pain is a rating of less than 3 on the 10-point scale (or the patient's goal for pain relief). The simplest way to assess the effectiveness of an epidural intervention is to reassess the patient's pain with the 10-point scale, but a narrative note is acceptable also. If pain was not lessened, document how the plan of care has changed to reduce the patient's pain. For optimal pain control, the epidural narcotic dose and/or frequency should be adjusted by the physician for patients who complain of inadequate analgesia (i.e., pain ratings over patient's reported acceptable range) [46]. Prior to administration, first check the infusion pump, catheter site, and connections for leakage. If no technical problems are discovered and the patient's pain has not been well controlled, assess whether everything that is indicated for the patient has been tried, such as systemic and adjuvant analgesics, cutaneous stimulation, distraction techniques, relaxation therapy, or imagery [6].

For this standard of pain management to be met, nurses must accept the responsibility of accurately reporting pain assessment findings. Alarmingly, the undertreatment of pain has continued to be widespread [67]. A 2009 study found that 53% of medical inpatients experienced pain (38% with severe pain), and 18% experienced less than 50% analgesic efficacy [68]. Subsequent studies have reported similar findings [69]. In a survey of nurses' decisions about assessment and treatment of pain in two different vignettes, nurses continued to undertreat severe pain [67]. Nurses in this study were more influenced by the patient's behavior than the patient's self-report of pain, especially in relation to decisions about opioid titration. Nurses were less likely to increase a previously safe (but ineffective) dose of opioid for a smiling versus a grimacing patient. Additionally, nurses tended to favor their personal opinions about the patient's pain rather than recorded pain assessments in making decisions regarding opioid dose. These findings contribute to the further undertreatment of pain [67]. Furthermore, studies have shown that patients avoid or delay communicating their pain. Many reasons may explain this behavior, such as not wanting to complain or concern about taking the provider away from other patients [70]. Teaching patients how to communicate their pain to healthcare providers may result in more accurate pain assessments and, therefore, better pain management. Such teaching can also emphasize that effective pain control can avert postoperative complications, such as atelectasis and immobility, and improve patient health outcomes [70].

VITAL SIGN ASSESSMENT

Monitoring of vital signs is imperative in patients with epidural catheters. Heart rate, blood pressure, and respiratory rate should be monitored hourly for the duration of analgesia. Specifically, vital signs should be monitored for 8 hours in patients receiving fentanyl and for 24 hours in patients receiving morphine [47].

In addition, pulse oximetry should be used to assess oxygen saturation. However, pulse oximetry should not replace routine assessment of respiratory rate as increased CO_2 levels can occur despite normal oxygen saturation values—especially if the patient is receiving supplemental oxygen therapy. Both respiratory rate and depth should be assessed every hour for the maximum duration of the first dose and then every four hours. The physician should be notified if the respiratory rate falls below baseline or to less than 10 breaths per minute. Arterial blood gas analysis should be performed if the patient exhibits signs of hypoventilation to confirm elevated CO_2 levels. Carbon dioxide levels greater than 50 mm Hg or a gradual rise from baseline are considered indicative of respiratory depression [2,46].

NEUROLOGIC ASSESSMENT

Neurologic assessment is the third component to monitor in the patient receiving epidural analgesia. Assessment of the patient's level of consciousness (LOC) is important because respiratory depression, a rare but life-threatening complication associated with epidural agents, may not be accompanied by a decrease in respiratory rate. A validated sedation scale (Table 2) should be used to assess for signs of respiratory depression [71]. Vital signs and neurologic assessment should be monitored longer than the duration of analgesia if the patient experiences a change in LOC or displays other signs of respiratory depression [4].

Table 2: SEDATION SCALE IN ASSESSING FOR SIGNS OF RESPIRATORY DEPRESSION

Sedation Level

Description

0 = No sedation

Awake and alert

1 = Mild sedation

Occasionally drowsy, easy to arouse

2 = Moderate sedation

Frequently drowsy, easy to arouse

3 = Severe sedation

Somnolent, difficult to arouse

S = Sleep

Normal sleep, easy to arouse

Source: [5,7,46,47]

A second component of the neurologic assessment should focus on the presence of paresthesias. Paresthesias may be due to the contact of the epidural catheter with neural tissue. Inform the patient that paresthesias are expected during catheter placement and will only last a short time. If numbness or tingling persists, contact the physician for verification of catheter placement. The administration of drugs with preservatives may also cause paresthesias [4]. If local anesthetics have been administered, assessment of motor function is important. Such assessment can be monitored on a 0–4 scale:

- 0 = No movement

- 1 = Moves legs on bed

- 2 = Lifts legs and falls back

- 3 = Lifts legs and holds

- 4 = Normal movement

CATHETER ASSESSMENT

At least every four hours, the catheter site should be checked for intactness or the presence of wetness and for signs of infection. Mild erythema and tenderness at the catheter site are considered normal findings due to bruising and trauma during catheter insertion. However, the physician should be notified if drainage, increasing redness or warmth, or fever is present so that the catheter may be removed. In addition, assess for other neurologic signs that may indicate the development of meningitis, such as headache, persistently high fevers, and nuchal rigidity [5,23,28,29].

9. SIDE EFFECTS AND COMPLICATIONS

A very important aspect of caring for the epidural analgesia patient is monitoring for narcotic-related side effects and catheter-related complications. The most common adverse effects and complications associated with epidural catheters and standard nursing assessments for patients receiving epidural narcotics and/or anesthetics are outlined in Table 3.

Table 3: NURSING ASSESSMENT FOR PATIENTS RECEIVING EPIDURAL ANALGESIA

Assessment

Data

Frequency

Pain

0–10 scale, objective indicators (e.g., increased heart rate, respiratory rate, blood pressure; pallor; nausea/vomiting)

Every two to four hours

Vital signs

Heart rate, blood pressure, respiratory rate and depth, and oxygen saturation

Arterial blood gases

Hourly for duration of analgesia

To validate elevated CO_2 levels

Neurologic status

Level of consciousness, sensory level, motor strength, paresthesias

Hourly for duration of analgesia

Epidural catheter site

Catheter site, dressing, complications (e.g., pain on injection, postdural headache, epidural abscess/hematoma, catheter occlusion/migration/shearing)

Every four hours

Narcotic-related side effects

Respiratory depression, hypotension, nausea/vomiting, pruritus, urinary retention

Every four hours

Source: [7]

NARCOTIC-RELATED SIDE EFFECTS

In general, the side effects of epidural narcotics are no different than those seen with opioids given by other routes. These side effects include respiratory depression, hypotension, nausea and vomiting, pruritus, constipation, and urinary retention [47]. With the exception of urinary retention, the incidence of narcotic-related side effects is dose-dependent. However, the incidence of side effects is higher with the intrathecal method [5]. While further research is needed to compare the rates of narcotic-related side effects of epidural versus systemic narcotics utilized in the management of postoperative patients, one systematic review found that epidural analgesia provided better pain management, reduced adverse events, and reduced length of stay compared with systemic administration [72].

The side effects of epidural local anesthetics may differ from those seen with opioids alone. Local anesthetics are often associated with sensory loss in the region of the block, motor weakness in the lower extremities, alterations in respiratory function, venous pooling and postural hypotension, and urinary retention [5].

Respiratory Depression

The most serious narcotic-related side effect associated with epidural analgesia is respiratory depression. It is manifested by a decrease in the depth of respirations or tidal volume, followed later by a decrease in respiratory rate. Initially, the patient may be able to maintain an adequate respiratory rate but the hyperventilation that occurs does not allow adequate oxygen CO_2 exchange. This impaired gas exchange leads to mental status changes indicative of increasing CO_2 levels. Therefore, a decrease in the patient's LOC or arousability is considered the first and the best indicator of respiratory depression [5]. Any changes in mentation, such as sedation or confusion, should be considered indicators of hypoxia and/or hypercarbia until ruled out by arterial blood gas levels. As discussed, frequent assessment of the patient's level of sedation is important for early detection and treatment [2]. Several factors place patients at greater risk for the development of respiratory depression (Table 4). Respiratory depression is rarely seen in chronic pain patients because many of these patients have developed a tolerance from previous narcotic administration [6].

Table 4: RESPIRATORY DEPRESSION: RISK FACTORS

Elderly patients (older than 70 years of age)

Impaired respiratory function

Poor medical condition

Higher epidural doses

Intrathecal technique

Water-soluble narcotics (e.g., morphine)

Residual systemic opioids given preoperatively or during surgery

Use of other concurrent systemic sedatives, opioids, or antiemetics

Thoracic placement of epidural catheter (greater proximity to 4th ventricle)

Marked changes in thoracic-abdominal pressure (e.g., mechanical ventilation)

Opioid-naïve or nontolerant patients

Source: [6,35,46,47]

Early-Onset Respiratory Depression

The incidence of early-onset respiratory depression is estimated to be less than 1%. It generally occurs within one to two hours of administration and is due to vascular uptake of the opioids from the epidural space. In other words, the narcotic is absorbed by the epidural veins into the systemic circulation. A second mechanism may be the rapid achievement of narcotic concentrations in the brain via the internal vertebral venous system [2,27,46,73].

Delayed-Onset Respiratory Depression

Delayed-onset respiratory depression is relatively uncommon, with an estimated incidence ranging from 0.3% to 5%. With an insidious onset, its peak incidence is 6 to 12 hours after the initial dose; however, it can occur up to 24 hours after administration of the last dose. Delayed-onset respiratory depression related to the lipid and water solubility of the opioids is caused by cephalad diffusion of the narcotic in the CSF to the fourth ventricle, where agonism with opioid receptors of central respiratory centers occurs. Peak CSF concentrations usually occur within five hours [2,27,46].

Because morphine is highly water soluble, it rapidly diffuses cephalad in the CSF via rostral spread. As a result, delayed-onset respiratory depression is more common with morphine. In contrast, fentanyl is highly lipid soluble with greater uptake by the spinal cord. Limited diffusion occurs into the CSF, and thus, respiratory depression in these patients is unlikely [2,5].

Treatment

The first step in managing patients with respiratory depression is withholding additional narcotic boluses or stopping the continuous epidural infusion. The patient should be placed on supplemental oxygen and arterial blood gases obtained. Naloxone, a narcotic antagonist, is also indicated to reverse the respiratory depressant effects, generally for respiratory rates less than eight breaths per minute. The goal of this treatment is to reverse the undesirable side effect while maintaining the beneficial analgesic effects. Naloxone is supplied in 0.4 mg/mL vials. The vial may be diluted with 9 mL of preservative-free normal saline to obtain a 0.04 mg/mL concentration. Small doses, ranging from 0.04–0.4 mg, are repeated (up to a maximum of 0.8 mg) until the desired effect is achieved [47].

After the initial dose, the patient should be continually assessed for the need for additional treatment. Because naloxone has a much shorter half-life (approximately 30 minutes) than narcotics (especially epidural narcotics), repeated administration by either bolus or an infusion may be needed to maintain sufficient plasma levels and reverse the respiratory depressant effects. Naloxone must be titrated slowly, as rapid narcotic reversal may result in hypertension, cardiac dysrhythmias, pulmonary edema, and cardiac arrest due to pain-induced activation of the sympathetic nervous system. Other causes of respiratory depression should be considered if improvement is not achieved with this treatment [47]. The return of pain is possible with naloxone administration, and it is important to review alternative pain management strategies with the patient because additional narcotic doses are not immediately advised [46].

Hypotension

Hypotension is a second potential narcotic-related side effect of epidural analgesia. However, as epidural narcotics have a localized action and do not produce sympathetic nervous system blockade, they generally have little effect on blood pressure. Therefore, if a patient who has received epidural narcotics becomes hypotensive, consider other more common etiologies. The hypotensive state may be a result of fluid volume changes or immobility postoperatively, in which case IV fluids are indicated [7,46]. More rarely, hypotension may be due to allergic reactions, ranging from mild urticaria to cardiovascular collapse. Treatment is determined by the severity of the reaction, from antihistamines to vasopressor support such as IV epinephrine. Other interventions to maintain airway, breathing, and circulation are indicated as needed [7].

Local anesthetics are not specific to sensory afferent fibers, and they do block autonomic and motor efferent fibers. This sympathetic blockade can lead to hypotension and exacerbate or intensify postural hypotension due to hypovolemia. As a result, postural hypotension may restrict early ambulation and potentially increase morbidity. Therefore, assessment of the patient's motor strength prior to ambulation is critical [5,74]. Additionally, assistance with ambulation should be provided to ensure patient safety. Olson and colleagues identified several risk factors for postoperative hypotension in total knee arthroplasty patients who received epidural analgesics/anesthetics [75]. These risk factors included the use of preoperative diuretics, low diastolic blood pressure in the post-anesthesia unit, low postoperative systolic blood pressure on the day of surgery, total fluid intake first postoperative day, and low hemoglobin the third postoperative day. Assessment of these parameters in this population is important in the surveillance of postoperative epidural analgesia.

Pruritus

Pruritus is the most frequently reported narcotic-related side effect of epidural analgesia. The incidence ranges from 28% to 100%, occurring with both acute and chronic administration [2]. Pruritus tends to increase during pregnancy and with co-administration of steroids. The greater intensity of pruritus with epidural narcotics may occur from altered cutaneous sensation or from the effect of the narcotic on the central mechanism located in the medulla [46]. While pruritus is not dose-related, it may continue for the duration of the narcotics' effect. However, some reports identify that pruritus may abate in 48 to 72 hours in patients receiving continuous morphine administration [6,7].

Itching may be local or generalized on the face (especially the nose and palate), trunk, and legs. It may mimic an allergic reaction with a rash, wheals, or edema. An increase in body temperature may also be an exacerbating factor. Treatment is symptomatic, and patients may respond to antihistamines such as 25–50 mg diphenhydramine IM/IV every six to eight hours or 25 mg hydroxyzine IM. In some cases, pruritus may be severe enough to warrant the administration of naloxone titrated to relief. The standard dose of IV naloxone ranges from 0.04–0.4 mg for the treatment of narcotic-related side effects [47].

Nausea and Vomiting

With an estimated incidence of 17% to 35%, nausea and vomiting may occur as the opioid diffuses from the site of the epidural injection to the chemoreceptor trigger zone for vomiting located in the 4th ventricle [2,46]. This side effect usually occurs four to six hours after administration and may be associated with activity, such as turning and coughing [7]. As with hypotension, searching for other causes of nausea and vomiting, such as abdominal distention or pain, should be attempted first.

Treatment is symptomatic with antiemetics such as prochlorperazine (2.5–10 mg every three to four hours IV, or 5–10 mg every three to four hours IM), metoclopramide (10–20 mg IV, IM), or droperidol (0.625–1.25 mg IV) [47]. However, use extreme caution with the concurrent administration of droperidol (maximum initial dose: 2.5 mg). Droperidol relieves nausea but may potentiate the respiratory depressant effects of epidural narcotics, as may other sedating medications, including midazolam, systemic narcotics, antihistamines, and psychotropics [47]. Small doses of naloxone may also be effective in reducing nausea and vomiting without interrupting analgesia [46].

Urinary Retention

Urinary retention is another frequently occurring narcotic-related side effect. With an incidence between 22% and 100%, it is the only narcotic-related side effect that does not appear to be dose-dependent [2,76]. It usually occurs in the first 24 to 48 hours and then resolves spontaneously. Signs and symptoms include a lack of urge to void and bladder distention. The underlying mechanism may be the action of the narcotic on the spinal nerves innervating the detrusor muscle, thereby altering bladder tone (atonia) and predisposing to bladder over distension and increased residual volumes [76]. For unknown reasons, urinary retention occurs more often in elderly men, patients with pre-existing bladder disorders, and during pregnancy and the postoperative period. A study of patients after total knee arthroplasty found that use of epidural analgesia was a significant predictor of urinary retention [77]. Urinary retention may lead to urinary tract infections, which in turn can cause hematogenous seeding and infection of the postoperative joint [6,46].

Nursing management involves monitoring intake and output and assessing for bladder distention. Many centers insert an indwelling Foley catheter for the duration that the epidural catheter remains in place. If a Foley catheter is not used, intermittent catheterization may be necessary. However, catheterization in some populations, like total knee arthroplasty, may in fact further increase the risk of infection [77]. The administration of bethanechol or 0.04–0.4 mg naloxone IV may also help reduce the occurrence of this side effect [46,47].

CATHETER-RELATED COMPLICATIONS

Although rare, a number of catheter-related complications may occur with epidural analgesia. These complications include pain on injection, postdural headache, epidural hematoma or infection, catheter occlusion, catheter migration, or catheter shearing.

Pain on Injection

Although epidural catheters are small and the resistance to injection is high, patients may feel the expansion of the epidural space and/or the cooler temperature of the medication. Pain on injection is usually felt at the site where the catheter empties into the epidural space and is most often caused by injecting the medication too quickly. As it may also indicate infection or a misplaced catheter, full assessment of catheter placement by the physician is warranted when there is pain on injection [46].

Postdural Puncture Headache

Postdural puncture headache, caused by epidural catheter placement, has an incidence ranging from less than 1% to 70%, depending on the needle used (size and type), procedure, and age and sex of the patient. Incidence has been found to be inversely related to the experience of the anesthetist [78]. Postdural puncture headache occurs more often in adults younger than 40 years of age, and men are affected twice as often as women [2,79]. Commonly, the headache occurs within 48 hours of the puncture and lasts from days to weeks [78]. Dural puncture may be intentional, as with intrathecal catheter placement, or accidental during epidural insertion, causing CSF to leak from the intrathecal space through the puncture hole and resulting in a decrease in CSF volume and intracranial pressure.

The use of smaller, blunt-ended needles has been shown to minimize the size of the dural opening and speed closure of the puncture [2]. One study found that use of the smallest gauge needles (of all styles) drops incidence rates of postdural puncture headache consistently below 4% in procedures not intended to pierce the dura [78]. Another study compared the force required for puncture associated with various needle designs and gauges in samples of bovine dura and found that, among needles of the same gauge, there was a significant variation in the amount of required force and CSF leakage based on design [80]. For example, pencil-point style needles required greater penetrating force and caused significantly less leakage than same gauge Quincke needles; however, for all styles, the smaller gauges resulted in less CSF loss upon puncture. More recent studies report that pencil-point needles are superior to cutting needles at reducing the occurrence of postdural headache, headache severity, and the need for epidural blood patches to seal the puncture [81,82].

The resultant headache is postural in nature, exacerbated by an upright position (such as standing), coughing, or shaking the head and is relieved by lying flat. It is the result of stretch and tension on pain-sensitive intracranial vessels, nerves, and tentorium when the upright position is assumed. The headache is described as dull or throbbing, occurring in the frontal or occipital regions. Other signs and symptoms that are often associated include nausea and vomiting, diplopia, photophobia, tinnitus, and diminished hearing. Conservative management includes bedrest, hydration (which helps the production of CSF), analgesics and antiemetics, and use of an abdominal binder. An autologous epidural blood patch may also be utilized to seal the dural puncture and prevent further leakage of CSF. With this technique, 10 cc of the patient's blood is removed from a peripheral vein and injected through an epidural needle at the location of the dural puncture. The patient's blood migrates and forms a venous clot to seal the dural puncture and stop the CSF leak. The blood patch has a success rate of 89% to 95% and is associated with few complications in low-risk (i.e., not immunocompromised) patients [7,79].

Infection

As with any indwelling percutaneous and tunneled catheter, there is the risk of superficial or deep skin and soft tissue infection with epidural analgesia, a risk that varies directly with the length of time the catheter is left in place. Careful aseptic insertion technique with a minimum of trauma, good skin surface and dressing management, and regular inspection of the catheter site for signs of inflammation are each important in minimizing the risk of infection.

Bacterial colonization of the subcutaneous catheter tract and tip is thought to be a major precursor to clinical infection. The rate of epidural catheter colonization has been assessed prospectively in 205 patients receiving short-term postoperative analgesia [83]. In one study of cultures obtained at the time of catheter removal, the rate of colonization of the subcutaneous and tip segments of the catheter was 10.5% and 12.2%, respectively. Skin flora such a coagulase-negative staphylococci (CNS) accounted for the majority of isolates. Eleven patients had positive catheter tip cultures: seven CNS, one Staphylococcus aureus, one Enterococcus, and one Acinetobacter; all had the same organism isolated in large numbers from the adjacent skin and catheter segment sites. Identified risk factors for bacterial colonization of the catheter were adverse catheter site events (e.g., accidental hub disconnection, damage to dressing), adjacent skin colonization, and blood transfusion. The authors concluded that strict aseptic technique at catheter placement and careful attention to maintenance of skin sterility adjacent to the site should reduce rates of catheter tip colonization and decrease the incidence of catheter-related infection [83].

Epidural catheter-associated infections are of two types: superficial (skin and soft tissue) and deep (meninges, epidural space). In one review, the incidence of superficial infection was 4.3%, while reported deep infection rates were much less frequent, ranging from 0% to 0.7% [23]. Common mechanisms of infection include contamination of the exit site and spread along the catheter tract, contamination during needle or catheter insertion, hematogenous seeding from a distant focus of infection, and intraluminal spread via contaminated epidural infusion solutions. Difficult catheter insertions that result in undue trauma at the level of the dura may play a role in the development of epidural space infection. The incidence of infection appears to vary with the site of catheter placement, as one report found that the risk of infection was highest with thoracic epidural catheter usage [23]. One retrospective analysis found that tunneling of thoracic epidural catheters is associated with a lower risk of catheter-related infections [84]. Early local signs of catheter-site infection are erythema, warmth, tenderness, subcutaneous induration, and drainage from the catheter tract [7].

Epidural Abscess or Hematoma

The development of an epidural abscess or hematoma deep to the catheter site is a rare yet potentially serious complication. Bleeding into the epidermal space, from catheter placement trauma or erosion of an epidural venule or arteriole, tends to occur early after catheter insertion and is extremely rare unless the patient has a coagulopathy (e.g., thrombocytopenia, clotting factor deficiency, anticoagulant therapy). As indicated, the incidence of epidural abscess is less than 1% [23].

While rare, epidural hematoma and abscess are potentially life-threatening complications. Clinically, both present as a mass effect: localized pain, swelling or tenderness at the catheter site, radiculopathy, and other spinal cord compression signs [7]. Compression of sensory and motor neural elements in and about the spinal cord results in a variety of neurologic deficits. These include heaviness, numbness and tingling, lancinating pain, and loss of motor function below the affected level (e.g., lower extremities with lumbar catheters). Therefore, the patient's neurologic status should be assessed at least every four hours, including degree of back discomfort, motor strength, and sensory level. The physician should be notified if the patient reports new or unexpected degree of back pain, experiences a change in sensation, or is found to have loss of sensation or diminished motor strength in the extremities. Careful neurologic examination and consideration of magnetic resonance imaging should follow [7,23].

Catheter Occlusion

Occlusion of the epidural catheter may be due to various causes. The most common causes include the development of a blood or fatty clot within the catheter, contact of the tip of the catheter against an epidural vein, or kinking of the catheter [7]. Some epidural catheters are virtually kink-resistant due to the coil housed within the lumen of the catheter. If the epidural catheter does become occluded, the patient will not receive analgesia and will complain of returning pain [7]. In this situation, reassessment of catheter patency and placement is warranted.

Catheter Migration

After the epidural catheter is placed and the needle is removed, it is unlikely that the catheter will migrate and penetrate the dura. While dural puncture most often occurs during placement, the catheter must always be aspirated to verify correct placement prior to administering an epidural narcotic. The catheter dressing should also be assessed routinely to confirm that it is dry and intact. If the dressing is wet and catheter migration is suspected, notify the physician [7].

If the epidural catheter does migrate, a larger amount of narcotic may enter the CSF. With increased analgesia, the patient has a greater risk of respiratory depression, cardiovascular collapse, and neurologic changes, such as altered LOC, seizures, and paresthesias [7]. In these situations, the narcotic should be withheld until catheter placement can be reassessed and alternative routes for the administration of analgesics should be selected.

If the patient is receiving local anesthetics and the epidural catheter migrates into the subarachnoid space, these agents can infuse directly into the CSF and cause the level of blockade to rise. This blockade may affect the respiratory muscles. In addition, local anesthetic toxicity may occur when serum concentrations of the drug elevate. Signs of symptoms of toxicity include tinnitus, visual disturbances, and seizures [5].

Catheter Shearing

Another rare catheter-related complication is shearing or breakage of the epidural catheter. This complication most often occurs during insertion or removal of the catheter. Shearing can be avoided by taping and stabilizing the catheter securely after insertion. Avoid bending the catheter. Again, if the dressing is wet or the catheter is leaking fluid, notify the physician [7]. If the catheter breaks off, the tip is generally not removed as these catheters are nontoxic and non-allergenic. If neurologic sequelae or infection develops, the catheter tip is retrieved surgically [4].

