Version May 2024
INTRODUCTION — Procedural sedation and analgesia (PSA) reduces the patient’s discomfort, apprehension, and potentially unpleasant memories associated with procedures. Selecting a medication for procedural sedation in adults, including discharge criteria after the sedation is complete, will be reviewed here. Well-trained clinicians experienced in performing PSA who are monitoring patients appropriately and who are prepared to manage potential complications should choose the clinically appropriate sedative they are most comfortable administering.
Preparation to perform a procedural sedation in adults, including monitoring and anticipating and managing complications, is discussed separately. (See "Procedural sedation in adults in the emergency department: General considerations, preparation, monitoring, and mitigating complications".)
TOPIC SCOPE — This topic provides guidance for procedural sedation in adult patients performed in the emergency department and other settings where the sedation is being performed by the proceduralist or a non-anesthesia clinician (eg, intensive care unit, procedural suite).
●Procedural sedation in children is discussed separately. (See "Procedural sedation in children: Approach" and "Procedural sedation in children: Preparation" and "Procedural sedation in children: Selection of medications".)
●Procedure sedation performed by endoscopists is discussed separately. (See "Gastrointestinal endoscopy in adults: Procedural sedation administered by endoscopists" and "Adverse events related to procedural sedation for gastrointestinal endoscopy in adults" and "Monitored anesthesia care in adults".)
●Monitored anesthesia care (MAC) by an anesthesia clinician is discussed separately. (See "Monitored anesthesia care in adults".)
CHOOSING A MEDICATION
Preferred medications in healthy patients: Propofol or etomidate — In relatively healthy and hemodynamically stable patients, we suggest performing procedural sedation and analgesia (PSA) with either propofol or etomidate, which are ultra-short-acting sedatives. Both medications are safe and effective, and both possess similar times to onset and recovery (table 1) [1,2]. Propofol may result in a higher procedural success rate since it does not cause myoclonus, which can interfere with procedures [1,3]. However, propofol may cause hypotension in patients with critical illnesses or decreased cardiac function since it is vasodilatory and a cardiac depressant. Respiratory depression occurs at comparable rates during PSA with either medication, but this rarely causes patient harm.
Propofol is preferable in the following circumstances:
●Musculoskeletal procedures – Etomidate can cause myoclonus, which appears to reduce the rate of procedural success [1,4-6]
●Patients with critical illnesses – Etomidate causes dose-dependent adrenal suppression, which is unlikely to be important in otherwise healthy patients but may be harmful in patients with critical illnesses (eg, sepsis, multiple trauma)
Etomidate is preferable in:
●Patients in whom hypotension is a particular concern, since it provides greater hemodynamic stability compared with propofol (see 'Patients at risk for hypotension' below)
Several trials have compared propofol and etomidate for PSA. A meta-analysis comparing PSA with etomidate versus propofol for electrical cardioversion (nine trials, 430 patients) found etomidate was less likely to cause hypoxia (10 versus 22 percent; RR 0.50, 95% CI 0.32-0.77) and hypotension (RR 0.11, 95% CI 0.02-0.74) and more likely to cause myoclonus (35 versus 3 percent; RR 8.89, 95% CI 4.59-17.23) and post-procedural nausea and vomiting (RR 5.13, 95% CI 1.72-15.3) [7]. There was no difference in the use of positive-pressure ventilation for hypoxia and no reported use of inotropes for hypotension. A trial of 214 emergency department patients undergoing various painful procedures (musculoskeletal and others) also found that myoclonus was more frequent with etomidate (20 versus less than 2 percent with propofol), likely accounting for the lower rate of procedural success in the etomidate group (89 versus 97 percent) [1]. There were no clinically significant complications (eg, prolonged hypoxia), and recovery after sedation was similar in the propofol and etomidate groups. Other studies of ocular and gastrointestinal procedures have shown similar quality of sedation and completion rates [8,9].
There is insufficient evidence that "ketofol" (ie, ketamine and propofol mixed in 1:1 ratio) improves clinically significant outcomes or reduces important complications as compared with propofol alone, although it is a safe and effective combination for PSA. (See 'Premixed with propofol (ketofol)' below.)
When ultra-short-acting agents are unavailable or a longer duration of PSA is required — In settings where propofol and etomidate are unavailable or a longer duration of PSA is required (eg, gastrointestinal endoscopy), a combination of midazolam plus fentanyl is commonly used. Although midazolam alone has not been shown to cause significant respiratory depression, the combination of midazolam and fentanyl can cause hypoxia and apnea and increases the need for airway intervention and medication reversal compared with PSA using ultra-short-acting agents (eg, propofol, etomidate) [10,11]. (See "Gastrointestinal endoscopy in adults: Procedural sedation administered by endoscopists", section on 'Sedatives and analgesics' and 'Coadministration of midazolam and fentanyl' below.)
Ketamine is also a reasonable option when a longer duration of PSA is required. (See 'Ketamine' below.)
Medication choice and dosing when increased risk of complications — In some circumstances, the benefits of completing a procedure outweigh the anticipated risks of complications of PSA. Suggestions for medication selection in several common scenarios are provided below, and the doses and duration of effect and common adverse effects are presented in the table (table 1). Relative contraindications to PSA and considerations in patients with obesity or during pregnancy are discussed in greater detail elsewhere. (See "Procedural sedation in adults in the emergency department: General considerations, preparation, monitoring, and mitigating complications", section on 'General considerations and precautions' and "Procedural sedation in adults in the emergency department: General considerations, preparation, monitoring, and mitigating complications", section on 'Pregnancy' and "Procedural sedation in adults in the emergency department: General considerations, preparation, monitoring, and mitigating complications", section on 'Obesity'.)
Patients at risk for hypotension — In patients at risk of hypotension due to recent illness, dehydration, cardiac disease, or some other condition, we suggest using either etomidate or ketamine for PSA since either agent is expected to maintain hemodynamic stability. In contrast, propofol has a greater hypotensive effect [1]. Propofol-induced hypotension is generally mild and transient, but this difference may be of importance in patients with hypovolemia or hypotension who require emergency PSA [12-14]. (See 'Etomidate' below and 'Ketamine sedation' below.)
