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248 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation finally, deflating the distal cuff. In the upper extremity, inflate the pneumatic tourniquet to 250 to 300 mm Hg (30 to 45 kPa) or 100 mm Hg (15 kPa) above the patient’s systolic blood pressure. In the leg, cuff inflation pressures are 350 to 400 mm Hg (45 to 55 kPa). The compression bandage should be removed if used. The limb should be pale, and pulses should not be palpable. Infuse the anesthetic via the small catheter of the affected limb. Most authors recommend diluting standard 1% lidocaine with equal parts normal saline to create a 0.5% (5 milligrams/mL) solution. The amount infused varies according to physician preference in the range of 1.5 to 3.0 milligrams/kg (3 to 6 mL of the 0.5% lidocaine solution for every 10 kg of body weight). 130 Onset of anesthesia is usually within 5 minutes. If inadequate anesthesia occurs when using a minidose (1.5 milligrams/kg), infuse additional lidocaine up to 3 milligrams/kg. If adequate anesthesia is not obtained with the maximum dose of lidocaine, infuse additional normal saline to help circulate the anesthetic. The patient may report a sensation of warmth or cold, and the skin will become mottled. The smaller nerve fibers are affected first, causing a reduction in pain and temperature sensation followed by loss of touch, deep pressure, and, finally, motor function. An ideal Bier block will provide complete anesthesia and muscle relaxation, but some patients may retain varying degrees of intact touch, deep pressure sensation, and motor function. Remove the IV in the affected extremity once adequate analgesia is obtained. Many patients will describe pain or pressure at the tourniquet site, usually within 30 minutes or so. This is handled by reinflating the previously deflated distal cuff. After ensuring that the distal cuff is inflated to the proper level and will hold pressure, the proximal cuff is slowly deflated. Adjuncts, such as ketorolac 30 milligrams, dexamethasone 8 milligrams, midazolam 50 micrograms/kg, ketamine 0.5 milligram/kg, or dexmedetomidine 1 microgram/kg, mixed with the local anesthetic can also be used to control the pain of tourniquet infla tion and provide postprocedure analgesia. 134-136 The cuff should not be released until a minimum of 30 minutes after the initial lidocaine infusion. Premature release of the cuff increases the chance of systemic toxicity from the anesthetic. Upon completion of the procedure, the pneumatic tourniquet should be cycled by lower ing the cuff pressure for 5 to 10 seconds and then reinflating it for 1 to 2 minutes. This cycle should be repeated three to five times to prevent any possible bolus of anesthetic into the central circulation. Additional analgesia is usually required after completion of the procedure because anesthesia rapidly dissipates after release of the tourniquet. The patient should be monitored for approximately 30 minutes to ensure that no adverse reaction to the anesthetic has occurred. Acknowledgment: We acknowledge the contributions of Douglas C. Sillon to this chapter in the previous edition. REFERENCES The complete reference list is available online at www.TintinalliEM.com. FIGURE 36-20. Hematoma block. After careful palpation for the fracture edge, the needle is inserted directly into the hematoma, with care taken to avoid regional vessels. [Illustration used with permission of Timothy Sweeney, MD.] Procedural Sedation and Analgesia in Adults Justin G.

ble online at www.TintinalliEM.com. FIGURE 36-20. Hematoma block. After careful palpation for the fracture edge, the needle is inserted directly into the hematoma, with care taken to avoid regional vessels. [Illustration used with permission of Timothy Sweeney, MD.] Procedural Sedation and Analgesia in Adults Justin G. Myers Jennifer Kelly INTRODUCTION Procedural sedation and analgesia (PSA) for unscheduled, time-sensitive procedures is a standard practice in the ED. 1,2 The accepted defini tion and goals of PSA are “the use of anxiolytic, sedative, hypnotic, analgesic, and/or dissociative medications(s) to attenuate anxiety, pain and/or motion. These agents are administered in order to facilitate amnesia or decreased awareness and/or patient comfort and safety during a diagnostic or therapeutic procedure. ” 1-5 Levels of sedation are defined by the patient’s level of responsiveness and cardiopul monary function, not by the agents used ( Table 37-1).6 Although these are the currently accepted definitions of levels of sedation, sedation is a continuum, and responsiveness alone is not a perfect tool to judge the level of sedation. 4,7,8 By definition, patients receiving PSA do not require routine airway protection with endotracheal intubation or other airway adjuncts. This is in contrast to provision of general anesthesia, which typically requires airway protection. This chapter focuses on PSA in adults. For children, see Chapter 115, “Pain Management and Procedural Sedation in Infants and Children. ” Minimal sedation is characterized by anxiolysis but with normal or slowed responses to verbal stimuli. Minimal sedation is typically used for minor procedures that require patient cooperation and for those in which pain is controlled by local or regional anesthesia. During minimal sedation, ventilatory function is usually maintained with a low risk of hypoxia or hypoventilation. Moderate sedation is characterized by a depressed level of con sciousness and a slower but purposeful motor response to simple verbal or tactile stimuli. Patients at this level generally have their eyes CHAPTER Tintinalli_Sec05_p0229-0266.indd 248 8/2/19 6:35 PM

maintained with a low risk of hypoxia or hypoventilation. Moderate sedation is characterized by a depressed level of con sciousness and a slower but purposeful motor response to simple verbal or tactile stimuli. Patients at this level generally have their eyes CHAPTER Tintinalli_Sec05_p0229-0266.indd 248 8/2/19 6:35 PM CHAPTER 37: Procedural Sedation and Analgesia in Adults 249 CLINICAL APPROACH TO PROCEDURAL SEDATION  PROCEDURAL SEDATION NEEDS ASSESSMENT As you consider PSA for an ED procedure, consider the urgency, the depth of sedation required, and the duration needed. Is analgesia, anx iolysis, or immobility required? Do the patient’s clinical condition or comorbidities place them at higher risk of adverse events? Can sedation be avoided altogether? Alternatives to PSA include systemic analgesics, regional nerve blocks, or local anesthesia. Some patients may be better served with general anesthesia. Decisions regarding the procedural sedation plan should balance the urgency of the procedure and the likelihood of difficult complications. These decisions should be made with the patient and/or caregivers when possible, with appropriate consent. 24-26 If the situation is deemed too high-risk for ED PSA, consult anesthesiology or other specialists for assistance or sedation in the operating room. 1,27,28 A common tool for assessing the patient’s suitability for procedural sedation is the American Society of Anesthesiologists (ASA) physical status classification system (Table 37-2). 29 The risk of a significant complication from ED PSA in ASA class I and II is usually less than 5%.14,30-32 The risk of an adverse PSA event increases as the ASA classification rises, 33,34 although safe ED procedural sedation for classes III and IV has also been reported.33,35  PRE-SEDATION PATIENT EVALUATION Perform a focused history and physical examination 36 to identify a potentially difficult airway or cardiorespiratory problem. Ask about prior experiences with sedation or anesthesia, current medications, and allergies. A potentially difficult airway should be anticipated when the following findings or conditions are present: short neck, micrognathia, large tongue, trismus, morbid obesity, a history of difficult intubation, or anatomic anomalies of the airway and neck. The implications of these individual factors vary, 37-39 partially due to the weak interobserver reproducibility.40 Studies on the association between these findings and TABLE 37-1 Levels of Sedation and Analgesia Responsiveness Airway Breathing Circulation Minimal sedation (“anxiolysis”) Normal but slowed response to verbal stimulation Unaffected Unaffected Unaffected Moderate sedation Purposeful response to verbal or physical stimulation Usually maintained Usually adequate Usually maintained Dissociative sedation Trance-like state with variable responsiveness Usually maintained Usually maintained Usually maintained Deep sedation Purposeful response after repeated or painful physical stimulation May be impaired May be suppressed Usually maintained General anesthesia Not arousable, even by painful stimulation Usually requires assistance Often impaired May be impaired closed or demonstrate ptosis and respond slowly to verbal commands. Moderate sedation can be used for procedures in which patient coop eration is not necessary and muscular relaxation is desired. During moderate sedation, the patient is usually able to maintain a patent air way with adequate respirations, 9 and cardiovascular function is usually maintained.2 Dissociative sedation does not easily fit into the PSA continuum outlined in Table 37-1. Dissociation is a state of detachment from immediate surroundings, in which the cortical centers are prevented from receiving sensory stimuli.

ir way with adequate respirations, 9 and cardiovascular function is usually maintained.2 Dissociative sedation does not easily fit into the PSA continuum outlined in Table 37-1. Dissociation is a state of detachment from immediate surroundings, in which the cortical centers are prevented from receiving sensory stimuli. It is a trance-like cataleptic state characterized by profound analgesia and amnesia, with retention of protective air way reflexes, spontaneous respirations, and cardiopulmonary stability. Nonresponsiveness of dissociated patients to stimuli, even when repeated or painful, means that such patients do not fit the “moderate sedation” or “deep sedation” categories. Ketamine and nitrous oxide are the ED PSA agents characterized by dissociative sedation. Deep sedation is characterized by a profoundly depressed level of consciousness, with a purposeful motor response elicited only after repeated or painful stimuli. Deep sedation may be required with painful procedures that require muscular relaxation and patient unre sponsiveness. The risk of losing airway patency or developing hypoxia or hypoventilation is greater with deep sedation than with moderate or minimal sedation. 11 Examples of ED procedures sometimes requiring deep sedation include burn wound care and reduction of open fractures or fracture dislocations. Deep sedation generally is achieved in the ED with the same agents as moderate sedation, but with larger or more frequent doses. General anesthesia is defined as a “drug-induced loss of conscious ness during which patients are not arousable, even by painful stimu lation. The ability to independently maintain ventilatory function is often impaired. Patients often require assistance in maintaining a patent airway, and positive-pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired. ” 1,12,13 PSA SEDATION POLICIES AND GUIDELINES PSA is a multidisciplinary activity. Formation of a hospital sedation committee allows for diverse representation to create collaborative, evidence-based, institution-specific policies. 1,14 The logistics and roles for PSA at each institution should be determined in advance, allowing the ED physician the freedom to create a situationally appropriate sedation plan for each patient. 1,15 In the emergency medicine model of PSA, clinical experience indi cates that one emergency physician—providing monitoring and seda tion and performing the procedure—is as effective as two physicians, one providing monitoring and the other performing the procedure. 2,16,17 Thus, one emergency physician simultaneously administering sedation and performing the procedure with a nurse or respiratory therapist monitoring the patient is an appropriate practice. However, the physi cian must be ready to resuscitate the patient immediately. 18 Nurses who have demonstrated the appropriate competencies can safely administer procedural medications, 19-22 even in resource-limited settings. 23 Emer gency physicians and nursing leadership should conjointly develop policies regarding the scope of nursing practice in PSA sedation at their institutions.