POSTPROCEDURE EVALUATION

Postprocedure evaluation is an important component of care in the patient receiving epidural analgesia for pain management. While ongoing analgesia is evaluated throughout the intervention, the final phase of evaluation begins with catheter removal. Evaluation helps measure the patient's progress (or lack of progress) toward the goal of controlling pain and minimizing side effects and/or complications. In addition to these physical aspects, the patient's perspective on the effectiveness of epidural analgesia as a pain management modality should also be assessed.

PHYSICAL ASPECTS

Epidural catheters generally remain in place until the patient is comfortable taking oral analgesics for approximately 24 hours. This point is critical because the time of changing narcotic routes is the most vulnerable period for undermedicating patients. The dose of narcotic for the new route should be calculated using an equianalgesic chart and the patient/family educated about the new route. Assess the patient's comfort level and either increase or decrease the dose according to the patient's individual response [6].

While dependent upon hospital policy, catheters are usually left in place for up to 96 hours after placement [4,7,28]. In many hospitals, physicians remove the dressing and catheter. However, the ASPMN has created a practice statement that supports the role of nurses in managing the catheter [51]. Although the placement of epidural catheters and initial testing and prescription of analgesic therapy lies with the responsibility of an anesthesiology professional, this practice statement advocates for the role of the RN in removing epidural catheters. Removal of epidural catheters by RNs is contingent upon a specific order from a qualified anesthesia professional or physician provider if educational criteria have been met and the procedure is permitted by both institutional policy/protocol and state law [51].

For catheter removal, the patient should be placed in the lateral decubitus position with full flexion of the spinal canal (just like with insertion) for maximal opening of the intervertebral spaces [4]. If hospital policy allows RNs to remove epidural catheters, gently remove the tape and transparent dressing from the patient's back. Then, remove the catheter by withdrawing slowly and using steady, gentle traction. Never apply force to the epidural catheter. If the catheter does not remove easily, leave the catheter and attempt later or contact the physician. Remember, the epidural catheter is only 3–5 cm in length and should come out easily.

After the catheter is removed, inspect the tip for intactness. Many epidural catheters have a colored mark at the tip for ease of identification. The presence of a mark at the tip indicates that the catheter is intact. If the catheter breaks, notify the physician. After removal, the catheter site should be inspected frequently for signs and symptoms of infection [4]. Patients should also be instructed not to get out of bed unassisted. It is not uncommon for patients to feel dizzy when first getting up and their legs may be weak, so assistance is necessary to promote safety. Further evaluation focuses on reviewing the effect of epidural analgesia on the patient's physiologic status. The expected patient outcomes that should be evaluated include [3,4,6,46]:

- Vital signs maintained at baseline

- Pulmonary system

- Adequate ventilation (respiratory rate >10 breaths per minute with adequate depth of respiration)

- Skin and mucous membrane color normal

- Arterial blood gases within normal range

- Patient able to cough and deep breathe with little difficulty

- Neurologic system

- LOC at baseline

- No motor or sensory changes (motor strength at baseline, no complaints of paresthesias)

- Pain

- Minimal discomfort (patient reports decreased level of pain on 0–10 scale and objective signs of pain absent)

- Patient able to move about freely (both in and out of bed)

- No immobility-related complications (e.g., pneumonia, deep vein thrombosis)

- Catheter

- Little or no pain on injection

- No signs/symptoms of infection at catheter site (e.g., redness, induration, exudate) or meningitis (elevated white blood cells, fever, nuchal rigidity, change in LOC, cloudy CSF aspirate)

- No catheter-related complications (e.g., catheter migration/shearing)

- Side effects

- Little or no pruritus

- Little or no nausea and vomiting

- Little or no urinary retention (i.e., patient able to void spontaneously, urinary output adequate)

- Patient verbalizes understanding of teaching related to epidural analgesia

Beyond the immediate postprocedure phase, quality improvement is another important mechanism to evaluate the effectiveness and safety of epidural analgesia for a population of patients. Tools may be developed to evaluate if: the narcotics administered were appropriate and effective for individual patients; the frequency of supplemental analgesics was adequate in relation to patient pain ratings; and assessment parameters were evaluated according to established protocols. In addition, the incidence of side effects and complications should be monitored, along with the appropriateness and effectiveness of nursing/medical interventions to treat these conditions [3].

EMOTIONAL ASPECTS

Some patients may need to talk about their experience with pain. This need may be present whether patients' pain was well controlled or not or if their pain has subsided and pain relief measures are no longer needed. Nurses can assist patients in assimilating their pain experience by encouraging expression of what they remember about the pain sensations, associated thoughts and feelings, reactions to pain, and how other people related to them while they were in pain. Actively listening to patients describe their experience and supporting their reactions may help some individuals emotionally assimilate the feelings that may continue after the pain sensations are over [6].

10. NURSING DIAGNOSES AND INTERVENTIONS

1. Alteration in pulmonary function related to epidural narcotic or anesthetic administration

Expected Outcomes

- Respiratory rate will be greater than 10 breaths per minute.

- Depth of respirations will be adequate.

- Arterial blood gases will remain at baseline.

- LOC will remain at baseline.

Nursing Interventions

- Monitor rate/depth of respirations and oxygen saturation per pulse oximeter and/or apnea monitor.

- Assess for neurologic signs of CO_2 retention (decreased LOC).

- Maintain patent IV or saline lock.

- Avoid concurrent administration of additional narcotics or sedatives without consulting a physician.

- If respiratory rate falls below 10 breaths per minute, contact a physician.

- Administer supplemental oxygen and obtain arterial blood gases to verify elevated CO_2 levels.

- Administer naloxone per protocol.

- Withhold additional epidural narcotic doses and review alternative pain management strategies with patient/family.

2. Potential alteration in hemodynamics secondary to sympathetic nervous system blockade associated with local anesthetics

Expected Outcomes

- Patient will experience minimal hypotension.

- Blood pressure will be maintained at baseline.

Nursing Interventions

- Monitor blood pressure every hour after administration of epidural anesthetic.

- Administer IV fluids per order if fluid volume deficit present.

- Monitor motor strength and orthostatic blood pressures prior to activity; ambulate patient with assistance only.

- If patient is receiving epidural opioids only, assess for other causes of hypotension, such as allergic reaction or postural hypotension. Administer IV fluids, antihistamines, or vasopressors as indicated per physician orders.

3. Potential alteration in comfort: Pain secondary to rapid injection of epidural narcotic, inadequate titration, or catheter occlusion, or postdural headache related to dural nick during catheter placement

Expected Outcomes

- Maximal pain relief will be obtained.

- Catheter will remain unoccluded.

- Patient will experience minimal discomfort related to postdural headache.

Nursing Interventions

- Administer epidural narcotic slowly if using intermittent technique to decrease pain associated with injection.

- Administer epidural narcotic via continuous infusion if possible to maintain consistent plasma opioid levels.

- Assess level of pain on 0–10 VAS every two to four hours; reassess effectiveness of epidural narcotic dosage based on patient's pain ratings and objective pain indicators.

- Assess catheter dressing and tape every shift to ensure site is dry and intact and that catheter is patent and unkinked.

- Notify physician of increased pain ratings or if catheter occlusion is suspected. Withhold analgesic until full catheter assessment is performed.

- Instruct patient to inform nurse of headache after catheter insertion.

- If the patient complains of a headache, maintain supine position, as the headache is postural in nature and worsens with the upright position.

- Administer analgesics per physician's order and encourage consumption of fluids.

- Assist with autologous blood patch if indicated; 10 cc of patient's blood will be inserted through the epidural catheter to clot and seal the dural puncture.

4. Alteration in comfort: Pruritus secondary to rostral spread of epidural narcotic

Expected Outcome

- Minimal pruritus will be experienced by the patient.

Nursing Interventions

- Monitor body temperature as pruritus may be exacerbated by an increased body temperature.

- Teach patient to inform nurse of any itching.

- Report any complaints of pruritus to the physician.

- Administer antihistamine, such as diphenhydramine (25–50 mg IV); repeat as needed to prevent further episodes.

- Administer small doses of naloxone (0.04–0.4 mg IV) as needed.

5. Alteration in comfort: Nausea and vomiting secondary to rostral spread of epidural narcotic

Expected Outcome

- Minimal nausea and vomiting will be experienced by the patient.

Nursing Interventions

- Instruct patient to inform nurse of nausea or vomiting episodes.

- Notify physician if patient complains of nausea and/or vomiting.

- Administer antiemetics (prochlorperazine or metoclopramide) or small doses of naloxone (0.04–0.4 mg) per protocol.

- Use extreme caution when administering sedating antiemetics such as droperidol. This medication may have a synergistic enhancement of the analgesic, increasing the risk of respiratory depression.

- As nausea and vomiting usually occur within the first four to six hours after administration, routine prophylaxis is not necessary.

6. Alteration in urinary elimination: Urinary retention secondary to effect of epidural narcotic on spinal nerves innervating bladder

Expected Outcomes

- Bladder distention will be absent.

- Urge to void will be intact.

Nursing Interventions

- Instruct patient to inform nurse of distended bladder. Notify physician of decreased urinary output or bladder distention.

- Administer bethanechol per physician's order.

- Catheterize as needed or insert indwelling Foley catheter per order.

- Remove Foley catheter when epidural catheter is discontinued and monitor elimination patterns.

7. Potential for infection related to indwelling epidural catheter or catheter shearing

Expected Outcomes

- Signs of redness, swelling, or purulent drainage at the catheter insertion site are absent.

- No signs or symptoms of meningitis will be present.

Nursing Interventions

- Assess catheter insertion site for pain, tenderness, or other signs of infection.

- Assess for fever, nuchal rigidity, or changes in LOC. Notify physician if present.

- Assess catheter tip upon removal. Verify that the tip is intact by the presence of a black-colored mark.

- Notify the physician if the catheter tip is not intact upon removal.

8. Potential for injury related to migration of epidural catheter into subarachnoid space or development of epidural abscess/hematoma

Expected Outcomes

- Catheter will not migrate out of epidural space.

- Epidural abscess or hematoma will be absent.

Nursing Interventions

- Assess catheter placement prior to administration of epidural narcotic. Aspirate catheter and assess returns. If no aspirate is obtained, epidural placement is confirmed. In the presence of bloody aspirate or more than 1 mL of clear fluid that tests positive for glucose, the catheter has most likely migrated into the subarachnoid space.

- Assess catheter insertion site every shift. Note that the dressing is dry and intact. If the dressing is wet or leaking fluid, notify the physician that catheter migration is suspected.

- Assess catheter site for signs/symptoms of infection and evidence of hematoma formation (enlarged hardened area) every four hours.

- Perform neurologic assessment every four hours (sensory level and motor function). Inform physician of loss of sensation or decreased motor strength.

9. Knowledge deficit related to use of epidural analgesia as a method of pain control

Expected Outcome

- Patient/family will understand purpose of epidural analgesia, including risks and benefits.

Nursing Interventions

- Inform the patient/family about the procedure used to insert the epidural catheter.

- Teach the patient how to use the pain rating scale and to inform the nurse of decreased levels of analgesia.

- Explain the onset and duration of analgesia that may be expected.

- Teach the patient/family that epidural analgesia will control pain and not totally eliminate pain (unless epidural anesthetics are used).

- Inform the patient to tell the nurse if side effects are experienced at the onset (e.g., nausea/vomiting, pruritus, bladder distention).

- If the epidural catheter is intended for long-term use, teach the patient/family about home care.

11. CASE STUDY

Patient A is 64 years of age and was scheduled to undergo a thoracotomy for the resection of a lung nodule. On the morning of surgery, Patient A was transferred to the preoperative holding area where an arterial line, peripheral IVs, and an epidural catheter were inserted. A 16F Foley catheter was also inserted to monitor urine output and prevent urinary retention associated with epidural analgesia.

For epidural catheter placement, the patient was positioned in the left lateral decubitus position with his hips and neck fully flexed. The selected site for the catheter, the T10–T11 interspace, was draped and prepped with antiseptic. The thoracic epidural catheter was then inserted using the loss of resistance technique. To verify placement, the catheter was aspirated with no returns of CSF or bloody fluid. A filter was attached to the slide-lock adapter, and the catheter port was cleansed with antiseptic prior to dosing the catheter. Patient A received an initial bolus of 5 mg morphine and 75 mcg fentanyl, followed by a continuous infusion of 0.3 mg morphine per hour. A sterile occlusive dressing was placed at the insertion site, and the catheter was taped securely along the patient's back, with the end of the catheter positioned over his shoulder. The administration set was clearly labeled "epidural catheter."

After he was transferred to the operating room, the patient was intubated and anesthetized. A left thoracotomy incision was made, and the procedure ensued. At the end of the procedure, one chest tube was placed in the left pleural space. After the operation was completed, the patient was extubated and placed on a 50% oxygen mask and transferred to the cardiothoracic ICU.

In the ICU, patient assessment included frequent monitoring of vital signs, especially respiratory rate and tidal volume. After the patient awoke from anesthesia, nursing assessment also focused on his level of pain, neurologic status, and observation for narcotic-related side effects and catheter-related complications. On initial assessment, Patient A's respiratory rate was 20 breaths per minute with an oxygen saturation of 100%. The electrocardiogram monitor showed sinus rhythm with a rate of 98 beats per minute and a few isolated unifocal premature ventricular contractions. Arterial blood pressure was 104/72 mm Hg. When he recovered from anesthesia, he was awake, alert and oriented, with a sedation rating of 2. Patient A rated his pain as a "3" on a 0–10 VAS and stated his pain primarily occurred with pulmonary toilet (coughing and deep breathing) and turning due to his bilateral chest tubes. The Pain Service continued orders for a 0.3 mg continuous infusion of morphine for pain management. Assessment of the epidural catheter revealed that the dressing was dry and intact. The site was slightly erythematous, with some bruising noted. However, the site was free of signs and symptoms of infection, abscess, or hematoma development. Later that evening, Patient A began complaining of pruritus. The itching was present in his face and neck but was especially intense in his truncal region. A slightly raised erythematous rash soon became apparent. Patient A was medicated with 25 mg IV diphenhydramine, which was repeated in six hours due to his continued complaints of intense itching.

On the morning of the first postoperative day, Patient A's respirations became shallow and his respiratory rate dropped to eight breaths per minute. Although he was still arousable with a sedation rating of 3, the physician ordered a set of arterial blood gases. The PCO_2 level had climbed to 63 from his baseline in the lower 50s. These assessment findings suggested delayed-onset respiratory depression. As a result, the continuous infusion of morphine was turned off and the patient received 0.2 mg of naloxone slow IV push. The naloxone dose was repeated in 30 minutes with an additional 0.1 mg IV. Patient A continued to rate his pain a "3" on a 0–10 VAS. Thus, the respiratory depressant effects were reversed without negating the beneficial analgesic effects of the morphine infusion. Patient A remained on a 50% face mask, which was supplemented with 7 L per nasal cannula.

Eight hours later, the patient's level of consciousness was at baseline and respirations were greater than 12 breaths per minute with a good tidal volume. The morphine infusion was restarted at 0.3 mg per hour. With good pain relief, Patient A was able to be assisted to the chair for activity. On the second postoperative day with continued good pain relief, the patient was up to the chair and ambulated twice for 150–250 feet with assistance from physical therapy.

After three days, the epidural catheter was removed by the anesthesiologist. Again, Patient A was placed in the lateral decubitus position with his hips and neck flexed and the occlusive dressing was removed. The epidural catheter was then slowly and carefully removed and the tip of the catheter was inspected. The black colored marking was present on the tip of the catheter, indicating it was fully intact upon removal. In assessing the catheter site, only a small degree of erythema was noted. After discontinuation of epidural analgesia, the patient's Foley catheter was removed and he obtained good pain relief with oxycodone/acetaminophen and nonsteroidal anti-inflammatory agents, including ibuprofen and ketorolac. Effective pain control helped Patient A meet his postoperative recovery goals, including pulmonary toilet, maintaining adequate nutrition for wound healing and general strength, and gradual activity progression. After the air leak sealed, the right mediastinal tube was discontinued.

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Evidence-Based Practice Recommendations Citations

1. Carmichael JC, Keller DS, Baldini G, et al. Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons. Dis Colon Rectum. 2017;60(8):761-784. Available at https://fascrs.org/ascrs/media/files/downloads/Clinical%20Practice%20Guidelines/clinical_practice_guidelines_for_enhanced_recovery-3.pdf. Last accessed March 4, 2021.

2. Galvagno SM Jr, Smith CE, Varon AJ, et al. Pain management for blunt thoracic trauma: a joint practice management guideline from the Eastern Association for the Surgery of Trauma and Trauma Anesthesiology Society. J Trauma Acute Care Surg. 2016;81(5):936-951. Available at https://www.east.org/education-career-development/practice-management-guidelines/details/thoracic-trauma-blunt-pain-management-of. Last accessed March 4, 2021.

95323 • Diabetes Pharmacology

Diane Thompson, RN, MSN, CDE, CLNC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and maintain various safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control. The emotional stressors can be a substantial barrier to success for individuals and their significant others and/or caregivers. These emotional interferences include needle fears and phobias, ignorance, and time constraints. Patients' responses to the medications, laboratory results for safe, efficacious dosing, and drug effects must all be monitored.

Table of Contents

95323 • Diabetes Pharmacology

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

1. INTRODUCTION

2. DIABETES EPIDEMIOLOGY

3. PATHOGENESIS OF DIABETES

PHYSIOLOGY OF INSULIN RELEASE IN FUEL METABOLISM

4. DIABETES RESEARCH

THE DIABETES PREVENTION PROGRAM

THE DIABETES COMPLICATION AND CONTROL TRIAL

THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY

TREAT-TO-TARGET TRIAL

4-T TRIAL

ORIGIN TRIAL

CAROLINA TRIAL

5. DIAGNOSIS OF DIABETES

TYPES OF DIABETES

SCREENING FOR DIABETES

DIAGNOSTIC CRITERIA

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

FIRST-GENERATION AGENTS

SECOND-GENERATION AGENTS

POTENTIAL SIDE EFFECTS

CASE STUDY

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

REPAGLINIDE

NATEGLINIDE

POTENTIAL SIDE EFFECTS

CASE STUDY

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

ACARBOSE

MIGLITOL

POTENTIAL SIDE EFFECTS

CASE STUDY

9. BIGUANIDE THERAPY

POTENTIAL SIDE EFFECTS

CASE STUDY

10. THIAZOLIDINEDIONE THERAPY

PIOGLITAZONE

ROSIGLITAZONE

POTENTIAL SIDE EFFECTS

CASE STUDY

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

SITAGLIPTIN

SAXAGLIPTIN

LINAGLIPTIN

ALOGLIPTIN

CASE STUDY

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

POTENTIAL SIDE EFFECTS

13. COMBINATION ORAL MEDICATION PREPARATIONS

CASE STUDY

14. BOLUS INSULIN THERAPY

INSULIN ASPART

INSULIN LISPRO

INSULIN GLULISINE

REGULAR INSULIN

HYPERGLYCEMIC CRISES

15. BASAL INSULIN

NPH (INTERMEDIATE-ACTING) INSULIN

INSULIN GLARGINE

INSULIN DETEMIR

POTENTIAL SIDE EFFECTS

16. COMBINATION INSULIN PREPARATIONS

17. INCRETIN MIMETICS

CASE STUDY

18. AMYLIN ANALOGS

19. PATIENT EDUCATION

ORAL DIABETES MEDICATIONS

HYPOGLYCEMIA

TIMING OF MEDICATIONS AND OTHER CONSIDERATIONS

INSULIN AND NONINSULIN INJECTABLES

20. CASE STUDIES

CASE STUDY 1

CASE STUDY 2

CASE STUDY 3

21. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95323 • Diabetes Pharmacology

Education Category. Pharmacology

Release Date. 11/01/2019

Expiration Date. 10/31/2022

Course Overview

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and maintain various safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control. The emotional stressors can be a substantial barrier to success for individuals and their significant others and/or caregivers. These emotional interferences include needle fears and phobias, ignorance, and time constraints. Patients' responses to the medications, laboratory results for safe, efficacious dosing, and drug effects must all be monitored.

Audience

This course is designed for pharmacy professionals and nurses in any practice setting with a desire to familiarize themselves with the medications used in the treatment of type 2 diabetes.

Course Objective

The purpose of this course is to meet the needs of healthcare professionals seeking a better understanding of the actions, dosages, onset of action, and adverse effects of diabetes medications in order to provide optimal care to their patient population.

Learning Objectives

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

1. Outline the epidemiology of diabetes in the United States.

2. Describe normal fuel metabolism and the pathogenesis of type 1 and type 2 diabetes.

3. Analyze the current state of diabetes research.

4. Identify the diagnostic criteria and screening guidelines for diabetes.

5. Discuss the role of sulfonylureas in the treatment of diabetes, including potential side effects.

6. Review the pharmacology of nonsulfonylurea secretagogues.

7. Compare and contrast the alpha-glucosidase inhibitors available for the treatment of diabetes.

8. Describe the role of metformin in diabetes management.

9. Assess the strengths and weaknesses of thiazolidinediones and dipeptidyl peptidase-4 inhibitors to control blood glucose levels.

10. Identify various bolus insulin options, and outline the risk and response to related hyperglycemic crises.

11. Discuss the importance of basal insulin in the treatment of type 1 and type 2 diabetes.

12. Compare the efficacy and actions of incretin mimetics and amylin analogs.

13. Choose key topics that should be included in patient education plans for individuals being treated with oral or injectable diabetes medications.

Faculty

Diane Thompson, RN, MSN, CDE, CLNC, has an extensive history in nursing and nursing education. She possesses a strong background in diabetes and cardiac care, starting her professional career at the cardiac care area of the Cleveland Clinic in Cleveland, Ohio. Ms. Thompson took the knowledge and experience she learned from the Cleveland Clinic and transferred it into the home health arena in rural Ohio, after which she moved to Florida and obtained further knowledge while working as a PRN nurse in all areas, including medical/surgical, intensive care, emergency, critical care, and cardiology. With a desire to have a specific area to concentrate her profession, Ms. Thompson accepted a position as a pneumonia case manager, which led into a diabetes case manager career.

Ms. Thompson has been employed in diabetes care since 2001, when she was hired as a diabetes case manager. After the completion of 1,000 hours of education to diabetes patients, Ms. Thompson earned her certification as a diabetes educator in 2003. From 2006 to 2018, Ms. Thompson was the Director of Diabetes Healthways at Munroe Regional Medical Center in Ocala, Florida. As the director of the diabetes center, Ms. Thompson was responsible for the hospital diabetes clinicians, hospital wound care clinicians, and out-patient education program. Today, she is the nurse manager of a heart, vascular, and pulmonary ambulatory clinic at Metro Health System in Cleveland, Ohio. Ms. Thompson has also lectured at the local, state, and national level regarding diabetes and the hospital management of hyperglycemia. Ms. Thompson is a member of the ADA, AADE, Florida Nurses Association, and the National Alliance of Certified Legal Nurse Consultants.

Ms. Thompson acknowledges her family as her greatest accomplishment. She is a wife of more than 30 years and a mother of a daughter and son, of which she is very proud. Ms. Thompson credits her husband for the support needed to set a goal and achieve it. He has been by her side through nursing school and completion of her Bachelor's degree and Master's degree, which she was awarded in 2015 from Jacksonville University in Florida.

Faculty Disclosure

Contributing faculty, Diane Thompson, RN, MSN, CDE, CLNC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

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

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Diabetes is a serious and growing problem in the United States. Behavior change, diet, and exercise are first in the line of treatment for this chronic disease. However, diabetes is a progressive disease, and these techniques will only work for a small portion of patients. Oral medications will eventually be necessarily incorporated into treatment plans in order to preserve control of the disease at an optimal level, and injectable medications are started in the second tier of therapy when glucose levels are significantly greater than the goal range [1]. Healthcare professionals are required to sustain a fundamental understanding of diabetes medication classes, including action, maximal safe dosing, and side effects, when caring for their patients. Oral medications for diabetes impact individuals to differing degrees and are associated with differing safe practice recommendations. Furthermore, although insulin and other injectable medications are beneficial, patient acceptance of injectable medications continues to be a significant barrier to achieving optimal blood glucose control [2]. Laboratory results, drug effects, and patient response to treatment should all be monitored.

