#40953: Moderate Sedation

The history should elicit the following information [7,11,28]:

Abnormalities of Major Organ Systems

Because most medications used for sedation/analgesia may result in respiratory depression, the risk for sedation-related complications may be increased for patients with a history of pulmonary disease, such as emphysema or asthma [6]. A history of cardiovascular disease may also increase the risk of complications [6]. In addition, determining if there is a history of liver disease is important, as most sedation/analgesia medications are hepatically metabolized [6]. Patients with renal disease may require further evaluation to determine the safety of administering some drugs that are excreted in the urine (e.g., benzodiazepines, opioid metabolites) [6]. Patients who have a history of seizure disorders treated with benzodiazepines should be identified, as a reversal agent may invoke a seizure [6]. Lastly, thyroid disease can affect the medication dose needed for adequate sedation [6].

History of Substance Abuse

The use of sedation/analgesia medications is typically safe for people with a history of substance abuse [6]. However, in some instances, the medication may have little effect and a patient may become combative or uncooperative during sedation [6]. The physician performing the procedure should be alerted to a history of substance abuse so a plan can be developed to address these issues, should they occur [6].

History of Stridor, Snoring, or Sleep Apnea

A history of stridor, snoring, or sleep apnea may make airway management difficult, as sedatives and analgesics alter normal respiratory responses to obstruction and apnea [42]. The ASA no longer recommends general anesthesia rather than moderate sedation for patients with obstructive sleep apnea who have a procedure involving the upper airway (such as upper endoscopy or bronchoscopy) [42]. If moderate sedation is used, capnography is recommended for monitoring during moderate sedation due to the risk of undetected airway obstruction. If deeper sedation is necessary for patients with obstructive sleep apnea, general anesthesia is recommended. Despite the presumed higher risk of cardiorespiratory complications, studies have shown that, in people who have endoscopy with moderate sedation, the rate of such complications does not differ between patients with or at high risk for obstructive sleep apnea and patients without or at low risk for sleep apnea [43,44,45].

Presence and Location of Any Piercings

Some piercings may need to be removed if it is thought that they will compromise patient safety. For example, a tongue piercing can become dislodged in the oral cavity, a piercing close to the procedure site may be a source of infection, or a piercing may be at risk for snagging on a surgical drape or monitoring leads [6].

Medication History

A clinician should document all medications—prescription and over-the-counter—that the patient currently takes. Many medications have the potential to interact with drugs used for sedation/analgesia or pose risks during invasive procedures (Table 7) [6]. Herbal and dietary supplements may also increase the risk for sedation-related or procedure-related risks, making it necessary to ask patients specifically about the use of such supplements. The use of herbal and dietary supplements is relatively common, with more than 55 million people taking them; however, less than half (about 45%) disclose the use of supplements to their healthcare provider [46]. The use of supplements is common before ambulatory surgery. In one study, nearly 43% of patients took a complementary or alternative medication in the two weeks preceding an ambulatory surgical procedure; approximately 20% of the patients took a supplement that inhibited coagulation, 14% took one that had cardiac effects, and 8% took one that had sedative effects [47]. This use is of particular concern because most supplements should be discontinued for one to two weeks before moderate sedation because of potential implications, including anticoagulation, cardiovascular, and sedative effects [6].

Time and Nature of Last Oral Intake

The ASA Committee on Standards and Practice Parameters notes that fasting before administration of moderate sedation decreases risks during sedation and recommends that patients who are to have sedation/analgesia for an elective procedure should not drink clear fluids for at least two hours or eat solid foods (a light meal) for at least six hours before the procedure [48]. However, meeting fasting requirements in the emergency department is difficult; one study showed that 70% of patients who had sedation in the emergency department had not been fasting [49]. Guidelines note that when urgent or emergent procedures must be done, recent food intake is not a contraindication for administering procedural sedation/analgesia in adults or children [7,11,13,30]. The potential risks of sedation without fasting (e.g., aspiration) must be weighed against the benefit of performing the procedure promptly [7,13]. In addition, the potential for aspiration must be considered in determining the target level of sedation, whether the procedure should be delayed, and whether intubation should be done to protect the trachea [7,11]. The ACEP states that sedation may be safely given to children and adolescents who have not fasted (level B recommendation) [7,30].

The focus of the physical examination should be on vital signs, auscultation of the heart and lungs, baseline level of consciousness, and evaluation of the airway, with attention paid to anatomic features that may affect administration of sedation [11]. For example, substantial obesity (especially involving the neck and face), limited neck extension, cervical spine disease or trauma, mouth opening of less than 3 cm in an adult, and malocclusion of the jaw are all factors that may be associated with difficulty in airway management in the event of respiratory compromise during the procedure [11]. In addition, the patient's overall health should be classified according to the ASA physical status classification (Table 8) [50].

The prevention and management of complications requires that physicians be able to accurately identify patients at high risk [6]. The primary patient-related factors associated with complications include obesity, chronic obstructive pulmonary disease, coronary artery disease, chronic renal failure, drug addiction, and age (children and individuals older than 65 years), and measures should be carried out to prevent complications in patients with these factors (Table 9) [6,13].