mediately. 18 Nurses who have demonstrated the appropriate competencies can safely administer procedural medications, 19-22 even in resource-limited settings. 23 Emer gency physicians and nursing leadership should conjointly develop policies regarding the scope of nursing practice in PSA sedation at their institutions. 15,20 TABLE 37-2 American Society of Anesthesiologists (ASA) Classification System ASA Class Description Examples Class I Healthy Class II Mild systemic disease Mild asthma, pregnancy, obesity, controlled diabetes Class III Severe systemic disease Pneumonia, moderate to severe asthma, premature infant with postconceptional age <60 wk, end-stage renal disease Class IV Severe systemic disease that is a constant threat to life Sepsis, severe cardiac dysfunction, disseminated intravascular coagulation Class V Moribund and not expected to survive without surgery Massive trauma, intracranial hemorrhage with mass effect, ischemic bowel with multiple organ system dysfunction Class VI Declared brain dead whose organs are being harvested Source: asa-physical-status-classification-system.pdf (American Society of Anesthesiologists: ASA Physical Status Classification System). Retrieved May 19, 2019. Tintinalli_Sec05_p0229-0266.indd 249 8/2/19 6:35 PM

15,20 TABLE 37-2 American Society of Anesthesiologists (ASA) Classification System ASA Class Description Examples Class I Healthy Class II Mild systemic disease Mild asthma, pregnancy, obesity, controlled diabetes Class III Severe systemic disease Pneumonia, moderate to severe asthma, premature infant with postconceptional age <60 wk, end-stage renal disease Class IV Severe systemic disease that is a constant threat to life Sepsis, severe cardiac dysfunction, disseminated intravascular coagulation Class V Moribund and not expected to survive without surgery Massive trauma, intracranial hemorrhage with mass effect, ischemic bowel with multiple organ system dysfunction Class VI Declared brain dead whose organs are being harvested Source: asa-physical-status-classification-system.pdf (American Society of Anesthesiologists: ASA Physical Status Classification System). Retrieved May 19, 2019. Tintinalli_Sec05_p0229-0266.indd 249 8/2/19 6:35 PM 250 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation difficult intubation are usually done on patients going to the operating room for general anesthesia, and these findings may not be entirely relevant to the ED patient. Predisposing conditions affect the selection and dose of the seda tive agent and also the timing of the procedure. Routine laboratory studies are not necessary in otherwise healthy patients. Directed ancillary testing may be useful in patients with comorbidities or dehy dration. Ask about pregnancy in females of childbearing age, due to physiologic changes in pregnancy and the potential for fetal distress with PSA. Most sedative agents can cause vasodilatation and hypotension, particularly in patients with preexisting hypovolemia. Clinically active obstructive pulmonary disease or upper respiratory infec tions may predispose the patient to periprocedural hypoventilation or heightened airway reactivity. Drug or alcohol intoxication or reduced level of consciousness increases the risk of hypoxemia and hypoventilation. If possible, delay PSA in intoxicated patients until mental status improves. These various conditions may increase the risk of hypotension, prolonged sedation, and/or hypox emia with PSA. The ASA guidelines for fasting prior to general anesthesia are of lim ited relevance to the risk of aspiration with ED procedural sedation. Pre-procedural fasting for any duration has not demonstrated a reduc tion in the risk of emesis or aspiration.2,18,43-47 It is not necessary to delay ED PSA for time-sensitive procedures in adults or children based on fasting time. 1,2 After pre-PSA patient evaluation, discuss general PSA risks and any specific risks attendant to the particular patient (e.g., older patient with airway disease) or selected drug regimen (e.g., delayed vomiting with ketamine) with the patient and/or family. Obtain informed consent for PSA just as for any other ED procedure and with the same caveats (e.g., intoxication and patient capacity to consent).  PREPARATION OF EQUIPMENT AND SUPPLIES The sedation area should include ready access to necessary size-appropriate equipment for airway management and resuscitation: oxygen, a bagmask ventilation device, suction, oral/nasal airway(s), intubation equipment, physiologic monitoring equipment, resuscitation medications, and a defibrillator. 1,14,36 IV fluids should be initiated or readily available, particularly if the PSA regimen will include drugs (e.g., propofol) often associated with hypotension. If using an opioid, have naloxone available. For benzodiazepines, have flumazenil on hand. Other drugs include antiemetics, agents used to treat allergic reactions, and push-dose vasopressors. 1,48,49 (See later section “Rescue Medications and Reversal Agents. ”) The incidence of oxygen desaturation during ED procedural sedation without supplemental oxygen varies widely, depending on the patient and PSA agent, from 6% to 40%. 50-52 Supplemental oxygen reduces the incidence of hypoxemia50-52 and has no adverse clinical effects. However, the administration of oxygen may mask hypoventilation, since oxygen saturation can be maintained despite rising carbon dioxide (a finding that would be readily identified by capnography). 50-52  PATIENT MONITORING AND INTERVENTION The safe practice of PSA requires both interactive and physiologic monitoring.

However, the administration of oxygen may mask hypoventilation, since oxygen saturation can be maintained despite rising carbon dioxide (a finding that would be readily identified by capnography). 50-52  PATIENT MONITORING AND INTERVENTION The safe practice of PSA requires both interactive and physiologic monitoring. 1 Interactive monitoring includes direct visualization of the patient’s airway (mouth, face) and chest wall motion, chest auscultation, monitoring patient responsiveness, and providing appropriate maneu vers to maintain the patient’s airway and ventilation. 1,8,18 Physiologic monitoring includes continual tracking of arterial oxygenation, ventilation, blood pressure, and cardiac rate/rhythm.1,53 Cardiac monitoring is particularly recommended for patients with preexisting cardiac disease or dysrhythmias or during procedures such as cardioversion. Monitor arterial oxygen saturation with pulse oxime try. Pulse oximetry is not a substitute for monitoring ventilation because hypoventilation or apnea develops before oxygen saturation decreases, especially in patients who receive supplemental oxygen. 50,51,54,55 Airway repositioning and bag-valve-mask ventilation are effective and usually the only interventions required. Once PSA has begun, observe the patient until the peak effect of the initial sedative dose has been reached; with ketamine PSA, monitor until dissociation occurs. If necessary, titrate with additional medications to the desired sedation level. Once the patient has achieved the target sedation level, the actual procedure may begin. If the patient begins to regain alertness before completion of the procedure, additional sedative doses may be required. However, additional sedative doses given to extend procedural sedation are usually associated with an increased risk of respiratory depression. Depending on the agent selected, as larger cumulative doses of the drug are given, the half-life of each bolus increases. As the patient recovers from sedation, administer analgesics as needed for patient comfort. The recommended extent of monitoring is determined by the level of sedation (Table 37-3). Check patients after each dose of medication to assess the response, determine the need for further doses, and make appropriate interventions if needed. The risk of adverse events increases with deeper levels of sedation. However, targeting moderate versus deep sedation is clinically difficult and unnecessary. Fortunately, no differences in pain, satisfaction, or recollection of procedures have been reported in patients who were sedated to a moderate versus a deep level. 9,34,56 Capnography The interactive observation of ventilation may be improved through physiologic monitoring of ventilation with electronic capnography 54,55,57-59 (see Chapter 16, “Blood Gases, Pulse Oximetry, and Capnography”). The partial pressure of carbon dioxide detected at the nares during the respiratory cycle is represented by the carbon dioxide waveform (capnogram) that is displayed on a monitor ( Figure 37-1). The end-tidal carbon dioxide correlates with arterial partial pressure of carbon dioxide, so that an end-tidal carbon dioxide >50 mm Hg or an increase in end-tidal carbon dioxide >10 mm Hg indicates hypoventilation. Capnography can assess the severity of ventilatory abnormalities and the response to interventions. Most importantly, capnography can detect changes in ventilation before clinical observation.

, so that an end-tidal carbon dioxide >50 mm Hg or an increase in end-tidal carbon dioxide >10 mm Hg indicates hypoventilation. Capnography can assess the severity of ventilatory abnormalities and the response to interventions. Most importantly, capnography can detect changes in ventilation before clinical observation. 2,54,55,60 Variations in the capnogram can identify specific conditions, such as apnea, upper airway obstruction, laryngospasm, bronchospasm, and TABLE 37-3 Recommendations for Procedural Sedation and Analgesia Monitoring by Target Sedation Level Target Level of Sedation Level of Consciousness Heart Rate Respiratory Rate Blood Pressure Oxygen Saturation Capnography End-Tidal CO Minimal Observe frequently Record every 15 min Record every 15 min Record every 15 min and after sedative boluses Monitor continuously No recommendation Dissociative Observe constantly Monitor continuously Continuous direct observation Record at initiation, frequent monitoring generally unnecessary Monitor continuously Recommend continuous monitoring Moderate Observe constantly Monitor continuously Continuous direct observation Record every 5 min and after sedative boluses Monitor continuously Recommend continuous monitoring Deep Observe constantly Monitor continuously Continuous direct observation Record every 5 min and after sedative boluses Monitor continuously Recommend continuous monitoring Tintinalli_Sec05_p0229-0266.indd 250 8/2/19 6:35 PM