Patients at risk for airway or respiratory complications — In patients who may have a potentially difficult airway or compromised respiratory function, we suggest using ketamine for PSA. Ketamine allows the patient to maintain protective airway reflexes and does not cause respiratory depression. Dexmedetomidine is an alternative option since it generally preserves muscle tone and respiratory effort. (See 'Ketamine sedation' below and 'Dexmedetomidine' below.)
Patients with obesity — The choice of medication for PSA is not affected by obesity, but dosing needs to be adjusted. Adjustments in the dosing of medications used for PSA should generally be based on ideal, adjusted, or lean body weight (not actual body weight [ABW]) to avoid oversedation and are described below. General principles regarding dosing of PSA medications in obesity are discussed in detail elsewhere. (See "Anesthesia for the patient with obesity", section on 'Dosing anesthetic drugs'.)
Calculators for ideal body weight (IBW) and adjusted body weight (AdjBW) (calculator 1), lean body weight in females and males (calculator 2 and calculator 3), and a table with IBW and approximate lean body weight (table 2) are provided.
Dosing in patients with obesity is discussed in the section on each medication below.
Older adult patients — Older adult patients are at increased risk of complications during PSA [15-17]. As a result, sedatives administered to older patients for PSA, regardless of the agent, should be given at a lower starting dose, using a slower rate of administration, and repeating dosing at less frequent intervals. Dosing for specific medications is provided in the sections on individual medications below. (See 'Medications' below.)
In older adult patients without major comorbidities or hemodynamic instability, it may be best to perform PSA using an ultra-short-acting sedative such as propofol (initial bolus of no more than 0.5 mg/kg). Procedures in older adult patients with major comorbidities are probably best performed in the operating room if the anesthesiologist and proceduralist are available and any associated delay would not be harmful.
Patients with major medical conditions — Patients with major comorbid medical conditions are at increased risk for adverse events with PSA. These conditions include heart failure, valvular (eg, aortic) stenosis, chronic obstructive pulmonary disease, pulmonary hypertension, and neuromuscular diseases and correlate with an American Society of Anesthesiologists (ASA) physical status classification of class III or greater (table 3). Similar to older patients, regardless of the sedative chosen for PSA, we suggest using a lower starting dose, slower rates of administration, and repeat dosing at less frequent intervals.
Dosing in patients with hepatic or renal insufficiency is discussed in the section on each medication below. A lower starting dose is recommended for most agents except for propofol and ketamine [18-21].
MEDICATIONS
General principles — Procedural sedation and analgesia (PSA) typically involves the intravenous (IV) administration of sedative or dissociative agents, sometimes in combination with short-acting opioids (table 1) [10]. Ideal medications for PSA have a rapid onset and short duration of action, maintain hemodynamic stability, and do not cause major side effects [22]. Several medications are commonly used, and no single drug is ideal for every situation.
In addition to PSA medications, use of non-opioid multimodal analgesia (eg, acetaminophen, ketorolac) and local/regional anesthesia, if appropriate, can reduce pain levels, minimize dose of PSA medications, and decrease risk of post-procedural respiratory depression. (See "Nonopioid pharmacotherapy for acute pain in adults" and "Overview of peripheral nerve blocks".)
Propofol — Propofol is a phenol derivative that provides effective PSA for emergency procedures [22,23]. Propofol is highly lipophilic and therefore crosses the blood-brain barrier rapidly. Onset of sedation is within approximately 40 seconds, and its duration of action is approximately six minutes [24,25]. Propofol acts as a sedative and amnestic but provides no analgesia. It can induce deep sedation rapidly and must be given with careful attention to dosing and monitoring. In addition to its use for PSA, propofol is used for long-term sedation in critically ill patients, which is discussed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propofol'.)
●Dosing – For PSA in adults, propofol is given by slow injection in an initial loading dose of 0.5 to 1 mg/kg IV followed by doses of 0.25 to 0.5 mg/kg IV every one to three minutes as necessary until the appropriate level of sedation is achieved [23]. One reasonable approach to administration is to give 20 mg every 10 seconds (eg, a 50 mg dose would be given over 25 seconds), although there is no direct evidence demonstrating improved efficacy or safety using this regimen.
•Older adults – In older adult patients, reduce the dose by 20 to 60 percent of a typical healthy young adult dose and administer slower, such as over three to five minutes [26]. The initial bolus dose should not exceed 0.5 mg/kg [15,16]. Plasma concentrations appear to be increased in older adult patients, which can lead to prolonged sedation and more pronounced cardiorespiratory depression. Patients over 55 are particularly sensitive [24]. (See 'Older adult patients' above.)
•Impaired kidney or liver function – No dose adjustments are required for propofol in patients with impaired kidney or liver function [27].
•Obesity – A reasonable strategy when performing PSA with propofol in the patient with obesity is to give an initial dose based on the patient's adjusted body weight (AdjBW) (calculator 1) and then give additional titrated doses as needed to achieve the desired level of sedation. Propofol's pharmacokinetics are highly dependent on cardiac output, which is elevated in patients with obesity. Propofol is also highly lipophilic and has a greater volume of distribution in patients with obesity. Both of these factors can lead to more rapid clearance and a shorter duration of effect. (See 'Patients with obesity' above.)