2. DIABETES EPIDEMIOLOGY

Diabetes, known clinically as diabetes mellitus, is a progressive disease process affecting the fuel metabolism functioning within the body [3]. According to the Centers for Disease Control and Prevention (CDC), the prevalence of diagnosed diabetes has increased from less than 1% of the U.S. population in 1958 to more than 7% in 2014 [4]. As of 2017, 9.4% of the U.S. population, or 30.3 million Americans, have diabetes. Unfortunately, 7.2 million of these individuals are unaware of their diabetes diagnosis [5,6]. Diabetes has been considered epidemic since the 1970s, and the percentage of Americans expected to have diabetes or impaired glucose tolerance (IGT) is estimated to reach 15% to 20% by the year 2025 [7].

The scope of the problem is vast and diverse. From 1994 through 2015, the prevalence of diagnosed diabetes increased across all states. In 1994, only one state had a prevalence greater than 6.0%. In 2015, all states had prevalences greater than 6.0%, and 27 exceeded 9.0% [8]. According to data from the Behavioral Risk Factor Surveillance System, West Virginia has the highest rate of adults with diabetes (16.2%). Nine of the 10 states with the highest rates (12% to 15.9%) are in the South. Colorado ranked last at 7.1% [8]. Genetics, race, age, and lifestyle influence the onset and progression of the disease process significantly [9]. According to 2013–2016 national survey data, diabetes was higher among non-Hispanic black (17.9%) and Hispanic (19.8%) adults compared with non-Hispanic white (12.4%) adults. The prevalence of diagnosed diabetes was higher in Hispanic (13.6%) and non-Hispanic black (13.9%) adults compared with non-Hispanic Asian (10.2%) and non-Hispanic white (8.5%) adults. The prevalence of undiagnosed diabetes is higher in Hispanic (6.2%) adults compared with non-Hispanic white (3.9%) and non-Hispanic black (4.0%) adults [10]. Native Americans/Alaskan Natives present the greatest risk for the development of type 2 diabetes; their risk is more than two times greater than that of white Americans. It is estimated that 15.1% of Native Americans/Alaskan Natives older than 20 years of age have diabetes [6]. The highest prevalence of diabetes in the United States is observed in Native Americans in southern Arizona, where an estimated 22% of the population has developed diabetes [6].

The most rapid increase in prevalence in the last decade has been among adolescents. Historically, children and adolescents with hyperglycemia have been diagnosed with type 1 diabetes, a result of the body being unable to produce adequate amounts of insulin. However, in 2012, researchers from the SEARCH for Diabetes in Youth study released data showing a 21% increase in type 2 diabetes between 2001 and 2009 in youth 10 to 19 years of age, with the number of cases rising faster among girls than boys [11]. Approximately 5,300 children and adolescents were newly diagnosed with type 2 diabetes during 2011–2012. Those who were members of racial or ethnic minority groups had the highest rates of new cases [6]. It has been predicted that children born in this millennium will have a one in three chance of developing diabetes in their lifetime; among high-risk ethnic groups, the estimate is as high as one in two [12].

3. PATHOGENESIS OF DIABETES

Individuals with type 1 diabetes typically present to their primary care office or hospital emergency department with a sudden weight loss and severe hyperglycemia [13]. The consequences of the disease can take years to impact the body if optimally controlled. In contrast, an individual with type 2 diabetes may be unaware of the disease process for years prior to being diagnosed. The onset of type 2 diabetes is insidious, with the loss of first-phase insulin response to postprandial levels. The first elevation may be detected at the time of screening as prediabetes or IGT [7]. During this time, the disease progression and hyperglycemia are ravening the body's micro- and macrovascular systems [3].

In a healthy body, carbohydrate consumption results in an initial swell in serum glucose levels and hyperglycemia. In response to this escalation, the body releases insulin from pancreatic beta cells into the circulatory system to assist with glucose transport into muscle, liver, and adipose tissues; this causes a lowering of the blood glucose levels.

In the case of type 1 diabetes, pancreatic beta cells fail to produce and release insulin, and the only treatment option is exogenous insulin and other appropriate injectables [7]. However, the pathogenesis of type 2 diabetes is more complex. Virtually all individuals diagnosed with type 2 diabetes have insulin resistance in conjunction with some degree of insulin deficiency [14]. In response, the body's inability to react to the mounting glucose level is magnified by insulin deficiency in the functioning pancreatic beta cells, insulin resistance in the muscular tissue, or both [3]. Unlike the therapy for type 1 diabetes, type 2 diabetes is initially treated with lifestyle modification therapy (e.g., medical nutrition therapy, exercise, behavior change) and frequently with an oral medication, such as a biguanide. Within five years of type 2 diabetes diagnosis, it is estimated that as many as 90% of people will fail this initial therapy and require further oral medications or injectables to achieve adequate glucose control. As a result of this failure rate, medication therapy is initiated early (in the prediabetes stage) in diabetes medical treatment algorithms [15].

PHYSIOLOGY OF INSULIN RELEASE IN FUEL METABOLISM

In order to fully comprehend the action of exogenous insulin, healthcare providers require a solid understanding of insulin physiology. Glucose regulation is maintained by a sophisticated mechanism of regulatory and counter-regulatory reactions. When an individual consumes food, specifically carbohydrates, sugars are released into the blood circulatory system [16]. The chemical reactions to this sugar introduction help maintain homeostasis in the body.

Phases of Insulin Response

The concentration of plasma glucose is dependent on the rate glucose enters the circulation in contrast to the rate it is removed [17]. Fuel homeostasis within the body can be explained in a five-phase approach [18]. Phase 1, or the fed state, occurs immediately and up to 3.9 hours after consumption of food. During this phase, the circulating glucose is predominantly from an exogenous source. Plasma insulin levels are elevated, glucagon levels are minimal, and triglycerides are synthesized in the liver. Insulin impedes the breakdown of glycogen and triglyceride reservoirs. The brain and other glucose-dependent organs utilize some of the glucose absorbed from the intestinal tract, and the excess glucose is stored in the liver, muscle, adipose tissue, and other tissues for use later.

Phase 2 occurs 4 to 15.9 hours after consumption of food and is referred to as the postabsorptive state. In phase 2, blood glucose originates from the breakdown of glycogen and hepatic gluconeogenesis. There is a decrease in plasma insulin levels, and glucagon levels begin to increase. Anabolism (energy storage) ends in this phase and catabolism (energy production) begins. There is a mobilization of carbohydrate and lipid stores. Hepatic glycogen breakdown provides maintenance of circulating plasma glucose to ensure an adequate supply of glucose to the brain and other organs. Adipocyte triglyceride begins to break down, and free fatty acids are released into the circulatory system for use by the liver and skeletal muscle as the primary energy source and as a substrate for gluconeogenesis. The brain continues to utilize glucose, provided mainly by gluconeogenesis, due to its inability to use free fatty acids.

Phase 3 is the early starvation state. About 16 to 47.9 hours after the consumption of food, the blood glucose is generated from hepatic gluconeogenesis and glycogenolysis. Gluconeogenesis continues to generate most of the hepatic glucose. In this phase of starvation, lactate makes up half of the gluconeogenesis substrate along with amino acids (specifically alanine) and glycerol. The secretion of insulin is suppressed, and counter-regulatory hormone (i.e., glucagon, cortisol, growth hormone, epinephrine) secretion is stimulated.

Phase 4 begins 48 hours to 23 days after food consumption. During this preliminary prolonged starvation state, blood glucose originates from hepatic and renal gluconeogenesis. Within 60 hours of starvation, gluconeogenesis provides more than 97% of hepatic glucose output. The secretion of insulin is distinctly diminished and counter-regulatory hormone secretion is stimulated.

Phase 5, or the secondary prolonged starvation state, begins 24 days after food consumption. Blood glucose during this phase originates from hepatic and renal gluconeogenesis, just as in phase 4. However, in phase 5 the rate of glucose being utilized by the brain and the rate of gluconeogenesis diminishes.

The relationship between the glucoregulatory and the counter-regulatory hormones and the many factors that contribute to the fuel metabolism should be considered. There is a sophisticated relationship between the metabolic-regulatory hormones insulin (a glucoregulatory hormone), glucagon, and epinephrine. When insulin is elevated, glucagon and epinephrine are suppressed [19]. This process occurs to prevent the continued rise of endogenous glucose levels. Conversely, when insulin levels decline in response to diminished circulating glucose levels, glucagon and epinephrine respond by increasing. These relationships are maintained when normal homeostasis is present. In patients with diabetes, there is a disruption of this homeostasis [20].

4. DIABETES RESEARCH

A strong focus has been placed on the area of prevention and treatment of type 2 diabetes with oral medications, lifestyle modification, and/or injectable medications. As the body of research grows, clinicians gain insights into possible treatment approaches and best practices.

THE DIABETES PREVENTION PROGRAM

The National Institute of Health's sponsored study, the Diabetes Prevention Program (DPP), was sanctioned to determine if diabetes could be prevented or delayed through the use of various interventions. The study was conducted in 27 centers throughout the United States, and the study participants were randomized into one of four treatment groups [21]. Treatment groups included lifestyle and behavior change or therapy with metformin, troglitazone, or placebo [21].

All 3,234 study participants were 25 years of age or older, overweight, and had IGT and elevated fasting plasma glucose, which are risk factors for the development of type 2 diabetes. In addition, 45% of the participants were from minority groups—African American, Alaskan Native, Native American, Asian American, Hispanic/Latino, or Pacific Islander—and 20% were 65 years of age or older. The study lasted more than three years but was halted earlier than expected due to 25 of the 27 centers demonstrating remarkable findings proving the hypothesis [21].

The first group, referred to as the lifestyle intervention group, received intensive education and counseling pertaining to diet, physical activity, and behavior modification. For individuals in this group, the overall goal was to maintain a loss of 7% of total body weight by consuming a decreased amount of fat and fewer calories and engaging in 150 minutes of exercise per week. The metformin treatment group was prescribed 850 mg of metformin twice per day, while the placebo group received placebo pills twice per day. Both the metformin and placebo groups also received education regarding lifestyle interventions (e.g., diet, exercise) but not intensive counseling. The troglitazone group was prescribed 400 mg of the drug daily, but this arm of the study was discontinued due to concerns that troglitazone was associated with liver toxicity. Participants in the troglitazone group continued to be followed but were not included as one of the intervention groups [21]. Troglitazone was removed from the U.S. market in 2000 [22].

The researchers found that participants who lost a modest amount of weight through dietary changes and increased physical activity sharply reduced their chances of developing diabetes [21]. The metformin treatment group also displayed a reduced risk for the development of diabetes, but the decrease was less dramatic.

THE DIABETES COMPLICATION AND CONTROL TRIAL

Research has also proven that tight glycemic control can prevent the development of chronic microvascular complications in diabetic patients. Initial research in the Diabetes Complication and Control Trial (DCCT) focused on the benefits of conventional versus intensive therapy for the prevention of complications related to type 1 diabetes [14,23]. The study involved 1441 individuals and demonstrated enough statistical power to unequivocally demonstrate the importance of glycemic control with utilization of multiple daily insulin injections [23,24].

This randomized controlled trial found that the risk of microvascular complications was reduced by intensive glycemic control in patients with type 1 diabetes. Participants in the intensively treated group (goal glycosylated hemoglobin [HbA1c]: <6.05%; mean achieved HbA1c: approximately 7%) demonstrated an approximately 60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy compared to the standard group (mean achieved HbA1c: approximately 9%) over an average of 6.5 years. The relationship between glucose control and risk of complications was linear and extended down to the normal HbA1c range (<6%) with no threshold noted [25].

When the DCCT ended in 1993, researchers began a follow-up study called the Epidemiology of Diabetes Interventions and Complications (EDIC). The EDIC continues to follow more than 90% of DCCT participants, assessing the incidence and predictors of cardiovascular disease events (e.g., heart attack, stroke, needed heart surgery) and diabetic complications related to the eye, kidney, and nerves. For example, the EDIC has shown that an individualized eye exam schedule results in fewer eye exams, lower costs, and faster diagnosis and treatment of advanced diabetic eye disease [26]. The EDIC also is examining the impact of intensive versus standard control on participants' quality of life [23].

THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY

Research from the DCCT trial was further substantiated in the United Kingdom Prospective Diabetes Study (UKPDS), a clinical trial of patients with newly diagnosed type 2 diabetes conducted between 1977 and 1997. Once more, the groups were separated into a conventional therapy study arm or an intensive therapy arm to determine the efficacy and outcomes of the differing treatments [14]. Intensive blood glucose control was achieved utilizing sulfonylurea medications or insulin in normal-weight people and metformin in participants who were overweight. The UKPDS aimed to treat patients using only a single medication even if blood glucose became quite high because, at the time, there were some concerns that utilizing multiple medications had the potential of being harmful. In the conventional therapy cohort, lifestyle alone was used to control blood glucose. This was the first study to establish the now well-known association between level of glucose control and the reduction of microvascular complications (i.e., retinopathy, nephropathy, neuropathy) in individuals with type 2 diabetes [27].

When researchers revisited the participants of the UKPDS after 10 years, it was found that those who had been in the tight glycemic control arm during the trial had a lower risk of myocardial infarction and death than those who participated in the conventional glycemic control arm [28]. This finding was somewhat surprising because within one year of UKPDS ending, differences in HbA1c levels between the intensive and conventional treatment groups had disappeared. However, 10 years later, the follow-up study reported that myocardial infarction risk was reduced 15% in the sulfonylurea/insulin group and 33% in the metformin group, while overall risk of death was reduced 13% and 27%, respectively [28]. With this knowledge, the goal for diabetes treatment is striving for euglycemia by utilizing behavior change, meal planning, and lifestyle change followed by medication management [7].

TREAT-TO-TARGET TRIAL

The Treat-to-Target Trial was designed to determine if the addition of basal insulin at bedtime to an existing oral therapy regimen could improve achievement of the recommended 7% HbA1c target. Its secondary goal was to assess the efficacy and safety of glargine compared to neutral protamine Hagedorn (NPH) insulin as the basal insulin of choice in this treatment approach [29].

Researchers found that the addition of bolus insulin at bedtime (either glargine or NPH) reduced the average HbA1c level from 8.6% to 7%, with almost 60% of patients reaching 7% or less [29]. This high success rate may be attributed to the fact that the average baseline HbA1c was lower than in most other studies, the majority of study participants had advanced diabetes (suggested by poor glucose control on two oral agents), and more than 90% of participants adhered to the treatment, indicating it was an easy regimen to follow. Researchers also systematically titrated the insulin dosage to target [29].

Although fasting glucose and HbA1c levels were similar with both types of insulin, glargine was associated with fewer symptoms of hypoglycemia and less variability in fasting glucose levels [29]. Rates of severe hypoglycemia were low for both insulins, but nocturnal hypoglycemia was significantly more likely with NPH insulin. Nocturnal hypoglycemia was reduced from 42% to 48% in the glargine group, indicating that this insulin's lower peak of action would make it a better choice for this treatment approach [29].

4-T TRIAL

The Treating to Target Type 2 Diabetes, or 4-T, Trial was established to determine the effects of adding biphasic, prandial, or basal insulin to oral therapy for type 2 diabetes [30]. Participants in the trial had suboptimally controlled diabetes (mean HbA1c: 8.5%) despite treatment with sulfonylurea plus metformin. Subjects were randomized into three treatment groups: biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily, as required). All patients continued their established oral therapy, and dose titration, glucose monitoring, and follow-up visits were provided for all. After one year, the mean HbA1c level had decreased in all treatment groups, to 7.3% with biphasic insulin, 7.2% with prandial insulin, and 7.6% with basal insulin. However, no group met the goal of 6.5% or less; only 17%, 23.9%, and 8.1% of participants, respectively, met the goal. Although biphasic and prandial insulin more effectively lowered mean HbA1c levels, they were associated with greater risks of hypoglycemia and weight gain [30]. The authors concluded, based on a comparison of the risks and benefits of each approach, that the treatment of choice would be adding once-daily basal insulin to an established oral medication regimen for type 2 diabetes patients [30,31]. Three years after the study concluded, the majority of patients in each group were receiving a second type of insulin (67.7% of the biphasic group, 81.6% of the prandial group, and 73.6% of the basal group) [30].

ORIGIN TRIAL

The Outcome Reduction with Initial Glargine Intervention (ORIGIN) Trial was a large study attempting to identify the advantages of insulin glargine therapy and omega-3 fatty acids (fish oil) in managing type 2 diabetes and associated cardiovascular risks. The trial was completed in 2013 [32]. Because the majority of individuals who experience a myocardial infarction have impaired fasting glucose and/or IGT, investigators believed that achieving lower blood glucose levels (using insulin) might reduce the risk of cardiovascular events. The ORIGIN Trial randomized participants into groups receiving standard insulin glargine or variable-dose glargine, and further into subgroups receiving 865 mg of omega-3 fatty acid or placebo. The trial followed 12,500 individuals to determine the effect on the incidence of cardiovascular events [32]. Results indicated no difference in the incidence of cardiovascular events between the insulin glargine and standard care groups. Additionally, there was no difference in the incidence of cardiovascular death between the omega-3 fatty acid supplement and placebo groups. Insulin glargine provided better glucose control and lower risk of new diabetes. Side effects included a small increase in risk of hypoglycemia and weight gain of approximately 1.6 kg over a period of more than six years [33].

CAROLINA TRIAL

The Cardiovascular Outcome Study of Linagliptin versus glimepiride (CAROLINA) trial was a randomized, noninferiority clinical trial that compared the effect of linagliptin with glimepiride on major cardiovascular events in more than 6,000 participants with type 2 diabetes and elevated cardiovascular risk [34]. Participants were randomized to receive 5 mg of linagliptin once daily or 1–4 mg of glimepiride once daily in addition to usual care. The primary outcomes were time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The median duration of follow-up was 6.3 years. A cardiovascular event occurred in 356 (11.8%) participants in the linagliptin group and 362 (12%) participants in the glimepiride group. Results indicated that the use of linagliptin compared with glimepiride resulted in a noninferior risk of composite cardiovascular outcome [34].

5. DIAGNOSIS OF DIABETES

TYPES OF DIABETES

As discussed, the most common types of diabetes are type 1 and type 2. However, gestational diabetes is also relatively common and is a source of significant morbidity and mortality. Gestational diabetes is first recognized in pregnancy, usually around the 24th week of gestation, and typically resolves after the birth of the child. Gestational diabetes is estimated to affect 10% of pregnancies [35,36]. Patients with gestational diabetes present special challenges, and the need for tight glycemic control often necessitates the use of insulin therapy. After conception and early in the first trimester, the risk of hypoglycemia is amplified as a result of increases in the peripheral utilization and storage of glucose. Late in the third trimester, overnight hypoglycemia can occur if a bedtime snack is insufficient to meet the intensified fetal demands for glucose. Lastly, during the postpartum period, the risk of hypoglycemia results from the loss of placental hormones [37].

Adequate glucose control should be maintained in order to prevent adverse effects to fetal health. Potential adverse effects include hyperbilirubinemia (jaundice), respiratory distress syndrome, hypocalcemia, polycythemia, macrosomia, and neonatal hypoglycemia [37,38].

Macrosomia occurs when a high level of glucose in the maternal blood results in the elevated glucose to the fetus. Sensing this elevation, the fetal pancreas begins producing insulin to normalize the glucose levels. The result of this is increased adipose tissue in the organs, chest, and abdomen, leading to disproportionate size of the trunk and shoulders in relationship to the head. These infants are often large for gestational age, increasing likelihood of cesarean delivery, vaginal tearing, and other birth traumas, such as shoulder dystocia, brachial plexus injury, Erb palsy, and asphyxia [38].

If the fetal pancreas has been overproducing insulin in response to elevated maternal blood glucose levels, hypoglycemia will occur when the umbilical cord is clamped and glucose-rich maternal blood is no longer circulating in the neonate. Neonatal hypoglycemia occurs in the first 12 hours of life and resolves with infusions or oral administration of glucose until euglycemia is restored. The risks associated with neonatal hypoglycemia include seizure, cerebral damage, and death [38].

The first-line treatment for gestational diabetes is conventional therapy of diet, exercise, and other lifestyle changes [39]. The goals for blood glucose levels during this period of pregnancy are very strict [40]:

- Before meals and at bedtime: less than 95 mg/dL

- One-hour postprandial: less than 140 mg/dL

- Two-hour postprandial: less than 120 mg/dL

When these goals are not being met, insulin therapy should be initiated, if needed, to achieve glycemic targets [41]. Insulin is the preferred medication, as it does not cross the placenta to a measurable extent. Metformin and glyburide should not be used as first-line agents, as they do cross the placenta. All oral agents lack long-term safety data [41].

Other less common types of diabetes do occur, and it is important to have a basic understanding of these forms as well. Less common types of diabetes include [7,14]:

- Maturity-onset diabetes of the young (MODY): A genetic, autosomal-dominant defect of the pancreatic beta cells that results in insulin deficiency and decreased insulin release without the presence of insulin resistance and obesity. This form of diabetes typically develops in patients younger than 25 years of age. This is a different clinical entity than type 2 diabetes of the adolescent, which presents with insulin resistance.

- Diabetes related to diseases of the exocrine pancreas, such as cystic fibrosis, and various endocrine diseases, such as Cushing syndrome, acromegaly, and chromocytoma

- Drug-induced diabetes resulting from the use of certain medications, particularly high-dose corticosteroids

SCREENING FOR DIABETES

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults 40 to 70 years of age who are overweight or obese.

https://annals.org/aim/fullarticle/2466368

Last Accessed: October 22, 2019

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

All adults older than 45 years of age should be screened for diabetes every three years or every two years if they have any risk factors for type 2 diabetes [14,41,42]. In addition, individuals of any age who are at risk or are suspect of having diabetes should be screened. Established risk factors for type 2 diabetes include [41,43,44]:

- Age older than 45 years

- Body mass index (BMI) greater than or equal to 25 kg/m^2

- Family history of type 2 diabetes

- Habitual physical inactivity

- Race/ethnicity (e.g., African American, Hispanic American, Native American, Alaskan Native, Pacific Islander)

- IGT or elevated fasting glucose

- Previous history of gestational diabetes or giving birth to a child weighing more than 9 pounds

- Hypertension (blood pressure greater than 140/90 mm Hg in adults)

- Abnormal lipid levels (high-density lipoprotein [HDL] level <35 mg/dL and/or triglyceride level >250 mg/dL)

- Polycystic ovarian syndrome

- History of vascular disease

- Acanthosis nigricans (most common among individuals of African descent)

DIAGNOSTIC CRITERIA

The diagnostic criteria for type 2 diabetes are fairly straightforward and are based on fasting plasma glucose and plasma glucose levels (Table 1). After a diagnosis of type 2 diabetes has been definitively made, education on self-care management is necessary in order to obtain euglycemia and prevent complications related to the detrimental effects of hyperglycemia [3]. The healthcare team involved in providing care should include, at a minimum, the primary care physician, certified diabetes educator, dietitian, and support person/system. Education should focus on healthy eating habits, blood glucose monitoring, exercise planning, medication management, risk reduction, and healthy coping techniques [45]. As previously stated, it is estimated that as many as 90% of patients with type 2 diabetes will require oral medications to achieve adequate glucose control within five years of diagnosis [15]. When glucose levels cannot be adequately controlled with oral medications, the use of injectable medications is necessary. If elevated blood glucose levels are untreated and continue to rise, the result can be hyperosmolar hyperglycemia syndrome (HHS) and ultimately death [2].

Table 1: DIAGNOSTIC CRITERIA FOR DIABETES

Stage

Fasting Plasma Glucose Levels

Two-Hour Postprandial Plasma Glucose Levels

Euglycemia

<100 mg/dL

<140 mg/dL

Prediabetes

>100 mg/dL but <126 mg/dL

>140 mg/dL but <200 mg/dL

Diabetes

≥126 mg/dL

≥200 mg/dL

Source: [14,45]

6. SULFONYLUREA THERAPY: FIRST AND SECOND GENERATIONS

Historically, there were few options to achieve control of blood glucose levels, and pharmacologic management was limited to the sulfonylureas [3]. Today, sulfonylurea medications are categorized as either first- or second-generation (Table 2). These medications are typically used as primary or secondary agents in the treatment of type 2 diabetes. Sulfonylureas can be rapid-acting, intermediate-acting, or long-acting based on their onset and duration of action. For sulfonylureas to be effective, the individual must have functioning pancreatic beta cells. Thus, they are not useful for patients with type 1 diabetes [46]. Some individuals will not respond to initial sulfonylurea therapy, and over time, most will experience failure with this therapy as the disease progresses. The ideal candidate for sulfonylurea therapy is a patient with [47]:

- Type 2 diabetes without dyslipidemia

- Normal weight

- Hyperglycemia despite following meal planning and an exercise program

- Ability and willingness to follow a reasonable dietary program

- Hyperglycemia for less than five years

- Age older than 30 years

Table 2: SULFONYLUREAS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

First-Generation

Chlorpropamide

Diabinese

100–500 mg daily

500 mg

Daily

1 hour

24 hours

Second-Generation

Glimepiride

Amaryl

1–2 mg daily

8 mg

Once or twice daily

2 to 3 hours

24 hours

Glipizide

Glucotrol

2–40 mg daily

40 mg

Three times daily

3.5 to 6 hours

12 to 16 hours

Glucotrol XL (extended-release)

20 mg daily

20 mg

Daily

3.5 to 6 hours

12 to 16 hours

Glyburide

Diabeta, Micronase

2.5–20 mg daily

20 mg

Once or twice daily

1.5 hours

16 to 24 hours

Glyburide (micronized)

Glynase

0.75–12 mg daily

12 mg

Once or twice daily

1.5 hours

12 to 24 hours

Source: [3,48,49,50,51]

Sulfonylurea preparations act to stimulate the release of insulin from functioning beta cells in the islets of Langerhans in the pancreas, which results in lowered blood glucose [46,49,52]. These agents close the energy-sensitive potassium channel in the cell membrane of the pancreatic beta cell. By accomplishing this, there is an increased amount of available insulin for action within the body [3]. It is important to keep in mind that individuals with impaired first-phase insulin release will experience a diminished effect from sulfonylurea therapy [53]. Duration of action is generally rapid, fairly complete, and basically unaffected by food, with the exception of glipizide [48].