rd every 5 min and after sedative boluses Monitor continuously Recommend continuous monitoring Deep Observe constantly Monitor continuously Continuous direct observation Record every 5 min and after sedative boluses Monitor continuously Recommend continuous monitoring Tintinalli_Sec05_p0229-0266.indd 250 8/2/19 6:35 PM CHAPTER 37: Procedural Sedation and Analgesia in Adults 251 respiratory failure.54 A flat-line capnogram can be due to apnea, upper airway obstruction, complete laryngospasm, or faulty equipment. Nor malization of the waveform after airway alignment maneuvers (chin lift, jaw thrust, or oral airway placement) confirms that apnea was due to upper airway obstruction. As of this writing, no cases of unexpected death or hypoxic neurologic injury from ED procedural sedation have been reported, with or without capnography. 47,61,62 There is a lack of evidence that capnography use, despite being possibly associated with increased airway intervention rates, reduces the incidence of serious adverse events such as hypoxic brain injury, aspiration, or death. 60,63 However, capnography is still recommended and may improve patient mm Hg Time (sec) Begin exhalation Begin inhalation III FIGURE 37-1. Normal capnogram. Phase I: At the start of exhalation, carbon dioxide concentration in the exhaled gas is essentially zero, representing gas from the anatomic dead space that does not participate in gas exchange. Phase II: As the anatomic dead space is exhaled, carbon dioxide concentration rises as alveolar gas exits the airway. Phase III: For most of exhalation, carbon dioxide concentration is constant and reflects the concentration of carbon dioxide in alveolar gas. Phase IV: During inhalation, carbon dioxide concentration decreases to zero as atmospheric air enters the airway. [Reproduced with permission from Krauss B, Hess DR: Capnography for procedural sedation and analgesia in the emergency department. Ann Emerg Med 50: 172, 2007 (Table 1, p. 176). Copyright Elsevier.] safety by reducing mild and severe oxygen desaturations as well as the need for assisted ventilation. 2,62  DOCUMENTING PSA Vital signs (pulse, blood pressure, and respiratory rate) and oxygen saturation should be obtained and recorded before the procedure, after each dose of medication, upon completion of the procedure, at the beginning of the recovery period, and before discharge. 32,36 For minimal sedation, intermittent measurements are sufficient. For other levels of sedation, 18 assess blood pressure every 5 minutes (unnecessary for ketamine dis sociative sedation) and monitor heart rate, capnography, and pulse oximetry continuously. Predesigned documentation templates are good practice because such forms can guide providers through the procedure, improve documentation quality, 64 and facilitate quality auditing for PSArelated events.65  PRE-PROCEDURAL ANALGESICS It may be necessary to give a short-acting opioid, such as fentanyl (often at doses of 1 to 2 micrograms/kg), 66 for pain control before the start of a procedure. If an opioid is to be used, it is best to initiate and titrate early to attain pain relief peak effect. 67 Delay the start of the procedure until after the peak effect of the opioid has been reached (2 to 3 minutes for IV fentanyl) to minimize the risk of respiratory depression and apnea. It may be unnecessary to await pain control by opioids if analgesia will be provided by the PSA regimen. Ketamine alone or in combination with propofol (ketofol) provides analgesia while avoiding concomitant use of opioids. 18,67,68 A further review of ketamine-based regimens will be discussed later in the chapter.

ea. It may be unnecessary to await pain control by opioids if analgesia will be provided by the PSA regimen. Ketamine alone or in combination with propofol (ketofol) provides analgesia while avoiding concomitant use of opioids. 18,67,68 A further review of ketamine-based regimens will be discussed later in the chapter. (See Chapter 35, “ Acute Pain Management, ” for further discussion.)  SELECTION AND DOSING OF PROCEDURAL SEDATION AGENTS Select the most appropriate agents for the PSA, taking into account the type and length of the procedure, the patient’s age and comorbidities, the sedation target level, and potential for adverse events during sedation. (See Table 37-4 and section titled “ Agents for Procedural Sedation. ”) TABLE 37-4 Agents for Procedural Sedation in Adults.68–105 Times May Vary With Different Dosing (Continued) Agent Recommended IV Dose Average Onset of Action Average Effective Action Advantages/Ideal Procedures Disadvantages/Side Effects Propofol 0.5–1.0 milligram/kg (elderly: 0.25–0.5 milligram/kg) Repeat dosing: 0.25–0.5 milligram/kg 10–50 s <10 min Rapid onset, short duration of action; good agent for orthopedic reductions Does not provide analgesia, may cause respiratory depression (increased risk in elderly patients), may burn on injection; lidocaine added to syringe can decrease pain (see discussion below) Ketamine 1.0–1.5 milligrams/kg (give over 30–60 s) Repeat dosing: 0.5–1.0 milligram/kg For analgesia only (subdissociative dose): 0.1–0.3 milligram/kg (same repeat doses as initial dose) 30–40 s 5–10 min Provides sedation, analgesia, cardiorespiratory stability; may be safer if comorbid conditions; may be useful for longer procedures; useful for patients at risk for bronchospasm Emergence reaction, vomiting, cardiac stimulation may increase blood pressure, heart rate, and cardiac output; rare muscle hypertonicity/rigidity; avoid in psychotic or schizophrenic patients; respiratory depression with rapid IV bolus push Etomidate 0.1–0.2 milligram/kg Repeat dosing: 0.05 milligram/kg 10–20 s 2–3 min for 0.15 milligram/kg dose min Minimal cardiovascular and respiratory depression; ideal for shorter procedures, cardioversion Myoclonus, adrenal suppression in critically ill Ketamine + propofol (“single syringe” ketofol, 1:1)

10–50 s <10 min Rapid onset, short duration of action; good agent for orthopedic reductions Does not provide analgesia, may cause respiratory depression (increased risk in elderly patients), may burn on injection; lidocaine added to syringe can decrease pain (see discussion below) Ketamine 1.0–1.5 milligrams/kg (give over 30–60 s) Repeat dosing: 0.5–1.0 milligram/kg For analgesia only (subdissociative dose): 0.1–0.3 milligram/kg (same repeat doses as initial dose) 30–40 s 5–10 min Provides sedation, analgesia, cardiorespiratory stability; may be safer if comorbid conditions; may be useful for longer procedures; useful for patients at risk for bronchospasm Emergence reaction, vomiting, cardiac stimulation may increase blood pressure, heart rate, and cardiac output; rare muscle hypertonicity/rigidity; avoid in psychotic or schizophrenic patients; respiratory depression with rapid IV bolus push Etomidate 0.1–0.2 milligram/kg Repeat dosing: 0.05 milligram/kg 10–20 s 2–3 min for 0.15 milligram/kg dose min Minimal cardiovascular and respiratory depression; ideal for shorter procedures, cardioversion Myoclonus, adrenal suppression in critically ill Ketamine + propofol (“single syringe” ketofol, 1:1) Same total milligram dose for two agents together as when using single agent alone (ie, 1:1 = 0.5 milligram/kg of ketamine + 0.5 milligram/kg of propofol) <1 min <10 min Ketamine adds analgesia without opioids; ketamine component blunts propofol-induced hypotension; combination good for prolonged procedures Higher ketamine:propofol ratios lead to longer recovery; do not reduce clinically important adverse events; while not harmful, objective benefits have mixed evidence (Continued) Tintinalli_Sec05_p0229-0266.indd 251 8/2/19 6:35 PM 252 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation TABLE 37-4 Agents for Procedural Sedation in Adults.68–105 Times May Vary With Different Dosing (Continued) Agent Recommended IV Dose Average Onset of Action Average Effective Action Advantages/Ideal Procedures Disadvantages/Side Effects Midazolam 1–2.5 milligrams; 0.5 milligram in elderly 0.1 milligram/kg; 0.05 milligram/ kg in elderly Repeat dosing: 0.5–2.5 milligrams; can repeat every 2–3 min (longer interval for elderly) 3–5 min 30–80 min Preferable for longer procedures requiring deep sedation

252 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation TABLE 37-4 Agents for Procedural Sedation in Adults.68–105 Times May Vary With Different Dosing (Continued) Agent Recommended IV Dose Average Onset of Action Average Effective Action Advantages/Ideal Procedures Disadvantages/Side Effects Midazolam 1–2.5 milligrams; 0.5 milligram in elderly 0.1 milligram/kg; 0.05 milligram/ kg in elderly Repeat dosing: 0.5–2.5 milligrams; can repeat every 2–3 min (longer interval for elderly) 3–5 min 30–80 min Preferable for longer procedures requiring deep sedation Provides no analgesia (must be combined with analgesic if pain reduction is desired) Increased cardiovascular and respiratory depression when combined with opioids Fentanyl 0.5–1.5 micrograms/kg; start with 0.25 microgram/kg in elderly Repeat dose: 0.5–1.5 micrograms/ kg, can repeat every 1–3 min (longer between-dose intervals are recommended if larger initial doses are given) Effect in 1–2 min 30–60 min Given in combination with sedatives that lack analgesic properties; monotherapy may be used for minimal sedation Monotherapy for moderate or deep sedation will not provide adequate sedation/amnestic effects Respiratory depression Alfentanil 10 micrograms/kg; decrease dose in elderly Repeat dose: 10 micrograms/kg; decrease dose in elderly Effect in <1 min 7–9 min Fast onset, short duration of action Studied for moderate sedation alone or in combination with propofol Increased risk of apnea Remifentanil 0.16 microgram/kg/min infusion 1 microgram/kg bolus; decrease dose in elderly Repeat dose (when using bolus dosing): 0.5 microgram/kg; decrease dose in elderly Nearly immediate 3–10 min Fast onset, short duration of action Does not rely on renal or hepatic function for metabolism or clearance Studied for moderate sedation alone or in combination with propofol Poor muscle relaxation Increased risk of apnea Dexmedetomidine 1 microgram/kg over 10 min, then maintenance infusion of 0.6 microgram/kg/h (range, 0.2–1.0 micrograms/kg/h) 4–5 min 45–90 min Potentially useful when cooperation is required or in a patient experiencing respiratory depression with opioids Hypotension (common); longer readiness to discharge; limited evidence for adults in ED setting Nitrous oxide 50%/50% mixture with oxygen self-administered by patient through a mask Repeat dosing: when needed Immediate Seconds

45–90 min Potentially useful when cooperation is required or in a patient experiencing respiratory depression with opioids Hypotension (common); longer readiness to discharge; limited evidence for adults in ED setting Nitrous oxide 50%/50% mixture with oxygen self-administered by patient through a mask Repeat dosing: when needed Immediate Seconds Mild anesthetic, strong analgesic, causes euphoria, anxiolytic Nearly immediate onset and recovery Ideal procedures: dressing changes, lumbar punctures, wound closure, vein puncture, IV placement, urine catheterization, gastric tube placement Risk for occupational exposure; should be given in well-ventilated room with scavenging system; potential for abuse by staff Methohexital 0.75–1.5 milligrams/kg Repeat dosing: 0.5 milligram/kg every 2–5 min <1 min <10 min Short procedures requiring moderate to deep sedation