ASA physical status is also a high-risk factor. As noted, the AGA Institute and the ASGE state that the use of an anesthesia professional should be "strongly considered" for endoscopy on patients who have an ASA physical status of IV or V [28,31]. The AAP encourages clinicians to consult with an anesthesiologist for children with an ASA class of III or IV and for children with special needs, anatomic airway abnormalities, or moderate-to-severe tonsillar hypertrophy [13].

The guidelines agree that routine laboratory or other diagnostic testing is not needed before moderate sedation [7,11,31]. However, if the results of testing may affect the management of sedation, such testing should be done before the patient is sedated [7,11,31].

The ASA and AGA Institute guidelines note that the risks, benefits, and limitations of moderate sedation, as well as possible alternatives (no sedation), should be discussed with patients, enabling them to make an informed decision [11,28]. For patients who are minors or legally incompetent adults, informed consent should be provided by a legal guardian [11]. The informed consent discussion should include risks after the procedure (e.g., related to vigorous exercise, use of alcohol, operation of heavy equipment) and should also confirm the availability of a competent adult to take the patient home after the procedure [28].

The AGA Institute notes that the endoscopist should discuss sedation as a distinct topic, in addition to the procedure, with separate documentation. The ASA also advocates for separate documentation of informed consent for sedation [28]. Ideally, sedation should be initially discussed at some point before the day of the endoscopic procedure to provide the patient with the best options and more flexibility in declining sedation [28].

The ACEP notes that verbal or written informed consent should be obtained in the emergency department [51]. Use of moderate sedation in the emergency department is often used for patients who have a limited ability to understand risks and benefits of treatment options because of age, pain, anxiety, or altered mental status; thus, implied consent may be appropriate according to institutional and departmental guidelines.

The results of all elements of the preprocedure assessment should be clearly documented before sedation is started. Vital signs (i.e., blood pressure, heart rate, temperature) should also be recorded as baseline measures, and the patient's level of consciousness should be evaluated and documented before the initiation of sedation [7,13,28,51]. In addition, the patient's name, birth date, and procedure should be confirmed prior to initiating sedation [11,13,51].

Because the history and informed consent are vital components of the preprocedure process and integral to patient safety and satisfaction, effective communication is key. This can be challenging with patients who have low literacy, low health literacy, and/or a native language and cultural context different from that of the clinician. According to the National Assessment of Health Literacy, 14% of individuals in the United States have "below basic" health literacy, which means they lack the ability to understand health information and make informed healthcare decisions [52,53]. Earlier studies indicated that as many as 26% of patients have inadequate health literacy, with an additional 20% having marginal health literacy [52,53,54]. More recently, two studies of patients in urban emergency departments showed that nearly 16% to 25% of patients had limited health literacy [55,56]. Health literacy varies widely according to race/ethnicity, level of education, and gender, and clinicians are often unaware of the literacy level of patients and their families [55,56,57,58]. Only 12% of American adults have a health literacy considered "proficient," while more than 33% (more than 80 million people) have difficulty with simple health tasks, such as following the directions of a prescription and adhering to a standardized childhood immunization schedule chart [52]. Ensuring that patients understand is essential, as limited health literacy has been associated with poor health outcomes [59].

Given these data, among the most important factors for effective communication are knowledge of the language preference of the patient; an awareness of the patient's health literacy level; and an understanding of and respect for the patient's and family's cultural values, beliefs, and practices (referred to as cultural competency) [57]. These issues are significant, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data, 21.5% of the American population speak a language other than English, and of those, 39.0% speak English less than "very well" [60]. The clinician taking the history or discussing the procedure for informed consent should ask the patient what language is spoken at home and what language he or she prefers for medical care information, as some patients prefer their native language even though they have said they can understand and discuss medical information in English [61]. When the healthcare professional and the patient speak different languages, the use of family members and/or friends as interpreters should be avoided if possible, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [62]. Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (e.g., untrained staff members, family members, friends) facilitates a broader understanding, leads to better outcomes, and is better aligned with patient preferences [63,64,65]. Clinicians should also check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [62].

Several instruments are available to test the health literacy level, and they vary in the amount of time needed to administer and the reliability in identifying low literacy. Among these is the Newest Vital Sign (NVS), an instrument named to promote the assessment of health literacy as part of the overall routine patient evaluation [66]. The NVS takes fewer than three minutes to administer, has correlated well with more extensive literacy tests, and has performed moderately well at identifying limited literacy [57,58]. Two questions have also been found to perform moderately well in identifying patients with inadequate or marginal literacy: "How confident are you in filling out medical forms by yourself?" and "How often do you have someone help you read health information?" [57]. Clinicians should adapt their discussions and educational resources to the patient's and family's identified health literacy level and degree of language proficiency and should also provide culturally appropriate and translated educational materials when possible.

The patient's level of consciousness should be evaluated and documented throughout the procedure to ensure that the patient is able to control his or her airway to take deep breaths if necessary [7,11,13]. Although several scales and scoring systems have been developed to describe the level of consciousness, none is ideal. One recommended tool is the Modified Observer's Assessment of Alertness/Sedation Scale (Table 10) [28,69]. The patient's response to verbal commands should be monitored routinely, except for patients who are unable to respond (e.g., very young children, mentally impaired individuals) or during procedures in which the lack of patient movement is essential [7,11]. For situations in which a verbal response is not possible (such as upper endoscopy), the patient and the clinician who is monitoring should determine hand signals before sedation is administered.

