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Procedural sedation in adults

Procedural sedation in adults

Author
Robert L Frank, MD, FACEP
Section Editor
Allan B Wolfson, MD
Deputy Editor
Jonathan Grayzel, MD, FAAEM

Disclosures

Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Wed Oct 19 00:00:00 GMT 2011 (More)

INTRODUCTION — The practice of acute care medicine often requires the performance of procedures that can cause pain and anxiety. Procedural sedation reduces the discomfort, apprehension, and potential unpleasant memories associated with such procedures and facilitates their performance.

The practice of procedural sedation in adults, including monitoring and medications, will be reviewed here. Procedural sedation in children and the sedation required for lengthier procedures, such as colonoscopy, are discussed separately. (See “Procedural sedation and analgesia in children” and “Overview of procedural sedation for gastrointestinal endoscopy”.)

DEFINITIONS — Procedural sedation involves the use of short-acting analgesic and sedative medications to enable clinicians to perform procedures effectively, while monitoring the patient closely for potential adverse effects. This process was previously (and inappropriately) termed “conscious sedation”, but because effective sedation often alters consciousness the preferred term is now “procedural sedation and analgesia” (PSA) [1].

The practice of providing sedation, once primarily the domain of anesthesia practitioners, is now routinely performed by other specialists, such as emergency clinicians, critical care specialists, and various nurse specialists [2].

Recognizing that PSA exists along a spectrum, the Joint Commission on Accreditation of Healthcare Organizations in the United States has attempted to define the levels of sedation, which range from minimal sedation to general anesthesia [3-5]. Common terms include the following:

  • Analgesia – Relief of pain without intentionally producing a sedated state. Altered mental status may occur as a secondary effect of medications administered for analgesia.
  • Minimal sedation – The patient responds normally to verbal commands. Cognitive function and coordination may be impaired, but ventilatory and cardiovascular functions are unaffected.
  • Moderate sedation and analgesia – The patient responds purposefully to verbal commands alone or when accompanied by light touch. Protective airway reflexes and adequate ventilation are maintained without intervention. Cardiovascular function remains stable.
  • Deep sedation and analgesia – The patient cannot be easily aroused, but responds purposefully to noxious stimulation. Assistance may be needed to ensure the airway is protected and adequate ventilation maintained. Cardiovascular function is usually stable.
  • General anesthesia – The patient cannot be aroused and often requires assistance to protect the airway and maintain ventilation. Cardiovascular function may be impaired.
  • Dissociative sedation – Dissociative sedation is a trance-like cataleptic state in which the patient experiences profound analgesia and amnesia, but retains airway protective reflexes, spontaneous respirations, and cardiopulmonary stability [6]. Ketamine is the pharmacologic agent used for procedural sedation that produces this state. (See ‘Ketamine’ below.)

Sedation exists on a continuum, and it is difficult to divide it into discrete clinical stages, the definitions above notwithstanding [5]. Moreover, many sedatives can cause rapid changes in the depth of sedation. Dissociative sedation stands apart from the continuum of sedation due to its unique characteristics.

INDICATIONS — There are no absolute indications for the performance of PSA. PSA may be used for any procedure in which a patient’s pain or anxiety may be excessive and may impede performance. PSA is often useful for procedures where deep relaxation facilitates performance (eg, closed reduction of a dislocated joint). Common procedures in which PSA may be beneficial include electrical cardioversion, closed joint reduction, complicated laceration repair, abscess incision and drainage, and lumbar puncture.

CONTRAINDICATIONS AND PRECAUTIONS

General considerations — There are no absolute contraindications to PSA. Relative contraindications may include: older age, significant medical comorbidities, and signs of a difficult airway. Whether the patient recently ate should be considered before performing PSA, although this does not appear to have a major impact on aspiration risk [7,8]. (See ‘Aspiration risk’ below.)

Several factors must be considered before proceeding with PSA. First, the clinician and the patient must agree that the potential benefit of PSA outweighs the risks. Risk depends upon the patient and the procedure.

There is no specific age above which PSA may not be performed. Nevertheless, the elderly have higher rates of adverse events [9]. This may be due to an increased sensitivity to sedative drugs, medication interactions, and higher peak serum levels of administered drugs [10-12].