FIRST-GENERATION AGENTS

The original sulfonylurea agents are now known as the first-generation sulfonylureas. Although effective in controlling hyperglycemia, first-generation sulfonylureas were hindered by the frequency of hypoglycemia related to therapy and high dosage requirements. The second-generation sulfonylureas have improved on the effectiveness of the earlier agents by requiring smaller doses and demonstrating a lower incidence of side effects [3,46]. Although the only currently utilized first-generation sulfonylurea agent in the United States is chlorpropamide, it is important to have an understanding of all medications within this category in the rare case a patient presents with a history of having taken one of these agents.

Chlorpropamide

Chlorpropamide is typically prescribed at 100–250 mg/day for stable diabetics; those with more severe disease may take up to the maximum safe dose of 500 mg/day [49]. Adjusting doses up or down should be accomplished by increasing or decreasing by 50–125 mg/day over three to five days. Chlorpropamide has an onset of action of one hour, a half-life of less than 36 hours, and a duration of action of 24 hours [49]. Chlorpropamide is primarily metabolized in the liver and excreted via the kidneys. This medication does cross the placenta and has been found in breast milk, and women of childbearing age should be educated regarding possible effects to their fetus or infant [7,49].

Discontinued Medications

Acetohexamide

Acetohexamide has a prescribing dose range from 250–1,500 mg daily, with a maximum safe dosage of 1,500 mg/day [46]. Acetohexamide may be taken in two divided doses per day to obtain maximum efficacy of the medication. It has an onset of action of 1 hour, and the duration of action is anywhere from 12 to 24 hours [54].

Tolazamide

Tolazamide has a prescribing dose range of 100 mg to a maximum safe dose of 1,000 mg daily and may be given in divided doses [46]. The onset of action for tolazamide is four to six hours, with a half-life of seven hours. The duration of action ranges between 10 and 14 hours. This medication is metabolized in the liver with excretion via the kidneys. Like chlorpropamide, tolazamide crosses the placenta [49].

Tolbutamide

Tolbutamide has a prescribing dose range of 500 mg to a maximum 3,000 mg/day [49]. A prescribed dose of tolbutamide is given in three divided doses in order to reach maximum efficacy. A larger dose is typically required to be effective. The onset of action for tolbutamide is 1 hour, with a half-life of 6 to 8 hours; the duration of action ranges from 12 to 18 hours. Tolbutamide is metabolized in the liver with excretion via the renal system [49]. It is important to note that levels of tolbutamide are not reduced by hemodialysis [7].

SECOND-GENERATION AGENTS

The second generation of sulfonylureas was developed to include a shorter duration of action and shorter half-lives, which decrease the frequency and severity of side effects related to medication therapy [3]. These agents are most commonly used in the treatment of type 2 diabetes today.

Glimepiride

Glimepiride is typically prescribed at a maintenance dose of 1–4 mg/day, with a maximum safe dose of 8 mg daily [49]. Glimepiride is usually taken once daily with breakfast or the first main meal. The onset of action is two to three hours, with a half-life of five to nine hours. The maximum effect is experienced within 2 to 6 hours, but the duration of action is 24 hours.

After oral administration, glimepiride is completely metabolized by oxidative biotransformation into the major metabolites cyclohexyl hydroxy methyl derivative (M1) and carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is about one-third as pharmacologically active as its parent; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear. When glimepiride is given orally, approximately 60% of the total radioactivity is recovered in the urine in seven days, and M1 (predominant) and M2 account for 80% to 90% of that recovered in the urine [49,52]. Because this medication can pass through the placenta to the fetus, care should be taken when treating women of childbearing age [7,49]. Agents other than glimepiride are currently recommended to treat diabetes in pregnant women [49]. Due to its different action and lack of effects on the coronary arteries, some have classified glimepiride as the first third-generation sulfonylurea.

Glipizide

Glipizide is initially prescribed at a dose of 2.5 mg/day, which may be titrated up in 2.5–5 mg increments until desired effects are achieved [49]. The maximum safe dose is 40 mg/day for the standard preparation and 20 mg/day for the extended-release formula [49]. The standard dose of glipizide is taken three times per day to obtain optimal effect; the extended-release formula is taken only once per day. The onset of action for both preparations is 3.5 to 6 hours, with the maximum effect obtained in 1 hour [7]. The duration of action for glipizide is 12 to 24 hours, and it has a half-life of approximately 2 to 5 hours [49]. Glipizide is extensively metabolized in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine [55]. As with other sulfonylureas, the medication crosses the placenta and may affect the fetus [7,49].

Glyburide

Glyburide is available in regular and micronized forms, and dosing will depend on the form prescribed [49]. The initial dose of the regular form is 2.5–5 mg/day, which may be increased weekly to desired effect or a maximum of 20 mg daily. The initial dose for the micronized tablets is 1.5–3 mg/day, which can also be titrated weekly. The maximum micronized dose is 12 mg/day [49].

The onset of action for glyburide is 90 minutes, with maximum effect noted at 60 minutes for micronized preparations and two to four hours for the nonmicronized formula. The half-life of glyburide is 10 hours regardless of micronization, and the drug has a duration of action of 12 to 24 hours (micronized) or 16 to 24 hours (nonmicronized) [48,49]. Glyburide is excreted as metabolites in the bile and urine. This dual excretory pathway is different from that of other sulfonylureas, which are excreted primarily in the urine [49,56]. Glyburide does cross the placenta, and precautions with women of childbearing age should be taken [7,49].

POTENTIAL SIDE EFFECTS

As with any drug therapy, a hypersensitivity reaction can potentially occur with sulfonylurea therapy. However, hypersensitivity to one agent does not necessarily indicate a cross-sensitivity with other sulfonamide agents. Care should be taken when treating geriatric, malnourished, or debilitated patients, as these groups are at particular risk for hypoglycemia. Furthermore, any person with adrenal, pituitary, or hepatic insufficiency who is particularly susceptible to the hypoglycemic effects of glucose-lowering agents should be closely monitored while on a sulfonylurea therapy regimen [3]. Alteration in hepatic enzyme activity may also alter the clearance of sulfonylurea agents.

A secondary side effect of sulfonylurea therapy is weight gain as a result of a greater amount of circulating insulin [49]. This increase results in a greater amount of circulating glucose being stored as adipose tissue. Less commonly seen sulfonylurea side effects include [49]:

- Skin rash (2%)

- Gastrointestinal disturbances (5%)

- Metabolic disorders (e.g., syndrome of inappropriate antidiuretic hormone hypersecretion associated with chlorpropamide use) (4%)

It is important to mention that there is ongoing research regarding a possible correlation between sulfonylurea therapy and suspected deaths in patients with a past myocardial infarction [57,58]. Although a causal relationship has not been established, it is important to understand this concept and to counsel patients to discuss any concerns with their primary care physician [59].

Sulfonylurea agents may also interact with a variety of other medications. These interactions have the potential to affect the action of the sulfonylurea agent, the other medication, or both. Drug-drug interactions are more commonly seen with the first-generation sulfonylurea agents [60]. One of the primary causes for drug interactions is a competition for protein binding sites, which results in a greater amount of circulating sulfonylurea agent in the bloodstream and can increase the hypoglycemic effect, seen more often with the longer acting agents (e.g., chlorpropamide, glibenclamide [i.e., glyburide]) [61]. Medications that may interact with sulfonylureas include beta blockers, corticosteroids, thiazide diuretics, cyclic antidepressants, and antifungals [49,61].

CASE STUDY

Patient M is a white woman, 32 years of age, presenting to her primary care physician with complaints of polyuria for the past four weeks. Further assessment reveals an upcoming appointment with her optometrist for new onset blurred vision. The patient is 5 feet 5 inches tall and weighs 142 pounds; her calculated BMI is 23.6 kg/m^2. She confirms a family history of diabetes on her father's side and admits to a generally sedentary occupation and lifestyle. A random finger stick reveals a blood glucose level of 257 mg/dL.

Rationale and comments : Patient M's evaluation has resulted in adequate findings to diagnose diabetes. Any random blood glucose greater than 200 mg/dL with additional symptoms (in this case, polyuria and blurred vision) is considered diagnostic for diabetes.

Patient M is referred for fasting blood work, which reveals the following results:

- HbA1c: 8.5% (estimated average glucose: 197 mg/dL)

- Fasting blood glucose: 147 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 240 mg/dL

- Triglycerides: 152 mg/dL

- Low-density lipoprotein (LDL): 97 mg/dL

- HDL: 35 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient M is referred to an ADA-recognized diabetes education program for further education in diabetes self-management, self-monitoring of blood glucose (SMBG), and exercise and meal planning education [62].

Patient M returns to her primary care physician after three months. Her follow-up HbA1c demonstrates minimal change, with a result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal blood glucose levels consistently between 135 mg/dL and 160 mg/dL fasting and between 230 mg/dL and 300 mg/dL postprandial. Patient M states that she is following her meal and exercise planning goals with little success.

The patient's physician evaluates all of her blood work and patient history information and determines that the best course of treatment would be to initiate sulfonylurea therapy. Patient M is started on glipizide 5 mg each morning, and continuation with her meal and exercise plans is emphasized.

Rationale and comments : This is an appropriate treatment plan for Patient M because, although she has a sedentary occupation, she is not considered obese. She has been adherent to her meal and exercise plan without success. Her fasting blood glucose levels are elevated, but it is the postprandial levels that have instigated the elevated HbA1c levels. The sulfonylurea secretagogue glipizide should improve the high postprandial levels resulting from loss of first-phase insulin release.

7. NONSULFONYLUREA SECRETAGOGUE (GLINIDE) THERAPY

The nonsulfonylurea secretagogues, more commonly known as meglitinides or glinides, are hypoglycemic agents that predominantly affect postprandial glucose levels (Table 3). There are two medications considered to be within this classification of hypoglycemic agents: repaglinide and nateglinide [7]. The ideal candidate for glinide therapy would have type 2 diabetes for which medical nutrition therapy and exercise has not achieved euglycemia, alone or in combination with other agents. In contrast, this therapy is not a viable option for patients with [3]:

- Type 1 diabetes

- Ketoacidosis

- Known hypersensitivity to either drug

- Severe infection

- Surgery

- Trauma

Table 3: NONSULFONYLUREA SECRETAGOGUES (GLINIDES)

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Repaglinide

Prandin

0.5–4.0 mg before meals

16 mg

Three times daily

25 to 30 minutes

4 to 6 hours

Nateglinide

Starlix

60–120 mg before meals

360 mg

Three times daily

Within 20 minutes

4 hours

Source: [3,48,49,50,51]

REPAGLINIDE

Repaglinide stimulates the release of insulin from functioning beta cells in the pancreatic islets. Repaglinide closes adenosine triphosphate (ATP)-dependent potassium channels in the beta-cell membrane, which depolarizes the beta cell and leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion [49]. This action is highly tissue selective, with low affinity for heart and skeletal muscle [63]. Results with repaglinide therapy are best achieved when taken within 15 to 30 minutes of a meal [7,49]. This results in a greater insulin release from the pancreas during the first phase. The onset of action is rapid (usually within 15 to 60 minutes), and the drug possesses a short half-life (about one hour), resulting in a low plasma level of the medication [3,49]. Excretion of repaglinide is completed via the intestinal system in the form of feces [7,49]. Repaglinide can be utilized as a monotherapy agent or in conjunction with a biguanide, thiazolidinedione (TZD), or both [49,50].

NATEGLINIDE

Nateglinide is a very rapid acting amino-acid derivative known as D-phenylalanine. Nateglinide interacts with the ATP-sensitive potassium channel on pancreatic beta cells to produce calcium influx and insulin secretion. As with repaglinide, the extent of insulin release is glucose dependent and diminishes at low glucose levels [49,64]. Nateglinide is rapidly absorbed, and the onset of action is approximately within 20 minutes of ingestion. This medication is taken just prior to a meal due to this mechanism of action [7,49]. Due to the short half-life (1.5 hours), nateglinide stops acting on the pancreatic beta cells shortly after the meal, decreasing the possibility of hypoglycemia. This medication is excreted in the feces after it is metabolized in the intestinal tract [7]. Nateglinide can be used as monotherapy or in combination with metformin, TZD, or both. It is important to note that if adequate control is not achieved using a sulfonylurea agent, it is unlikely that nateglinide will be effective [49].

POTENTIAL SIDE EFFECTS

As with all medications, there are precautions when considering glinide therapy. These medications should not be used during pregnancy, in women who are breastfeeding, or in children [41]. Repaglinide should be used cautiously in persons with hepatic dysfunction, and routine, close monitoring of liver function is necessary. Individuals who are elderly, malnourished, debilitated, or have adrenal or pituitary dysfunction are particularly susceptible to hypoglycemia, the most common side effect related to this class of medication (<10%). The key measure for preventing hypoglycemia in patients taking glinides is patient education stressing the need to omit the medication if a meal is not going to be consumed [49].

Aside from hypoglycemia, there are less common side effects associated with glinides, including [3]:

- Bronchitis, sinusitis, rhinitis (<10%)

- Nausea/vomiting, diarrhea, constipation (2% to 5%)

- Headache, chest pain, urinary tract infection, back pain (2% to 9%)

- Dizziness (3.6%)

As with any pharmaceutical preparation, healthcare professionals should be aware of potential interactions between medications that an individual is prescribed. In the case of both sulfonylureas and nonsulfonylurea secretagogues, potential effects of drug-to-drug interactions include [50]:

- Drug level and/or effect decreased by: carbamazepine, charcoal, corticosteroids, estrogens, isoniazid, nicotinic acid, nonsteroidal anti-inflammatory drugs, oral contraceptives, phenobarbital, primidone, rifampin, sympathomimetics, thiazide and other diuretics, thyroid products, urinary alkalinizers

- Drug level and/or effect increased by: beta blockers, chloramphenicol, cimetidine, delavirdine, diclofenac, fibric acid derivatives, fluconazole, gemfibrozil, ketoconazole, nicardipine, salicylates, sulfonamides, telithromycin, tricyclic antidepressants

Herbs that may increase the effects of secretagogues include burdock, dandelion, eucalyptus, and marshmallow. As noted, it is imperative to understand these interactions and the impact they have on blood glucose levels. Rapid identification of hypoglycemic or hyperglycemic emergencies utilizing blood glucose monitoring and assessment skills is also critical [50].

CASE STUDY

Patient L is an African American man, 52 years of age, presenting to his primary care physician with complaints of frequent urination and excessive thirst, particularly in the late afternoon and early evening. He is a truck driver and works 12 hours each day. Patient L is 6 feet 1 inch tall and weighs 215 pounds, with a calculated BMI of 28.4 kg/m^2. He confirms a family history of diabetes on both his father's and mother's sides. A random finger stick results in a blood glucose level of 243 mg/dL.

Rationale and comments : The information gained from Patient L's initial examination indicates diabetes. Again, any random blood glucose greater than 200 mg/dL, accompanied by symptoms (polyuria and excessive thirst for this patient), is considered diagnostic for diabetes.

Patient L is referred for fasting blood work, which reveals the following:

- HbA1c: 9.1% (estimated average glucose: 214 mg/dL)

- Fasting blood glucose: 132 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 310 mg/dL

- Triglycerides: 147 mg/dL

- LDL: 102 mg/dL

- HDL: 46 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient L is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. A follow-up appointment in three months is scheduled.

Upon the follow-up primary care appointment, Patient L's HbA1c shows minimal change, with a result of 8.8% (estimated average glucose: 206 mg/dL) and a fasting blood glucose level of 148 mg/dL. The patient's SMBG records reveal fasting blood glucose levels consistently between 150 mg/dL and 165 mg/dL and postprandial levels steadily between 230 mg/dL and 290 mg/dL. Patient L states that he has difficulty eating meals at consistent times due to his profession and exercises when he is able. There has been little change in his weight since his last visit.

Patient L's physician determines that the best course of therapy would be to initiate nonsulfonylurea secretagogue therapy. The patient is started on repaglinide 2 mg 15 minutes prior to his first three main meals. He is advised not to take the medication if he does not eat the meal. He is strongly encouraged to continue with his meal and exercise plans.

Rationale and comments : This is an appropriate choice of medication for Patient L due to his inconsistent eating habits and continued postprandial hyperglycemia, his sedentary occupation, and his weight (not considered obese). His postprandial levels are the problematic factor, and repaglinide will allow Patient L the freedom to adjust his medication therapy to his eating schedule.

8. ALPHA-GLUCOSIDASE INHIBITOR THERAPY

There are two available oral antihyperglycemic agents in the category of alpha-glucosidase inhibitors: acarbose and miglitol (Table 4). In contrast to sulfonylureas, alpha-glucosidase inhibitors do not enhance insulin secretion. The antihyperglycemic action of these agents is a result of a reversible inhibition of membrane-bound intestinal alpha-glucoside hydrolase enzymes. In addition, acarbose inhibits pancreatic alpha-amylase. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine; membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. When these factors are inhibited, glucose absorption is delayed and postprandial blood glucose levels remain within the normal range. Because their mechanism of action is different, alpha-glucosidase inhibitors enhance glycemic control achieved by sulfonylureas, insulin, or metformin when used in combination. In addition, alpha-glucosidase inhibitors diminish the insulinotropic and weight-increasing effects of sulfonylureas [65].

Table 4: ALPHA-GLUCOSIDASE INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Acarbose

Precose

25–100 mg before meals

300 mg

Three times daily

Immediate

6 hours

Miglitol

Glyset

25–100 mg before meals

300 mg

Three times daily

Rapid

Less than 4 hours

Source: [3,46,47,48,49]

An ideal candidate for alpha-glucosidase therapy will have:

- Dyslipidemia

- Obesity

- Symptoms suggesting postprandial hyperglycemia

ACARBOSE

Acarbose is prescribed in doses of 25–100 mg, with a maximum daily dose of 300 mg [7,49]. Acarbose should be taken in equal doses three times a day for maximum efficacy [7]. The onset of action of acarbose is immediate, with peak effect seen in one hour. Acarbose has a half-life of two hours and a duration of action of approximately six hours [49,50]. Acarbose is excreted via the renal and fecal routes without being metabolized [7].

MIGLITOL

Miglitol has a dose range of 25–100 mg taken at the beginning of each meal, up to a maximum of 300 mg/day. Miglitol has a rapid onset of action, and peak effect is reached in about two to three hours. The half-life is roughly two hours, and the duration of action is believed to be less than four hours [49,50]. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or presystemic metabolism [49,66]. The drug is excreted via the renal route [7,49].

POTENTIAL SIDE EFFECTS

Due to the location and mechanism of action, alpha-glucosidase inhibitors are not well absorbed in the intestinal tract. Elevated plasma levels of acarbose have been found in persons with a creatinine clearance of less than 25 mL per minute, suggesting accumulation. With this in mind, caution should be used in these patients. In addition, use of alpha-glucosidase inhibitors is contraindicated in patients with [49]:

- Small bowel disease

- Colonic ulceration

- Obstructive bowel disorder

- Chronic intestinal disorders of digestion or absorption

- Cirrhosis of the liver

- Elevated creatinine levels >2.0 mg/mL

Furthermore, women who are pregnant or breastfeeding and children should not use these agents [49].

Side effects for alpha-glucosidase inhibitors are typically confined to the gastrointestinal system and usually occur during initiation of therapy or when adjustments to the dose are made [49]. Potential side effects of alpha-glucosidase inhibitors include [49]:

- Gastrointestinal effects

- Abdominal pain: 12% to 21%

- Diarrhea: 29% to 33%

- Flatulence: 42% to 77%

- Increased plasma concentration relative to the degree of renal dysfunction

- Elevation in transaminases with acarbose (believed to be related to the use of higher-than-recommended dosages)

These side effects are generally self-limiting and transient and can be minimized by starting with a lower dosage and titrating up to desired effect or maximum therapeutic dose [49,50]. When caring for a patient being treated with alpha-glucosidase inhibitors, two-hour postprandial blood glucose levels should be monitored to identify effectiveness of the therapy [3,49]. Studies have demonstrated elevations in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]), so liver function should also be monitored periodically.

Lastly, alpha-glucosidase inhibitors' effects have the potential to be altered by charcoal products and may diminish the bioavailability of ranitidine, propranolol, and digoxin [49,67].

Potential drug-drug interactions with the use of acarbose include decreased drug levels and/or efficacy when taken in combination with calcium channel blockers, corticosteroids, estrogens, fosphenytoin, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazine, phenytoin, sympathomimetics, thiazides and other diuretics, and thyroid products [49]. Digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) and intestinal absorbents (e.g., activated charcoal) may reduce the effects of acarbose [49]. As mentioned, digoxin levels may be reduced when taken in combination with acarbose.

Although in the same category as acarbose, miglitol has different drug interactions including [49,50,67]:

- Digoxin, propranolol, and ranitidine, which may decrease the bioavailability of miglitol

- Charcoal and digestive enzyme preparations such as amylase and pancreatin, which reduce the effect of miglitol

CASE STUDY

Patient V is a Hispanic man, 61 years of age, presenting to the primary care physician with complaints of polydipsia, polyphagia, and fatigue for the past month. Upon further assessment, he states that he has recently had his eyeglass prescription adjusted due to blurred vision. He is 5 feet 10 inches tall and weighs 245 pounds; his calculated BMI is 35.2 kg/m^2. The patient reveals a family history of diabetes on both sides. He works a physical job in a warehouse lifting 50-pound boxes. A random finger stick reveals a blood glucose level of 220 mg/dL. As previously discussed, this is sufficient information to diagnose diabetes.

Patient V's fasting blood work reveals the following:

- HbA1c: 8.7% (estimated average glucose: 203 mg/dL)

- Fasting blood glucose: 151 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 233 mg/dL

- Triglycerides: 210 mg/dL

- LDL: 112 mg/dL

- HDL: 35 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Patient V is referred to an ADA-recognized diabetes education program and is instructed to return for follow-up in three months.

When the patient returns to his primary care physician, his follow-up HbA1c demonstrates minimal change with the result of 8.2% (estimated average glucose: 189 mg/dL) and a fasting blood glucose level of 156 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 135 mg/dL and 160 mg/dL and postprandial levels steadily between 220 mg/dL and 248 mg/dL. His lipid levels remain greater than goal as well. Patient V indicates that he has been following his meal and exercise planning goals but has experienced minimal success.

After evaluation of the patient's blood work, history, and progress to date, the physician decides to utilize the alpha-glucosidase inhibitor, acarbose. Patient V is started on acarbose 25 mg with each meal, and adherence to his culturally specific meal and exercise plans is stressed.

Rationale and comments : Although not commonly utilized, acarbose is appropriate for Patient V due to his elevated lipid levels and postprandial hyperglycemia. His fasting blood glucose levels are above normal, and the physician has determined that his postprandial levels are the cause of the elevated HbA1c levels. Acarbose should improve the patient's postprandial glucose levels and his lipid levels.

9. BIGUANIDE THERAPY

Biguanides are popular medications in diabetes treatment. Primitive versions of guanidines were used historically, in the form of extracts of Galega officinalis (goat's rue or French lilac), for blood glucose control [7]. The modern form was first introduced in Europe in the late 1950s. There is only one agent, metformin, available in this class of diabetes medications (Table 5) [49].