●Analgesic coadministration – Short-acting opioids (eg, fentanyl) are commonly coadministered during PSA with propofol. The decision to coadminister an analgesic should be individualized based on the patient's pre-procedure pain, expected pain course during and after the procedure, and risk of complications from administering a synergistic agent. Patients often receive analgesia while awaiting the PSA and procedure, and that may be sufficient if pain is adequately controlled. In many instances, patients experience little or no pain before, during, or after a procedure (eg, lumbar puncture, cardioversion) and little or no additional analgesia is necessary to supplement propofol. In procedures that lead to a substantial decrease in pain (eg, dislocation reduction), either no additional analgesic or a short-acting analgesic (eg, fentanyl) may be all that is needed, anticipating that the greatest risk of hypoventilation occurs immediately following relief of pain (eg, when the joint is reduced). In a trial of patients who had adequate analgesia with morphine prior to PSA, the combination of propofol and alfentanil did not improve pain levels compared with propofol alone, and the alfentanil group required more stimulation to induce respiration [28]. (See 'Short-acting opioids (fentanyl, others)' below.)
In patients who are expected to have procedural pain and are at risk of hypoventilation, an alternative to short-acting opioids is pretreatment with a sub-dissociative dose of ketamine, which appears to provide comparable analgesia with less risk of respiratory depression [29,30].
●Allergic reactions – Significant allergic reactions to the preparation of propofol available in the Unites States and Canada appear to be rare even though the manufacturer lists egg or soybean allergies as contraindications to its use. A discussion on anaphylactic reactions to a previous formulation of propofol and allergic reactions to the current emulsion can be found elsewhere. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Hypnotic induction agents'.)
●Adverse effects – Potential side effects include hypotension (due to myocardial depression) and respiratory depression. These side effects generally resolve quickly and uneventfully because of propofol's brief duration of action. However, hypotension can produce complications in patients with severe medical problems (eg, sepsis, cardiac dysfunction) or hypovolemia [24].
Respiratory depression usually manifests as a mild oxygen desaturation. Coadministration with other sedatives or analgesics (eg, fentanyl) can exacerbate respiratory problems. Episodes of hypoxia are generally insignificant, successfully treated with supplemental oxygen and patient stimulation, and less commonly require short periods of assisted ventilation with a bag-valve mask. Endotracheal intubation due to propofol-induced respiratory depression during PSA is not reported [24].
●Reducing injection site pain – Propofol injection through an IV catheter causes pain in up to 80 percent of patients, although the pain is typically mild and many patients do not recall the discomfort [29,30]. Injecting through a larger venous catheter placed in the largest vein possible (eg, antecubital fossa) reduces the pain [31,32]. Multiple methods to reduce pain have been studied, and lidocaine has demonstrated the most consistent benefit. The small doses of lidocaine are unlikely to cause any significant cardiac or neurologic adverse effects. The following techniques are effective, but the venous occlusion technique was found to provide the best pain relief in a meta-analysis of randomized trials [31,33]:
•Place a tourniquet proximal to the venipuncture site. Inject lidocaine 1% 40 to 60 mg (0.5 to 1 mg/kg) into the vein. After 60 seconds, release the tourniquet and inject propofol.
•Mix lidocaine 1% 40 mg with propofol 200 mg in the same syringe and inject with or without vein occlusion.
Pretreatment with multiple other agents, including ondansetron, opioids (eg, fentanyl, remifentanil), steroids (eg, methylprednisolone, dexamethasone), ketamine, acetaminophen, ketorolac, and esmolol, has been found to effectively reduce pain [29,30,32,34-43].
●Emergency department use – Multiple trials and prospective studies have found propofol to be safe and effective for PSA in the emergency department [15,24,44,45]. Evidence supports the safety and efficacy of nurse-administered propofol PSA, during which the only physician present is performing the procedure (eg, outpatient endoscopy) [46-53].
Despite the evidence above, not all clinicians who are qualified and wish to administer propofol for PSA are allowed to do so. Reasons for this are complex and beyond the scope of this discussion but may include misunderstandings about patient safety as well as political and economic factors [54,55]. The manufacturer's label states, "only those persons trained in the administration of general anesthesia should administer the drug," and goes on to state, "only those persons not involved in the conduct of the surgical/diagnostic procedure should administer the drug" [56]. In the United States, these statements have led some nursing organizations to question whether nurses other than certified registered nurse anesthetists should administer propofol. However, nursing regulatory agencies are now actively involved in education, training, and certification of nurses to safely provide propofol PSA.
Etomidate — Etomidate, an imidazole derivative, is a sedative that is commonly used for PSA. Several randomized trials and prospective observational studies have found that etomidate is an effective sedation agent for PSA and does not cause major complications (eg, respiratory depression requiring endotracheal intubation) [1,57-59]. However, myoclonus occurs with regularity, and procedure success rates may be lower when compared with propofol or ketamine. The use of etomidate for rapid sequence intubation is discussed elsewhere. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care".)
●Dosing – For PSA in adults, etomidate is given IV over 30 to 60 seconds in doses of 0.1 to 0.15 mg/kg (which is lower than the rapid sequence intubation dose). It can be redosed at 0.05 mg/kg approximately every three to five minutes as needed. The onset of action of etomidate is almost immediate, and its duration of effect is 5 to 15 minutes [1,4].
•Older adults or impaired kidney or liver function – Etomidate can have more profound and prolonged effects in older patients and patients with renal or hepatic insufficiency [60]. In such patients, doses in the lower dosing range should be used. An important benefit of etomidate is that it maintains cardiovascular stability.
•Obesity – Etomidate has pharmacokinetic and pharmacodynamic properties similar to propofol. Thus, we suggest basing dosing on AdjBW (calculator 1) with additional titrated doses given as needed [61,62]. Actual body weight (ABW) dosing is recommended for tracheal intubation in patients with a BMI 30 to 39 kg/m2 to prevent risk of underdosing (eg, awake while paralyzed), which is not a concern during PSA. (See 'Patients with obesity' above.)
●Addition of analgesic agent – Etomidate has no analgesic properties and often requires the coadministration of a short-acting opioid, such as fentanyl, which increases the risk of respiratory depression [4]. We suggest that not exceeding 0.5 mcg/kg fentanyl in any single dose when given with etomidate and keeping the total amount of fentanyl to a minimum.