A noninvasive method of assessing the level of consciousness is bispectral index (BIS) monitoring, which has been used since the mid-1990s in the setting of general anesthesia. BIS records electroencephalographic (EEG) waveforms from a probe adhered to the forehead, and the EEG recording is analyzed with an algorithm to generate a score on a scale of 0 to 100. EEG activity is a sensitive measure of sedation, with a low-amplitude, high-frequency signal representing the awake state and a high-amplitude, low-frequency signal representing sedation. BIS monitoring is helpful in ensuring that patients are not oversedated or undersedated, and research has shown that BIS results correlate with validated sedation scales. The ASA guideline does not mention BIS explicitly and notes that although monitoring of the level of consciousness reduces the risk of deep sedation, no data have shown that such monitoring improves outcomes [11]. The ACEP and the ASGE found insufficient or poor evidence to recommend the routine use of BIS [31,69]. The AAP recommends against the routine use of BIS monitoring in children [13].

The patient's respiratory effort (ventilatory function) should be monitored with direct observation and/or auscultation [11]. This assessment may be supplemented by the use of pulse oximetry to continuously measure arterial hemoglobin oxygen saturation and heart rate. The value of measuring oxygen saturation is unclear. Although several studies have shown that pulse oximetry accurately detects desaturation during procedural sedation, the clinical significance of transient desaturation is uncertain [11]. In addition, oxygen saturation is relatively insensitive to early signs of hypoventilation, and studies have not shown that the use of oximetry reduces the incidence of cardiopulmonary complications. Oximetry is not able to detect an adequate signal during hypothermia, low cardiac output, and motion (such as a tremor) [11].

Despite these drawbacks, the ASA recommends pulse oximetry for all patients undergoing sedation/analgesia, and the AGA Institute and the ASGE recommend this monitoring tool as well [11,28,31]. A survey of endoscopists indicated that most (98.6%) routinely use pulse oximetry [24]. The ACEP recommends the use of pulse oximetry for patients at increased risk of hypoxemia, such as those with substantial comorbidity or when high doses of drugs or multiple drugs are used (level B recommendation) [7]. The ACEP notes that pulse oximetry may not be necessary when the patient's level of consciousness is minimally depressed and verbal communication can be continually monitored (level C recommendation) [7]. The AAP supports the use of newer pulse oximeters (e.g., less susceptible to motion artifacts, change in audible tone with changes in hemoglobin saturation) during pediatric sedation, and data on sedation practices among the Pediatric Sedation Research Consortium (PSRC) for 114,855 children showed 95% overall use of oximetry [13,67]. However, the PSRC data also demonstrated much lower use (33%) among radiologists [67].

Recommendations about noninvasive monitoring of end-tidal carbon dioxide with capnography have evolved. At the time of their guidelines on monitoring during moderate sedation, the ASA and the AGA Institute found insufficient evidence to recommend the routine use of capnography, and the ASA only recommended capnography during moderate sedation when ventilation could not be directly observed. The ACEP noted only that procedural monitoring "may include" capnography, and the ASGE stated that capnography may improve patient safety [7,11,28,31]. However, since the publication of those guidelines, several studies have demonstrated that capnography readings are a more sensitive measure of ventilatory function, detecting hypoventilation earlier than changes in vital signs, clinical observations, or pulse oximetry [70,71,72,73]. In a study in the emergency department setting, capnography had a sensitivity of 100% (and specificity of 64%) in detecting hypoxia before onset [72]. In addition, a meta-analysis (five studies) demonstrated that respiratory depression was more than 17 times more likely to be detected during procedural sedation when capnography was used than when it was not used [73]. In 2010, the ASA issued standards for anesthetic monitoring (reaffirmed in 2020) stating that monitoring for the presence of exhaled carbon dioxide should be carried out during moderate (or deep) sedation. This is supported in the 2018 ASGE guidelines [31,74]. In 2018, the ASA issued updated guidelines for moderate procedural sedation that include a new recommendation for continual monitoring with capnography to supplement observation and pulse oximetry [11]. Use of capnography during sedation is also recommended by the Emergency Nurses Association, and, in a joint position statement, the ASGE, the AASLD, the ACG, and the AGA Institute acknowledge that capnography reduces the occurrence of apnea and hypoxemia during gastrointestinal endoscopy with propofol sedation [41,75]. A multisociety-developed curriculum on sedation during gastrointestinal endoscopy notes that proper training should include interpretation of capnography readings [69].

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

(https://www.giejournal.org/article/S0016-5107(13)01777-X/pdf Last Accessed: September 26, 2022)

Level of Evidence: +++O (Moderate quality evidence. Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.)

Guidelines from the AAP/American Academy of Pediatric Dentistry support the use of capnography (preferred) during pediatric sedation. However, it was used by less than half (45%) of practitioners in a large study of high-functioning pediatric sedation systems [13,67].

The routine use of supplemental oxygen has also been debated. The ASA and ASGE guidelines note that supplemental oxygen should be considered for moderate sedation, and the ASGE states that supplemental oxygen can reduce the magnitude of oxygen desaturation during sedated endoscopy [11,31]. The ASGE additionally states that supplemental oxygen should be administered if hypoxemia is anticipated or develops [31]. However, the AGA Institute asserts that there is little evidence to indicate that the use of supplemental oxygen reduces the incidence of significant cardiopulmonary complications in patients monitored with pulse oximetry [28]. In addition, the results of several studies have shown that supplemental oxygen may actually increase the rate of complications associated with sedation, as its use may delay recognition of hypoxemia and apnea [76,77]. As a result, the AGA Institute recommends the use of supplemental oxygen during endoscopy only for older individuals and people with significant comorbid disease (ASA class IV and V) [28]. According to one survey, approximately 73% of endoscopists routinely use supplemental oxygen [24].