Mild anesthetic, strong analgesic, causes euphoria, anxiolytic Nearly immediate onset and recovery Ideal procedures: dressing changes, lumbar punctures, wound closure, vein puncture, IV placement, urine catheterization, gastric tube placement Risk for occupational exposure; should be given in well-ventilated room with scavenging system; potential for abuse by staff Methohexital 0.75–1.5 milligrams/kg Repeat dosing: 0.5 milligram/kg every 2–5 min <1 min <10 min Short procedures requiring moderate to deep sedation Respiratory depression (common) 87; myocardial depressant; avoid in hemodynamically unstable patients Data adapted from Rahman, N.70 References for table: 68–105.  COMPLETION OF PROCEDURAL SEDATION At the completion of sedation and the procedure, patients should be monitored until they return to their baseline mental status and car diopulmonary function. A structured assessment, such as the Aldrete Score ©,107 can be used to assess the patient’s recovery and safety for discharge. Such assessment tools are typically part of procedural sedation documentation forms. The duration of observation before terminating monitoring or dis charge is variable. It depends on the quantity of sedatives given, the patient’s response, the duration of the procedure, and the occurrence of any adverse events. Generally, patients who have returned to a baseline level of consciousness are unlikely to have further negative changes in level of consciousness. Most adverse events occur during procedural sedation itself, typically within a few minutes of sedative administration. The occurrence of major adverse events >5 minutes after completion of the procedure is rare (<1%). 108 The occurrence of life-threatening adverse events after discharge of an ED patient who has undergone procedural sedation has not been reported. Patients should be instructed to return if they develop respiratory complaints or nausea or repetitive vomiting. The follow-up interval required for patients who undergo ED procedural sedation is usually related to the procedure rather than the sedation. AGENTS FOR PROCEDURAL SEDATION  PROPOFOL Propofol is a safe and efficacious medication for providing moderate and deep procedural sedation in the ED. 2,18,34,71,109-114 Predictable, ultra-rapid Tintinalli_Sec05_p0229-0266.indd 252 8/2/19 6:35 PM

al sedation is usually related to the procedure rather than the sedation. AGENTS FOR PROCEDURAL SEDATION  PROPOFOL Propofol is a safe and efficacious medication for providing moderate and deep procedural sedation in the ED. 2,18,34,71,109-114 Predictable, ultra-rapid Tintinalli_Sec05_p0229-0266.indd 252 8/2/19 6:35 PM CHAPTER 37: Procedural Sedation and Analgesia in Adults 253 onset; short duration of action; and the combined effects of sedation, amnesia, and muscle relaxation render propofol an excellent choice for most procedures requiring moderate or deep sedation in the ED.2,18,56,71,109,115-118 Because the most serious adverse effects of propofol are rapidly developing respiratory depression and apnea, 44,119 have ventilatory support equipment at the bedside. Propofol can produce hypotension as a result of both negative inotropy and vasodilatation. Hypotension is more common in hypovolemic patients and those with ASA physi cal status scores of III or IV . 81 Correct hypovolemia before propofol administration. Sedation from propofol occurs within 30 to 60 seconds after injection and lasts for about 5 to 6 minutes. Propofol is rapidly distributed into tissues, and once tissues are saturated, subsequent doses will have a greater effect than the initial bolus. The recommended dose for ED procedural sedation in healthy nonelderly adults is 0.5 to 1.0 milligram/kg IV , followed by 0.5 milligram/kg IV every 3 minutes if needed. Higher doses are associated with more respiratory depression. Exercise caution with subsequent doses, because repeat dosing can lead to variable depths of sedation and prolonged duration of action. 18 In elderly patients, use 50% lower doses (0.25 to 0.5 milligram/kg) and titrate more slowly. (See section titled “Dosing Considerations in Special Populations”). Propofol target-controlled infusion, an alternative to bolus dosing, is executed using a targeted plasma concentration from a loading dose (based on volume of distribution and targeted drug concentration), which is followed by a decreasing rate of infusion. Propofol targetcontrolled infusion may be a safer route of delivery and is undergoing further study for ED sedation. 120-122 Propofol Safety With Soy and Egg Allergies Propofol was previously considered contraindicated for patients allergic to eggs or soy protein. The contraindication was based on case reports of possible allergy and also on theoretical risk based on propofol’s formulation with soybean oil, glycerol, and egg lecithin emulsion. 123 However, during the manufacture and formulation of the soybean oil and egg lecithin in propofol, clinically significant allergy-mediating proteins are likely removed. 124 Furthermore, propofol has been administered safely to patients with soy, egg, and peanut allergies.125-128 The American Academy of Allergy, Asthma, and Immunology supports the safety of propofol in patients with soy and egg allergies, and recent emergency medicine practice guidelines state that propofol’s only true immunologic contraindication is an allergy to the drug itself. 18,129 Pain on Injection Propofol may cause local pain at the IV site during administration. Suggested methods to reduce propofol infusion burning include pretreating the injection-site vein with lidocaine or mixing the lidocaine with the initial propofol injection. With pretreatment, a tour niquet is placed proximal to the injection-site vein and 0.5 milligram/kg of lidocaine is injected approximately 60 seconds prior to propofol infusion. When the alternative method of combining lidocaine with the initial propofol dose is used, add 0.5 to 1.0 milligram/kg of lidocaine to the first bolus of propofol.

tour niquet is placed proximal to the injection-site vein and 0.5 milligram/kg of lidocaine is injected approximately 60 seconds prior to propofol infusion. When the alternative method of combining lidocaine with the initial propofol dose is used, add 0.5 to 1.0 milligram/kg of lidocaine to the first bolus of propofol. 130,131  KETAMINE Ketamine produces a state of dissociation, or detachment from immediate surroundings, characterized by profound analgesia, sedation, and amnesia. Unlike other agents used for procedural sedation, ketamine possesses both analgesic and anxiolytic properties. 10 Ketamine is an effective agent for ED and prehospital PSA and is safe and versatile.10,132-136 Ketamine is a derivative of the drug phencyclidine and is an N-methyl-d-aspartate glutamate receptor antagonist. It exerts its effects through a wide range of spinal and cortical pathways via dopamine, norepinephrine, serotonin, and opioid receptor antagonism. 137-139 Reported psychotropic effects of ketamine include hallucinations, synesthesia, pronounced derealization and depersonalization, a “detachment from the body, ” and a preoccupation with unimportant sounds. 140 At higher doses, users have described being “lost in the K-hole, ” a term used for the pronounced depersonalization or “out of body” experience, perceptions that can be quite frightening to patients. 139,141 Ketamine does not have a typical dose-response continuum with progressive titration. At low doses, between 0.1 and 0.3 milligram/kg, analgesia and minimal sedation occur. 142-149 Low-dose ketamine for minimal sedation or analgesia is a reasonable choice either with or without opioids. 142-149 Side effects, such as dizziness or psychoperceptual disturbances, are seen with higher doses (see below) and may also occur during emergence. 150,151 Other side effects to be prepared for when using ketamine are increased muscle tone, clonus, or the rare case of sudden muscle rigidity, which can be alleviated with midazolam. Once a critical dosing threshold is exceeded (about 1.0 to 1.5 milligrams/ kg IV or 3 to 4 milligrams/kg IM), ketamine’s characteristic dissocia tive state abruptly appears. This dissociation has no observable levels of depth. The only value of additional ketamine is to prolong the dis sociative state for extended procedures. Ketamine can be given either IV or IM. The IM route allows for approximately 40 minutes of sedation, compared with 10 minutes by the IV route. Ketamine preserves a patient’s ventilatory effort and has mini mal depressant effect on blood pressure. However, ketamine can cause transient apnea (approximately 20 seconds), particularly when administered rapidly IV . 101,150,153,154 Ketamine Emergence Reactions and Other Effects Emergence reactions after ketamine range from mild agitation to nightmares and hallucinations. 134,155 Midazolam or propofol can be given along with ketamine to minimize the development of emergence reactions. 155,156 In one study, coadministered IV midazolam in adults (0.03 milligram/ kg IV) who were receiving IV ketamine (1.5 milligrams/kg) reduced recovery agitation by about 4% without an increase in respiratory events. 156 A single dose of propofol (30 to 40 milligrams for adults younger than age 50 years, with lower doses in older adults), given when distressing symptoms are recognized, has anecdotally been reported to reduce the incidence and severity of emergence reactions, hyperten sion, and muscle rigidity. 157 Further evidence of propofol’s mitigation of ketamine-associated recovery agitation is supported by the finding that ketofol produces fewer emergence reactions than ketamine alone. 158 It is sufficient to give ketamine without midazolam or propofol and then treat patients who develop emergence reactions with midazolam as they occur.