Table 5: BIGUANIDES

Drug Name

Trade Name(s)

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Metformin

Glucophage, Fortamet

500 mg twice daily or 850 mg once daily

2,550 mg

Two or three times daily

Within days

6 hours

Glucophage XL (extended-release)

500–2,000 mg daily with evening meal or 1,000 mg two times daily

2,500 mg

Once or twice daily

Within days

Up to 24 hours

Metformin liquid

Riomet

500 mg twice daily or 850 mg once daily

1,000 mg

Twice daily

—

—

Source: [3,48,49,50,51]

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends clinicians should initiate metformin as first-line pharmacotherapy for patients with type 2 diabetes, unless medically contraindicated.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence/Strength of Recommendation: High/Strong

Metformin therapy is now frequently utilized due to the lack of hypoglycemia as a side effect [68]. If not contraindicated and if tolerated, metformin is the ADA-preferred initial pharmacologic agent for management of type 2 diabetes [41]. It is an antihyperglycemic agent that lowers both basal and postprandial plasma glucose and improves glucose tolerance. Metformin acts in several ways to achieve this effect, including inhibiting hepatic glucose production and intestinal absorption of glucose [68]. It also increases peripheral glucose uptake and utilization [49]. Unlike sulfonylureas, metformin does not increase the risk of hypoglycemia and does not cause hyperinsulinemia [69]. Insulin secretion remains unchanged using metformin, but fasting plasma insulin levels and day-long plasma insulin response may actually decrease [3].

Metformin therapy has been extensively studied, and a meta-analysis of randomized controlled trials supports the benefit of metformin use in comparison to sulfonylureas [7]. Patients on metformin therapy demonstrated greater fasting blood glucose reduction and improvement in weight [7]. Compared with treatment with a sulfonylurea, monotherapy treatment with metformin is associated with a lower risk of major adverse cardiovascular events among patients with diabetes and reduced kidney function [70]. Although the benefits are well-documented, metformin therapy may not be the treatment of choice in all cases. The optimal candidate would present with:

- Type 2 diabetes

- Dyslipidemia

- Obesity or a genetic factor increasing the potential for insulin resistance

- Elevated fasting blood glucose level

- Tendency for hypoglycemia with sulfonylurea therapy

Additionally, metformin is approved for use in children 10 years of age and older [49]. It is the only oral diabetes medication approved for children.

Metformin is available in both immediate-release and extended-release tablets. The initial recommended dose for adults is 500 mg once or twice daily or 850 mg once daily, which may be titrated up every one to two weeks to a maximum safe dose of 2,550 mg/day [48,49]. In general, doses of at least 1,500 mg/day are necessary to produce clinically significant effects. Although the maximum safe dose is 2,250 mg/day, most preparations contain a maximum of 2,000 mg of active ingredient [71]. Metformin should be started in the evening and can be taken in two or three divided doses to improve efficacy [7]. The extended-release formulation is initially prescribed at dosages of 500–1,000/day, which may be titrated weekly to a maximum dose of 2,000 mg daily [49].

The onset of action for metformin is within days, but the peak effect of the immediate-release form is typically seen in two to four hours [50]. Peak effect with the use of the extended-release form is in four to eight hours. The duration of action is approximately 6 hours for immediate-release metformin, while the extended-release preparation is up to 24 hours [48]. The drug has a plasma half-life of four to nine hours [49].

Metformin is not metabolized by the liver [49]. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the unchanged drug is excreted in the urine [69].

Metformin is used both as a single agent and in combination with other therapies. It has been formulated into a multitude of combination preparations to increase the efficacy of both medications. The use of these combination formulations is cost effective and results in improvements in patient adherence to their medication regimen.

POTENTIAL SIDE EFFECTS

Although metformin is beneficial for many people, it should be used with caution in some populations. Women who are pregnant or breastfeeding should not utilize metformin therapy. There have been no formal studies to show benefit or risk analysis when metformin is used during pregnancy. Metformin use should also be temporarily halted in patients who are acutely ill or who are predisposed to acute renal failure or tissue hypoperfusion. Lastly, metformin should be withheld for a minimum of two days or until renal function has returned following any radiologic test utilizing iodinated contrast media [49]. Examples of such tests include urograms, angiography, intravenous cholangiography, and any scans using intravascular contrast media.

Metformin therapy is contraindicated in patients for whom the adverse effects may be life-threatening. This includes patients with elevated serum creatinine levels greater than 1.5 mg/dL for men or greater than 1.4 mg/dL for women, abnormal creatinine clearance from any cause, and patients with an eGFR <30 mL/minute/1.73 m^2 [7,49,72]. Because metformin is excreted through the kidneys, accumulation of the medication can occur in the presence of renal dysfunction. In 2016, the FDA issued a drug safety communication, new recommendations, and a label change requirement for metformin and metformin-containing medications for use in certain patients with mild-to-moderate renal impairment. The new FDA recommendations include [72]:

- Obtain eGFR prior to initiating metformin therapy.

- Initiate metformin in patients with an eGFR between 30–45 mL/minute/1.73 m^2 is not recommended.

- Obtain an eGFR at least annually in all patients taking metformin; assess renal function more frequently in patients at increased risk for renal impairment (e.g., the elderly).

- Assess the benefits of continuing metformin treatment in patients whose eGFR falls below 45 mL/minute/1.73 m^2; discontinue if the eGFR falls below 30/mL/minute/1.73 m^2.

Individuals with hepatic dysfunction who are receiving biguanide therapy can be predisposed to lactic acidosis [49]. Due to the potential damaging effects of alcohol on the liver, any individual with a history of alcohol abuse or binge drinking would not be a good candidate for metformin therapy. Finally, individuals with a history of chronic obstructive pulmonary disease or cardiac function impairment should not be prescribed metformin due to the potential of lactate accumulation in these hypoxic conditions [7,49].

Side effects of metformin are relatively mild and self-limiting, with the exception of lactic acidosis. Typically, the side effects are gastrointestinal in nature and resolve within the first few weeks of therapy. Potential side effects include [49]:

- Lactic acidosis (0.03/1,000 patient years)

- Diarrhea, nausea/vomiting, flatulence, bloating, anorexia (>10% during initiation)

- Metallic taste (3% during initiation)

- Decrease of vitamin B12 to subnormal levels (7% in one study)

- Impaired hepatic function

Biguanide therapy rarely causes serious side effects, but lactic acidosis has occurred in some cases and is an important consideration for patients taking metformin [49]. Lactic acidosis, although rare, is a potentially fatal metabolic complication. Persons at risk include those with renal insufficiency and those with acute or unstable heart failure who are at risk for hypoperfusion and hypoxemia. Characteristics of lactic acidosis include:

- Serum lactate levels greater than 5 mmol/L

- Decreased blood pH

- Electrolyte abnormalities resulting in an elevated anion gap

- Increased lactate/pyruvate ratio

The onset of lactic acidosis symptoms are generally vague and subtle at presentation [3]. The person's symptoms may include malaise, myalgia, nonspecific abdominal pain, increased somnolence, and/or respiratory distress. Serum lactate levels should be monitored periodically or when a patient is at risk for lactate accumulation [67]. If a patient develops symptoms of lactic acidosis while taking metformin, the agent should be discontinued immediately [49,67].

Metformin can interact with other medications and herbs. Knowledge of these interactions is necessary to ensure appropriate patient care. If taken with metformin, beta blockers may potentiate hypoglycemia. There are many medications that may potentiate hyperglycemia, including [50]:

- Calcium channel blockers

- Corticosteroids

- Estrogens

- Fosphenytoin

- Hormonal contraceptives

- Isoniazid

- Nicotinic acid

- Phenothiazines

- Phenytoin

- Sympathomimetics

- Thiazides and other diuretics

- Thyroid drugs

Several medications compete for the same renal tubular transport systems as metformin, which can increase the serum levels of both drugs. Medications with this effect include amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin [49]. In addition to these interactions, consumption of guar gum may decrease hypoglycemic effect of metformin.

CASE STUDY

Patient K is a white woman, 71 years of age, presenting to her primary care physician with complaints of fatigue, polyuria, polyphagia, and polydipsia for the past few months. She is 5 feet 4 inches tall and weighs 205 pounds, with a calculated BMI of 35.3 kg/m^2. She confirms a family history of diabetes on her mother's side, a personal history of having given birth to a child weighing more than 9 pounds, and arthritis of her bilateral knees. A finger stick reveals a blood glucose level of 198 mg/dL.

Rationale and comments : Based on the information gathered during the initial examination, Patient K cannot be definitively diagnosed with diabetes. Although symptoms of diabetes are present, a blood glucose level of 198 mg/dL is not diagnostic unless further laboratory testing is completed.

In order to gain additional information, Patient K is referred for a complete blood work-up. The results of this work-up reveal:

- HbA1c: 8.0% (estimated average glucose: 183 mg/dL)

- Fasting blood glucose: 195 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 160 mg/dL

- Triglycerides: 167 mg/dL

- LDL: 123 mg/dL

- HDL: 29 mg/dL

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Based on this additional information, Patient K is diagnosed with type 2 diabetes and is referred to an ADA-recognized diabetes education program. At her three-month follow-up appointment, the patient's HbA1c level has increased to 8.6% (estimated average glucose: 200 mg/dL) and her fasting blood glucose level is 205 mg/dL. Sporadic SMBG records reveal fasting levels consistently between 180 mg/dL and 210 mg/dL and postprandial levels between 150 mg/dL and 170 mg/dL. Patient K states she did not attend the education class as recommended but has attempted to limit her sugar intake. She denies starting an exercise program because of the pain she experiences in her knees when she tries to walk.

It is determined, taking into account Patient K's blood glucose level and failure to make lifestyle changes, that the best course of treatment is medication therapy utilizing metformin. The patient is prescribed metformin 500 mg each evening and water aerobics for exercise. Her physician again stresses the importance of SMBG and participation in diabetes self-management education.

Rationale and comments : The therapy prescribed is appropriate for Patient K for many reasons. Her fasting blood glucose levels are higher than normal, her postprandial levels are slightly elevated, and she is suspected to have insulin resistance. She is obese and has been non-adherent to her meal and exercise plans. Her SMBG has been erratic. Metformin will positively impact the patient's fasting blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut.

10. THIAZOLIDINEDIONE THERAPY

The group of antihyperglycemic agents referred to as the thiazolidinediones, or TZDs, is one of the more modern classes of diabetes medications (Table 6). These agents improve blood glucose levels by increasing the body's sensitivity to insulin [3]. TZDs are not hypoglycemic agents and do not precipitate hypoglycemia, but when used in combination with a sulfonylurea, there is a synergistic effect to improve glucose tolerance by complimentary mechanisms [67].

Table 6: THIAZOLIDINEDIONES

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Pioglitazone

Actos

15–45 mg daily

45 mg

Once daily

Days

Unknown

Rosiglitazone

Avandia

4–8 mg daily

8 mg

Once or twice daily

Days to weeks

Unknown

Source: [3,48,49,50,51]

TZDs depend on the presence of insulin to act. Insulin resistance is decreased in the periphery and in the liver when TZD therapy is utilized, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. TZDs are a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver, and also in the vascular endothelium, macrophages and other cell types [7,49,67]. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism [49,67].

TZDs have been found to reduce the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by TZDs result in increased responsiveness of insulin-dependent tissues [67,73]. TZDs enhance the action of insulin at the receptor or post-receptor level in the peripheral hepatic tissues, reversing or partially reversing insulin resistance [74]. In addition, TZDs improve insulin sensitivity within the muscle and adipose tissues, further improving blood glucose levels [50].

In addition to their blood glucose-regulating effects, TZDs can improve the efficiency of the cardiac work load [3]. Adipose tissue expression of adiponectin is lowered in the presence of insulin resistance. As a result, lower plasma levels have been documented in humans with obesity, type 2 diabetes, and/or coronary artery disease. Research and trials have also demonstrated a close correlation between changes in adiponectin plasma levels after TZD treatment and measures of insulin-mediated glucose metabolism and adipose tissue distribution [7].

TZDs can be utilized as a monotherapy or in combination with metformin, a sulfonylurea, a secretagogue, and/or insulin. They should be used as monotherapy agents only when insulin production appears to be adequate [3]. Due to the adiponectin relationship, this is an ideal medication regimen for patients with type 2 diabetes complicated by obesity and/or coronary artery disease. However, TZD therapy is contraindicated in some cases, including for patients with [49,67]:

- Acute liver disease or ALT levels greater than 2.5 times the upper limit

- Symptomatic class III or IV heart failure (black box warning)

- Jaundice

- Hypersensitivity to the medication

- Type 1 diabetes

- Diabetic ketoacidosis

Although TZDs are contraindicated for the treatment of type 1 diabetes, research is being done to identify the risks and benefits associated with TZD therapy in type 1 diabetics with a BMI greater than 27 kg/m^2 [7].

PIOGLITAZONE

Pioglitazone is initially prescribed at a dose of 15–30 mg once daily, which may be increased to the desired response up to a maximum of 45 mg/day [49]. The exact onset of action of pioglitazone is unknown, but peak effect is reached in approximately two hours, a time that may be delayed with food. The half-life of pioglitazone is 16 to 24 hours [49,50]. Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Following oral administration, approximately 15% to 30% of the dose is excreted in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces [73].

ROSIGLITAZONE

Rosiglitazone should be started at an initial daily dose of 4 mg, regardless of whether it is being used as monotherapy or as part of combination therapy [49]. After several weeks, the dose may be titrated up, if necessary, to a maximum of 8 mg/day. Rosiglitazone may be taken in two divided doses [48,49]. The onset of action for rosiglitazone is unknown; maximum effects may not be present for up to 12 weeks. The drug has a peak action time of about one hour with a half-life of three to four hours [49,50]. Rosiglitazone is extensively metabolized, and the major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than the parent drug and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone. The majority of rosiglitazone metabolites are eliminated in the urine (64%) and the feces (23%) [49,75].

POTENTIAL SIDE EFFECTS

Weight gain is the most recognized side effect with TZD therapy and is thought to be a result of plasma volume expansion leading to edema [49]. As a result of this plasma volume expansion, there is also a small reduction in hemoglobin, hematocrit, and neutrophil counts [7]. Other notable side effects include [3,49]:

- Increased total serum cholesterol

- Fluid retention (5% with monotherapy and 15% with insulin therapy)

- Headache, arthralgia, back pain (5% to 14%)

- Nausea and diarrhea (4% to 6%)

- Small decrease in hemoglobin, hematocrit, and neutrophil counts (5%)

- Elevation in ALT levels (1.9%)

In addition, rosiglitazone is associated with specific adverse effect risks, such as [3,49]:

- Bone fracture in women

- Decreased efficacy of oral contraceptives

- Resumption of ovulation in premenopausal anovulatory women

- Potential increased risk of heart failure

TZD therapy has several known drug-drug interactions, including [50,67]:

- Atorvastatin: may decrease atorvastatin and pioglitazone levels

- Hormonal contraceptives in conjunction with pioglitazone may decrease the level of hormonal contraceptives, reducing the effectiveness of the contraceptive

- Ketoconazole may inhibit pioglitazone metabolism

The concurrent administration of certain herbs, such as burdock, dandelion, eucalyptus, and marshmallow, can result in potentiation of TZDs' hypoglycemic effects.

CASE STUDY

Patient H is an African American woman, 38 years of age, presenting to her primary care physician for a routine physical with complaints of fatigue and constant hunger. She is 5 feet 7 inches tall and weighs 235 pounds, with a calculated BMI of 36.9 kg/m^2. She has a strong history of diabetes and coronary artery disease on both sides of her family, a personal history of gestational diabetes with her last two children, and is employed as a legal secretary. A finger stick reveals a blood glucose level of 213 mg/dL. A diagnosis of diabetes is made, and the patient is referred for fasting blood work, which reveals:

- HbA1c: 7.8% (estimated average glucose: 177 mg/dL)

- Fasting blood glucose: 137 mg/dL

- Two-hour glucose level (after 75 g oral glucose tolerance test): 187 mg/dL

- Triglycerides: 178 mg/dL

- LDL: 131 mg/dL

- HDL: 21 mg/dL

The physician refers Patient H to an ADA-recognized diabetes education program so she may receive information regarding blood glucose monitoring and exercise and meal planning. At her follow-up appointment, the patient's HbA1c has not significantly changed, with a result of 7.7% (estimated average glucose: 174 mg/dL) and a fasting blood glucose level of 172 mg/dL. SMBG records reveal fasting blood glucose levels consistently between 155 mg/dL and 190 mg/dL and postprandial levels steadily between 190 mg/dL and 213 mg/dL. Patient H claims to be adherent to her meal and exercise planning goals but is struggling with weight loss and hunger. As a result, her physician initiates her on TZD therapy. The patient is prescribed pioglitazone 15 mg each morning, and she is advised to continue with her meal and exercise plans. Patient H is also given instructions to report any signs of sudden weight gain, shortness of breath, or chest pains, as these could be signs of excessive fluid retention related to TZD therapy.

Rationale and comments : Patient H has been adherent to her meal and exercise plan with little success and growing frustration. Her morning and postprandial blood glucose levels are above normal, and both contribute to the elevated HbA1c levels. TZD therapy is indicated for Patient H because of her family history of coronary heart disease, obesity, and suspected insulin resistance.

11. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THERAPY

A more recent addition to the available treatments for type 2 diabetes is the dipeptidyl peptidase-4 (DPP-4) inhibitor, of which there are four approved medications: sitagliptin, linagliptin, saxagliptin, and alogliptin (Table 7). This discovery has launched a new era in the management of hyperglycemia. The two well-characterized incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both cause an increase in insulin synthesis and release from pancreatic beta cells in response to normal or increased blood glucose levels [76,77]. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adenosine monophosphate. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production [51]. DPP-4 inhibitors are believed to exert their action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by these agents, thereby strengthening and prolonging their action. GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4.

Table 7: DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Onset of Action

Duration of Action

Sitagliptin

Januvia

25–100 mg daily

100 mg

Once daily

1 to 4 hours

24 hours

Linagliptin

Tradjenta

5 mg daily

5 mg

Once daily

1.5 hours

24 hours

Saxagliptin

Onglyza

2.5–5 mg daily

5 mg

Once daily

2 hours

24 hours

Alogliptin

Nesina

12.5–25 mg daily

25 mg

Once daily

—

24 hours

Source: [3,48,49,50,51,78]

SITAGLIPTIN

Sitagliptin is generally dosed at 100 mg/day, with decreased doses necessary for patients with renal impairment [49]. It is given once daily and may be used alone or with other medications to obtain the best results. The drug is rapidly absorbed, with time to peak action within one to four hours after ingestion. Sitagliptin has a half-life of 12 hours, with a duration of action equaling 24 hours. Metabolism is a minor pathway of elimination [49]. Six metabolites have been detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. Following administration of sitagliptin, approximately all of the active drug was eliminated in feces (13%) or urine (87%) within one week of dosing, and renal clearance is approximately 350 mL/minute [51]. An estimated 79% of sitagliptin that is excreted in the urine is unchanged drug [49].

Sitagliptin is indicated for patients with type 2 diabetes who are not achieving adequate blood glucose control with medical nutrition therapy and exercise alone. It can be utilized as a monotherapy or in combination with metformin, a secretagogue, or a TZD [7,49]. Sitagliptin may be used for a person with mild renal insufficiency at the full dosage. For patients with moderate renal insufficiency (creatinine clearance of 30–50 mL/minute), the dose should be 50 mg, and for those with a creatinine clearance of less than 30 mL/minute or end-stage renal disease and hemodialysis, the dosage should be 25 mg [48,49].

Side Effects

The most common adverse effect associated with sitagliptin monotherapy is nasopharyngitis, which occurs in 5% of patients [49]. Additional adverse effects include [67]:

- Upper respiratory infection (6.2% in combination therapy)

- Headache (5.9%)

- Abdominal pain (2.2%)

- Diarrhea (2.4%)

- Nausea (1.3%)

When caring for an individual receiving sitagliptin therapy, it is also important to be aware of reports to the U.S. Food and Drug Administration (FDA) regarding 88 post-marketing cases of pancreatitis, 2 of which were hemorrhagic or necrotizing, in patients receiving sitagliptin therapy. These cases of pancreatitis were reported to the FDA between October 2006 and February 2009 [79]. In 2009, the FDA issued a special alert regarding the possible association of sitagliptin/metformin combination with acute pancreatitis [79]. A study that examined insurance records found that the use of sitagliptin could double the risk of developing acute pancreatitis [80]. Additionally, in 2013 the FDA announced that it is evaluating unpublished findings that suggest precancerous cellular changes (i.e., pancreatic duct metaplasia) in patients with type 2 diabetes treated with sitagliptin. The findings are based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes [81]. Patients taking sitagliptin should be advised regarding symptoms of pancreatitis (i.e., persistent severe abdominal pain, anorexia, nausea, vomiting) and instructed to contact their physician should they experience these symptoms. In the case of sitagliptin, there are no known significant drug-herb interactions [50].

SAXAGLIPTIN

Saxagliptin is dosed at 2.5–5mg/day, with a lower dose used in patients with moderate or severe renal impairment or when the agent is prescribed in conjunction with a strong cytochrome P450 3A4 inhibitor [49,82]. This agent is approved for use with other drugs or as monotherapy for the treatment of type 2 diabetes in adults. The time to peak action for saxagliptin is approximately two hours, and the drug is metabolized hepatically to 5-hydroxy saxagliptin, an active metabolite [82]. The majority of the drug and the metabolite are excreted in the urine (75%) and the feces (22%) [49].

Saxagliptin may be initiated as a single therapy or in conjunction with metformin, under the brand name Kombiglyze XR. It may also be added on to an ongoing metformin, sulfonylurea, or TZD regimen. No adjustment of dosage is necessary for BMI, gender, or age. For patients with a creatinine clearance of 50 mL/minute or less, the recommended dosage is 2.5 mg once daily; for those with end-stage renal disease, a dose of 2.5 mg should be given once daily after dialysis [49].

Side Effects

The most common adverse reactions associated with saxagliptin are upper respiratory tract infection (7.7%), headache (6.5%), nasopharyngitis (6.9%), and urinary tract infection (6.8%) [67,83]. Anyone with a hypersensitivity reaction should discontinue the drug immediately. There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin [67,83]. After initiating treatment, observe patients carefully for signs and symptoms of pancreatitis. An FDA safety review also has found that saxagliptin may increase the risk of heart failure, particularly in patients with heart or kidney disease [84]. As a result, the agency has added new warnings to drug labels.

LINAGLIPTIN

Linagliptin was approved by the FDA in 2011 for the treatment of patients with type 2 diabetes that is uncontrolled by diet modification and exercise [82]. In addition to monotherapy, it has also been studied as add-on therapy with metformin, pioglitazone, and a sulfonylurea. When used with a secretagogue, the dose of the secretagogue should be lowered in order to reduce the risk of hypoglycemia [67,85]. Linagliptin is absorbed rapidly, with an onset of action of about 1.5 hours [49]. It is primarily excreted as unchanged drug in the feces (80%) and urine (5%) [49].

No dosage adjustment is necessary for patients with renal or hepatic impairment. Concurrent use of linagliptin with either insulin or a secretagogue is associated with an increased risk for hypoglycemia [49]. The medication may be taken with or without food, and the only significant contraindication is allergy or hypersensitivity to linagliptin [49,82].

Side Effects

Side effects most commonly associated with linagliptin include headache (6%), nasopharyngitis (6% to 7%), arthralgia (6%), and back pain (6%) [49]. Drug interactions are also possible. Clinicians should consider using an alternative to any strong cytochrome P450 3A4 inducer in patients who are being treated with linagliptin, as the combination can reduce the effectiveness of linagliptin [49]. The FDA has advised of postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin [85,86]. If pancreatitis is suspected, the drug should be promptly discontinued.

ALOGLIPTIN

Approved by the FDA in 2013, alogliptin is now available in the United States. It is usually dosed at 12.5–25 mg/day and is available in fixed-dose formulations with metformin (brand name Kazano) and with pioglitazone (brand name Oseni) [78]. Alogliptin is approved for use with diet and exercise to improve blood sugar control in adult patients with type 2 diabetes.

Alogliptin or its combination formulations may be added to an ongoing regimen. It has been shown to be safe and effective in reducing HbA1c in 14 clinical trials involving more than 8,500 patients [78]. The most common side effects are nasal congestion, headache, and upper respiratory tract infection [49]. In 2013, the FDA requested that the manufacturer complete postmarking studies related to the safety of the drug, including a cardiovascular outcomes trial, a study monitoring for liver abnormalities, and three pediatric studies [78]. A safety review published by the agency in 2016 found that alogliptin may increase the risk of heart failure, particularly in patients with heart or kidney disease [84]. As a result, the agency has added new warnings to drug labels.