Heart rate and blood pressure should be monitored throughout the procedure. Although there is no evidence base for the intervals for this monitoring, three- to five-minute intervals have been suggested [11,28]. Tachycardia and hypertension may be a sign of inadequate sedation, whereas bradycardia and hypotension may be an early sign of oversedation. The AAP recommends documentation of heart rate and blood pressure at a minimum of every 10 minutes throughout the procedure for children, and 87% of practitioners in the PSRC study monitored blood pressure [13,67].

There is no evidence to indicate that continuous electrocardiography (ECG) monitoring is of benefit during moderate sedation, especially for patients who have no underlying cardiopulmonary disease [7]. Guidelines from the ASA, the AGA Institute, and the ASGE all note that ECG monitoring is not needed for low-risk patients [11,28,31]. The ASA guidelines suggest ECG monitoring to decrease risks for patients who have significant cardiovascular disease or dysrhythmia, and the AGA Institute and the ASGE state that ECG monitoring should be considered for high-risk patients, such as patients with a history of significant cardiac or pulmonary disease [11,28,31]. The AAP recommends that an ECG monitor and defibrillator be readily available [13].

Benzodiazepines have anxiolytic, muscle relaxant, sedative, and amnesic effects [31,68]. They have a high therapeutic index, meaning the serum drug level needed for effect is significantly lower than that which produces adverse effects [79]. In healthy people, the effect of benzodiazepines on the cardiovascular and respiratory systems is minimal when the dose is titrated appropriately [6]. Care must be taken, however, when opioids are used in conjunction with benzodiazepines, as the synergy of the drugs increases the potential for respiratory depression [6].

The three benzodiazepines most often used for moderate sedation are midazolam (Versed), diazepam (Valium), and lorazepam (Ativan).

Midazolam

Since its introduction in the mid-1980s, midazolam has replaced diazepam as the sedative of choice for moderate sedation because of its greater potency, more rapid onset of action, slightly shorter duration of action, and greater amnesic effect [28,79]. The drug has no analgesic effect [31].

Pharmacokinetics. The time of onset is one to two minutes for intravenous midazolam, with the peak effect within three to four minutes [69]. The duration of the drug's effect is 15 to 80 minutes [69].

Dosage. In adults, the usual starting dose of intravenous midazolam is 1–2 mg given slowly over one to two minutes while observing for sedation or slurred speech [28,69]. The drug should be titrated slowly and never administered by a rapid or single bolus [6]. If the initial dosage is insufficient to achieve or maintain the desired level of sedation, additional 0.5- to 1-mg doses may be given at two-minute intervals, to a maximum total dose of 6 mg (although a dose of 5 mg or greater is rarely needed) [69,86]. The pediatric dose is 0.05 mg/kg [86]. Because of the drug's synergistic effect with opioids, the dose of midazolam should be reduced by approximately 30% when the patient has also received an opioid [6,28].

Contraindications and Precautions. Midazolam should be administered with caution in the elderly and in patients with congestive heart failure, renal impairment, pulmonary disease, or hepatic dysfunction [6]. Fluctuations in vital signs (e.g., blood pressure, pulse), decreases in respiratory rate, and apnea have been reported after IV administration of midazolam [6].

Potential Adverse Events and Side Effects. The rates of side effects are low (1% to 4%) and include (in order of frequency) hiccups, nausea, vomiting, cough, headache, and drowsiness [6]. As with all benzodiazepines, disinhibition reactions such as rage, hostility, and aggression may occur [69].

Special Populations. The dose of midazolam should be reduced by about 20% to 30% for patients older than 60 years of age or who have an ASA physical status of III or higher [28,69]. The risk of hypoventilation or apnea is increased among older patients and those with chronic disease; the drug should be titrated at smaller increments and at a slower rate [6].

Diazepam

Diazepam is among the oldest of the benzodiazepines and has been useful as a premedication for surgical and diagnostic procedures [28].

Pharmacokinetics. The time to onset of diazepam is two to three minutes when given intravenously. Its peak is at three to five minutes, and its duration is approximately six hours [69]. This long length of action may preclude its use for short-term moderate sedation.

Dosage. The target dose of intravenous diazepam is typically 5–10 mg, administered slowly in 2.5- to 5-mg increments at one- to two-minute intervals while observing carefully for signs of sedation (e.g., slurred speech) and avoiding respiratory depression. The required dose usually does not exceed 10 mg, although up to 20 mg may be needed to achieve a moderate level of sedation if no premedication has been given [6,69].

Contraindications and Precautions. Diazepam should not be given to individuals with acute narrow-angle glaucoma (unless the condition is medically managed) [6]. The drug should be used cautiously in patients with compromised hepatic or renal function. The central nervous system (CNS) effects of diazepam may be potentiated by other CNS-depressant drugs, such as opioids, barbiturates, monoamine oxidase (MAO) inhibitors, and other psychotropic drugs [6].