Patients with major comorbid medical conditions are at increased risk for adverse events with PSA. This correlates with an ASA physical status classification of Class III or greater (table 1) [10,12]. Important comorbidities are those that increase patient susceptibility to the cardiorespiratory depressant effects of sedatives. They include heart failure, chronic obstructive pulmonary disease, neuromuscular disease, dehydration, and anemia. Unfortunately, there is no evidence that alternative approaches (eg, monitored anesthesia care or general anesthesia in the operating room) are safer for patients at increased risk from PSA.

To reduce the risk of adverse events in the elderly and patients with major comorbid disease, we suggest a more conservative approach to PSA medications, including:

  • Giving a lower starting dose
  • Using slower rates of administration
  • Repeated dosing of medications at less frequent intervals

PSA is relatively contraindicated in patients who are likely to be difficult to ventilate or oxygenate should respiratory difficulties arise while the patient is sedated. Alternatives to PSA may be preferable if signs suggesting a difficult airway are identified. (See “The difficult airway in adults”.)

No data clearly demonstrate that a longer duration of PSA correlates with an increase in adverse outcomes. Nevertheless, common sense suggests that it is preferable to sedate patients for the shortest period necessary to perform the procedure.

Aspiration risk — Aspiration of gastric contents during anesthesia or PSA is a rare, though much feared complication [7,8]. Patients undergoing emergency procedures requiring sedation are thought to be at increased risk of aspiration because their stomachs are often full, and the procedure cannot be delayed. Aspiration frequently does not cause harm. However, aspirated gastric contents above a critical volume and acidity can cause severe respiratory and systemic consequences [13]. The importance of fasting for preventing aspiration during PSA remains unclear.

Guidelines to reduce aspiration risk were put forth in a consensus statement by the American Society of Anesthesiologists (ASA) [3]. These guidelines are based upon expert opinion and to a lesser extent extrapolated from general anesthesia data, in which aspiration with serious consequences is rare [3,14]. The ASA guidelines recommend that patients undergoing PSA for “elective procedures” fast according to the standards used for general anesthesia. This requires that patients not eat or drink for two hours after drinking clear liquids and six hours after ingesting solid foods or cow’s milk [3]. If these standards cannot be met, the guidelines recommend that the clinician consider delaying the procedure, reducing the level of sedation, or protecting the airway with endotracheal intubation.

Implementing these guidelines in the emergency department (ED) presents several problems. First, it is rare that patients requiring emergent PSA meet these fasting criteria. Second, emergent procedures cannot be delayed. Finally, although fasting to reduce the risk of aspiration during PSA or elective surgery makes intuitive sense, there is little evidence to support this approach [14-18].

According to one review, patients who fast for two hours have the same gastric volume and pH as those who fast for longer periods [13]. Furthermore, there is no clear evidence that a relationship exists among fasting time, gastric volume, gastric pH, depth of sedation, and the likelihood of aspiration [6,12,16,18-20]. Clinically significant aspiration during emergency department PSA appears to be rare [7]. Furthermore, endotracheal intubation may not protect the patient from aspiration [14,18,19,21-23]. Aspiration can occur despite the presence of an endotracheal tube, while the airway manipulation involved in performing intubation appears to increase the risk of aspiration.

In light of the available literature, the American College of Emergency Physicians policy statement on PSA states: “Recent food intake is not a contraindication for administering procedural sedation and analgesia, but should be considered in choosing the timing and target of sedation” [24]. We concur and suggest the following approach to reducing aspiration risk:

  • Carefully consider the risks and benefits of performing the procedure emergently. Although there is no proof that longer fasting times reduce aspiration risk, it is reasonable to wait if the patient’s stomach is full and the procedure is not a true emergency [25]. This is particularly true when a potentially difficult airway or an increased risk for aspiration exists, such as with the following circumstances [18]:
  • Conditions predisposing to esophageal reflux (eg, bowel obstruction, hiatal hernia)
  • Extremes of age (<6 months or >70 years old)
  • Severe systemic disease (ASA class III or greater)
  • Other concerning conditions (eg, depressed mental status)
  • Avoid deep sedation. No evidence clearly demonstrates that deeper levels of sedation increase the risk of aspiration [18]. Nevertheless, lighter sedation may permit the patient to maintain protective airway reflexes, which reduces risk.
  • We do not suggest administration of pre-procedural antacids or motility agents to reduce aspiration risk. These medications have not been shown to reduce such risk [16].