ce of propofol’s mitigation of ketamine-associated recovery agitation is supported by the finding that ketofol produces fewer emergence reactions than ketamine alone. 158 It is sufficient to give ketamine without midazolam or propofol and then treat patients who develop emergence reactions with midazolam as they occur. It is also reasonable to coadminister a dose of 0.03 milligram/kg of midazolam when ketamine is used in adults, both to reduce risk of emergence reactions and also to potentially reduce chances of postpro cedural vomiting. Because of the possibility of emergence reactions, do not use ketamine in patients with schizophrenia and psychosis. Anorexia, nausea, and vomiting have been reported with ketamine use in approximately 5% to 15% of patients. 10 However, these effects are not normally severe, with most patients able to drink shortly after regaining consciousness. 159 Emesis typically occurs during the recovery phase when the patient is alert and can clear his or her airway. 10 Consider using an antiemetic when using ketamine for PSA. Ketamine induces a hypersympathetic state, leading to hyperten sion and an increase in intraocular pressure. Blood pressure eleva tions begin shortly following administration, reaching peak levels in a few minutes. Blood pressure typically returns to preanesthetic levels 15 minutes following administration of the last dose. 159 Systolic and diastolic pressures typically peak at 10% to 50% above preanesthetic levels. However, elevations may be higher or last longer in individual cases. For this reason, avoid ketamine in patients in whom a signifi cant elevation in blood pressure would constitute a serious hazard (e.g., coronary artery disease) . 69,159 Increases in intraocular pressure with ketamine are minimal, 159 but the evidence for use of ketamine in patients with acute globe injury or glaucoma is inconclusive. 10,69 There is some evidence that the hypersympathetic state resulting from ketamine administration may be more profound in patients with por phyria and thyroid disorders. Although rare, hypersalivation and bronchorrhea have been reported with ketamine administration through the stimulation of tracheobronchial secretions. 10,69 Be prepared to suction patients with respiratory tract concerns and those with an impaired ability to mobi lize secretions. 10 Glycopyrrolate or atropine can be given to blunt this effect, but these drugs are not routinely or prophylactically recommended because they are associated with significantly more airway and respiratory events. 10,69 It is historically stated that ketamine increases intracranial pressure (ICP), limiting its use in emergent situations.160,161 The experimental data from animal studies and human observations are conflicting, depending Tintinalli_Sec05_p0229-0266.indd 253 8/2/19 6:35 PM

icantly more airway and respiratory events. 10,69 It is historically stated that ketamine increases intracranial pressure (ICP), limiting its use in emergent situations.160,161 The experimental data from animal studies and human observations are conflicting, depending Tintinalli_Sec05_p0229-0266.indd 253 8/2/19 6:35 PM 254 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation on the specific circumstances. 160,161 However, prospective controlled data in patients with brain injury and ICP monitoring demonstrate that ketamine does not increase ICP (it may actually decrease ICP), and the drug blunts adverse ICP response to stimulation. 162 At least two systematic reviews since 2014 have concluded that there is no evidence to support concerns that ketamine has an adverse ICP effect. 163,164 Experts in the use of ketamine in the ED have concluded that in the absence of hydrocephalus, there is no evidence to support concerns about ketamine and adverse ICP effect. 165 The weight of available evidence, including expert opinion, favors use of ketamine without concerns over ICP when the drug is otherwise the correct choice for PSA. Thus, there is no clear evidence that ketamine is harmful as an induction or sedation agent in patients with a potential head injury if it is the appropriate sedative choice based on other considerations. There are growing reports of successful use of ketamine in resourcelimited settings including the prehospital environment. 166-168 In austere settings, ketamine can facilitate procedures such as fracture splinting, chest tube placement, extrication, and field amputations. 169-172  ETOMIDATE Etomidate is a unique nonbarbiturate sedative-hypnotic agent with minimal side effects, a rapid onset, and short duration of action. 92,95,173 It is an excellent tool for clinicians and is frequently used for rapid-sequence intubation (RSI) in the ED. 69 The recommended dose for etomidate in procedural sedation is 0.1 to 0.2 milligram/kg,69,90,92,95,100,173 with optional repeat doses of 0.05 milligram/kg administered every 3 to 5 minutes. 173 Etomidate has an onset of less than 1 minute and a duration of 4 to 15 minutes. 69,90,92,95,100,173 When compared with propofol for procedural sedation, etomidate appears equally effective at achieving deep sedation and enabling suc cessful procedure completion (89% with etomidate, 97% with propofol). Respiratory adverse event rates appear similar between the two drugs. Propofol results in more hypotension, whereas etomidate results in more myoclonus. When compared with midazolam use for shoulder reduction, etomi date PSA has similar rates of successful reductions. However, patients experienced faster recovery rates when receiving etomidate (10 minutes) as compared to midazolam (23 minutes). Etomidate is typically well tolerated and has a uniquely neutral car diovascular profile when compared to other PSA sedatives. Its minimal hemodynamic effects, combined with a short duration of action, make etomidate an excellent agent for procedures such as cardioversion. Etomidate’s short duration of action makes it an unfavorable choice for procedures requiring a longer duration of sedation. Etomidate is characterized by two issues, adrenocortical suppression and myoclonus, that are not commonly seen with other PSA agents. Etomidate’s known effect of adrenocortical suppression has long been a source of controversy. 69,95,175 Even one dose of etomidate has been associated with lowering of cortisol levels after surgery, but without adverse outcomes. 176 Many surveys, emergency RSI series, and expert editorials worldwide have highlighted the high frequency with which etomidate is endorsed for use in stable or unstable patients, including patients with sepsis or trauma.

has been associated with lowering of cortisol levels after surgery, but without adverse outcomes. 176 Many surveys, emergency RSI series, and expert editorials worldwide have highlighted the high frequency with which etomidate is endorsed for use in stable or unstable patients, including patients with sepsis or trauma. 177-180 However, a 2018 survey of emergency medicine physicians and anesthesiologists identified the etomidate issue as “significant and not adequately resolved. ” 181 Fortunately, septic patients, the group for which there is the most support for risk due to etomidate’s adrenocortical axis effects, 180 are infrequent candidates for ED PSA. Myoclonus is sufficiently frequent (seen to some degree in up to half or more of patients receiving the drug 182) that PSA planning with etomidate should account for the side effect. Myoclonus is likely due to subcortical disinhibition. Pretreatment with midazolam, suggested for over a decade as effectively blocking disinhibition, can reduce the inci dence and severity of myoclonus. 182 Depending on situational characteristics related to the patient and procedure, PSA using etomidate may be accompanied by pretreatment with midazolam in a 1- to 2-milligram IV dose for adults. Other etomidate side effects include emergence nausea and vomit ing (up to 40% of patients), which can be severe and interfere with the procedure being performed. 2,69,90,95,173,174 Consider coadministration of an antiemetic when etomidate is being used for PSA.  KETAMINE AND PROPOFOL (KETOFOL) The combination of ketamine and propofol for ED procedural sedation has a well-documented safety and efficacy profile. 66,73,158,183-190 Propofol is an excellent sedative, but respiratory depression and hypotension are important adverse events. In addition to providing analgesia (which propofol does not), ketamine coadministration may mitigate propofol’s respiratory and hemodynamic depression. In turn, the adverse events associated with ketamine (vomiting and emergence reactions) can be mitigated by propofol’s antiemetic and hypnotic properties. The “ketofol” combination is safe and effective for ED PSA. 66,73,158,183,185,186,188-190 Published ketofol ED procedural sedation stud ies have used a variety of combinations, from equal mixtures of propofol and ketamine to normal doses of propofol with subdissociative doses of ketamine (used for analgesia only). Adding ketamine to propofol promotes hemodynamic stability, which is reassuring in patients with known or potentially reduced cardiac function. 73 There is also evidence of synergism between the two drugs; data indicate that as compared to propofol alone, ketofol provides improved, less erratic sedation. 187,191,192 The analgesic properties of ketamine preclude the need for (and risks of) opioids that are administered with propofol. 66,73,193 Most studies to date have failed to demonstrate a consistent differ ence in complications between ketofol (mixtures of ketamine and pro pofol from 1:1 to 1:4) compared with propofol alone. 189,191 However, a meta-analysis of five randomized controlled trials published between 1990 and 2017 found that, as compared to propofol alone, ketofol was associated with fewer respiratory adverse events. 193 Editorial ists assessing the ketofol evidence base have also concluded that the combination agent is arguably preferable (as compared to propofol or ketamine alone) in patients with risk of hypotension; propofol alone risks hemodynamic depression, and ketamine alone risks recovery agitation. Another advantage of ketofol is that it may be able to achieve adequate sedation with lower total doses, as compared with either propofol or ketamine used alone.

to propofol or ketamine alone) in patients with risk of hypotension; propofol alone risks hemodynamic depression, and ketamine alone risks recovery agitation. Another advantage of ketofol is that it may be able to achieve adequate sedation with lower total doses, as compared with either propofol or ketamine used alone. Ketofol prolongs the duration of sedation beyond that expected with propofol alone; this may reduce the need for repeat propofol boluses and be useful for procedures anticipated to take more time.  MIDAZOLAM Benzodiazepines have amnestic, anxiolytic, and sedative properties. Midazolam is the preferred agent in this drug class because of its rapid onset, short duration of action, and ability to be given via multiple routes (IV , IM, intranasal, and PO). 69,96 Midazolam is not an analgesic, so the drug is often combined with analgesics such as fentanyl or ketamine. 69,103 The combina tions of midazolam/ketamine and midazolam/fentanyl have both been found to be effective for ED orthopedic procedures, although there was more hypotension seen in the midazolam/fentanyl group. When compared to combination propofol/fentanyl PSA, midazolam/ fentanyl combination therapy is equally efficacious (although with longer recovery time). 71,104 Recommended dosing for midazolam in procedural sedation is 1 to 2.5 milligrams given as a slow IV push. Weight-based dosing of 0.1 milligram/kg has also been evaluated, but these larger doses (e.g., 7 milligrams in a 70-kg adult) have more adverse effects. 103,104 Titrate midazolam slowly, with the dose repeated every 2 to 5 minutes. 69,96,105 The onset of action is 1 to 3 minutes, with peak effect seen in 3 to 5 minutes. The duration of sedation correlates linearly with the amount of drug administered, with sedation times reported to be as long as 17 to 80 minutes. 69,96,105,195 The IV route is preferred because other administration routes are subject to erratic absorption and corresponding delayed onset.86 Common side effects include hypotension, hypoventilation, and hypoxia. These effects are exacerbated when midazolam is combined with other medications such as opioids. Tintinalli_Sec05_p0229-0266.indd 254 8/2/19 6:35 PM