Potential Adverse Events and Side Effects. Respiratory depression is a potential adverse event and is dose dependent; it is more likely to occur in patients with respiratory disease or who receive diazepam with an opioid [69]. The primary side effects are coughing and dyspnea, and pain at the injection site may also occur [28,69].

Special Populations. Lower doses should be used in older or debilitated patients [69].

Lorazepam

Lorazepam has anxiolytic, sedative, and amnesic properties, but the time to peak effect and duration of action are long, making other benzodiazepines the preferred choice [79]. The drug is sometimes used for procedures that are expected to last longer than two hours [6].

Pharmacokinetics. The time of onset of lorazepam is 1 to 2 minutes when given intravenously, with a peak effect at 15 to 30 minutes [79]. When the drug is given intramuscularly, the time of onset is 15 to 30 minutes with a peak effect at 60 to 90 minutes [6]. The drug's duration of action is six to eight hours [6].

Dosage. As a premedication, lorazepam is given intramuscularly at a dose of 2–4 mg (0.05 mg/kg) two hours before the procedure or intravenously at a dose of 0.044 mg/kg, 15 to 20 minutes before the procedure [6,86,87]. The maximum dose (regardless of route) is 4 mg (or 2 mg for patients older than 50 years of age) [28,87].

Contraindications and Precautions. Lorazepam is associated with a risk of underventilation and apnea, so should be given with caution to people who are very ill or who have limited pulmonary reserve [6].

Potential Adverse Events and Side Effects. Among the most common side effects are hallucinations, dizziness, change in blood pressure, blurred vision, nausea and vomiting, and tinnitus [6].

Propofol

The American College of Emergency Physicians asserts that propofol can be safely administered to children and adults for procedural sedation and analgesia in the emergency department.

(https://www.acep.org/patient-care/clinical-policies/procedural-sedation-and-analgesia Last Accessed: September 26, 2022)

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

Propofol is a sedative hypnotic that is being used more frequently for moderate sedation across settings, especially as its availability has increased. The drug offers very short action, with the patient awakening very rapidly after administration of the drug is stopped. Propofol offers the effects of sedation, amnesia, and antiemesis but has no analgesic properties [69,80]. The therapeutic index is narrow, and the risk for deep sedation is high [11]. Therefore, the ASA recommends that patients who receive propofol (by any route) should receive care that is consistent with that required for deep sedation [11]. The ASA also notes that clinicians who administer propofol should be qualified to rescue patients from any level of sedation, including general anesthesia [11]. Propofol has no antagonist.

Pharmacokinetics. The onset of action is less than one minute (typically 30 to 45 seconds), the peak effect occurs within one to two minutes, and the duration of effect is four to eight minutes [69,80].

Dosage and Administration. Propofol is administered as a continuous IV infusion. For endoscopic procedures, the initial dose is typically 10–40 mg, with a maximum dose of 400 mg [28]. In the emergency department setting, the most common starting dose is 1.0 mg/kg given as a slow bolus infusion, followed by 0.5 mg/kg given every three minutes as needed [80]. The sedative effect of propofol is more pronounced in the elderly; therefore, in patients older than 55 years of age, it is recommended that the dose be reduced by 20% and the initial injection given more slowly (over three to five minutes). Pain at the injection site has been reported by up to 20% of patients [80]. Lidocaine (0.5 mg/kg), given either before administration or in combination with the propofol bolus, may help to decrease the risk of injection site pain [80]. The pediatric dose is 1–2 mg/kg, given as a bolus over 30 seconds [87].

Propofol is not an antimicrobially preserved product under U.S. Pharmacopeia Convention standards, and because of this, the FDA makes several recommendations regarding administration [88]:

Contraindications and Precautions. Because the formulation of propofol includes soybean oil (10%) and purified egg phophatide (1.2%), there was some concern that it might induce an allergic reaction in patients with allergy to egg or soy [69,80]. However, allergic reactions are to proteins (not fats), and these patients can receive propofol without any special precautions.

Potential Adverse Events and Side Effects. Respiratory depression and cardiovascular instability are the major potential adverse events associated with propofol [69]. The drug produces negative inotropic effects on the cardiovascular system, which can result in a substantial decrease in blood pressure after administration [80]. However, these effects tend to resolve rapidly because of the drug's short duration of action. Hiccups, wheezing, and coughing may occur as a result of the respiratory effects of the drug. Other side effects that have been reported include headache, confusion, and euphoria [6]. Many patients have also described sexually explicit dreams during sedation with the drug [89].

Special Populations. Patients with an ASA physical status of III or IV are at higher risk for propofol-associated hypotension [80].

Etomidate

Like propofol, etomidate (Amidate) is an ultrashort-acting sedative hypnotic. It has been traditionally used as induction for general anesthesia and for rapid sequence intubation in the emergency department [90,91]. An advantage of etomidate is an absence of any effect on cardiovascular stability. The drug is used for sedation for short procedures, primarily in the emergency department setting; it is not routinely used in the endoscopy setting. Etomidate has no antagonist.

Pharmacokinetics. The onset of action of etomidate is less than one minute, with the peak effect reached within one minute. The duration of effect is 5 to 15 minutes [81,82]. Full recovery is achieved in approximately 13 to 30 minutes [83,84].