In some cases it may be best to perform the procedure under general anesthesia in the operating room, although this approach has not been proven to reduce the risk of aspiration [20,21].

PERFORMING PROCEDURAL SEDATION

Informed consent — Before performing PSA, the clinician must discuss the risks, benefits, and alternatives of the procedure and the planned sedation with the patient and answer any questions. A printed informed consent form may be used. Implied consent is acceptable in some cases where the patient is unable to provide explicit consent due to severe pain or altered mental status [24].

Prerequisites and personnel — Although previously the domain of anesthesia practitioners, PSA is performed safely by other clinicians, including emergency and critical care physicians and nurse specialists [26]. Clinicians providing PSA should have in-depth knowledge of the relevant drugs, including their mechanism of action, doses, side effects, and reversal agents. Such clinicians must also be well versed in advanced cardiovascular life support, including airway management. (See “Advanced cardiac life support (ACLS) in adults”.)

The number of clinicians needed to perform PSA and the procedure safely may vary according to the patient and the procedure. In most cases, one clinician performs the procedure while another (usually a nurse) administers the sedative agents and monitors and records the patient’s vital signs and clinical status. Whenever possible, we suggest that this minimum standard be met.

It remains controversial whether an additional clinician, separate from the clinician performing the procedure, who is skilled in deep sedation administration and airway management should be present [12,24]. Guidelines from the American Society of Anesthesiologists (ASA) call for someone with “advanced life support skills” to be immediately available (within five minutes) for PSA and present in the procedure room whenever deep sedation is being performed [3]. Large case series of propofol sedation administered by nurses for ambulatory procedures demonstrate that serious adverse events can occur [27]. However, one prospective observational study of over 1000 procedural sedations found that PSA performed by a single emergency clinician (EP) had comparably low complication and high success rates when compared with PSA performed with both an EP and a nurse present [28].

Equipment — All equipment necessary to perform the procedure and manage the airway should be available at the bedside during the performance of PSA. Such equipment includes suction to manage vomiting or oral secretions, airway adjuncts, such as a bag-valve mask and oral and nasal airways, and equipment to perform endotracheal intubation. Intravenous access should be established. Resuscitation medications, including advanced cardiac life support medications and reversal agents (ie, naloxone and flumazenil) should be available. Appropriate monitors should be in place. (See ‘Monitoring and preoxygenation’ below.)

Monitoring and preoxygenation — Proper monitoring during the performance of PSA is crucial. The patient’s blood pressure, heart rate, and respiratory rate should be measured at frequent, regular intervals; the oxygen saturation (SpO2), end-tidal carbon dioxide level (EtCO2), and cardiac rhythm should be monitored continuously [12].

The patient’s response to medications and the procedure must also be closely monitored during PSA. The patient’s level of alertness, depth of respiration, and response to painful stimuli (eg, fracture reduction) are all important factors in determining subsequent medication doses. Sedation scales, such as the Richmond Agitation Sedation Scale and the Ramsay Score, have not been adequately studied in the setting of PSA. They may be more useful in determining the appropriate titration of sedatives during long-term procedures (eg, mechanical ventilation).

Supplemental oxygen is often recommended during PSA to maintain oxygen reserves and prevent hypoxemia caused by hypoventilation [3]. However, there is little evidence to show that this is beneficial and some researchers question the practice.

The best evidence supporting the use of oxygen is a double blind, randomized trial of adults undergoing PSA with propofol in which episodes of hypoxia (SpO2 <93 percent) lasting longer than 15 seconds occurred significantly more often (41 percent) among the 58 patients given compressed air by face mask compared to the 59 patients given high flow oxygen (19 percent) using the same delivery system (difference 23 percent; 95 percent CI 6 to 38 percent). [29]. However, the clinical significance of such transient episodes of hypoxia remains debatable.

Several observational studies have found that supplemental oxygen at lower concentrations does not reliably prevent hypoxemia during PSA [30,31], and delays the detection of respiratory depression in patients without EtCO2 monitors, since SpO2 levels may not fall until a prolonged period of hypoventilation or apnea has occurred [32,33]. Nevertheless, we suggest that high flow oxygen by face mask be given to patients undergoing PSA because it may reduce the likelihood of hypoxic episodes, particularly with prolonged procedures, is easy to perform, and is highly unlikely to cause harm.