●Adverse effects – Potential side effects of etomidate include myoclonus, respiratory depression, adrenal suppression, and nausea and vomiting. Myoclonus is the most frequently reported side effect. It is thought to be related to subcortical disinhibition and has been reported in up to 80 percent of patients who receive etomidate for PSA [59,63-65]. The degree of myoclonus may be dose dependent and ranges from mild and transient to severe enough to prevent completion of the procedure [1].
•Myoclonus – Reports of severe myoclonus associated with PSA are rare. In such cases, we suggest immediate airway support and treatment with midazolam 1 to 2 mg IV approximately every 60 seconds until myoclonus abates. Alternative benzodiazepines may be used if midazolam is unavailable. Small trials have shown a reduction of myoclonus in patients given a pretreatment etomidate dose (0.03 to 0.05 mg/kg), a concurrent midazolam dose (0.015 mg/kg), or a pretreatment magnesium sulfate dose (60 mg); however, these are not routinely used, and there is insufficient evidence to support any specific approach [63,66,67].
•Respiratory depression – Respiratory depression occurred in approximately 10 percent of cases in a systematic review of etomidate for PSA [57]. In this review, respiratory depression was defined as a fall in oxygen saturation below 90 percent or occurrence of apnea. There were no serious complications, and respiratory depression resolved quickly without major interventions in the great majority of cases. Nevertheless, clinicians must be prepared to support the patient's airway and breathing in the event of respiratory compromise, as is true whenever PSA is performed.
•Adrenal suppression – Etomidate causes adrenal insufficiency when given by continuous infusion. Reductions in plasma cortisol concentrations have also been reported in patients receiving a single induction dose of etomidate [68,69]. However, the clinical significance of transient reductions in cortisol in patients undergoing PSA with etomidate remains unclear. Most such patients are relatively healthy and receive a single sedating dose, and complications related to adrenal suppression have not been reported.
●Reducing injection site pain – Etomidate causes pain during injection into peripheral veins. Strategies similar to those used for propofol can be used to reduce such pain. (See 'Propofol' above.)
Benzodiazepines (midazolam, others) — Benzodiazepines are commonly used for minimal sedation (anxiolysis) but less often for deeper sedation due to the superior effectiveness of the ultra-short-acting agents propofol and etomidate. Benzodiazepines produce anxiolysis and amnesia but have no analgesic properties. Compared with ultra-short-acting agents, midazolam has a longer duration of action that makes it better suited for anxiolysis than for PSA [64].
●Midazolam – Midazolam is the benzodiazepine used most often for PSA. Because it is lipophilic, midazolam penetrates the blood-brain barrier quickly. Midazolam can be used alone for anxiolysis or in combination with short-acting opioids (eg, fentanyl) for deeper levels of sedation and analgesia. Its time of onset is two to five minutes, and its duration of action is 30 to 60 minutes [11,70].
•Dosing – Midazolam is usually given IV over one to two minutes in doses of 0.02 to 0.03 mg/kg. Often in adults, midazolam is given in individual doses of 0.5 or 1 mg and titrated to effect. No single dose should exceed 2.5 mg. Repeat doses may be given every two to five minutes as necessary. The total dose necessary for adequate sedation varies based upon many factors, including patient weight and age, medication tolerance, comorbidities, and the duration of the procedure. In most cases, PSA can be performed using no more than 5 mg of midazolam.
-Anxiolysis - A single midazolam dose of 0.02 mg/kg (approximately 1 to 2 mg) is usually sufficient.
-Older adults or impaired kidney or liver function – Use lower doses, longer dosing intervals, and smaller total amounts to reduce the risk of prolonged sedation and delirium.
-Obesity – We suggest using a standard, non-weight-based dose or AdjBW dose to determine the initial dose. Regardless of whether benzodiazepines are used alone or in combination with other medications, it is safer to administer smaller supplemental doses as needed until the desired effect is achieved [62]. The half-life and volume of distribution of benzodiazepines increases with body weight, and so there is the potential for the medication and metabolites to accumulate with additional doses, potentially causing adverse effects such as oversedation and respiratory depression. (See 'Patients with obesity' above.)
•Adverse effects – Midazolam can cause respiratory depression in high doses or when given concomitantly with other sedatives or opioids. With repeated doses, midazolam accumulates in adipose tissue, which can significantly prolong sedation [70].
●Other benzodiazepines - Lorazepam and diazepam are less suited for PSA due to their relatively prolonged onset and duration of action. They also have more side effects and inferior amnestic properties compared with midazolam [11,71].
In 2020, the US Food and Drug Administration (FDA) approved remimazolam, an ultra-short-acting IV benzodiazepine, for induction and maintenance of sedation in adults undergoing procedures lasting ≤30 minutes. Its advantages, disadvantages, and potential uses are discussed elsewhere. (See "Monitored anesthesia care in adults", section on 'Remimazolam'.)
Short-acting opioids (fentanyl, others) — Short-acting opioids (eg, fentanyl, alfentanil, remifentanil) are often given alone or in combination with sedatives for PSA.
Fentanyl is a synthetic opioid that was frequently used in combination with midazolam to provide analgesia during PSA before propofol and etomidate became widely available. It has 75 to 125 times the potency of morphine, a rapid onset of action (two to three minutes), and a short duration of effect (30 to 60 minutes) but has no amnestic properties [11].
Remifentanil and alfentanil are opioids similar in structure to fentanyl with a rapid onset and duration of action of approximately five minutes, and both are used for PSA [72,73]. The potency of remifentanil and fentanyl are comparable, but alfentanil is one-fifth to one-tenth as potent. Remifentanil can be given in combination with propofol for PSA [74-76]. Few studies have assessed alfentanil as a sole agent for PSA, and there are no published guidelines for its use in this manner. There is no evidence that PSA using remifentanil and propofol is superior to propofol alone, nor is there evidence that either remifentanil or alfentanil is superior to fentanyl.
●Dosing
•Fentanyl adjunct – When used in combination with a sedative for PSA, fentanyl is usually given by slow IV push in doses of 0.5 mcg/kg every two minutes until an appropriate level of sedation and analgesia is achieved [11]. The maximum total dose is generally 5 mcg/kg or approximately 250 mcg, but higher doses may be needed in some instances.