Dosage and Administration. The usual initial dose of etomidate (for both adults and children) is 0.2–0.6 mg/kg given IV over 30 to 60 seconds [86]. This may be repeated at three- to five-minute intervals, as needed, to a total of three doses given [82,83,85].

Contraindications and Precautions. Etomidate is contraindicated in patients with hypersensitivity to the drug [82].

Potential Adverse Events and Side Effects. Respiratory depression may occur, but myoclonus is the most common side effect, reported in 20% to 45% of patients during procedural sedation. In one small study, myoclonus occurred in 72% of patients receiving etomidate [81,90,92,93]. There are protocols for minimizing myoclonus, including pretreatment with a fraction dose of etomidate or a small dose of a short-acting benzodiazepine. Pain at the injection site has also been common, occurring in up to 40% of patients [81]. Nausea and vomiting during emergence have also been reported at low rates [83,90].

Special Populations. Respiratory depression may be more common in older patients (older than 55 years of age), especially at higher-than-average doses [84]. Among older patients, no significant differences in the rate of complications or length of stay in the emergency department have been found compared with younger patients [94].

Meperidine (Demerol) provides good control of substantial pain, but other opioids provide better and safer sedation [79].

Pharmacokinetics

The time to onset of action is three to six minutes, with the peak effect at five to seven minutes [69]. The effect of the drug lasts one to three hours [69].

Dosage

The typical starting dose of meperidine is 25–50 mg [69]. Additional doses of 25 mg may be given every two to five minutes, up to a maximum dose of 150 mg [28].

Contraindications and Precautions

Meperidine is contraindicated for patients taking an MAO inhibitor, as life-threatening complications may develop from the interaction of these two drugs [28]. The drug should be used with caution in patients with renal disease because the accumulation of normeperidine can lead to a neurotoxic reaction [69].

Potential Adverse Events and Side Effects

Respiratory depression is a potential adverse event; cardiovascular instability has also been noted, but to a lesser extent [69]. The most common side effects are pruritus and vomiting [69,79].

Ketamine (Ketalar) is a dissociative drug, or one that "dissociates" the thalamus from the limbic system. Ketamine provides both analgesia and amnesia; as such, it is one of the few drugs other than opioids that provide pain relief with moderate sedation. Another benefit is its minimal effect on the cardiovascular and respiratory systems [69]. Ketamine produces a cataleptic state, and the onset of sedation is marked by the development of nystagmus and an open-eye gaze. Once dissociation occurs, patients are unable to respond to external stimuli, making the level of sedation inconsistent with the definition of moderate sedation [96]. Dissociation may also cause random body movements, which means the drug is not appropriate for procedures that require the patient to be motionless (such as imaging studies) [96]. The drug has a bronchodilation effect, making it useful for patients with asthma [79]. Ketamine is often used in combination with propofol (known as "ketofol").

Pharmacokinetics

Ketamine has an onset of action of less than one minute, with the peak effect occurring at one minute. The duration of the drug's effect is 10 to 20 minutes [69].

Dosage and Administration

In the endoscopy setting, the typical initial dose of IV ketamine is 0.5 mg/kg, and the dose is titrated to effect [28]. In the emergency department setting, IV administration is preferred for adults because of the ease of repeated doses and association with less vomiting [96]. The initial dose for adults is 1.0 mg/kg, given over 30 to 60 seconds, with repeat doses (0.5 mg/kg) given every 5 to 15 minutes as needed [96]. For children, the initial dose is 1.5–2.0 mg/kg, with repeat doses of 0.5–1.0 mg/kg given every 5 to 15 minutes [96]. The initial dose of intramuscular ketamine is 4–5 mg/kg for adults and children, with 2–4 mg/kg given 10 minutes after the initial dose if sedation is not adequate [96].

Contraindications and Precautions

Absolute contraindications for ketamine include an age younger than 3 months (because of the high risk of airway-related complications) and known or suspected schizophrenia [79,96]. Relative contraindications include major procedures that stimulate the posterior pharynx; a history of airway instability; active pulmonary infection or disease; significant cardiac arrhythmia, coronary artery disease, or hypertension; CNS abnormalities; glaucoma or acute globe injury; and thyroid disorders [96]. Head trauma, minor oropharyngeal procedures, and an age of 3 to 12 months are no longer contraindications [96].

Potential Adverse Events and Side Effects

Emergence reactions have occurred in approximately 10% to 30% of adults who receive ketamine [69]. These reactions range from vivid dreams to hallucinations and delirium [69]. Because of the risk for emergence reactions, ketamine is not usually used alone in adults [97]. The concomitant use of midazolam may help reduce this risk [69]. Vomiting occurs in approximately 5% to 15% of adults and less commonly in children and adolescents; it is more likely when the drug is given intramuscularly [96]. Airway or respiratory complications have occurred in approximately 4% of children [96].

Prophylactic anticholinergics were once recommended for adults to reduce the risk of airway-related adverse events (by preventing oral secretions), but studies showed no benefit to this prophylaxis [96]. Benzodiazepines were once recommended to combat emergence reactions in children but these reactions are rare in children and this prophylaxis is no longer recommended [96].

For adults in the endoscopy setting, the combination of a benzodiazepine and an opioid is used most often for moderate sedation. A national survey showed that approximately 74% of endoscopists were using this approach, typically combining midazolam and fentanyl [24]. Propofol was used by approximately 26%; this rate may reflect restrictive guidance on the use of propofol and may have increased since the time of the survey [24].