CASE STUDY

Patient B is a Pacific Islander woman, 64 years of age, presenting to the primary care physician with complaints of a urinary tract infection (UTI) and fatigue. She attributes the fatigue to waking frequently at night due to the UTI. The patient denies any recent history of febrile states or pain with urination. She is 5 feet 1 inch tall and weighs 170 pounds, with a calculated BMI of 32.2 kg/m^2. She confirms a family history of diabetes on her mother's side and admits to a sedentary lifestyle.

Patient B's urine sample is negative for infection. A random finger stick reveals a blood glucose level of 207 mg/dL. She is diagnosed with type 2 diabetes based on her blood glucose level and the characteristic symptoms (polyuria and fatigue).

In order to gain additional information, Patient B is referred for fasting blood work. The results of this blood work indicate:

- HbA1c: 7.8% (estimated average glucose: 177 mg/dL)

- Fasting blood glucose: 147 mg/dL

- Triglycerides: 167 mg/dL

- LDL: 199 mg/dL

- HDL: 32 mg/dL

Patient B is referred to an ADA-recognized diabetes education program and is initiated on treatment for dyslipidemia based on her very high LDL level and borderline high triglycerides.

When Patient B returns for her three-month follow-up appointment, she acknowledges compliance to her meal and exercise planning goals with very little success. Her repeat HbA1c demonstrates minimal change with a result of 7.6% (estimated average glucose: 171 mg/dL) and a fasting blood glucose level of 165 mg/dL. Her fasting levels during SMBG are generally between 145 mg/dL and 170 mg/dL; her postprandial levels are between 170 mg/dL and 190 mg/dL.

DPP-4 therapy is determined to be the best treatment choice to control Patient B's diabetes. She is started on sitagliptin 100 mg each morning and continues her meal plan and exercise program.

Rationale and comments : Patient B's higher than normal fasting and postprandial blood glucose levels are contributing to the elevated HbA1c levels, and she has been adherent to her meal plan and exercise program with minimal success. This treatment is appropriate for Patient B because DPP-4 therapy assists in weight loss while impacting blood glucose levels.

12. SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Canagliflozin, the first in the new class of diabetes medications referred to as sodium-glucose co-transporter 2 (SGLT2) inhibitors, was approved by the FDA in 2013, with two additional agents, dapaglifozin and empagliflozin, approved in 2014, and another, ertugliflozin, approved in 2017 (Table 8) [87,88,89]. This class of drugs acts by inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, which reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose. SGLT2 is the main site of filtered glucose reabsorption, and reduction of filtered glucose reabsorption and lowering the renal threshold result in increased urinary excretion of glucose and improved plasma glucose concentrations [49].

Table 8: SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Drug Name

Trade Name

Dose Range

Maximum Daily Dose

Frequency

Time to Peak Action

Duration of Action

Canagliflozin

Invokana

100–300 mg daily

300 mg

Daily

1–2 hours

24 hours

Dapagliflozin

Farxiga

5–10 mg daily

10 mg

Daily

2 hours

24 hours

Empagliflozin

Jardiance

10–25 mg daily

25 mg

Daily

1.5 hours

24 hours

Ertugliflozin

Steglatro

5–15 mg daily

15 mg

Daily

1–2 hours

24 hours

Source: [49,87,88,89]

The recommended initial dose of canagliflozin is 100 mg once daily prior to the first meal of the day [49,87]. The dose may be increased up to 300 mg/day, unless the patient has impaired renal function. Dapagliflozin is dosed at 5 mg once daily in the morning and may be increased to 10 mg/day, while empagliflozin is started at 10 mg daily and may be increased to 25 mg per day, if necessary [49,88,89]. Ertugliflozin is started at a dose of 5 mg daily, with possible titration up to 15 mg/day [49]. These agents are approved for use with diet and exercise to improve the control of type 2 diabetes in adult patients. They have been studied for use as monotherapy and in combination with other antidiabetics, including metformin, sulfonylureas, pioglitazone, and insulin [87].

POTENTIAL SIDE EFFECTS

The most common side effects associated with SGLT2 inhibitors are vulvovaginal candidiasis and urinary tract infection [87]. Other possible adverse effects include increased serum potassium, renal insufficiency, and hypoglycemia [49]. In 2013, the FDA requested that the manufacturer of canagliflozin complete postmarking studies, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, liver abnormalities, pancreatitis, hypersensitivity reactions, photosensitivity reactions, and adverse pregnancy outcomes; a bone safety trial; and two pediatric studies [87].

In 2015, the FDA issued a warning that canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis. The warning was based on the identification of 20 cases of diabetic ketoacidosis requiring hospitalization in patients treated with SGLT2 inhibitors between March 2013 and June 2014. Later in the year, the FDA revised the labels of SGLT2 inhibitors, warning about the risks of ketoacidosis as well as serious urinary tract infections. Additionally, the FDA is requiring manufacturers of the drugs to conduct enhanced pharmacovigilance studies to evaluate spontaneous reports of ketoacidosis in patients treated with SGLT2 inhibitors. The enhanced studies include a five-year period of specialized follow-up to collect additional information [90,91,92].

In 2016, the FDA alerted the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with canagliflozin. Also in 2016, the FDA strengthened the existing warning about the risk of acute kidney injury with canagliflozin and dapagliflozin. The warning was based on reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use [94].

In 2017, based on data from two large clinical trials, the FDA confirmed the increased risk of leg and foot amputations with canagliflozin and issued requirements for a new boxed warning [93]. In 2018, the FDA issued a warning about rare but serious necrotizing fasciitis of the perineum associated with SGLT2 inhibitor therapy [95].

13. COMBINATION ORAL MEDICATION PREPARATIONS

Due to the success of using multiple agents concurrently to combat diabetes, many medications have been combined into one preparation to provide the benefits of both drugs and lessen the number of pills necessary (Table 9) [7]. Research has demonstrated a greater level of success utilizing combination therapy as opposed to separate prescriptions [96]. The ideal candidate for combination preparations is being treated with separate classifications of antihyperglycemic agents for which a single, combination form is available. However, combination therapy is not without risks. When formulations are combined, the adverse effects and contraindications associated with both must be taken into consideration [49]. Combination medications are only available in fixed dosages and may not meet the needs of every individual. Furthermore, in some instances, these combined formulas may be more expensive than the separate agents [3].

Table 9: COMBINATION PREPARATIONS OF ORAL DIABETES MEDICATIONS

Agents

Brand Name

Available Dosages

Pioglitazone and metformin

Actoplus Met

15 mg/500 mg

15 mg/850 mg

Pioglitazone and metformin

Actoplus Met XR

15 mg/1,000 mg

30 mg/1,000 mg

Pioglitazone and glimepiride

Duetact

30 mg/2 mg

30 mg/4 mg

Glyburide and metformin

Glucovance

1.25mg/250 mg

2.5 mg/500 mg

5 mg/500 mg

Sitagliptin and metformin

Janumet

50 mg/500 mg

50 mg/1,000 mg

Sitagliptin and metformin

Janumet XR

50 mg/500 mg

50 mg/1,000 mg

100 mg/1,000 mg

Glipizide and metformin

Metaglip

2.5 mg/250 mg

2.5 mg/500 mg

5 mg/500 mg

Alogliptin and metformin

Kazano

12.5 mg/500 mg

12.5 mg/1,000 mg

Alogliptin and pioglitazone

Oseni

12.5 mg/15 mg

12.5 mg/30 mg

12.5 mg/45 mg

25 mg/15 mg

25 mg/30 mg

25 mg/45 mg

Dapagliflozin and metformin

Xigduo

5 mg/500 mg

5 mg/1,000 mg

10 mg/500 mg

10 mg/1,000 mg

Canagliflozin and metformin

Invokamet

50 mg/500 mg

50 mg/1,000 mg

150 mg/500 mg

150 mg/1,000 mg

Linagliptin and metformin

Jentadueto

2.5 mg/500 mg

2.5 mg/1,000 mg

Linagliptin and metformin

Jentadueto XR

5 mg/1,000 mg

5 mg/2,000 mg

Saxagliptin and metformin

Kombiglyze XR

5 mg/500 mg

5 mg/1,000 mg

2.5 mg/1,000 mg

Empagliflozin and metformin

Synjardy

5 mg/500 mg

5 mg/1,000 mg

12.5 mg/500 mg

12.5 mg/1,000 mg

Empagliflozin and metformin

Synjardy XR

5 mg/1,000 mg

10 mg/1,000 mg

12.5 mg/1,000 mg

25 mg/1,000 mg

Ertugliflozin and metformin

Segluromet

2.5 mg/500 mg

2.5 mg/1,000 mg

7 mg/500 mg

7 mg/1,000 mg

Dapagliflozin and saxagliptin

Qtern

10 mg/5 mg

Ertugliflozin and sitagliptin

Steglujan

5 mg/100 mg

15 mg/100 mg

Empagliflozin and linagliptin

Glyxambi

10 mg/5 mg

25 mg/5 mg

Empagliflozin, linagliptin, and metformin

Trijardy XR

5 mg/2.5 mg/1,000 mg

10 mg/5 mg/1,000 mg

12.5 mg/2.5 mg/1,000 mg

25 mg/5 mg/1,000 mg

Source: [3,48,49,50,51,78,97]

CASE STUDY

Let us revisit Patient K, who has been taking metformin to control her type 2 diabetes. One year ago, Patient K was started on metformin 500 mg each evening with recommendations to attend diabetes self-management education. Since then, her dosage has been titrated up, and she currently takes metformin 1,000 mg twice per day. At her scheduled appointment, Patient K has an HbA1c level of 8.8% (estimated average glucose: 206 mg/dL) and claims to be adherent with her meal and exercise plan the majority of the time. Occasional SMBG indicates fasting levels between 145 mg/dL and 170 mg/dL and postprandial levels between 180 mg/dL and 230 mg/dL. Although the metformin achieved a small decrease in Patient K's blood glucose levels, she has not obtained satisfactory results. More intensive therapy, with a second antihyperglycemic agent, is necessary, and the physician prescribes glyburide 2.5 mg daily. Upon hearing this, the patient becomes teary-eyed and expresses concerns about the cost of the new medication. She states she is on a fixed income and can barely make ends meet. The physician offers to prescribe a combination medication that is less expensive than the two agents separately. Patient K agrees and is prescribed Glucovance 2.5 mg/500 mg in the morning and continues with metformin 1,000 mg in the evening.

Patient K returns for a three-month follow-up. Her HbA1c demonstrates a decrease, with the result of 8.1% (estimated average glucose: 186 mg/dL) and a fasting blood glucose level of 110 mg/dL. SMBG records show fasting blood glucose levels consistently between 98 mg/dL and 120 mg/dL and postprandial levels between 160 mg/dL and 200 mg/dL. The patient has also made great improvements in adhering to meal plans, exercise goals, and SMBG. However, the physician stresses the need for Patient K's HbA1c level to be less than 7.0%, and they agree to change therapy to Glucovance 2.5 mg/500 mg twice per day. The patient agrees to wake at 3 a.m. at least twice in the first week to test her morning blood glucose level to assess for nocturnal hypoglycemia.

Rationale and comments : Patient K's morning blood glucose levels are close to optimal, but her postprandial levels remain elevated and her HbA1c level remains suboptimal. She has demonstrated greater adherence to her meal, exercise, and SMBG plans. Metformin will continue to impact her fasting and mid-day blood glucose levels by decreasing the liver's production of endogenous glucose, decreasing insulin resistance, and decreasing the reabsorption of carbohydrates in the gut. In addition, glyburide will assist the pancreas in the production of insulin. Patient K will require education regarding the importance of determining the presence of nocturnal hypoglycemia, signs and symptoms of hypoglycemia, and conditions that require communication with her primary care physician.

14. BOLUS INSULIN THERAPY

A bolus of insulin refers to the administration of insulin over a short period of time, usually after ingestion of carbohydrates (meal bolus) or in reaction to an elevated glucose level (correction bolus) [98]. Bolus insulin therapy can be administered via a single injection, an insulin pump, or inhaled mist and is used in the treatment of both type 1 and type 2 diabetes [2]. In 2016, the FDA approved the first automated insulin delivery device for individuals 14 years of age and older with type 1 diabetes. The device is a hybrid closed-loop system that automatically monitors glucose and provides appropriate basal insulin doses [99].

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, insulin dosing schedules should be individualized based on a variety of factors, including the severity of diabetes, oral intake, severity of illness, and other concurrent diabetic medication. It is not feasible to design a single algorithm for determining an insulin regimen in every patient.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Meal bolus therapy provides more flexibility to individuals with diabetes, but it requires competency in carbohydrate counting and a working knowledge of the rapid-acting insulin analog's impact within the body [100]. When administering a meal bolus, the dosage of insulin is determined by the amount of carbohydrates to be ingested. This amount is divided by the insulin-to-carbohydrate ratio (the number of grams of carbohydrate that one unit of insulin covers). The ratio must be individualized and will vary among patients [98]. For example, a patient may have an insulin-to-carbohydrate ratio requiring 1 unit of insulin for every 15 g of carbohydrate. If this patient consumed a meal containing 60 g carbohydrates, 4 units of insulin would be needed. Alternatively, if this patient attends a party and chooses to consume a piece of cake with ice cream for a total of 120 g carbohydrate, the flexibility provided by meal bolus insulin therapy will allow the patient to administer the insulin needed (8 units).

Correction bolus is an infusion or injection of insulin delivered quickly to bring high blood glucose levels back within a goal range [101]. The dose of insulin administered for a correction bolus is determined by the sensitivity factor (the amount the blood glucose level will decrease with 1 unit of insulin). As with the meal bolus, the correction bolus will vary depending on certain factors, including an individual's weight. The sensitivity factor is calculated by dividing 2,000 (2,200 for less tight control, 1,800 for tighter control) by the individual's total daily dose of insulin [98]. For example, if a patient takes an average of 100 units of insulin each day, his or her sensitivity factor would be 20, meaning 1 unit of insulin would decrease the blood glucose level by 20 mg/dL. If this same patient has a target blood glucose level of 110 mg/dL and a blood glucose test indicating a current blood glucose level of 240 mg/dL, he or she could utilize a correction bolus to lower the blood glucose level by 130 mg/dL to the target. The necessary dose is calculated by dividing the difference (130 mg/dL) by the correction factor of 20 to determine the amount of insulin needed—6.5 units of insulin in this case.

Several insulin preparations may be administered via bolus for use in meal or correction bolus therapy. The most commonly used types will be discussed in length in the following sections.

INSULIN ASPART

One available insulin analog that may be administered in bolus therapy is insulin aspart (recombinant DNA [rDNA] origin). This type of insulin is rapid-acting and is nearly homologous with regular human insulin. It is produced using Pichia pastoris or Saccharomyces cerevisiae, also known as baker's yeast [102]. A slight change in the insulin chain makes insulin aspart more rapidly absorbed than regular insulin. Insulin aspart is available in a concentration of 100 units/mL (U100). Its onset of action is 5 to 15 minutes, and the peak of action is one to three hours. The effective duration of action for insulin aspart is less than five hours [48,49]. Unlike oral antihypoglycemic agents, insulin aspart does not have a maximum dosage, but is specific to the individual [103].

Insulin aspart is available in 10 mL vials containing U100 insulin aspart and in prefilled and cartridge pens containing 3 mL of U100 insulin. These preparations can be stored unopened until the expiration date; however, once opened or punctured, insulin aspart will expire in 28 days regardless of storage location [49,50]. If stored in a refrigerator, it is important to allow the insulin aspart to warm to room temperature before administration for greater absorption rates and comfort [102]. It is important to note that although refrigeration is permissible, cartridges should not be refrigerated after they are punctured [50,102]. Although cartridge pens have been available for several years, in 2010 and 2011 the manufacturer began to discontinue these pens in favor of the prefilled types.

INSULIN LISPRO

Insulin lispro (rDNA origin) is also a rapid-acting human insulin analog. This type of insulin is created from a non-pathogenic strain of Escherichia coli that has been genetically altered by the addition of the gene for insulin lispro [104]. Like insulin aspart, insulin lispro is available in a U100 concentration and has no labeled maximum dose [103]. Its onset of action is 15 to 30 minutes, and peak effect is experienced in 30 minutes to 2.5 hours. Insulin lispro has an effective duration of action of less than five hours [48,49].

Insulin lispro is available in 10 mL vials for subcutaneous injection, intravenous injection, or infusion via insulin pump. It can be stored at room temperature or refrigerated unopened until the expiration date [49,50]. After the vial has been opened, it must be used within 28 days. If the vial is stored in the refrigerator, it should be allowed to warm to room temperature prior to use [104].

INSULIN GLULISINE

Insulin glulisine (rDNA origin) is another rapid-acting insulin analog. As with insulin lispro, insulin glulisine is synthesized from non-pathogenic E. coli. It is available in U100 concentration in 10 mL vials or 3 mL cartridges [48,49,50]. The onset of action for insulin glulisine is 15 to 30 minutes, with peak action reached within approximately 1.5 to 2.5 and a duration of action of three to four hours [49].

Insulin glulisine may be administered via subcutaneous injection, intravenous injection, or insulin pump. Like other insulin analogs, opened vials of insulin glulisine must be used within 28 days and may be stored at room temperature or refrigerated. Refrigerated vials should be brought to room temperature before use [49]. Preparations mixed for intravenous use are stable at room temperature for 48 hours [49].

REGULAR INSULIN

There are two preparations of regular human insulin on the market: Humulin R and Novolin R. Both preparations are similar in action but differ in chemical make-up. Both have an onset of action of 15 to 30 minutes, and peak action is noted at 2.5 to 5 hours. The effective duration of action is between 2 to 12 hours [49]. Regular insulin can be utilized as a subcutaneous injection, intravenous infusion, insulin pump infusion, or inhaled mist, although insulin analogs are now more widely used [98,105].

Humulin R is created in a non-pathogenic strain of E. coli and consists of zinc-insulin crystals dissolved in a clear fluid. It is a sterile solution and is for subcutaneous, not intramuscular, injection [106]. The concentration of Humulin R is U100 or U500 [49,50].

Novolin R (rDNA origin) is structurally identical to natural human insulin and is produced utilizing S. cerevisiae [107]. Novolin R is only available in the U100 concentration in 10 mL vials [50]. Humulin R and Novolin R may be stored at room temperature until expiration or up to 31 days after the vial is opened [49].

HYPERGLYCEMIC CRISES

In addition to their use in the everyday management of diabetes, the action and short half-life of these insulins, both regular and analogs, makes them well suited for use in the treatment of hyperglycemic states resulting from metabolic changes in response to system stresses, such as surgery, trauma, and sepsis. Hyperglycemia and insulin resistance are common in critically ill patients, even when glucose homeostasis has previously been normal. This effect is amplified in diabetics because diabetic patients cannot increase insulin production to counteract the effect of the increase in catabolic hormones. In some patients, the insulin requirements may increase more than 10-fold [108]. Many critically ill patients are also receiving high-carbohydrate feedings in the form of hyperalimentation or enteral feeding, which can contribute to increased blood glucose levels. Therefore, providing adequate amounts of insulin to promote euglycemia and enough nutrition to avoid hypoglycemia, proteolysis, and lipolysis is a challenge in critically ill patients [109]. When this balance is not maintained, either due to poor diabetes control or illness/trauma, hyperglycemic crises, such as diabetic ketoacidosis or HHS, may develop.

Diabetic Ketoacidosis

Diabetic ketoacidosis is caused by the body's inability to utilize glucose due to a lack of insulin. Because glucose is unavailable for energy needs, fat is used as a fuel source. The byproducts of this fat metabolism (i.e., ketones) accumulate, and electrolyte disturbances, acidosis, and severe dehydration result [110]. It occurs most often in persons with type 1 diabetes, but it can occur in patients with type 2 diabetes as well [111]. Children younger than 5 years of age and those without ready access to health care are at the greatest risk to develop diabetic ketoacidosis [112]. Factors that can precipitate the development of this disorder include [98,111]:

- Severe infection

- Serious illness, such as myocardial infarction

- Inappropriate dosing or skipped or missed doses of insulin

- Continuous subcutaneous insulin infusion failure

- Leaving insulin pump infusion sets intact for longer than the manufacturer recommendation

- Growth spurts in children and adolescents

- Steroid therapy

- Stress

The diagnostic criteria for diabetic ketoacidosis includes a plasma glucose level greater than 250 mg/dL and an arterial pH less than 7.3 [113]. It is further classified based on arterial pH level and mental status as mild (pH 7.25–7.3, alert), moderate (pH 7–7.24, alert/drowsy), or severe (pH <7, stupor/coma). Conditions associated with diabetic ketoacidosis requiring prompt treatment and correction include [2]:

- Chronic hyperglycemia and glucotoxicity

- Acidosis

- Low blood volume

- Hyperosmolality and associated potassium loss

Diabetic ketoacidosis is considered a medical emergency, and if left untreated, it can result in death. Healthcare professionals require the knowledge and critical thinking skills to swiftly recognize the signs and symptoms of diabetic ketoacidosis and provide rapid treatment [111].

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends that for insulin-deficient patients, despite reductions or the absence of caloric intake, basal insulin must be provided to prevent diabetic ketoacidosis.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

In critically ill patients, symptoms of diabetic ketoacidosis can prevent the treatment of the triggering condition. The early signs of ketoacidosis, such as unexplained hyperglycemia, nausea, weakness, fatigue, and confusion, can prevent the individual from partaking in SMBG and insulin administration [98,111].

A successful outcome is based on the recognition and prompt treatment of this medical emergency, initiation of intensive therapy, and careful clinical follow-up. Goals for treatment include rehydration, providing adequate insulin to restore normal glucose metabolism, and correction of electrolyte deficiencies and acidosis [111,114].

Fluid Replacement

The partial correction of dehydration within the first few hours of therapy is necessary to significantly reduce hyperglycemia and ketonemia. This is accomplished by fluid replacement [113]. Adults with diabetic ketoacidosis may present with a deficit of more than 6 liters of fluid [115]. Initial fluid replacement consists of 50% normal saline or 100% normal saline, depending on serum sodium levels, urine output, and the individual's state of dehydration [113,114].

Phosphate concentration decreases with insulin therapy. Although studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in diabetic ketoacidosis, the ADA states that phosphate replacement may be indicated in patients with cardiac dysfunction, anemia, or respiratory depression, or in patients whose serum phosphate concentration is less than 1.0 mg/dL. The ADA recommends that 20–30 mEq/L potassium phosphate be added to replacement fluids when needed [113].

Insulin Replacement

All individuals with diabetic ketoacidosis require insulin therapy. This is best accomplished by a continuous insulin infusion of rapid- or short-acting insulin [111,114]. Intravenous insulin is the most effective route in this case because it can be adjusted rapidly and is not dependent on tissue perfusion for absorption, as is subcutaneous delivery [111,113]. The initial intravenous bolus of regular insulin or insulin analog is 0.1–0.15 units/kg. This is followed by an infusion of 0.1 units/kg/hour, which is titrated to lower blood glucose 50–75 mg/dL/hour. A decrease in blood glucose greater than 75 mg/dL/hour is associated with the potential complication of cerebral edema [111,114]. Insulin therapy should continue until metabolic control is achieved [111].

Correction of Electrolyte Imbalances

It is necessary to provide aggressive potassium supplementation for all individuals with diabetic ketoacidosis, as depletion of potassium can lead to cardiac dysrhythmias. However, renal function must be replaced prior to the administration of potassium [115]. If the potassium level is 4.5–6 mEq/L, administer 10 mEq/h of potassium chloride. If the level is 3–4.5 mEq/L, administer 20 mEq/h of potassium chloride. Supplementation is not needed if the potassium level is greater than 6 mEq/L. Monitor serum potassium levels hourly and stop if the level is greater than 5 mEq/L [111].

The use of bicarbonate for the treatment of acidosis is no longer routine unless the metabolic acidosis is severe [111,113,114,115]. If bicarbonate therapy is utilized, 1–2 mEq/kg should be administered over two hours followed by an assessment of plasma bicarbonate levels until the venous pH is >7.0 [113]. Total bicarbonate treatment should not exceed 5 mEq/kg in a 12-hour period [116].

Prevention

The prevention of diabetic ketoacidosis can often be accomplished with patient education regarding the condition and recognition of the initial signs and symptoms. Patients with type 1 diabetes or ketosis-prone type 2 diabetes should be educated and assessed for understanding regarding the recognition of the early warning signs. Individuals with infections or who are on injection or infusion insulin therapy may benefit from regularly measuring urine ketones and adjusting insulin doses and diet in accordance with findings [117].