•Remifentanil adjunct – When used in combination with propofol for PSA, remifentanil is given in a dose of 0.5 mcg/kg (and propofol 0.5 mg/kg) over one minute [75]. Subsequent doses of remifentanil 0.25 mcg/kg and propofol 0.25 mg/kg may be given approximately every one to two minutes.
Remifentanil alone – When remifentanil is used alone for PSA, the initial dose is 0.5 to 3 mcg/kg, and subsequent doses of 0.25 to 1 mcg/kg may be given approximately every two minutes as needed [74].
•Alfentanil adjunct – Alfentanil may be used as an adjunct for PSA with propofol and is given in a dose of 2.5 mcg/kg (along with propofol 0.5 mg/kg). Both may be repeated approximately every two minutes as needed.
•Older adults or impaired kidney or liver function – Use lower doses, longer dosing intervals, and smaller total amounts to reduce the risk of prolonged sedation.
•Obesity – We suggest using a standard, non-weight-based dose or AdjBW dose to determine the initial dose of fentanyl, alfentanil, and remifentanil, then titrating to clinical effect. Doses based on ABW increase the risk for respiratory depression, hypotension, and bradycardia [61,62]. (See 'Patients with obesity' above.)
●Adverse effects – The primary side effect of opioids is respiratory depression, which is potentiated by the coadministration of sedatives. Fentanyl rarely causes hypotension and does not stimulate histamine release. Older patients and patients with renal or hepatic disease can experience more prolonged or profound effects.
In a prospective study of 148 adults given alfentanil for PSA, 58 (39 percent) developed minor respiratory complications requiring intervention (eg, increased oxygen, brief bag-mask ventilation) despite achieving lighter levels of sedation than typically reached with propofol [77].
Coadministration of midazolam and fentanyl — In settings where ultra-short-acting agents are unavailable or a longer duration of PSA is required (eg, gastrointestinal endoscopy), the combination of midazolam and fentanyl is sometimes used for PSA [10,78-80]. The combination of midazolam and fentanyl can cause hypoxia and apnea and may require airway intervention and medication reversal [10,11]. To minimize the risk of respiratory depression, we suggest administering midazolam first and then titrating fentanyl carefully, but either sequence is acceptable. Regardless of the sequence, clinicians must titrate these medications carefully to minimize the risk of oversedation and respiratory compromise.
A reasonable approach to dosing these medications when they are used together is as follows:
●Give midazolam first: 0.02 mg/kg (maximum 2 mg)
●Wait two minutes and observe patient response; give second dose of midazolam if necessary
●Give fentanyl 0.5 mcg/kg
●Observe patient; may repeat fentanyl dose every two minutes as necessary; titrate to effect
●Use smaller doses and longer intervals between doses in older patients and patients with compromised hepatic or renal function
Ketamine — For PSA, ketamine can be used to provide sedation either as a single agent or premixed with propofol in a single syringe ("ketofol"), or to provide analgesia instead of an opioid (typically combined with propofol but not premixed in a single syringe).
Ketamine sedation — Ketamine, a phencyclidine derivative that acts as a dissociative sedative, is commonly used in pediatric PSA and has gained acceptance for adult PSA. It produces a trance-like state and provides sedation, analgesia, and amnesia while preserving upper airway muscle tone, airway protective reflexes, and spontaneous breathing. Because of its rapid onset, relatively short duration of effect (10 to 20 minutes), and excellent sedative and analgesic properties, it is often used for painful procedures such as fracture reduction or laceration repair [4,81].
Ketamine may be preferable to propofol when hypotension is a particular concern, in patients who may have developed a significant tolerance to GABAergic agents (whereas ketamine would not need titration), for lengthier procedures (ie, longer than 5 to 10 minutes), and when maintaining airway protective reflexes may be critical.
Ketamine can exacerbate schizophrenia and should be avoided in patients with this condition [82,83].
●Dosing – For PSA in adults, a dose of 1 to 2 mg/kg is given IV over one to two minutes. Subsequent doses of 0.25 to 1 mg/kg may be repeated every 5 to 10 minutes thereafter. If ketamine is being used as a single agent for sedation, the subsequent doses are usually at the higher end of the range, typically 0.5 to 1 mg/kg. If ketamine is being used in combination with other agents, subsequent doses are at the lower end of the range, typically 0.25 to 0.5 mg/kg. Ketamine can also be given intramuscularly.
As with any sedative, the decision about appropriate repeat doses should take into consideration the effect of the initial dose, the duration of the procedure, and the depth of sedation required for its completion.
•Impaired kidney or liver function – No dose adjustments are required for ketamine in patients with impaired kidney or liver function.
•Obesity – We suggest using AdjBW (calculator 1) to determine the initial dosing of ketamine for PSA with additional titrated doses provided as needed [62]. There is insufficient evidence to determine the best dosing regimen for ketamine when used for PSA in patients with obesity. Basing dose on ABW may increase the risk of side effects and oversedation, but some experts would recommend ABW dosing in patients with a BMI 30 to 39 kg/m2 [84]. (See 'Patients with obesity' above.)
●Preventing and managing adverse effects – The reported side effects of ketamine include tachycardia, hypertension, emergence reactions, nausea, vomiting, laryngospasm, hypersalivation, and increased intracranial and intraocular pressure [4,85-87]. Tachycardia and hypertension (from increased sympathetic tone) are generally mild and transient, and significant cardiorespiratory events are rare. There is theoretical concern that ketamine could cause myocardial ischemia in patients with underlying coronary artery disease. Serious adverse reactions rarely occur when ketamine is used for PSA in adults according to a systematic review of 87 studies involving over 70,000 patients [85]. Anticipated adverse effects can be mitigated as follows:
•Emergence reactions – These are the most commonly reported side effects of ketamine, occurring in up to 20 percent of adults [85]. We believe that the decision to use pretreatment versus to intervene, if necessary, when a reaction occurs can be left to the clinician's discretion. These reactions vary in their intensity and have been described as disorientation, dreamlike experiences, or hallucinations that may be frightening. Although disturbing in some cases, emergence reactions are often benign and self-limited, requiring no pharmacologic treatment.