As noted, the safety of propofol and the restrictions regarding the professionals qualified to administer it have been the subject of intense debate. However, several studies have shown that propofol is safe when administered by non-anesthesia personnel in the endoscopy setting. In a report involving nearly 650,000 cases worldwide of endoscopist-directed sedation with propofol, 11 patients required endotracheal intubations, no patient had permanent neurologic injury, and four patients died [35]. The four people who died included two with pancreatic cancer, one with severe mental retardation, and one with severe cardiomyopathy [35]. The authors estimated that, if anesthesia specialists had been used in all these cases (and had prevented the four deaths), the estimated cost per life-year saved would be $5.3 million [35].

In a subsequent literature review, propofol administered by non-anesthesia clinicians (including specially trained nurses) for sedation during endoscopy was safe, with minor adverse events in less than 1% of patients [36]. There were no deaths and no patients who required endotracheal intubation [36].

When compared with traditional drugs for sedation during colonoscopy, propofol has been as safe as benzodiazepines and/or opioids, with a faster onset of action and a deeper level of sedation. A systematic review demonstrated that procedure time, pain control, and rate of complications were similar for propofol and traditional drugs, but propofol was associated with shorter recovery and discharge times and higher rates of patient satisfaction [100]. These benefits have been observed in other studies, along with lower rates of memory and recall of pain and gagging during the procedure among patients who received propofol [25,101,102]. Clinician satisfaction has also been reported to be significantly higher for propofol than conventional sedation [24]. Shorter recovery and discharge times also help to enhance the efficiency in endoscopy suites [103].

A meta-analysis (22 trials, 1,798 adults) demonstrated that propofol for gastrointestinal endoscopy was comparable to traditional sedative agents in terms of safety [104]. The rates of cardiopulmonary complications (i.e., hypoxia, hypotension, arrhythmia, and apnea) were similar for patients who received propofol and those who received traditional sedative agents, even among high-risk patients [104]. Lastly, a 2013 study and statistical analysis (200 patients) found that deep sedation during endoscopy occurred more frequently and recovery times were shorter with propofol/fentanyl than with midazolam/fentanyl [102].

Propofol offers an additional benefit in that it has increased the completion rate for complicated procedures. For example, endoscopic retrograde cholangiopancreatography (ERCP) with traditional sedation is poorly tolerated by patients, and in many cases, the procedure must be interrupted before satisfactory images have been obtained, necessitating additional interventions with associated risks and added cost. In a study of 252 patients who had ERCP, propofol significantly decreased the rate of incomplete procedures compared with sedation using a benzodiazepine (4% vs. 11%) [105]. The median hospital stay was similar for the two agents, as were the rates of mild sedation-related complications and mild procedural complications.

Data on sedation for children and adolescents undergoing endoscopy are limited. The authors of a systematic review published in 2012 (11 randomized and 15 nonrandomized controlled trials) targeted studies involving children and adolescents younger than 18 years of age [106]. Few of the trials compared different drugs, but the review demonstrated that propofol-based sedation had a safety profile similar to that of an opioid and benzodiazepine [106]. Data on midazolam- and ketamine-based sedation were too limited to draw conclusions. Sedation was most effective with propofol; the authors noted that adding midazolam, fentanyl, or ketamine to propofol may enhance the effectiveness without increasing adverse events [106].

The evidence for the safety of propofol among children includes data collected by the PSRC (which included gastrointestinal procedures as well as radiographic studies, hematology/oncology procedures, and others) regarding propofol sedation/anesthesia at 27 locations within the United States. Overall, the rate of pulmonary complications was 235 per 10,000 sedations; the rate of unintended deep sedation was low (0.9 per 10,000), as was use of a reversal agent (0.4 per 10,000) [107]. No patient died, and two patients required cardiopulmonary resuscitation.

In its clinical policy on procedural sedation and analgesia in the emergency department, the ACEP provided evidence-based recommendations regarding etomidate, "ketofol," and propofol (Table 13) [7,80]. Ketamine alone was also recommended for children (Level A recommendation) and adults (Level C recommendation) in the ACEP clinical policy. The ACEP suggests that when using any opioid and benzodiazepine, as with fentanyl and midazolam, the opioid should be given first, as it presents the greater risk of respiratory depression; the dose of the benzodiazepine should then be titrated [7].

Etomidate has many advantages for use in the emergency department, including a rapid onset of action, short duration of action, stable hemodynamic profile, and favorable side effect profile [81,83,90]. It is used for short procedures, such as joint relocations, fracture care, cardioversion, removal of foreign bodies, and repair of lacerations, and rates of procedure completion and patient satisfaction have been high [14,15,83,84,92]. The ACEP notes that the drug can be safely used for procedural sedation and analgesia (level B recommendation), but careful dosing and monitoring must be carried out, as the drug can quickly induce deep sedation [7,90].

The use of propofol has increased as the safety and efficacy of the drug has been demonstrated and the drug has become more accessible [111,112]. The drug has been found to have many benefits, with similar or lower rates of adverse events compared with traditional drugs used for moderate sedation (Table 14) [92,111,113,114,115,116,117].

Propofol has also been found to be more cost-effective than traditional drugs, primarily because of decreased staff time and shorter lengths of stay [115,118]. One study showed an approximate savings of $597 per successful sedation with propofol [119].