use other administration routes are subject to erratic absorption and corresponding delayed onset.86 Common side effects include hypotension, hypoventilation, and hypoxia. These effects are exacerbated when midazolam is combined with other medications such as opioids. Tintinalli_Sec05_p0229-0266.indd 254 8/2/19 6:35 PM CHAPTER 37: Procedural Sedation and Analgesia in Adults 255  SYNTHETIC OPIOIDS Synthetic opioids, such as fentanyl, alfentanil, sufentanil, and remifentanil, have a role in procedural sedation as both monotherapy and in combination with sedative agents. Opioids alone may be sufficient in procedures where deep levels of sedation are not required.74 The analgesia provided by the opioid complements the sedation and amnesia (which is not expected with opioids) provided by the sedative. 79,196 Synthetic opioids are rapid-acting opioids and are the preferred analgesics for PSA. Their pharmacokinetic profiles make them eas ily titratable and offer advantages over other common opioids such as morphine. As compared to fentanyl, for instance, morphine and hydromorphone have longer times to onset, longer durations of action, and higher incidences of emesis and are associated with more hemodynamic effects. 79,196 Fentanyl is a synthetic opioid 50 to 100 times as potent as morphine.91 Fentanyl has become the analgesic of choice for PSA in the ED. It is highly lipophilic, which results in a very rapid onset of action (typically 1 to 2 minutes) and a short duration of action (30 to 60 minutes). 91,97 Dosing for fentanyl is recommended to start at 0.5 to 1.5 micrograms/kg in most patients (with a 0.25 microgram/kg lower dose in elderly patients) and can be repeated every 1 to 3 minutes. 79,91,97 Although typically not associated with hypotension and respiratory depression when used as monotherapy, fentanyl can cause these effects in certain patient populations; the incidence of hemodynamic or ventilatory depression is higher when fentanyl is used in combination with sedatives. 18,67,69 Alfentanil and remifentanil are ultra-short-acting opioids that have been used for the induction of moderate sedation. As compared to fentanyl, alfentanil is one-fourth as potent, has one-third the duration, and exerts a more rapid onset of sedation. 93,98 The recommended dose for alfentanil in PSA is 10 micrograms/kg, with an expected duration of sedation of 7 to 9 minutes. 74 Alfentanil has been studied as both mono therapy and in combination with propofol for moderate sedation. When used for ED PSA, alfentanil and propofol have similar major airway and respiratory adverse events, but alfentanil has higher rates of reported pain and patient recall of the procedure. 74-76 Sufentanil is more lipid soluble than either fentanyl or alfentanil. Its onset is rapid, and its half-life falls between that of fentanyl and alfen tanil. Although used primarily for analgesia, sufentanil (by infusion) is useful for intensive care sedation. 197 There are few data reporting on acute care sufentanil use, and the drug’s potential role in ED PSA remains to be seen. Remifentanil offers some pharmacokinetic advantages over both alfentanil and fentanyl. Its onset of action is nearly immediate, and its recovery time is equally rapid. It is metabolized by plasma esterase in the blood and therefore does not rely on hepatic metabolism, as do fentanyl and alfentanil. 91,94,97,98,198 This allows for fast clearance and recovery, even in the setting of organ dysfunction, comorbidities, or advanced age. 199 Due to the pharmacokinetics of remifentanil, it is typically administered as a continuous infusion. A study evaluating remifentanil given as a continuous infusion in the ED found efficacy in short, painful procedures using a dose of 0.16 microgram/kg/min.

etting of organ dysfunction, comorbidities, or advanced age. 199 Due to the pharmacokinetics of remifentanil, it is typically administered as a continuous infusion. A study evaluating remifentanil given as a continuous infusion in the ED found efficacy in short, painful procedures using a dose of 0.16 microgram/kg/min. Multiple trials have evaluated bolus dosing of remifentanil for procedural sedation in the ED in adult patients.78,79,200 In one study,78 remifentanil 1 microgram/kg was combined with propofol 0.5 milligram/kg with rescue doses of 0.5 microgram/kg and 0.25 milligram/kg, respectively. This regimen was found to have equal efficacy and a faster recovery when compared to the combination of midazolam/morphine. Another study compared monotherapy of remifentanil to the combination of propofol and fentanyl for anterior shoulder reductions. 79 In this study, the bolus dose for remifentanil was 1 microgram/kg with a 0.5 microgram/kg rescue dose. The results showed equal efficacy for pain management when compared to propofol/fentanyl for shoulder reduction. However, as compared to the other agents, remifentanil demonstrated a lower success rate in muscle relaxation as well as a significantly higher rate of apnea. Rigid Chest Syndrome A rare side effect of synthetic opioids is skel etal muscle rigidity, which primarily affects the chest and abdominal muscles. Chest wall rigidity decreases chest wall compliance and may result in the inability to effectively ventilate. 201 Although the exact mechanism is unknown, skeletal muscle rigidity is related to both the dose and rate of administration. 94,98,201 Chest wall rigidity has been reported with low doses of synthetic opioids. However, the rigid chest syndrome is predictably seen only with high doses (exceeding 3 to 5 micrograms/kg of fentanyl, 130 micrograms/kg of alfentanil, and >1 microgram/kg of remifentanil), particularly if given by rapid IV push. 91,93,94,97,201 To prevent this complication, administer synthetic opioids in multiple low doses, each by slow IV push, rather than rapidly administering them as a single large dose. If chest wall rigidity occurs, stop administration. The use of concur rent propofol or thiopental may attenuate the rigidity, and naloxone has been occasionally reported to be of use. 201 In rare cases, administration of a neuromuscular blocker (e.g., succinylcholine) and intubation may be required. 94,97,98  LESS COMMONLY USED AGENTS The medications previously discussed in this chapter demonstrate suit able pharmacodynamics and evidence for procedural sedation and have optimized the care patients receive. As with many older drugs, a gap of evidence develops over time comparing older to newer agents. 85 Despite an evidence base that may be more limited than that addressing some of the medications discussed earlier, these drugs remain plausible agents for adult procedural sedation in the ED. 69,85,86 Dexmedetomidine Dexmedetomidine achieved U.S. Food and Drug Administration approval for procedural sedation in 2003. 202 It can provide sedation without respiratory depression.203,204 It has not been extensively studied in the ED. Some emergency medicine investigators have found high rates of hemodynamic compromise with dexmedetomidine use in the ED, and there are insufficient data to currently support a recommendation for its routine use for ED PSA. Dexmedetomidine is an α 2-adenoreceptor agonist and possesses sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, with minimal respiratory depression. 82,202 It exerts its anxiolytic and sedative properties by reducing sympathetic tone.

currently support a recommendation for its routine use for ED PSA. Dexmedetomidine is an α 2-adenoreceptor agonist and possesses sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, with minimal respiratory depression. 82,202 It exerts its anxiolytic and sedative properties by reducing sympathetic tone. The sedative effects are reversible: The patient can be easily roused to a lucid state with stimulation, and then can fall back into a state similar to natural sleep when stimulation is removed. The degree of sedation is dose dependent, with effects ranging from minimal to deep sedation. 82,83 The U.S. Food and Drug Administration approved dose for dexme detomidine in procedural sedation is a 1 µg/kg loading dose given over 10 minutes followed by a maintenance infusion of 0.6 microgram/kg/h. It can then be titrated to clinical effect with a dosing range of 0.2 to 1 microgram/kg/h. 82,83,202 Although clinical trials have not studied bolus dosing in the setting of ED PSA, case reports have demonstrated success using bolus dosing of dexmedetomidine 1 to 2 micrograms/kg for shoulder reductions. 84 Intranasal administration may also be effective, but the long time to peak sedation (20 to 30 minutes) and long duration of sedation (45 to 90 minutes) limit intranasal dexmedetomidine use in the ED.205 Dexmedetomidine has moderately slow pharmacokinetics compared with other agents used for procedural sedation.83 It is hepatically cleared, so elimination may be affected with hepatic impairment.202 The half-life is relatively short at 6 minutes.89,202 However, time to sedation following a bolus dose is typically longer at 4 to 5 minutes. 84 When compared to propofol (in pediatric patients), dexmedetomidine was found to have longer time to recovery. 80 Even during recovery, patients may be drowsy when not stimulated.83 Dexmedetomidine does not directly impair respiratory drive, but it may alter respiratory responses to hypoxia and hypercapnia. This effect can be more profound when given concomitantly with other sedatives or opioids. Hemodynamic effects include hypertension, hypotension, and bradycardia as a result of vasoconstriction, sympatholysis, and baroreflex-mediated parasympathetic activation. 82,99,202 Nitrous Oxide Nitrous oxide (N 2O) is one of the oldest drugs still used in medicine and remains the fastest “in/out” anesthetic drug in use today. 85 It possesses mild anesthetic, dissociative, and muscle relax ant properties. N2O works by stabilizing axonal membranes to partially inhibit action potentials, leading to sedation. Its analgesic properties are similar to morphine through its action on opiate receptor systems. 85,99 Tintinalli_Sec05_p0229-0266.indd 255 8/2/19 6:35 PM

mild anesthetic, dissociative, and muscle relax ant properties. N2O works by stabilizing axonal membranes to partially inhibit action potentials, leading to sedation. Its analgesic properties are similar to morphine through its action on opiate receptor systems. 85,99 Tintinalli_Sec05_p0229-0266.indd 255 8/2/19 6:35 PM 256 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation N2O has been used in the ED for mildly painful procedures, includ ing dressing changes, lumbar punctures, wound closure, vein puncture, IV placement, urine catheterization, and gastric tube placement. 85 It does not work well for orthopedic procedures. It does not provide adequate analgesia or sedation for procedures of moderate to severe pain intensity. There is also an issue surrounding occupational N 2O exposure for staff administering the medication. Administer in well-ventilated areas with scavenger systems available to minimize risk to staff. 85,86 Because of the euphoria induced by N 2O, there is a high potential for abuse in healthcare workers.86 N2O is typically administered as a 50%/50% mixture with oxygen through a mask. Patients can self-administer the medication through the mask provided. 85 N2O use in adult patients in the ED has been criticized due to difficulties with administration and a lack of recent evidence. However, N 2O may see increased utilization in the prehospital setting based on evidence of efficacy in prehospital acute traumatic pain relief and improved delivery systems. Barbiturates Barbiturates have intermittently had a role in PSA. Barbiturates work by depressing the sensory cortex, decreasing motor activity, and altering cerebellar function. These actions produce drowsiness, sedation, and hypnosis. Of the barbiturates, methohexital is the best drug for adult ED procedural sedation. 69,86 Methohexital’s overall risk profile renders it an unusual agent for IV ED PSA, but it remains a viable choice in selected circumstances. Methohexital is an ultra-short-acting barbiturate that provides sedation while leaving airway protective measures intact. It does not deposit in fat tissue to the extent of other barbiturates, resulting in faster clearance. Older ED PSA trials demonstrated some potential utility for methohexital but with concerns for respiratory depression. The usual IV dose range is 0.75 to 1.5 milligrams/kg; additional doses of 0.5 milligrams/kg can be given every 2 to 5 minutes as needed. 86-88 The time to onset is less than 1 minute, and sedation typically lasts less than 10 minutes. 86,87 One report of IV methohexital reported the drug potentially use ful for adult PSA in a trial in which a mean dose of 88 milligrams was used. Apnea requiring bag-valve-mask ventilation was noted in 10.5% of cases. 88 Another older series of methohexital use for ED orthopedic procedures reported that methohexital (mean dose of 1.4 milligrams/kg) facilitated PSA in 81% of patients; 20.2% had complications, mainly respiratory depression and vomiting. Methohexital has a direct myocardial depressive effect, which can decrease blood pressure with a compensatory rise in heart rate. For this reason, it should be avoided in hemodynamically unstable patients. ED PSA expert reviews caution that adding methohexital to opioids increases risk of respiratory depression. 86 As compared to propofol when used for orthopedic sedation, methohexital exhibited similar rates of recall, sedation, pain relief, satisfaction, and time to return of baseline mental status. DOSING CONSIDERATIONS IN SPECIAL POPULATIONS  OBESITY Obesity remains a widespread problem, and clinicians should be aware that the physiologic changes associated with obesity can affect the dis tribution, clearance, and binding of many medications.