Emergence reactions can be prevented with midazolam pretreatment [22,85,88-91]. A typical adult IV pretreatment dose of midazolam is 2 to 4 mg (approximately 0.05 mg/kg) given slowly (over about two minutes) prior to administering ketamine. An alternative agent is haloperidol (5 mg), which was found to produce a comparable reduction in emergence reactions in a small randomized trial [92]. When given as pretreatments for emergence delirium, midazolam and haloperidol appear to cause no adverse clinical effects, but both slightly prolong recovery time (17 and 32 minutes, respectively) [92].
Emergence reactions, when they do occur, can be promptly and effectively treated with small doses of benzodiazepines such as midazolam [93,94].
•Pretreatment with antiemetic – Pretreatment with ondansetron or comparable agents may be helpful to prevent nausea and vomiting associated with ketamine administration that occurs in approximately 4 percent of adults. Nausea and vomiting usually occur when the patient is awake and alert and thus probably do not predispose the patient to aspiration. (See "Pediatric procedural sedation: Pharmacologic agents", section on 'Ketamine'.)
•Preventing laryngospasm – Laryngospasm is a rare complication, occurring more frequently in children than adults, and is typically either transient or improves with bag-mask ventilation. We agree with guidelines published by the American College of Emergency Physicians that recommend minimizing triggers of laryngospasm in patients receiving ketamine for PSA, such as preventing secretions or blood from accumulating in the posterior oropharynx and avoiding excessive stimulation of the oropharynx with suction devices or other instruments [87]. The risk of laryngospasm may be greater in patients with anatomic abnormalities of the upper airway (eg, tracheal stenosis, tracheomalacia) or those undergoing procedures involving significant or prolonged stimulation of the oropharynx.
•Pretreatment with anticholinergic not needed – Hypersalivation commonly occurs from ketamine but is rarely of clinical significance in adult patients. There is no established benefit of premedicating with glycopyrrolate or atropine to prevent the hypersalivation associated with ketamine [11].
Ketamine analgesia for sedation — Ketamine coadministered during PSA in sub-dissociative dosing (0.25 to 0.5 mg/kg bolus, maximum bolus 35 mg), as compared with opioids, can provide adequate analgesia with possibly fewer complications. Trials suggest that adding ketamine to propofol provides more consistent sedation, reduces pain, decreases the need for post-procedural analgesics, results in fewer episodes of desaturation, and requires smaller cumulative doses of propofol [95,96]. A small trial found that patients given ketamine (0.3 mg/kg IV) and propofol during PSA achieved similar analgesia but experienced five-times fewer complications (eg, hypoxia) compared with patients given fentanyl (1.5 mcg/kg IV) and propofol [97].
Premixed with propofol (ketofol) — "Ketofol," which refers to a 1:1 mixture of ketamine and propofol for use in PSA, purportedly reduces the risk for potential side effects (eg, propofol-induced hypotension and ketamine-induced vomiting and emergence reactions) since the two medications act synergistically, thus allowing lower doses of each as well as increasing ease of administration [97,98]. There is no standard for mixing or dose regimen; a common approach is to mix 10 mg/mL ketamine and 10 mg/mL propofol into a 20-mL syringe. The initial dose is 0.375 to 0.5 mg/kg (0.0375 to 0.05 mL/kg of this mixture), and half of this dose can be repeated as needed.
However, some of the better-designed studies of ketofol have shown that this combination therapy is not more efficacious or safer (ie, improving clinically significant outcomes or reducing important complications) than propofol or ketamine alone, but it may provide a more consistent level of sedation [3,96,99-102]. Additionally, by not premixing these agents, even though administration is not as simple, ketamine premedication can still be given in a sub-dissociative dose followed by titrating propofol as a single agent. (See 'Ketamine analgesia for sedation' above.)
●A meta-analysis of patients given ketofol compared with propofol alone for PSA in emergency departments (6 trials, 932 patients) found fewer adverse respiratory events from ketofol (29.0 versus 35.4 percent, RR 0.82, 95% CI 0.68-0.99) [103]. However, many of these adverse events were not clinically important (eg, brief oxygen desaturation), and the review found no significant difference in the overall rate of adverse events or in the time required to complete procedures.
●Another meta-analysis of patients given ketofol compared with propofol alone for PSA not limited to the emergency department setting (18 trials, 1917 patients) found that ketofol caused less respiratory depression requiring intervention (14 trials, 6.0 versus 11.5 percent, RR 0.47, 95% CI 0.31-0.70) and less bradycardia (8 trials, 2.4 versus 6.5 percent, RR 0.47, 95% CI 0.27-0.82) and hypotension (9 trials, 2.3 versus 8.7 percent, RR 0.41, 95% CI 0.17-0.97) [104]. Although the interventions required to correct respiratory problems were not described, transient respiratory depression, bradycardia, or hypotension in patients receiving PSA in the emergency department is generally not considered clinically significant.
●A randomized, double-blind, multicenter trial of ketofol compared with propofol alone for PSA in the emergency department included 573 patients (powered to detect 10 percent difference) and found no clinically significant differences in the primary outcome of respiratory adverse events (desaturation, apnea, or hypoventilation) that required an intervention (3 versus 5 percent) [105]. Patients receiving ketofol were less likely to have hypotensive events (1 versus 8 percent) but more likely to experience severe emergence delirium (5 versus 2 percent).