However, among patients not provided with supplemental oxygen, respiratory difficulty during PSA can manifest earlier as hypoxia, as detected by pulse oximetry, rather than as hypoventilation, as determined by EtCO2 monitors, according to a small nested randomized trial [34]. Therefore, close attention to pulse oximetry readings remains critical in patients’ breathing room air during PSA.

We recommend pulse oximetry and EtCO2 monitoring for all patients undergoing PSA. EtCO2 measurements correlate closely with arterial CO2 and provide an early sign of hypoventilation or apnea, especially if supplemental oxygen is used [32,33,35-37]. EtCO2 is discussed in detail separately. (See “Carbon dioxide monitoring (capnography)”.)

While intuitively it makes sense that early detection of hypoxemia and hypoventilation is beneficial, there is no data to suggest that brief episodes of either have a negative impact on patient outcome, especially if recognized quickly and treated appropriately [24,38].

Bispectral analysis monitoring (BIS), a technology developed to monitor the level of general anesthesia, does not appear to be useful for monitoring the depth of procedural sedation [39-41]. BIS measurements do not appear to correlate well with clinical sedation and have poor reproducibility.

Considerations in pregnancy — Modifications of procedural sedation guidelines recommended for pregnant women include:

  • Preprocedural administration of medication to improve gastroesophageal sphincter tone and reduce gastric volume (eg, metoclopramide) and decrease stomach acidity (eg, H2 antagonists, sodium citrate) may reduce the risk of vomiting and aspiration and is unlikely to cause harm. Aspiration risk is discussed separately. (See ‘Aspiration risk’ above.)
  • Preprocedural hydration and left lateral displacement of the uterus (in the late second and the third trimester) helps to reduce the risk of hypotension, uteroplacental insufficiency, and resultant fetal hypoxemia. Fetal monitoring is not required, but should be considered for women in the third trimester. (See “Antepartum fetal heart rate assessment”.)
  • Oxygen by face-mask is administered because of the risk of sedation-related maternal desaturation (primarily due to decreased functional residual capacity). (See “Respiratory tract changes during pregnancy” and “Maternal cardiovascular and hemodynamic adaptations to pregnancy”.)

COMPLICATIONS — Serious complications attributable to PSA rarely occur. Significant respiratory compromise, the most concerning potential complication, develops in less than one percent of cases [42]. Adverse outcomes may include respiratory depression with hypoxia or hypercarbia, cardiovascular instability, vomiting and aspiration, emergence reactions, and inadequate sedation preventing completion of the procedure [10].

Multiple studies of pediatric patients have found that PSA is safe, with no deaths reported and few serious consequences [27,43-45]. One observational case series of 640 patients undergoing PSA reported a 15 percent combined adverse event rate (adverse event and failure to perform procedure) [9]. In this study, factors associated with adverse events included older age, the presence of multiple medical conditions (ie, higher ASA class), and the performance of esophagoscopy or cardioversion.

Many complications can be prevented through appropriate selection of patients, proper use of sedative medication, and careful monitoring of sedation. Particular attention should be paid to patients in whom oxygenation and ventilation may be difficult, should the need for airway management arise. Such patients may not be appropriate candidates for PSA. (See ‘Contraindications and precautions’ above.)

Nearly all of the sedative agents used for PSA can cause dose-dependent respiratory depression [10]. Therefore, respiratory complications are the most common adverse events. Oxygen desaturation develops in up to 11 percent of adults who receive PSA with either propofol or etomidate and are given supplemental oxygen [12]. Rates are slightly higher if supplemental oxygen is not used. Oxygen desaturation can be minimized by cautious, unhurried medication administration [10].

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Hypoventilation and apnea may occur but are usually short-lived due to the brief duration of the drugs used for PSA. These complications nearly always resolve with patient stimulation, supplemental oxygen, positioning of the airway, or brief ventilatory support using a bag-valve mask. Treatment with the reversal agent naloxone or flumazenil may be necessary with more severe or prolonged respiratory depression during PSA using opioids or benzodiazepines. The use of naloxone and flumazenil are reviewed separately. (See “Opioid intoxication in adults”, section on ‘Basic measures and antidotal therapy’ and “Benzodiazepine poisoning and withdrawal”, section on ‘Antidote (Flumazenil)’.)