n relief, satisfaction, and time to return of baseline mental status. DOSING CONSIDERATIONS IN SPECIAL POPULATIONS  OBESITY Obesity remains a widespread problem, and clinicians should be aware that the physiologic changes associated with obesity can affect the dis tribution, clearance, and binding of many medications. 209 This includes many sedatives and analgesics, which are highly fat soluble, and obese patients exhibit marked changes in clearance and volume of distribution. There is no consensus or ED evidence on the optimal dosing strategy based on body habitus. Despite an absence of data directly addressing PSA drug dosing in obese ED patients, clinical decisions may be informed by pharma cokinetic drug properties and data extrapolated from the anesthesia evidence base. 210 Standardized dosing equations used to modify dosing weight are detailed in Table 37-5.211 Propofol is highly lipophilic and distributes rapidly to the tissues from the plasma.212 Data from morbidly obese subjects undergoing anesthesia induction have shown a similar response to doses based on lean body weight as lean control subjects who received doses based on total body weight. 213 Additionally, studies evaluating procedural sedation in children with obesity revealed that children could be successfully sedated with less propofol on a per-weight basis compared with children of normal weight, suggesting that dosing propofol by ideal body weight is an appropriate strategy. Etomidate, ketamine, and synthetic opioids such as fentanyl possess very similar pharmacodynamic properties to propofol, because they are also highly lipophilic and protein bound. 211,214 Anesthesia studies evaluating etomidate in obese patients have found that using lean body weight and ideal body weight was equally as effective as using total body weight. 211,214 Pharmacokinetic data for fentanyl in morbidly obese patients found a correlation between clearance of fentanyl and lean body weight, concluding that dosing should be based on lean body weight. Ketamine has not been thoroughly investigated in obesity. However, based on its lipophilicity and large volume of distribution, ketamine is recommended (in the anesthesia literature) to be dosed based on ideal body weight. 211,215 Benzodiazepines, while similarly lipophilic as the other sedative agents used in procedural sedation, have a volume of distribution that correlates with excess fat tissue. When single IV boluses are given, regardless of which benzodiazepine is used, the dose should be increased in proportion with total body weight . 195,209 Integration of pharmacokinetic data from non-ED settings should potentially inform, but not dictate, EM PSA. Many other factors besides body habitus influence drug dosing. In balancing a common-sense approach of sound pharmacology and practice based on EM evidence, two recommendations can be made. First, scale the dose based on ideal body weight or lean body weight for propofol, fentanyl, etomidate, and ketamine in obese patients. Second, benzodiazepines should be dosed based on total body weight. 209-211,213,214  ELDERLY, UNDERWEIGHT, AND COMORBID CONDITIONS Patient age, weight, and comorbidities can have marked effects on the pharmacokinetics of anesthetics. Changes in cardiac output, total blood volume, and alterations of plasma protein binding can affect peak plasma concentrations, metabolism, and elimination half-life. In addition, elderly patients may demonstrate a low physiologic reserve, potentially leading to increased adverse event rates. 216 It is prudent for a clinician to consider patient-specific factors when choosing the appro priate drug and dose in procedural sedation. Elderly and underweight individuals can have a more profound response to anesthetic agents.

nstrate a low physiologic reserve, potentially leading to increased adverse event rates. 216 It is prudent for a clinician to consider patient-specific factors when choosing the appro priate drug and dose in procedural sedation. Elderly and underweight individuals can have a more profound response to anesthetic agents. This is largely due to a small central compartment and a lower body fat percentage. 217 Medications such as propofol, ketamine, benzodiazepines, etomidate, and fentanyl are highly lipophilic with large volumes of distribution. In situa tions where there is less fat mass and therefore a smaller peripheral compartment, larger quantities of drugs remain in the serum and are available to cross the blood–brain barrier. 210 This can be further exacerbated by hypoalbuminemia as many anesthetics are highly protein bound. 95,97,159,195,212 ED studies evaluating propofol in elderly patients recommend using half the dose recommended in healthy adults (0.5 milligrams/kg with additional doses of 0.25 milligrams/kg as needed). 18,216,217 Although TABLE 37-5 Standardized Dosing Equations in Obesity Total body weight (TBW) Measured body weight (kg) Ideal body weight (IBW) Men (kg) = 50 + (2.3 [height (in.) – 60]) Women (kg) = 45.5 + (2.3 [height (in.) – 60]) Lean body weight (LBW) Men (kg) = (9270 × TBW)/[6680 + (216 × BMI)] Women (kg) = (9270 × TBW)/[8780 + (244 × BMI)] Body mass index (BMI) Weight (kg)/height (m) Source: Modified with permission from Willis S, Bordelon GJ, Rana MV. Perioperative pharmacologic considerations in obesity. Anesthesiol Clin 2017 Jun;35(2):247-257. Copyright Elsevier. Tintinalli_Sec05_p0229-0266.indd 256 8/2/19 6:35 PM

) = (9270 × TBW)/[8780 + (244 × BMI)] Body mass index (BMI) Weight (kg)/height (m) Source: Modified with permission from Willis S, Bordelon GJ, Rana MV. Perioperative pharmacologic considerations in obesity. Anesthesiol Clin 2017 Jun;35(2):247-257. Copyright Elsevier. Tintinalli_Sec05_p0229-0266.indd 256 8/2/19 6:35 PM CHAPTER 37: Procedural Sedation and Analgesia in Adults 257 guiding ED data are sparse, the lower dosing may be prudent for medi cations (e.g., fentanyl, ketamine) with pharmacokinetics similar to those of propofol.97,159 Etomidate has demonstrated higher free serum levels in the setting of cirrhosis, renal failure, and advanced age. However, a study specifically evaluating its use in elderly patients found similar efficacy and adverse event rates as seen in young, healthy patients receiving the same dose (average dose 0.14 milligram/kg for both groups). 100 Elderly patients between the age of 75 and 101 years old have been safely sedated for procedures in the ED. The volume of distribution for midazolam fluctuates in patients with advanced age, obesity, congestive heart failure, hepatic impairment, and renal failure. It also has decreased clearance in patients with cirrho sis. 96,195 It may be preferred to choose another agent over midazolam in these patient populations. If midazolam is to be used, lower initial doses of 0.5 to 1.5 milligrams should be administered, repeat doses should not exceed 1 milligram, and more time should be allowed between repeat doses (at least 3 to 5 minutes) when titrating to the desired level of sedation. Total doses in these patient populations typically do not exceed 3.5 milligrams. 96,195  PREGNANCY Pregnant woman present unique challenges in PSA. Maternal physi ologic changes impact functional residual capacity, oxygen consump tion, and ventilatory compensation. Pregnant women may develop hypotension when placed in the supine position due to aortocaval compression from a gravid uterus. 42 See Chapter 99, “Comorbid Disorders in Pregnancy, ” Chapter 256, “Trauma in Pregnancy, ” and Chapter 25, “Resuscitation in Pregnancy, ” for detailed discussions of the physiologic changes in pregnancy that would affect PSA in pregnancy. Acute fracture/dislocations, sprains, and severe open wounds are examples of situations that may require PSA for effective treatment. Unfortunately, there is no specific evidence base to specifically guide PSA in pregnancy. None of the medications discussed below have been studied in well-controlled trials to evaluate their use in preg nancy. Because of this, use medications for PSA only when clearly indicated. If possible, consult with obstetrics or obstetrical anesthesia to help determine the best PSA agent. However, such consultation may not be available in real emergencies or in rural, low-resource, or commu nity settings. Although no specific recommendations exist for PSA in pregnancy, the following information regarding monitoring and drug selection provides a guide for how to proceed. The adage “the best maternal care is the best fetal care” applies. Fol low the general principles of patient evaluation and monitoring for PSA. Discuss risks and benefits. Maternal vital sign monitoring, including capnography; fetal tocodynamometry or, if not available, intermittent fetal heart tone auscultation; maintenance of maternal oxygenation and ventilation; and fluid resuscitation are mainstays of treatment. Exposure to PSA medication is typically brief, and the exact effects of these medications in pregnancy are unknown. Rapid-acting, short duration of action synthetic opioids such as remifentanil or fentanyl are not considered to be human teratogens. They cross the placenta but should be rapidly metabolized by the fetus.