●A randomized, double-blind trial of ketofol compared with propofol alone for PSA in a community hospital emergency department setting included 284 patients and found no clinically significant difference in the primary outcome of respiratory adverse events (30 versus 32 percent) [106]. Three patients receiving ketofol and one patient receiving propofol required bag-mask ventilation. Patients receiving ketofol had more consistent sedation and received fewer repeat doses (46 versus 65 percent), but these did not appear to be important clinical differences. Patients given ketofol had less agitation during the procedure (3.5 versus 10.5 percent), while the opposite was true during recovery (7 versus 5 percent).
Dexmedetomidine — The use of dexmedetomidine as a sole agent for PSA generally does not have significant advantages compared with other sedatives with regards to efficacy and side effects. Dexmedetomidine PSA may be a reasonable choice when loss of the airway would be catastrophic (eg, potentially difficult airway) or when tachycardia or hypertension would be particularly dangerous. Sedation with dexmedetomidine is characterized by generally preserved muscle tone and respiratory effort (even at 10 times the maximum recommended dosage), spontaneous movement, and easy arousal, enabling the patient to obey simple instructions [107-111]. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Dexmedetomidine'.)
Dexmedetomidine is an alpha agonist that acts at the locus coeruleus in the pons to reduce release of norepinephrine, resulting in sedation that is more similar to a natural sleep-like state than sedation produced by GABAergic agents (eg, propofol, benzodiazepines). It appears to reduce pain through modulation of alpha receptors in the spinal cord [112,113].
●Dosing – When used as a sedative agent (ie, mechanically ventilated patients), dexmedetomidine is usually given as an infusion at a rate of 0.2 to 1 mcg/kg/hour. A bolus of 0.5 to 1 mcg/kg can be given over 10 minutes prior to starting infusion. Dexmedetomidine can also be given intranasally in doses of 2 to 3 mcg/kg for anxiolysis and sedation when other routes of administration are felt not to be optimal choices [114,115].
Dexmedetomidine (same dose as above) combined with ketamine (1 to 2 mg/kg) provided effective procedural sedation while minimizing cardiovascular depression in several small trials [116-118].
•Impaired kidney or liver function – Lower starting doses are recommended in patients with liver disease but not with kidney disease [119].
•Obesity - We suggest using AdjBW (calculator 1) to determine the dosing of dexmedetomidine for PSA [62,120]. Dexmedetomidine's pharmacodynamics and pharmacokinetics differ in patients with obesity, and lower doses are needed to reach a given plasma concentration and level of sedation. (See 'Patients with obesity' above.)
●Adverse effects – Although uncommon, potentially serious events include decreased respiratory drive and airway obstruction [121-124]. Dose-dependent bradycardia and hypotension can occur, although hypertension may be seen initially during high-dose infusion due to stimulation of alpha 2B receptors [112]. Small observational studies have found that dexmedetomidine, when used alone, may provide unpredictable degrees of amnesia and sedation as well as unacceptable levels of bradycardia and hypotension, often requiring termination of the procedure or use of adjunctive sedatives [125,126].
Barbiturates — Barbiturates cause sedation by suppressing the reticular activating center in the brainstem and cerebral cortex. Methohexital and thiopental are barbiturates occasionally used for PSA.
●Methohexital – This is the most commonly used barbiturate for PSA but has largely been supplanted by etomidate and propofol. Methohexital has immediate onset and a duration of action less than 10 minutes, and it provides sedation and amnesia but no analgesia. It is often given in combination with opioids. One small randomized trial found methohexital and propofol to have comparable safety and efficacy when used for fracture and dislocation reduction [127]. A small study found methohexital to have similar efficacy and hemodynamic changes compared with propofol and etomidate when used for electrical cardioversion in the emergency department [128].
•Dosing – The initial dose of methohexital is 0.75 to 1 mg/kg given IV; repeat doses of 0.5 mg/kg IV can be given every two minutes.
-Older adults or impaired kidney or liver function – Use lower doses, longer dosing intervals, and smaller total amounts.
-Obesity – We suggest using IBW to calculate the initial doses of methohexital with additional titrated doses given as needed to achieve adequate sedation [129]. Patients with obesity have increased cardiac output, leading to more rapid redistribution and thus more rapid awakening after a single bolus dose [61]. (See 'Patients with obesity' above.)
•Adverse effects – Methohexital causes myocardial depression, which can lead to hypotension and tachycardia. Methohexital can cause respiratory depression, especially when coadministered with opioids. Unlike other barbiturates, methohexital can precipitate or exacerbate seizures and should be avoided in patients with a seizure disorder [130].
●Thiopental – This barbiturate is used for induction of general anesthesia and rarely used in the performance of PSA. It is similar in efficacy and side effects to methohexital but suppresses seizures. Dosing in patients with obesity, older adults, or patients with impaired kidney or liver function is similar to methohexital.
Nitrous oxide — Nitrous oxide (N2O) is an ultra-short-acting agent used for PSA that is inhaled as a 30 to 50 percent mixture combined with 30 percent oxygen to avoid hypoxemia. N2O has an immediate onset of action and provides analgesia, anxiolysis, and sedation and does not require IV access. The major disadvantage to N2O is that it must be administered in a well-ventilated room with a scavenging system to prevent clinician exposure [11].
Studies in children have generally found N2O to be safe, but it may not provide adequate analgesia for more painful procedures such as fracture reduction. N2O has been safely used for decades for labor pain in Great Britain, Scandinavia, Australia, New Zealand, Canada, and other countries but less commonly in the United States. (See "Pediatric procedural sedation: Pharmacologic agents", section on 'Nitrous oxide' and "Pharmacologic management of pain during labor and delivery", section on 'Nitrous oxide'.)