Propofol has also been evaluated in combination with a low dose of ketamine. The rationale for this combination is that using lower doses of each agent may reduce the undesirable adverse effects of both agents while maintaining optimal sedation during procedures [120,121]. The two drugs can either be drawn up in the same syringe or be given in two syringes. When given separately, an IV bolus of ketamine is given first, followed by a bolus of propofol, with additional boluses of propofol given to maintain sedation [97]. A 1:1 ratio is typically used when given in the same syringe, but the ratio of propofol to ketamine has varied among trials (range: 10:1 to 2:1), and the optimum dose of the agents in combination is unclear [97,120]. In a study of 114 procedural sedation and analgesia events (primarily orthopedic procedures), the combination (a 1:1 mixture of ketamine 10 mg/mL and propofol 10 mg/mL) was associated with few adverse events, which were either self-limited or responded to minimal interventions [122]. No patient had hypotension or vomiting or received endotracheal intubation. The procedure was successfully performed without the need for other sedatives in approximately 97% of patients. The median recovery time was 15 minutes (range: 5 to 45 minutes), and both clinician and patient satisfaction was high, with median scores of 10 on a scale of 1 to 10 [122].

An early review of studies in which the propofol/ketamine combination was compared with propofol alone provided insufficient evidence to recommend its use [109]. Significant hemodynamic and respiratory compromise occurred in fewer patients who received the combination, but the need for active interventions did not differ between the combination and propofol alone [109]. In addition, higher doses of ketamine were associated with increased rates of nausea, vomiting, and emergence reactions following the procedure [109]. The findings of a subsequent systematic review (eight trials) confirmed these results, with no superior clinical efficacy for the combination compared with propofol alone, conflicting data on reduced hemodynamic and respiratory complications with the combination, and an increased rate of adverse events with higher doses of ketamine [120].

Later studies have shown benefit in both efficacy and safety. In a small study comparing ketamine and propofol with propofol alone, the effectiveness was similar, but the combination was associated with better quality of sedation, enhanced patient comfort, and higher rates of clinician satisfaction, as well as a smaller decline in systolic blood pressure [108]. In another study (in adults and children), the combination was associated with a trend toward better quality of sedation, lower doses of propofol, and greater staff satisfaction; the rate of respiratory depression was similar [123]. The findings of a 2011 review of 10 trials also suggested that the combination was associated with a lower rate of hypotension and respiratory depression [97]. Results of a study published in 2015 found that the combination resulted in a lower frequency of adverse respiratory events compared with propofol alone [124].

When considering drugs for moderate sedation for children and adolescents in the emergency department, clinicians should choose a drug with the highest therapeutic index and administer the lowest possible dose [13]. Analgesics should be used for painful procedures, and sedative/hypnotics should be used for nonpainful procedures (such as imaging studies) [13]. Either a single agent or a combination of drugs may be used when both sedation and analgesia are desired. Deep or dissociative sedation is often required for children who are to undergo a painful procedure [30].

The ACEP has outlined the evidence base for the safety of sedation drugs for children undergoing procedures in the emergency department (Table 15) [10]. Options for painful procedures include but are not limited to opioids, benzodiazepines, and barbiturates, and specific agents such as ketamine, propofol, remifentanil, dexmedetomidine, etomidate, and nitrous oxide [29]. In an effort to best achieve the goals of sedation in children, many studies have evaluated combinations of these drugs. The ACEP no longer makes specific recommendations for the use of a single agent or combination of agents for patients or sedation procedures [29]. A 2011 ACEP policy statement acknowledges that emergency department physicians are highly skilled in selecting and performing sedation and note that the relative needs of analgesia and sedation should be weighed against the potential risks, benefits, and alternatives when individualizing their plan for patient sedation.

When ketamine and midazolam was compared with etomidate and fentanyl in a small study (23 children), ketamine and midazolam was more effective at reducing pain and distress (as scored on the Observational Scale of Behavioral Distress-Revised) during sedation for a procedure (orthopedic reduction) [125]. However, etomidate and fentanyl may be suitable for short, simple procedures, as the combination was associated with significantly shorter total sedation times (approximately 50 minutes vs. 78 minutes) and recovery times (approximately 25 minutes vs. 61 minutes) [125]. The adverse effect profiles of the two drug combinations differed; dysphoric emergence reaction and vomiting occurred among children who received ketamine and midazolam, and vomiting, injection-site pain, and myoclonus occurred in children who received etomidate and fentanyl [125].

Etomidate and fentanyl was found to be safe and effective in children in another study, in which an initial dose of 0.2 mg/kg IV was associated with adequate sedation in 60% to 67% of children, depending on the procedure [85]. The procedure was successfully completed in all but one child, and no significant adverse respiratory events occurred [85].

The combination of ketamine and propofol has also been evaluated in children. In one study, the combination (median dose: 0.8 mg/kg of each drug) was effective in 219 young individuals (1 to 20 years of age) having a procedure in the emergency department [126]. Sedation was effective in all patients, with a median recovery time of 14 minutes (range: 3 to 41 minutes). The rate of adverse events was low; three patients (1.4%) experienced an airway event requiring intervention (with positive pressure ventilation needed in one patient) and two patients (0.9%) had emergence reactions requiring treatment [126].