Hyperosmolar Hyperglycemic Syndrome

HHS is an acute metabolic complication characterized by insulin deficiency. The condition was formerly referred to as hyperosmolar hyperglycemic nonketotic syndrome, but the terminology was changed because coma is found in fewer than 20% of patients with HHS. It is a life-threatening crisis with a high rate of mortality [118,119]. The syndrome is typically seen in individuals with undiagnosed diabetes, patients who are diagnosed after a long period of hyperglycemia, and elderly patients with type 2 diabetes, especially those who reside in long-term care facilities [2]. Blood glucose levels increase in response to a precipitating stressful situation or event. As the stress continues, the hyperglycemia is exacerbated and the evolution of HHS begins [118]. If untreated, blood glucose levels will exceed 180 mg/dL, the level at which the kidneys are no longer able to reabsorb glucose. At the same time, water loss reduces renal perfusion and causes further dehydration. This cascade of events results in more extreme levels of hyperglycemia and osmolarity with HHS than those found with diabetic ketoacidosis [114,118]. As the patient becomes increasingly dehydrated and hyperosmolar, mental status will be impaired. Like diabetic ketoacidosis, HHS will result in death if left untreated [118].

Patients experiencing HHS may present to the emergency department with seizures or symptoms that mimic a cerebrovascular accident. In most cases, physical examination will demonstrate evidence of extreme dehydration, orthostatic hypotension, and a frank hypovolemic shock. The plasma glucose level is typically greater than 600 mg/dL, with a serum osmolality level greater than 320 mOsm/kg [118]. Anything that elevates blood glucose levels or reduces hydration can contribute to the development of HHS, including [114,118]:

- Infection (the precipitating factor in 60% of cases)

- Surgery

- Myocardial infarction

- Gastrointestinal hemorrhage

- Pancreatitis

- Pulmonary embolism

- Medications that impact carbohydrate metabolism (e.g., glucocorticoids, thiazides, phenytoin, beta blockers)

Fluid and Electrolyte Replacement

The main goal in the treatment of HHS is providing adequate fluids for rehydration [114]. Aggressive fluid replacement is crucial, as patients have an average fluid loss of 9 liters [118]. The guideline for fluid replacement is to infuse half of the fluid deficit over the initial 12 hours and the remainder during the subsequent 12 to 24 hours [114,118]. When administering hypertonic solutions, it is important to be alert to the potential of cerebral edema due to the rapid decrease in serum osmolality [118].

Laboratory values provide critical information to guide electrolyte replacement decisions. The potassium replacement strategy is similar to that with diabetic ketoacidosis, and evidence of the deficit may be initially evident by an electrocardiogram [114]. The total body potassium loss is significant and can equal 4–6 mEq/kg. Furthermore, after insulin therapy is initiated, the potassium level may drop even further [118]. For this reason, insulin therapy should be withheld if the serum potassium is less than 3.3 mEq/L [114].

Insulin Therapy

After hydration is re-established, insulin therapy is usually, but not always, required to obtain euglycemia. The treatment of acidosis is not a part of the treatment plan of HHS; therefore, insulin requirements are not as high [114]. The initial insulin intravenous bolus should be 0.1 units/kg of rapid- or short-acting insulin followed by a consistent infusion at the same rate. When glucose levels reach 300 mg/dL, the infusion may be decreased to 0.05 units/kg. The infusion should be maintained to keep the glucose level between 250–300 mg/dL until the osmolality is less than 315 mOsm/kg and the individual is alert [118].

Prevention

The most important tactic in the prevention of hyperglycemic crises is patient and family education regarding the early identification, treatment, and management of illnesses. Patients with a history of HHS are at risk for further episodes [118]. Patients with type 1 diabetes should be taught about urine ketone testing and appropriate steps should the test return a positive result, including communication with a physician, increased non-caloric fluid intake, and insulin therapy [118]. Additionally, increasing the frequency of SMBG can help prevent the progression and potential complications related to diabetic ketoacidosis and HHS. Key patient and family teaching points include [120]:

- Always take diabetes medications as prescribed. Patients having trouble tolerating the medication due to vomiting should notify their primary care provider.

- Monitor blood glucose levels at least four times a day. If a patient is too sick to self-test, a family member, caregiver, or trusted support person should provide assistance.

- Maintain a blood glucose log and keep it readily available in case the primary care provider is called.

- Monitor for ketones any time blood glucose levels are 250 mg/dL or greater. Levels should be recorded.

- Maintain adherence to the normal meal plan whenever possible.

- Drink plenty of sugar-free liquids to prevent dehydration.

Conditions that require the immediate notification of a physician include [120]:

- A fever greater than 38 degrees Celsius (100.5 degrees Fahrenheit)

- Vomiting or diarrhea for more than two hours

- Blood glucose levels of 250 mg/dL or greater after two checks or after additional insulin injections

- Moderate or large urine ketones

Case Study

Patient A is a white man, 19 years of age, with a history of type 1 diabetes. He is currently in the end of his first year of college and studying for his final examinations. He has been unable to exercise due to the amount of time devoted to studying. His eating has been erratic, and he has forgotten to cover his meals with insulin aspart. He presents to the emergency department with a six-hour history of abdominal pain, nausea, and confusion as reported by his roommate. The roommate also recalls a fruity odor to Patient A's breath and knows he has not been consuming alcohol. When asked questions regarding his blood glucose levels, Patient A is confused and unable to recall any past history of testing. The roommate states he did not witness the patient assessing any glucose levels. The patient's laboratory evaluation reveals:

- Blood glucose: 531 mg/dL

- Strong serum ketones

- Bicarbonate: 3 mEq/L

- Arterial pH: 7.1

- Potassium: 5.3

- CO_2: 10 mmol/L

- Liver function tests: Within normal limits

- Renal function: Within normal limits

Rationale and Comments : Diabetic ketoacidosis should be the expected diagnosis. Signs and symptoms that support this diagnosis include:

- History of type 1 diabetes

- High level of stress related to upcoming examinations

- Erratic eating patterns

- Not covering carbohydrates with insulin

- Acetone breath, confusion, nausea

- Laboratory glucose, bicarbonate, pH, CO_2, and serum ketone levels

Based on the laboratory values and patient history, the attending physician diagnoses diabetic ketoacidosis and orders insulin therapy: a bolus of regular insulin at 0.1 units/kg followed by an insulin infusion of 0.1 units/kg/hour. An infusion of 0.9% sodium chloride at 20 mL/kg/hour is administered for the first hour. Blood glucose levels are monitored hourly, and adjustments to the infusion are made based on hospital policy.

Eighteen hours after admission, Patient A awakes. His blood glucose is well controlled on the insulin infusion, and his acidosis is resolved. One hour prior to discontinuation of the insulin infusion, he is started on his home dose of insulin glargine, as his HbA1c level was assessed to be 7.1%. The next morning, the patient remains stable and his glucose status is controlled.

Before Patient A is discharged, important patient education points are reviewed and reinforced. The nurse assesses the patient's insulin administration technique by allowing him to demonstrate drawing up and administering his insulin injections. An overview of the onset, peak action times, and duration of all prescribed insulin preparations is provided. The need for injection site rotation and appropriate storage of insulin vials are stressed. The nurse also provides Patient A with information on stress management techniques. Finally, the nurse gives the patient written information regarding sick day management and encourages him to share the handout with his roommate or anyone else who will be involved with his care or well-being.

15. BASAL INSULIN

Basal insulin refers to the steady background insulin that controls blood glucose levels in the fasting state (overnight and between meals). In nondiabetic individuals, healthy beta cells release insulin into the circulatory system throughout the day [5]. This basal or background insulin enables stored fat and glucose to be released in the appropriate amounts to sustain metabolism during times when fuel is not being consumed and metabolized. A consistent insulin level throughout the day regulates glucose production from the hepatic system, the breakdown and production of fat as fuel, and the entry of amino acids into the cells for the creation of enzymes and structural proteins [98]. Basal insulin can be utilized to successfully control blood glucose levels in individuals with either type 1 or type 2 diabetes, but it is one of the cornerstones of therapy for those with type 1 diabetes [5].

Basal insulin therapy may be administered via an injection or with a continuous subcutaneous insulin infusion. For patients with type 2 diabetes with a less than optimal blood glucose level, basal insulin may be added to oral agents to achieve the most advantageous level of metabolic control [2]. A patient's basal insulin needs can be met using a variety of preparations and routes, including intermediate-acting insulin, long-acting insulin, basal/bolus combination in multiple daily dosages, or continuous subcutaneous insulin infusions via an insulin pump.

NPH (INTERMEDIATE-ACTING) INSULIN

NPH insulin is manufactured by two companies and marketed in the United States as Novolin N or Humulin N [49]. NPH is a zinc insulin suspension that includes the polypeptide protamine. It is produced in a concentration of 100 units/mL and generally appears cloudy or milky [121]. As with some insulin analogs, the insulin in NPH is synthesized using noninfectious E. coli bacteria.

NPH is available only in U100 concentration vials or pre-filled pen preparations [50]. The onset of action is within 1 to 2 hours, with peak effect to be expected within 4 to 12 hours [49]. NPH is considered an intermediate-acting insulin as its effective duration is longer than regular insulin or insulin aspart but not as long as insulin glargine or detemir [48,49]. Due to its wide variation in effective action time, this insulin may be prescribed once or twice per day [2]. As with most insulin preparations, NPH can be stored at room temperature or refrigerated until it expires or for 31 days after it is opened. As with any injectable insulin, it should be room temperature prior to injection [50].

INSULIN GLARGINE

Insulin glargine is a long-acting recombinant human insulin analog. It is available in U100 concentration vials, 3-mL cartridges, or 3-mL disposable devices [50,67]. The onset of action is three to four hours, and glargine is considered to be peakless in terms of action [49]. Insulin glargine was the first insulin to be truly long acting, with an effective duration of action of 20 to 24 hours [48]. The rate of absorption does not differ among various sites of injection, and the pharmacokinetics within various individuals is fairly consistent [2].

In 2021, the first biosimilar insulin (insulin glargine-yfgn) was approved by the FDA [153]. As an agent that is readily interchangeable with insulin glargine, it is hoped that this approval with improve availability and affordability of insulin therapy.

INSULIN DETEMIR

Like insulin glargine, insulin detemir is a long-acting basal insulin analog with up to 24 hours duration of action [67,122]. It was approved in 2005 by the FDA for use in maintaining background insulin in patients with type 1 or type 2 diabetes [123].

Insulin detemir is available in U100 concentration vials, 3-mL cartridges, and 3-mL prefilled syringes [49,50]. The onset of action for insulin detemir ranges from three to eight hours, and it is also considered a peakless insulin. The effective duration of action of insulin detemir is dose-dependent and varies from just under 6 hours to 23 hours [48,49]. The duration is mediated by slow absorption from the injection site and slow distribution to target tissues due to a strong self-association and albumin binding [2].

In 2009, the FDA issued a public health advisory regarding stolen vials of insulin detemir [124]. Stolen vials had reappeared on the market, and because handling and storage of these vials (lots XZF0036, XZF0037, and XZF0038) is unknown, patients should not use them.

Insulin glargine, insulin detemir, and NPH preparations are not appropriate for continuous subcutaneous insulin infusion or intravenous infusions and should only be considered for basal insulin therapy [2]. Subcutaneous injection sites for intermediate- or long-acting insulins include the abdomen, buttocks, posterior-lateral area of the arm, and lateral area of the thigh [125].

POTENTIAL SIDE EFFECTS

As with any other insulin therapy, the greatest side effect risk is hypoglycemia [49]. Hypoglycemia is a result of one of two different issues: hyperinsulinemia (resulting from too much exogenous insulin, an insulin-secreting pancreatic tumor, or excessive diabetes medication) or iatrogenic (alteration in glucose counter-regulation) [126]. In the case of exogenous insulin therapy, hypoglycemia is due to the effects of hyperinsulinemia [101].

The benefits of the intermediate- and long-acting insulins include the benefit of improved blood glucose control with a minimized risk of hypoglycemia [127]. For many patients, the greatest benefit of basal therapy is achieved when used in combination with bolus insulin to more effectively mimic the normal physiology of the pancreas [127].

16. COMBINATION INSULIN PREPARATIONS

Many insulin preparations can be utilized in combination to achieve greater efficacy, coverage, and accuracy [49,67]. Most insulin combinations can be mixed in the same syringe, requiring only one injection rather than two [128]. However, insulins glargine and detemir and injectables exenatide and pramlintide cannot be mixed in the same syringe with additional insulin formulations [50].

Multiple combination insulin preparations are available in premixed solutions in vial or pen form [49,67]. These combinations provide the benefit of NPH and a rapid- or short-acting insulin for greater glycemic control and management [50]. All of the fixed combinations are only available in U100 concentration to prevent potential hypoglycemia. Available fixed combinations include [48,49,67]:

- Humulin or Novolin 70/30 (70% NPH and 30% regular insulin)

- Humalog 75/25 (75% NPH and 25% insulin lispro)

- NovoLog 70/30 (70% NPH and 30% insulin aspart)

17. INCRETIN MIMETICS

The first agent in this category of antihyperglycemics, exenatide, was approved for the adjunctive treatment of diabetes in 2005 [129]. Exendin-4 is a naturally occurring incretin mimetic originally isolated from the salivary secretions of the Heloderma suspectum lizard [2]. The action of exenatide differs from other available diabetes medications. It enhances insulin secretion by pancreatic beta cells, slows gastric emptying, and suppresses glucagon secretion [49]. Exenatide has been shown to bind and activate the GLP-1 receptor, which increases both synthesis and secretion of insulin [130].

As it primarily acts to stimulate insulin secretion, exenatide is approved for patients with type 2 diabetes [49]. For these patients, use of this agent results in improved glycemic control. It is important to note that exenatide does not impair the normal glucagon response to hypoglycemia.

Though mainly used for patients with type 2 diabetes, studies have shown exenatide to be a useful adjunctive therapy for patients with type 1 diabetes, although this is an off-label use. Its effect of delaying gastric emptying has been found to reduce postprandial hyperglycemia in adults and adolescents with type 1 diabetes [131].

Exenatide is available in prefilled injection pens and as a kit containing 2 mg of the drug and a diluent [50,67]. The recommended initial dosage for the pen preparation is 5 mcg twice daily within one hour prior to a meal [49]. The dose may be increased to a maximum of 10 mcg twice per day. The recommended dosage for the 2-mg kit is once every seven days (weekly); it can be administered at any time of day, with or without meals [67]. Exenatide has an onset of action of 30 minutes and effective duration of action of approximately 10 hours [48]. The greatest side effect risk and disadvantage with exenatide is nausea, which is reported by 44% of patients who take the drug [128]. Other possible side effects include vomiting, diarrhea, dizziness, headache, and dyspepsia [128]. However, the drug has the beneficial effects of beta cell rejuvenation, decreased glucagon production, and weight loss [103]. Concurrent use of insulin, metformin, sulfonylureas, or a combination of these medications with exenatide is not recommended [49]. Exenatide is best indicated for individuals who have not achieved adequate control on combination medication therapy [2].

In 2010, a second incretin mimetic, liraglutide (Victoza), was approved by the FDA [132]. Liraglutide is a long-acting GLP-1 analog that acts by suppressing glucagon secretion, stimulating insulin secretion, and inhibiting gastric motility [49,133]. Like exenatide, it has also been linked to weight loss and improvements in beta-cell function and mass. However, because liraglutide has a longer action than exenatide, it may be administered only once per day.

Liraglutide is started at a dose of 0.6 mg/day for one week, administered subcutaneously via a prefilled injectable pen, after which the dose is increased to 1.2 mg/day [49]. The dose may be titrated to a maximum of 1.8 mg/day if necessary. Its peak serum concentration is generally reached within 8 to 12 hours, with a half-life of approximately 13 hours [49].

The most common side effects observed with liraglutide are headache, nausea, vomiting, and diarrhea [49,134]. Other side effects include allergic-like injection site reactions, such as hives. Albiglutide is administered at a dose of 30 mg once weekly, though the dose may be titrated to 50 mg once weekly to effect [135]. The initial dose of dulaglutide is 0.75–1.5 mg once weekly [136]. These weekly medications should be administered on the same day each week. Common side effects include hypoglycemia, diarrhea, nausea, and local site reactions [49]. As with exenatide, these drugs are approved for monotherapy or as an addition to an existing regimen. However, albiglutide, dulaglutide, and liraglutide are considered second-line therapies [41].

Another GLP-1 receptor agonist, lixisenatide, received FDA approval in 2016 [49]. Lixisenatide is administered at a dose of 10 mcg once daily. Lixisenatide is available as a kit containing 10 mcg of the drug and a diluent. Common side effects include nausea, vomiting, and headache [49].

In 2019, the FDA approved semaglutide, the first oral treatment for type 2 diabetes [137]. It is not recommended as first-line therapy and is contraindicated in patients with type 1 diabetes or diabetic ketoacidosis [137]. Semaglutide is administered at a dose of 0.25 mg once per week for four weeks via a prefilled injectable pen, then increased to 0.5 mg once weekly for four weeks. The maximum dose is 1 mg once weekly. Gastrointestinal adverse effects are common [49].

Clinical studies have indicated that the incretin mimetics are associated with an increased risk for the development of thyroid tumors, and their labeling includes a black box warning regarding the increased risk of thyroid C-cell tumors. Therefore, these patients should be assessed for elevated calcitonin concentrations and should be counseled on the risk and symptoms (e.g., neck mass, dysphagia, dyspnea, persistent hoarseness) of thyroid tumors [49]. Patients with a personal or family history of medullary thyroid cancer or with multiple endocrine neoplasia syndrome type 2 should not take liraglutide. In 2013, the FDA began investigating unpublished new findings by a group of researchers that suggest an increased risk of pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes treated with incretin mimetics [81].

CASE STUDY

Patient T is a defense attorney in a busy prestigious law firm. She has dealt with type 1 diabetes since the age of 13 years. She was started on an insulin pump in order to improve her blood glucose control and her overall health. Patient T has been happy with the results achieved with the pump, with the exception of a recent weight gain of 10 pounds and increases in her postprandial blood glucose levels. She confers with her endocrinologist regarding options to decrease the postprandial levels and alleviate any further weight gain.

The endocrinologist suggests treatment with exenatide. However, Patient T is concerned with returning to a twice-daily injection, which is one reason she appreciates insulin pump therapy. The patient and her endocrinologist discuss this option, and although she is hesitant to return to daily injections, the patient chooses to attempt the therapy. The endocrinologist prescribes exenatide 5 mcg twice daily.

After four weeks of therapy with exenatide, Patient T returns for follow-up. She states that although she initially experienced nausea, her weight is starting to trend down and her postprandial levels are improving. Patient T indicates she would like to continue with the exenatide therapy based on seen benefits.

18. AMYLIN ANALOGS

Like exenatide, pramlintide is another relatively new antihyperglycemic medication available to help obtain and maintain glycemic control [128]. FDA approved in 2005, pramlintide is utilized in combination with insulin therapy for patients with type 1 or type 2 diabetes [49,138]. Pramlintide mimics the human hormone amylin, a neuroendocrine hormone that contributes to glucose control during the postprandial period. As a synthetic analog of amylin, pramlintide primarily acts by promoting satiety, slowing gastric emptying, and decreasing postprandial glucagon secretion. Because use of pramlintide is associated with feelings of fullness and a reduction in caloric intake, one benefit of use is potential weight loss. Slowed gastric emptying, an effect that lasts for approximately three hours following administration, reduces the initial postprandial increase in plasma glucose, but it does not alter absorption of carbohydrates, fats, or other nutrients.

Pramlintide is contraindicated for patients with gastroparesis or who are prescribed medications that affect gastrointestinal motility or slow the absorption of nutrients [49,128]. Potential side effects include nausea, anorexia, dizziness, and pharyngitis, but the greatest risk is the development of hypoglycemia [50]. Particularly among individuals with type 1 diabetes, pramlintide taken in addition to insulin is associated with an increased risk of severe hypoglycemia [49]. When it does occur, severe hypoglycemia usually develops within three hours of administration of pramlintide injection. Complete patient education and monitoring insulin dose response can help prevent this untoward effect [139].

A patient with type 1 diabetes who uses bolus insulin at mealtime and has not achieved optimum glycemic control is a prime candidate for the addition of pramlintide [49,50]. In addition, pramlintide is indicated for patients with type 2 diabetes who utilize bolus insulin at mealtimes and have failed to achieve adequate glycemic control, with or without a concurrent sulfonylurea and/or metformin therapy [49,103].

For the management of type 1 diabetes, pramlintide is started at a dose of 15 mcg before each meal [49]. This can be titrated up every three days in 15 mcg increments to a maximum of 60 mcg. If pramlintide is prescribed for type 2 diabetes, the initial dose is 60 mcg immediately before eating [49]. Again, this can be titrated up to 120 mcg after three to seven days, if necessary [49]. The onset of action for this medication is 30 minutes, with a duration of action of three hours [48,49]. Pramlintide is primarily metabolized in the kidneys to an active metabolite with a short half-life [49,128].

19. PATIENT EDUCATION

ORAL DIABETES MEDICATIONS

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, nonadherence with diabetes medications can limit the success of therapy and help to explain why a patient is not achieving treatment goals. To screen for nonadherence, clinicians can ask patients open-ended, non-threatening questions at each office visit.

https://www.icsi.org/wp-content/uploads/2019/02/Diabetes.pdf

Last Accessed: October 22, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Patient education is of the utmost importance when it comes to prevention of adverse effects and detrimental outcomes related to diabetes medication therapy. Each class of diabetes medication requires specific instructions and education. Many healthcare providers leave diabetes self-management education to a certified diabetes educator prepared to provide this type of formal education, which is optimal. However, consistent reinforcement is needed and is best done at every patient interaction in the form of teachable moments [14]. It is important to consider each individual's specific comprehension and comfort level. Encompassing a variety of theories and teaching styles is paramount [3].

Fundamental topics for all individuals taking a medication to prevent and correct hyperglycemia include [3,50]:

- Adherence to the medication regimen

- Adherence to the meal and exercise regimen

- Importance of wearing medical identification at all times

- Symptoms of hypoglycemia and necessary treatment

- Consultation with physician regarding the use of over-the-counter medications and herbal medications

HYPOGLYCEMIA

Any person receiving medication therapy for diabetes should be educated regarding the prevention, signs and symptoms, and treatment of hypoglycemia. Overmedication, meal skipping, alcohol consumption, excessive exercise, drug interactions, illness or infection, and trauma can all precipitate hypoglycemia in patients taking certain medications, particularly insulin secretagogues.

Prevention of hypoglycemia includes not skipping meals and eating prior to exercise. Additionally, patients should be advised regarding what to do in the event of a missed medication dose. Most medication preparations should be taken as soon as the missed dose is realized, with a few exceptions. If the medication is repaglinide or nateglinide, or if it is too close to the time of the next dose, the dose should be skipped altogether [50]. Patients should also know the signs and symptoms of hypoglycemia, which include [140]:

- Dizziness or lightheadedness

- Weakness

- Hunger

- Numbness or tingling around the mouth

- Headache

- Palpitations

- Confusion

- Shakiness

- Sweating

- Irritability or nervousness

In general, patients can manage instances of hypoglycemia using the 15:15 rule. According to this rule, patients should treat low blood glucose with 15 grams of carbohydrate and recheck their blood glucose level in 15 minutes. Fifteen grams of carbohydrate would consist of three to four glucose tablets, 4 ounces of fruit juice, one-half can of regular soda, or one tube of glucose gel. In cases of severe hypoglycemia, when the individual is unable to swallow or has a potential of choking, the treatment includes dextrose 50% intravenously or, if intravenous access is unavailable, an intramuscular injection of glucagon [2].

TIMING OF MEDICATIONS AND OTHER CONSIDERATIONS

Sulfonylureas

Sulfonylurea medications should be taken with breakfast or with the first main meal of the day to maximize effect and safety [50]. In addition, there is a risk for hypoglycemia, and steps should be taken to prevent this complication. This includes spacing meals no more than four hours apart and avoiding situations when meals may be missed [5]. Individuals taking a sulfonylurea should carry a rapid-acting glucose source, such as glucose tablets or gel, in order to swiftly treat the onset of hypoglycemia at the initial signs of low blood glucose [50]. Finally, it is essential to advise these patients regarding safe alcohol practices [3].

Nonsulfonylurea Secretagogues

Timing is essential for the prevention of hypoglycemia while utilizing the nonsulfonylurea secretagogues repaglinide and nateglinide. Patients should be instructed to take the medication no more than 30 minutes prior to the meal [50]. Often, patients are advised to take this medication with the first bite of a meal [3]. If a meal is not going to be consumed, the prescribed doses of the medication should also be skipped [50].

Alpha-Glucosidase Inhibitors

Patients prescribed acarbose or miglitol should be instructed to take the medication immediately before the three main meals of the day [50]. Instruction regarding the action of alpha-glucosidase inhibitors and the need to treat incidents of hypoglycemia with simple sugar sources is imperative. These patients should carry glucose tablets or gel with them at all times to prevent severe hypoglycemia [3].