Significant hypotension and bradycardia seldom occur, but may develop in patients with significant cardiac morbidity and those taking cardiodepressant medications (eg, beta blockers) [10,42,46,47]. The problems are usually transient and resolve without intervention. Hemodynamically neutral sedatives (eg, etomidate) may be preferable for patients at risk from changes in blood pressure or heart rate.

Nausea and vomiting occur in about 5 percent of patients undergoing PSA, although rates may be higher when opioids are used [48-51]. Antiemetics may be used as needed. There is little evidence about the prophylactic use of antiemetics or which agent is preferable. In one randomized trial involving PSA with ketamine, 16 of 127 children managed without antiemetics experienced post-procedural vomiting versus 6 of 128 children pretreated with ondansetron, a 7.9 percent reduction in absolute risk (95% CI 1.1-14.7) [52].

MEDICATIONS — Procedural sedation and analgesia (PSA) typically involves the intravenous (IV) administration of sedative or dissociative agents, sometimes in combination with short-acting opioids (table 2) [24]. Ideal drugs for PSA have a rapid onset and short duration of action, maintain hemodynamic stability, and do not cause major side effects [2]. Several medications are commonly used and no single drug is ideal for all situations.

Propofol — Propofol is a phenol derivative that has been shown to provide effective PSA for emergent procedures [2,53]. Propofol is highly lipophilic and therefore crosses the blood-brain barrier rapidly. The drug takes effect within approximately 40 seconds, and its duration of action is approximately six minutes [12,53]. Propofol acts as a sedative and amnestic, but provides no analgesia.

Propofol can induce deep sedation rapidly and must be given with careful attention to dosing and monitoring. 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 0.5 mg/kg IV every three to five minutes as necessary until the appropriate level of sedation is achieved [12]. 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. (See ‘Monitoring and preoxygenation’ above.)

The pharmacokinetics of propofol appear to be unchanged in patients with impaired kidney or liver function. However, plasma levels appear to be increased in elder patients, which can lead to prolonged sedation and more pronounced cardiorespiratory depression. Patients over 55 are particularly sensitive [12]. The manufacturer recommends that doses in elders be reduced by 20 percent and that the drug be given more slowly (over three to five minutes) [54]. Reductions from 20 to 60 percent of the dose used in a healthy young adult are reasonable (See ‘Elderly patients’ below.)

The propofol formulation contains egg lecithin and soybean oil, and therefore is contraindicated in patients with a sensitivity to either of these substances [55].

Potential side effects include hypotension (due to myocardial depression) and respiratory depression. These side effects generally resolve quickly and uneventfully because of the brief duration of action. However, hypotension can produce complications in patients with severe medical problems (eg, sepsis, cardiac dysfunction) or hypovolemia [12].

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 uneventful and successfully treated with supplemental oxygen and patient stimulation, and less commonly require short periods of assisted ventilation with a bag-valve mask. There are no reports of endotracheal intubation due to propofol-induced respiratory depression during PSA [12].

Propofol provides no analgesia and can cause pain during injection through an intravenous catheter. According to a systematic review of 177 randomized controlled trials involving 25,260 adult patients, the following measures are significantly effective at reducing pain caused by propofol injection [56]:

  • Injecting into an antecubital vein rather than a hand vein (relative risk [RR] 0.14; 95% CI 0.07-0.30)
  • Lidocaine pretreatment while occluding the vein (RR 0.29; 95% CI 0.22-0.38)
  • Pretreatment with lidocaine-propofol admixture (RR 0.40; 95% CI 0.33-0.48)
  • Lidocaine pretreatment without vein occlusion (RR 0.47; 95% CI 0.40-0.56)
  • Opioid pretreatment (RR 0.49; 95% CI 0.41-0.59)
  • Ketamine pretreatment (RR 0.52; 95% CI 0.46-0.57)

Pain during injection can also be reduced by using larger catheters placed in larger veins.

Pretreatment with any of several analgesics can reduce the pain caused by propofol. One effective approach is to place a tourniquet on the arm proximal to the injection site and then give 0.5 mg/kg of lidocaine IV 30 to 120 seconds before propofol is injected [53].