Exposure to PSA medication is typically brief, and the exact effects of these medications in pregnancy are unknown. Rapid-acting, short duration of action synthetic opioids such as remifentanil or fentanyl are not considered to be human teratogens. They cross the placenta but should be rapidly metabolized by the fetus. 94,97 Propofol is not considered a teratogen and is considered safe in pregnancy, but is associated with maternal hypotension. 212 However, propofol reportedly dilates fetal placental blood vessels and maintains umbilical blood flow. 42 This likely mitigates some of the hypotensive effects on the fetus. Administer pre-PSA fluids to minimize hypotension asso ciated with propofol. Neonatal depression may occur from propofol used close to delivery. 212 There are no human data about the teratoge nicity of ketamine, and therefore, its use cannot be recommended. 159 Additionally, ketamine can increase blood pressure and therefore is not a good choice in hypertensive pregnant women or those with eclampsia or preeclampsia. Neonatal depression can occur if ket amine is given close to delivery. Effects on uterine contractility are reported as variable. 42 Nitrous oxide and methohexital appear to be safe in pregnancy when exposure is short, like that seen in PSA. 206,207 There is no data regarding the use of etomidate in pregnancy, so its use is not recommended at this time. 95,195 Although medications such as N 2O and methohexital have shown no teratogenic effects in ani mals, the results are not always predictive of human response. 206,207,212 RESCUE MEDICATIONS AND REVERSAL AGENTS All sedatives and analgesics used for procedural sedation carry some risk of transient hypotension. 218 Although the prevalence is highest with propofol, blood pressure drops can be seen even with drugs such as ketamine and etomidate (which are typically viewed as hemodynamically neutral). 18 For any drug reducing sympathetic outflow, hemodynamic depression will be more likely and more profound in a volume-depleted patient. For patients with a history of dehydration, blood loss, or a pro longed fasting state, the clinician should optimize volume status before sedation. Most incidents of transient hypotension associated with ED PSA can be easily reversed with an infusion of crystalloid; sequalae are rare. 18 If a fluid bolus is inadequate or contraindicated, bolus-dose vasopressors, often referred to as “push-dose pressors, ” can be considered. Push-dose pressors are administered in a titratable fashion, with incremental dos ing by manual, intermittent, slow IV push from a syringe. Dosing can be repeated according to patient response. 48 Preferred agents for short-lived hypotension are phenylephrine and epinephrine.48,49 Phenylephrine is a pure vasoconstrictor through agonism of α 1adrenergic receptors. The onset of effect is less than 1 minute. Duration of effect can be up to 20 minutes but is typically less than 5 minutes. 49,219 The recommended dose of phenylephrine is 40 to 200 micrograms (0.5 to 2 mL based on a 40 to 50 micrograms/mL concentration) given every 1 to 5 minutes. 48,49,219 Epinephrine causes both vasoconstriction and inotropy through its effects on both α- and β-adrenergic receptors. Epinephrine’s β activity may render the drug preferable to phenylephrine in patients benefiting from an increase in heart rate and cardiac output. The onset of effect is less than 1 minute, with a duration of less than 10 minutes. 49,220 The recommended dose is 5 to 20 micrograms (0.5 to 2 mL based on a 10 micrograms/mL concentration) every 1 to 5 minutes. Push-dose pressors have a role in increasing patient safety in ED PSA.

ase in heart rate and cardiac output. The onset of effect is less than 1 minute, with a duration of less than 10 minutes. 49,220 The recommended dose is 5 to 20 micrograms (0.5 to 2 mL based on a 10 micrograms/mL concentration) every 1 to 5 minutes. Push-dose pressors have a role in increasing patient safety in ED PSA. However, because some of the dosing will be less familiar to EM clinicians, meticulous attention must be paid to confirming proper drug administration. Mixing and dosing should be done carefully because high doses (such as those used in resuscitation) can lead to malignant hypertension, dysrhythmias, and cardiac arrest. 48,49 Flumazenil and naloxone are the two most commonly discussed pharmacologic reversal agents with PSA applicability. 97,195 In ED PSA, both of these agents should be readily available.102 However, routine use is not encouraged. 69 Reasons for this are based on practical consider ations if the reversal agents work. A PSA patient receiving naloxone may pose pain control challenges, and flumazenil administration can pre cipitate seizures in patients chronically exposed to benzodiazepines. 69,195 Reversal agents should be used only when there is concern for a major complication, such as aspiration, need for intubation, or cardiovascular decompensation. If the situation allows, when reversal agents are used in the setting of PSA, use these drugs at the lower end of the effective range. Dosing for naloxone is 0.1 to 0.4 milligram IV , with peak effect seen after 2 to 3 minutes. The dosing for flumazenil is 0.2 milligram IV , and its peak effect is seen in 6 to 10 minutes. Effects of both agents should last 45 to 60 minutes, but be vigilant for possible recurrent sedation as early as 20 minutes after giving reversal drugs. COMPLICATIONS OF ED PSA A 2016 meta-analysis evaluated 55 studies with 9652 procedural sedations. 47 Rates of adverse events with ED PSA are quite low, and there have been no known deaths reported. 16,216,218,221-223 Prior single studies reported complication rates between 2.3% and 11%. 16,216,221-223 However, pooled complication rates from 25 randomized controlled trials found rates of adverse events between 0% and 8.7%; adverse event Tintinalli_Sec05_p0229-0266.indd 257 8/2/19 6:35 PM

no known deaths reported. 16,216,218,221-223 Prior single studies reported complication rates between 2.3% and 11%. 16,216,221-223 However, pooled complication rates from 25 randomized controlled trials found rates of adverse events between 0% and 8.7%; adverse event Tintinalli_Sec05_p0229-0266.indd 257 8/2/19 6:35 PM 258 SECTION 5: Analgesia, Anesthesia, and Procedural Sedation rates were even lower (0% to 4%) when all 55 studies were included 47 (Table 37-6). Most ED PSA complications can be categorized as minor adverse events. These include sedation to a deeper level than intended, agita tion, transient hypoxia, hypotension, or emesis. Factors associated with an increased rate of complications include age >65 years, 35,221,223 level of sedation, 222,223 premedication with fentanyl, 223 use of shortacting agents, and sedation for a procedure (as compared to imaging). Analgesia performed at night may be another risk factor for adverse events; this is likely due to PSA being administered by inexperienced providers. Serious adverse events include the need for assisted ventilation, endotracheal intubation, or treatment of hypotension or cardiac dys rhythmias. In pooled analysis, serious adverse events requiring emer gent intervention were rare and included one case of aspiration (out of 2370 sedations), one case of laryngospasm (out of 883 sedations), and two intubations (out of 3636 sedations). 47 Although drug-specific content (i.e., particular risks associated with the planned PSA approach in a given case) should constitute the main basis for PSA discussions with patients, the pooled-review data can inform conversations about general ED PSA risks, benefits, and alternatives. The estimated incidences of adverse events per 1000 procedural sedations are shown in Table 37-6. Failure to successfully complete a procedure during ED procedural sedation occurs in about 5% of patients and is more common with cer tain joint reductions (hips, mandibles) and with increased patient body weight >100 kg. These overarching summary data for ED PSA success and complications are based on the best available data, but data are heterogenous due to variation in individual study approaches and even definition of important terms such as respiratory depression. Further research and multicenter collaboration are underway to standardize adverse event definitions and reporting, and these endeavors will improve quality monitoring and patient safety in ED PSA. 3,5,225-227 COMMON PROCEDURAL SEDATION ERRORS IN THE ED  CHOOSING THE WRONG DRUG FOR THE PROCEDURE All sedatives and analgesics offer different benefits and have different side effect profiles. 105 For example, propofol offers excellent muscle relaxation and may be a preferred option for a joint reduction, but etomidate’s hemodynamic profile may translate into preference for this drug in a patient in whom there is significant concern for hypotension. On the other hand, etomidate’s myoclonus may render the drug suboptimal for procedures (e.g., lumbar puncture, fine suturing) for which patient immobility is important (Table 37-4). TABLE 37-6 Estimated Rate of Adverse Events in ED Procedural Sedation Agent No. of Studies/No.

ere is significant concern for hypotension. On the other hand, etomidate’s myoclonus may render the drug suboptimal for procedures (e.g., lumbar puncture, fine suturing) for which patient immobility is important (Table 37-4). TABLE 37-6 Estimated Rate of Adverse Events in ED Procedural Sedation Agent No. of Studies/No. of Sedations Estimate per 1000 Sedations Approximate % of All Sedations Agent with Most Frequent Adverse Event Agitation 33/6631 9.8 1% Ketamine, ketamine/propofol Apnea 22/3264 12.4 1% Midazolam, midazolam/opioid Aspiration 10/2370 1.2 0.1% Propofol and fentanyl (n = 1) Bradycardia 5/837 6.5 0.5% Etomidate, midazolam/opioid Hypotension 27/5801 15.2 2% Propofol, midazolam/opioid Hypoxia 42/7116 40.2 4% Propofol, midazolam/opioid Intubation 19/3636 1.6 0.2% Laryngospasm 5/883 4.2 0.4% Ketamine (n = 1) Vomiting 25/3319 16.4 2% Ketamine Source: Table adapted from Bellolio et al 47 and Rezaie.225  CHOOSING THE WRONG DOSE FOR THE PATIENT A patient’s age, weight, and comorbidities will impact response to medications. Account for these factors in PSA drug selection and dosing. 105 In particular, elderly patients have a lower physiologic reserve and have more profound effects to sedation; consider empirically decreasing sedation doses and titrate based on patient response. (See section titled “Dosing Considerations in Special Populations. ”) 18,210,216,217,228  NOT BEING PREPARED Prepare for procedural sedation by ensuring the right people, equip ment, and drugs are in the room. ED PSA safety is enhanced when there is ready availability of airway equipment, IV fluids, and situationally indicated rescue or reversal drugs. 2,228  NOT USING CAPNOGRAPHY End-tidal carbon dioxide monitoring is a low-cost, minimally invasive, easily used tool allowing early recognition of hypoventilation. Capnog raphy provides earlier indication of respiratory depression than either pulse oximetry or physical assessment. The presence of a waveform may provide more utility than pulse oximetry alone in determining respira tory status. 67,102,218,228,229  NOT OPTIMIZING FLUIDS Any sedative or analgesic can cause hypotension in volume-depleted patients due to decreased sympathetic outflow and blocking of com pensatory mechanisms. 18 Volume status should be corrected prior to ED PSA if this is feasible. In most cases (ketamine IM sedation being a noteworthy exception), IV access is necessary for ED PSA, and crystal loids should be readily available.  AGGRESSIVE USE OF THE BAG-VALVE MASK During PSA, hypoventilation is likely due to airway and ventilation issues. Repositioning the patient, performing a chin lift or jaw thrust, or suctioning may be adequate. Bag-valve mask may be used to facilitate ventilation while awaiting medication clearance. However, bag-valve mask carries a risk of vomiting and aspiration (in nonparalyzed, nonintubated PSA cases) and thus should be employed only when necessary for oxygenation and ventilation. 67,228 Acknowledgments: The authors would like to thank Chris Weaver and Andrew Beckman for previous work on this chapter. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec05_p0229-0266.indd 258 8/2/19 6:35 PM