Biguanides

Metformin should be given with a meal, taking into consideration that maximum doses will be better tolerated if divided into three doses and taken with each main meal [50]. Additional education regarding metformin therapy should include the discontinuation of the medication for 48 hours or until appropriate renal function has been verified following procedures involving iodized contrast media [49]. As stated, the FDA has issued a drug safety communication for metformin and metformin-containing medications for use in certain patients with mild-to-moderate renal impairment [72]. Some individuals may experience a metallic taste, but this should subside in time [3]. Lastly, patients should be instructed to avoid excessive alcohol consumption while utilizing this medication [50].

TZDs

Education regarding TZD therapy should be centered on identification of developing or worsening heart failure. It is essential that patients monitor weight daily and report any weight gain of 5 pounds or more over a two-day period to their physician immediately [50]. Moreover, monitoring liver function to evaluate safe levels is critical [3]. Patients should be instructed to notify their healthcare provider immediately if unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine occurs, as these symptoms may indicate liver problems [50].

DPP-4 Inhibitors

Sitagliptin can be taken during the day regardless of food intake. Patient education regarding sitagliptin should include the nasopharyngeal and upper respiratory side effects discussed previously [49]. Because weight loss is a benefit of DPP-4 therapy, it is imperative to stress that the medication is not a substitute for a healthy diet and exercise, and that the prescribed medical nutrition and exercise therapy should be followed [50]. As discussed, the FDA is evaluating findings that suggest pancreatic duct metaplasia in patients with type 2 diabetes treated with sitagliptin [81].

INSULIN AND NONINSULIN INJECTABLES

Patient selection is critical to the successful use of insulin or noninsulin injectable therapy. The ideal candidate would be motivated, compliant, educable, and without any other medical condition or physical limitations that preclude accurate and reliable SMBG and insulin administration [2]. Caution is required in the elderly population or for any individual who could have difficulty with the identification of signs and symptoms of hypoglycemia. For patients with type 2 diabetes, insulin therapy is most commonly reserved for individuals in whom a sufficient trial of diet, exercise, and oral medication therapy has proven ineffective [2].

Any individual initiating injectable therapy to control diabetes requires specific instructions to safely administer the medications. Necessary education related to injectable therapy includes injection techniques, site rotation, needle disposal, and identification of signs and symptoms of hypoglycemia [141].

Injection Techniques

If insulin is being used, it may be available in a prepared pen or cartridge or the patient may be required to prepare a syringe. Steps to correct syringe preparation for a single type of insulin are:

- Wash hands with soap and water.

- Clean the top of the vial with an alcohol wipe.

- Pull enough air into the syringe to replace the prescribed amount of insulin to be taken from the vacuum-sealed vial.

- Insert the air into the vial, and invert the vial.

- Pull back the total amount of insulin prescribed.

- Assess the syringe for any air pockets.

- If air pockets are present, lightly tap the syringe to elevate the air to the top of the syringe and release the bubble back into the vial.

- Remove the needle from the vial

Vials of suspension preparations, such as NPH, should be rolled gently to mix the components prior to administration. In cases of mixed insulins, most commonly when a rapid- or short-acting insulin is utilized in tandem with NPH insulin, additional steps are required. For example, a patient administering NPH and insulin lispro would complete the following steps [142]:

- Wash hands with soap and water.

- Clean the top of the vial with an alcohol wipe.

- Roll the vial of NPH 10 times on its side to thoroughly combine the active components.

- Pull 10 units of air into the syringe to replace the prescribed amount of NPH insulin to be taken from the vacuum-sealed vial.

- Insert the air into the vial, and invert the vial.

- Remove the needle from the vial of NPH.

- Pull 7 units of air into the syringe to replace the 7 units of insulin lispro to be removed from the vacuum-sealed vial.

- Insert the air, and invert the vial.

- Pull back 7 units of insulin lispro.

- Assess the syringe for any air pockets.

- If air pockets are present, lightly tap the syringe to elevate the air to the top of the syringe and release the bubble back into the vial.

- Remove the needle from the vial.

- Insert the needle into the vial of NPH. Do not insert the insulin lispro into the NPH.

- Pull back 10 units of NPH into the syringe containing the insulin lispro.

- Assess for the presence of air pockets. If present, tap the syringe lightly and release only the air back into the vial.

- Remove the needle.

It is important to note that insulin glargine and insulin detemir cannot be mixed with any other insulin or fluid. Therefore, if glargine or detemir is prescribed with rapid- or short-acting insulin, this will require two separate injections [50]. Furthermore, pramlintide and exenatide should not be combined with any other injectable medication due to the chemical composition [143].

Preparation of the site requires cleaning the area of injection with soap and water. Alcohol can be an alternative when soap and water are unavailable. After the site has dried completely, the patient will pinch the skin into a tent with the non-dominate hand and insert the needle at a 90-degree angle. He or she should then count to three; this will allow time for the insulin to start to disperse. It will also decrease the chance of removing the needle too rapidly, allowing the medication to back out of the subcutaneous tissue along with the needle [142]. The needle should then be disposed of in adherence with local requirements. The patient may utilize a commercial container or something as simple as a detergent bottle. When the container is full to within one inch of the top, recap the container and place strong tape around the top or follow the manufacturer's specific instructions [142].

It is important for patients to not reuse the needle due to the risk of infection and contamination of the medication vial. Patients should also be advised to assess needles prior to use and discard any that appear dull or bent to prevent injury [142]. A new needle should be used with each injection regardless of delivery method (e.g., syringe, pen device). This is a crucial topic of education [128].

Site Selection and Rotation

Injectables should be administered into specific locations to allow for the greatest absorption [128]. The first choice is usually the abdomen, which is considered the most consistent and rapid; the posterior upper arm is the second choice and is considered fast absorbing. The anterior thigh is appropriate, but the absorption is considered slow. Lastly, the buttocks can be utilized but will result in the slowest route of absorption [141].

Injection site rotation is of significant importance due to the potential development of a scar tissue related to overuse of a particular site of injection [141]. Insulin does not absorb into scar tissue; therefore, sites with overuse injuries will be ineffective [141]. For this same reason, it is important for patients to avoid areas where there are surgical or trauma scars. No one particular site-rotation technique is preferred as long as the chosen method is performed consistently by the person responsible for the injections [128].

Hypoglycemia

The development of hypoglycemia is a concern for all individuals on an injectable therapy regimen. Education should include information regarding oral and injectable combination medication management, insulin and injectable medication management, exercise considerations, and specific patient-centered issues to maintain safe use of medications in daily life [5].

Injectable medications alone or in combination with another antihyperglycemic agent increase the potential for an adverse hypoglycemia reaction [50]. Preventative measures include not skipping meals, eating prior to exercise, and appropriately timing insulin bolus therapy [50,98].

With the greater potential for hypoglycemia reactions, caregivers or significant others will require specialized training in the preparation and administration of glucagon. The caregiver should receive instruction on how to prepare the solution. He or she should inject saline from the prefilled syringe into the vial of powdered hormone and shake to assure the complete mixing of the solution. Then the preparation may be drawn back into the syringe for injection into the upper arm, leg, or buttock [98].

Accurate and frequent SMBG is vital. Patients should report frequent blood glucose levels below 70 mg/dL to their primary care provider [144]. Communication among the entire team, including the patient, the certified diabetes educator, and the primary care provider, is an optimal approach to patient education regarding the prevention of hypoglycemia [128]. Individuals should communicate frequent and multiple episodes of hypoglycemia to their primary care provider for adjustments in basal insulin, bolus insulin, or a combination, depending on the timing of the hypoglycemic event(s). This will allow for the fine tuning of the insulin regimen, which should result in optimized glycemic control and reduction of adverse outcomes [145].

For patients on an insulin regimen, exercise can significantly increase the potential for hypoglycemia [41,146]. Education related to exercise should focus on the assessment of pre-exercise blood glucose levels and determination if additional carbohydrates are needed. The patient should have a carbohydrate source available for treatment if signs or symptoms of hypoglycemia develop. Longstanding guidelines recommend consuming 10–15 grams of carbohydrate to prevent exercise-induced hypoglycemia [147]. However, subsequent research has illustrated that carbohydrate supplementation should be individualized to the patient's type of insulin and absorptive state [148,149]. Patient education should include information about how different therapies affect timing of peak insulin levels and duration of insulin action [150]. Patients should not exercise during periods of hypoglycemia and should be advised to avoid exercise for 24 hours after an episode of hypoglycemia [151]. The risk for hypoglycemia increases as the duration or intensity of the activity increases. Patients should be advised to avoid exercise when their insulin is at peak effect. Lastly, patients should avoid injection into the muscle on which exercise will be focused. This is because as a muscle is exercised, blood flow increases the utilization of glucose transport into the skeletal muscle, leading to greater decreases in blood glucose levels [151].

Patients who have or who are suspected to have nocturnal hypoglycemia as a result of insulin therapy should monitor blood glucose levels prior to going to bed. When the blood glucose level is less than 90 mg/dL, the individual should be instructed to consume a snack that includes a carbohydrate and a protein. Specific signs and/or symptoms of nocturnal hypoglycemia should be provided, and patients should be instructed to notify the primary care provider of suspected episodes. When nocturnal hypoglycemia is suspected, patients will be required to test blood glucose levels at 3 a.m.; this will provide vital information for the primary care provider [152].

Storage Issues

As discussed, insulin and injectables should be stored in a cool place or refrigerated until the preparation is used or has expired. If the preparation becomes frozen, it should be discarded [49]. Once opened, vials should be discarded after 31 days. After a pen or cartridge is pierced for the first time, the preparation should be refrigerated [2]. Combination NPH and insulin in the pen or cartridge form should only be used for 10 to 14 days (depending on preparation) prior to replacement. Insulin lispro, insulin glargine, and insulin glulisine pen preparations can be stored at room temperature and utilized for 28 days. Lastly, insulin detemir vials or pens can be utilized for 42 days once opened [49].

20. CASE STUDIES

CASE STUDY 1

Patient W is a Native American woman, 48 years of age, who is admitted to the hospital with complaints of chest pain. She is 5 feet 6 inches tall and weighs 256 pounds; her BMI is 41.4 kg/m^2. Her vital signs are assessed; her heart rate is 122 beats per minute, regular rate and rhythm, blood pressure is 198/101 mm Hg, and oral temperature is 37.4 degrees Celsius. Her past medical history is positive for gestational diabetes with her fourth child (five years previous), bilateral arthritis of the knees, and tobacco use. Patient W denies use of recreational drugs and homeopathic pharmaceuticals, but she does admit to occasional alcohol usage, generally two beers per day on the weekend. Her family history includes diabetes, heart disease, stroke, lung cancer, and alcohol abuse. Although her electrocardiogram is negative for myocardial infarction, her stress test reveals left coronary artery ischemia. Her cardiac enzymes are negative, but other significant laboratory results include:

- Triglycerides: 250 mg/dL

- LDL: 141 mg/dL

- HDL: 22 mg/dL

- Blood urea nitrogen (BUN): 35 mg/dL

- Creatinine: 1.5 mg/dL

- Random blood glucose: 310 mg/dL

- HbA1c: 9.5% (estimated average glucose: 226 mg/dL)

- Liver function tests: Within normal limits

- eGFR: 43 mL/min/1.73 m^2

Patient W is admitted for a cardiac catheterization and further cardiac work-up. She is started on blood glucose monitoring before meals and at bedtime with weight-based insulin correction with analog (rapid-acting) insulin, a calorie-controlled cardiac diet, antihypertensive medication, a statin for lipid management, an angiotensin-converting enzyme inhibitor, and pain medications as needed for chest pain or discomfort.

On hospital day 2, Patient W has a fasting blood glucose of 210 mg/dL. She receives rapid-acting insulin coverage per weight-based protocol even though she is being prepared for cardiac catheterization in the late morning and has not eaten. At approximately 10 a.m., the patient is taken for a cardiac catheterization, which reveals a 90% blockage of the left coronary artery, and subsequently undergoes percutaneous coronary intervention (PCI). A drug-eluting stent is placed. Postprocedure, Patient W returns to her room mildly sedated with an arterial line in place and a blood glucose level of 201 mg/dL, for which she receives weight-based coverage. At 5 p.m., the patient is alert and hungry. Her arterial line is discontinued, and her blood glucose is 220 mg/dL, for which she again receives weight-based coverage. At 9 p.m., Patient W has been pain free throughout the day and is ready to sleep. Her blood glucose level is 201 mg/dL. She is given insulin and is instructed to notify the nurse of any pain, palpitations, sweating, shakiness, and/or dizziness.

On hospital day 3, Patient W awakens with a blood glucose level of 248 mg/dL. Her physician initiates basal insulin to obtain better glucose control. She is cleared for discharge by her cardiologist, but her primary care physician would prefer to monitor her glucose levels for one more day, including her two-hour postprandial level after her evening meal. Throughout the day, the following blood glucose levels are documented:

- 7 a.m.: 248 mg/dL

- 11 a.m.: 121 mg/dL

- 5 p.m.: 118 mg/dL

- 7 p.m. (two-hour postprandial): 210 mg/dL

- 9 p.m.: 178 mg/dL

The following morning, Patient W is discharged to home with a prescription for glyburide 2.5 mg twice a day for her newly diagnosed type 2 diabetes. She is also referred to an ADA-recognized education program. She receives survival skills education prior to leaving the hospital and is encouraged to contact the outpatient education center within the first week after discharge. Patient W agrees with her discharge plan and states understanding of all instructions given.

Rationale and comments : The treatment approach appears appropriate to manage Patient W's diabetes. Patient education will be extensive for this patient given the many new medications and changes associated with the PCI and her various conditions. Education specific to the glyburide should include instructions to eat meals at a consistent time (not skipping meals) and information regarding the signs, symptoms, and treatment of hypoglycemia.

At her follow-up appointment, Patient W has completed her self-management education and set personal behavior change goals for meal planning and exercise. She is demonstrating competent SMBG assessment; her fasting levels are between 140 mg/dL and 170 mg/dL, and her postprandial levels range from 160 mg/dL to 200 mg/dL. The patient's occasional two-hour postprandial readings range from 190 mg/dL to 230 mg/dL. Her fasting laboratory results are as follows:

- Fasting blood glucose: 167 mg/dL

- HbA1c: 8.6% (estimated average glucose: 200 mg/dL)

- Triglycerides: 220 mg/dL

- LDL: 110 mg/dL

- HDL: 33 mg/dL

- BUN: 35 mg/dL

- Creatinine: 1.5 mg/dL

- Liver function tests: Within normal limits

In order to improve Patient W's blood glucose control, her physician chooses to increase her glyburide to 5 mg twice a day with instruction to return for follow-up in one month to assess the efficacy of treatment. In one month, Patient W continues to have difficulties achieving optimal control on monotherapy. The decision is made to start combination therapy with pioglitazone, a TZD.

Rationale and comments : Combination therapy with a TZD is the correct choice for Patient W because her BUN and creatinine levels are too high to safely utilize metformin. Furthermore, her casual use of alcohol on the weekends can be an area of concern with the potential for liver dysfunction. Pioglitazone will address the issue of insulin resistance in the presence of the metabolic syndrome and has beneficial effects on coronary artery disease in the presence of type 2 diabetes.

Prior to leaving the physician's office, the nurse reviews the signs and symptoms of hypoglycemia with Patient W. The patient is instructed to alert her primary care physician of frequent episodes of hypoglycemia. She is also counseled regarding the need to eat meals at spaced intervals throughout the day to decrease the chances of developing hypoglycemia.

The heart failure risks associated with TZD use are discussed as well as the need to report any weight increase of 3 to 5 pounds over a two-day period to her primary care physician. Patient W is also advised to contact her primary care physician if she experiences any symptoms related to liver dysfunction/failure, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Finally, the patient is reminded of the need to monitor her liver function by venipuncture periodically while on pioglitazone.

CASE STUDY 2

Patient O is a Hispanic male, 48 years of age, with a seven-year history of type 2 diabetes. He presents to his primary care physician's office for a routine follow-up appointment to assess his diabetes control. His only complaint at the time of his appointment is an occasional burning sensation in his bilateral lower extremities.

Patient O's past medical history is positive for type 2 diabetes diagnosed at 41 years of age, hypertension for the past two years, and new onset of hyperlipidemia within the past six months. He is negative for renal disease, retinopathy, and peripheral vascular disease. The patient's family history is positive for type 2 diabetes, coronary artery disease, cerebral vascular accident, hyperlipidemia, and obesity.

During the physical assessment, Patient O is alert and oriented. His height (5 feet 10 inches), weight (239 pounds), and BMI (34.4 kg/m^2) are measured and documented. Blood pressure is 128/68 mm Hg on medications, pulse is 74 beats per minute, and oral temperature is 37 degrees Celsius. Lungs are clear to auscultation, and heart sounds are clear without rubs or murmurs. The patient's abdomen is soft and nontender at all quadrants. Peripheral pulses are present at +2 at all extremities, and feet are free from lesions with a positive Babinski reflex. All extremities are warm to touch and responsive to monofilament test.

Patient O's laboratory results include:

- HbA1c: 8.1% (estimated average glucose: 186 mg/dL)

- Fasting blood glucose: 155 mg/dL

- BUN: 24 mg/dL

- Creatinine: 1.3 mg/dL

- ALT: 16 U/L

- HDL: 31 mg/dL

- LDL: 122 mg/dL

- Triglycerides: 201 mg/dL

- Microalbuminuria: 312 mcg/mg

The patient is currently prescribed captopril 25 mg twice a day, simvastatin 40 mg daily at bedtime, metformin 1,000 mg twice per day, and glipizide extended-release 20 mg daily. He has previously met with a registered nurse certified diabetes educator and registered dietitian certified diabetes educator regarding self-care management, blood glucose monitoring, behavior change, meal planning, and goal setting. He tests his blood glucose levels twice a day at various times.

At this visit, Patient O receives the results of his blood work and has expressed concerns regarding his recent SMBG numbers and new onset of burning in his lower extremities. He presents verbalizing frustration and feeling like a failure. It is vital to actively listen to the patient regarding his frustrations and fears related to his diabetes. It is also important to educate him regarding the progressive nature of diabetes, regardless of the attentiveness a person gives to the care of the disease [2].

The nurse reviews Patient O's eating and exercise habits to see if any changes could be made to optimize control. Furthermore, sources of stress are discussed. Patient O is told that worrying about the progression of his diabetes and having anxiety regarding adherence to his meal or exercise plan is normal, but it is possible for this additional stress and anxiety to result in increased blood glucose levels [7]. Patient O states that he was unaware of the impact stress was having on his body.

Due to the continued elevated blood glucose levels, the primary care physician wants to maximize oral medication therapy, most likely by adding a DPP-4 inhibitor, an alpha-glucosidase inhibitor, or a TZD [2]. In order to make a decision regarding the most appropriate agent, each of the classes' benefits and risks should be considered with Patient O in mind. The addition of a DPP-4 inhibitor has been shown to be weight neutral, occasionally demonstrating a reduction in weight. The dose can be decreased for safe use in those individuals who have some renal impairment, such as Patient O [51]. The greatest drawback of DPP-4 inhibitor therapy is the cost.

The addition of an alpha-glucosidase inhibitor is a less expensive option and would benefit Patient O by decreasing the absorption of complex carbohydrates in the intestinal tract. The alpha-glucosidase inhibitors do have objectionable side effects, such as recurrent flatulence, that some patients are unable to tolerate [50]. Patient education needs for those taking alpha-glucosidase inhibitors include timing of medication with meals, gastrointestinal side effects, and the treatment of hypoglycemia [49,50,65].

The addition of a TZD would reduce insulin resistance and reduce cardiovascular risk factors, including markers of vascular inflammation [2]. However, precautions should be taken when this therapy is prescribed. Weight gain and liver damage are possible, and laboratory levels should be regularly monitored. Patient education regarding weight gain and shortness of breath is necessary as these are signs of impending heart failure.

The final option for Patient O would be to continue current therapy and add basal insulin. This would provide long-acting coverage to allow the metformin and extended-release glipizide to have a greater effect. This also has obstacles to acceptance, including fear of injection, fear of acute hypoglycemia, and misconceptions about insulin therapy. All therapy choices would be viable options for Patient O, and as a healthcare provider, understanding of all available agents is needed to support the final decision.

CASE STUDY 3

Patient F is a black female resident of a local long-term care facility. She is 87 years of age and has had type 2 diabetes for the past 25 years. In addition to diabetes, Patient F has a past medical history of hypertension, cardiovascular disease, peripheral neuropathy, and mild Alzheimer disease. Her son and daughter-in-law came to visit and found the patient confused, wet with foul urine, and begging for water. She had a temperature of 38.5 degrees Celsius. The family requested her transfer to the emergency department for evaluation and treatment.

Upon admission to the emergency department, Patient F is increasingly confused and combative, with a body temperature of 38.8 degrees Celsius. She is started on oxygen at 2 liters for an oxygen saturation of 88%. Laboratory samples are obtained, and an infusion of 0.9% sodium chloride is initiated at 75 mL/hour for observed signs of dehydration. The laboratory results indicate:

- Blood glucose: 1179 mg/dL

- Potassium: 5.2 mEq/L

- Phosphorus: 3.4 mmol/L

- Ketones: Minimal

- Serum osmolality: 420 mOsm/kg

- HbA1c: 11.9%

- White blood cell count: 46,000

- Urinalysis: Positive for bacteria

Based on this information, a diagnosis of HHS is made. Because HHS is characterized by profound dehydration, management is initially focused on rehydration. The physician orders an increase in the current 0.9% sodium chloride infusion to 100 mL/hour. Because there are no dysrhythmias noted on the telemetry monitor, the physician continues to monitor the potassium level with subsequent laboratory assessments. Patient F is also started on empirical antibiotic therapy for a suspected UTI until the results of urine and blood culture are known. An additional intravenous access is initiated in order to administer insulin. A regular insulin bolus of 0.1 units/kg followed by an infusion of regular insulin is ordered to run at a rate of 0.1 units/kg/hour.

Patient F's blood glucose levels slowly drop to 275 mg/dL, but her osmolality is 365 mOsm/kg and she remains confused. Because the patient's osmolality remains greater than 350 mOsm/kg and her confusion is unresolved, her blood glucose levels should be maintained between 250 mg/dL and 300 mg/dL. Her potassium level stabilizes without intravenous therapy and is currently 4.2 mEq/L. Her telemetry readings remain in sinus rhythm.

After 36 hours of therapy, Patient F has an osmolality of less than 315 mOsm/kg, and she is back to her baseline mentation. Her blood glucose level is 225 mg/dL, and she is getting prepared to transfer off of the insulin infusion.

Rationale and comments : Several considerations should be made in order to continue to achieve optimal glycemic control. The patient's HbA1c is 11.9%, which is considered uncontrolled. If a long-acting insulin is not started, the glucose levels will rebound. Also, it is vital that hydration status is maintained. Basal insulin should be given at least one hour prior to the discontinuation of the insulin infusion in order to prevent rebound hyperglycemia, which is a risk due to Patient F's continuing UTI and high HbA1c.

Patient F is maintained on 0.9% sodium chloride 75 mL/hour until adequate oral intake is established. She also starts insulin detemir 0.2 units/kg (total dose: 15 units) to be given once per day at night, which should provide weight-based coverage for correction of glucose elevations.

After three days, Patient F's HHS has been resolved, and the team is preparing the patient for discharge. However, she continues to have blood glucose levels between 280 mg/dL and 400 mg/dL.

Rationale and comments : There are several available options for Patient F. Insulin detemir may be continuously increased to desired effect and/or split to a twice daily schedule. If glycemic control is not achieved on the long-acting insulin preparation, addition of bolus insulin therapy may be necessary. Because the patient is a resident of a long-term care facility and has a history of cognitive impairment, the better option for her may be combination therapy.

To combat the consistently high blood glucose levels, Patient F's insulin detemir dose is increased to 15 units twice a day. The next day, the patient has the following glucose results: 146 mg/dL, 175 mg/dL, 188 mg/dL, and 136 mg/dL. Her primary care provider is satisfied with these readings and plans to discharge her the following day.

21. CONCLUSION

As the prevalence of diabetes increases, it is important to have a general understanding of the many options for treatment. Each of the various drug classes has specific contraindications and potential side effects, and all members of the interdisciplinary team should be involved with assessing the efficacy of the treatments and patients' quality of life. This approach is best to ensure optimal outcomes and prevention of long- and short-term complications. With the constant evolutions and advances being made in the management of diabetes, healthcare professionals should frequently review and renew their professional knowledge to ensure the care provided to diabetic patients is the most accurate and up-to-date possible.

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