DISCHARGE CRITERIA — Certain conditions should be met before a patient can be considered safe for discharge following PSA:
●Symptoms such as pain, lightheadedness, and nausea should be well controlled
●Vital signs and respiratory and cardiac function should be stable
●Mental status and physical function should have returned to a point where the patient can care for themselves with minimal to no assistance
●A reliable person who can provide support and supervision should be present at the patient's home for at least a few hours
●Monitoring of complications from the procedure itself is unnecessary
Clear written discharge instructions should be given and explained to the patient and to the family member or other person who will be assisting with the patient's care following PSA. The clinician should explain what was done, the expected course, potential problems, what to do if problems arise, when and where to follow up, and when to return to normal activities. Inform the patient that it is not uncommon to experience mild symptoms such as nausea, lightheadedness, fatigue, or unsteadiness for up to 24 hours [131-133]. The patient should be instructed to avoid driving a motor vehicle, operating machinery, or consuming alcohol until the following day. Even though several small studies have shown that baseline neuromotor function may return as quickly as two hours after propofol PSA, their results are insufficient to recommend rapid return to operating a motor vehicle or dangerous machinery [134-136].
Some clinicians believe that patients can be safely discharged within 30 minutes of receiving their last dose of sedative, even if they have not entirely returned to baseline (eg, still exhibit mild drowsiness), provided that no significant adverse events occurred during the procedure, they did not receive a reversal agent (eg, naloxone, flumazenil), and a reliable person is available to provide support. A study of 1341 pediatric patients undergoing PSA with longer-acting agents (ie, ketamine, midazolam, fentanyl) found that almost all new adverse post-sedation events (eg, hypoxia, hypotension) occurred within 25 minutes of the last dose of sedative administration [137]. Rarely, episodes of hypoxia developed up to 40 minutes after the last medication dose, but in all such cases, these had been preceded by a prior episode of hypoxia. Given these findings, it is unlikely that a longer period of observation would be necessary following PSA with ultra-short-acting agents [24].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Procedural sedation in adults".)
SUMMARY AND RECOMMENDATIONS
●Choosing a medication – Ideal medications for procedural sedation and analgesia (PSA) have a rapid onset and short duration of action, maintain hemodynamic stability, and do not cause major side effects. No single drug is ideal for all situations. Medications used for PSA include propofol, etomidate, midazolam, fentanyl, ketamine, dexmedetomidine, and methohexital; dosing, onset, duration, and common adverse effect are presented in the table (table 1). (See 'Choosing a medication' above.)
•Patients without increased risk – In patients without major comorbidities or hemodynamic instability, we suggest that PSA be performed using propofol or etomidate (Grade 2C). Both medications are safe and effective and possess similar times to onset and recovery, but propofol may result in a higher procedural success rate because it causes less myoclonus compared with etomidate. (See 'Preferred medications in healthy patients: Propofol or etomidate' above and 'Propofol' above and 'Etomidate' above.)
"Ketofol" (1:1 mixture of ketamine and propofol) is an alternative option that is not more efficacious or safer than propofol or ketamine alone but may provide a more consistent level of sedation (eg, fewer repeat sedative doses, less procedural agitation). By not premixing ketamine and propofol, even though administration is not as simple, ketamine premedication can still be given followed by titrating propofol as a single agent. (See 'Premixed with propofol (ketofol)' above and 'Propofol' above.)
In settings where propofol and etomidate are unavailable or a longer duration of PSA is required (eg, gastrointestinal endoscopy), a combination of midazolam and fentanyl are commonly used, and ketamine is also a reasonable option. (See 'Coadministration of midazolam and fentanyl' above and 'Ketamine' above.)
•Older patients – Regardless of the sedative, administer using a lower starting dose and with slower rates of administration and less frequent dosing intervals since older patients are at increased risk of complications during PSA. The initial bolus dose of propofol should not exceed 0.5 mg/kg. (See 'Older adult patients' above.)
•Patients with obesity – Adjustments in the dosing of medications used for PSA should generally be based on ideal, adjusted, or lean body weight to avoid oversedation and are described in detail in the text. (See 'Patients with obesity' above.)
•Patients at risk of hypotension – In patients at risk of hypotension, we suggest using either etomidate or ketamine for PSA instead of another sedative (Grade 2C). Either agent will maintain hemodynamic stability. (See 'Patients at risk for hypotension' above and 'Etomidate' above and 'Ketamine sedation' above.)
•Patients with potentially difficult airway – In patients who may have a potentially difficult airway or have compromised respiratory function, we suggest using ketamine for PSA instead of another sedative (Grade 2C). Ketamine allows the patient to maintain protective airway reflexes and does not cause respiratory depression. Dexmedetomidine is an alternative option since it generally preserves muscle tone and respiratory effort. (See 'Patients at risk for airway or respiratory complications' above and 'Ketamine sedation' above and 'Dexmedetomidine' above.)
•Patients with major medical conditions – Conditions such as heart failure, chronic obstructive pulmonary disease, and neuromuscular diseases (ie, correlating with an American Society of Anesthesiologists [ASA] physical status classification of class III or greater) (table 3) place patients at increased risk for adverse events with PSA. Similar to older patients, regardless of the sedative chosen for PSA, use a lower starting dose, slower rates of administration, and repeat dosing at less frequent intervals. (See 'Patients with major medical conditions' above.)
●Coadministration of analgesics – The decision to coadminister an analgesic should be individualized based on the patient's pre-procedure pain, expected pain course during and after the procedure, and risk of complications from administering a synergistic agent. Short-acting opioids (eg, fentanyl, alfentanil, remifentanil) are often given in combination with sedatives that provide no analgesia (eg, propofol, etomidate, benzodiazepines). Ketamine administered in sub-dissociative dosing (0.25 to 0.5 mg/kg bolus, maximum bolus 35 mg) is another analgesic option that does not have the risk of respiratory depression that occurs with opioids. (See 'Short-acting opioids (fentanyl, others)' above and 'Ketamine analgesia for sedation' above.)
●Discharge criteria – Criteria for safe discharge following PSA include the following (see 'Discharge criteria' above):
•Symptoms such as pain, lightheadedness, and nausea should be well-controlled
•Vital signs and respiratory and cardiac function should be stable
•Mental status and physical function should have returned to a point where the patient can care for themselves with minimal to no assistance
•A reliable person who can provide support and supervision should be present at the patient's home for at least a few hours
•Monitoring of complications from the procedure itself is unnecessary
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