Another approach is pretreatment with short-acting opioids (eg, fentanyl). Unfortunately, the addition of opioids increases the likelihood of respiratory complications. As an example, fentanyl at a dose of 1.5 mcg/kg increases the risk of respiratory depression. To reduce this risk, smaller doses of fentanyl should be used. The best dose to provide adequate analgesia with minimal respiratory risk has yet to be identified. We suggest that no single dose of fentanyl exceed 0.5 mcg/kg when given with propofol and that the total amount of fentanyl be kept to the minimum required for effective analgesia.

It may not be necessary to combine propofol with a short-acting opioid if the patient’s pain is adequately treated prior to the procedure. This approach is supported by an unblinded randomized trial in which patients given PSA consisting of propofol alone had pain levels identical to those treated with both propofol and alfentanil [57]. For both treatment groups, intravenous morphine was given at least 20 minutes prior to the procedure to all patients experiencing pain until their symptoms were adequately relieved. Of note, patients given both alfentanil and propofol required stimulation to induce respiration more often than those given only propofol.

Another alternative to pretreatment with short-acting opioids is to use sub-dissociative doses of ketamine (0.3 mg/kg). Ketamine appears to provide comparable analgesia with less risk of respiratory depression. (See ‘Ketamine versus short-acting opioids for analgesia’ below.)

In some instances, patients experience little or no pain before or after a procedure (eg, lumbar puncture, cardioversion) and little if any analgesia may be necessary to supplement propofol. In addition, some procedures lead to a substantial reduction in pain (eg, dislocation reduction), decreasing the need for analgesics as part of PSA.

Multiple randomized trials and prospective observational studies have found propofol to be safe and effective for PSA in the emergency department [12]. Even in the contentious area of nurse-administered propofol sedation, where typically the only physician present is performing the procedure (eg, outpatient endoscopy), there is a large body of evidence documenting the safety and efficacy of propofol [58,59].

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 [60,61]. 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” [62]. In the United States, these statements have led some nursing organizations to question whether nurses other than certified registered nurse anesthetists should administer propofol.

Etomidate — Etomidate, an imidazole derivative, is a sedative that is commonly used for PSA. The use of etomidate for rapid sequence intubation is discussed elsewhere. (See “Sedation or induction agents for rapid sequence intubation in adults”.)

For PSA in adults, etomidate is given IV over 30 to 60 seconds in doses of 0.1 to 0.15 mg/kg, less than the dose used for rapid sequence intubation. It can be redosed 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 [63,64].

Etomidate can have more profound and prolonged effects in the elderly and patients with renal or hepatic dysfunction. In such patients, doses in the lower dosing range should be used. An important benefit of etomidate is that it maintains cardiovascular stability.

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 [64]. To reduce this risk, smaller doses of fentanyl should be used. The best dose to provide adequate analgesia with minimal respiratory risk has yet to be identified. We suggest that no single dose of fentanyl exceed 0.5 mcg/kg when given with etomidate and that the total amount of fentanyl be kept to a minimum.

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.)

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) [63,65-67]. However, side effects, particularly myoclonus, occur with regularity and procedure success rates may be lower when compared with propofol or ketamine. (See ‘Propofol versus etomidate’ below.)

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 [67-70]. The degree of myoclonus may be dose dependent and ranges from mild and transient to severe enough to prevent completion of the procedure [63].

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.

Strategies to prevent myoclonus vary and there is insufficient evidence to support any one approach:

  • According to one small randomized trial, a pretreatment dose of 0.03 to 0.05 mg/kg of etomidate given 50 seconds before the PSA dose reduces myoclonus [68].
  • Another small randomized trial in patients undergoing cardioversion found that a small dose of midazolam (0.015 mg/kg) given at the same time as etomidate prevents myoclonus [71].
  • In another randomized trial, magnesium sulfate administered 90 seconds prior to etomidate was found to reduce myoclonus [72].

According to a systematic review of etomidate for PSA, respiratory depression occurs in approximately ten percent of cases [65]. In this review, respiratory depression was defined as a fall in oxygen saturation below 90 percent or apnea. No serious complications occurred as a result 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.

When given by continuous infusion, etomidate causes adrenal insufficiency. In addition, reductions in plasma cortisol concentrations have been reported in patients receiving a single induction dose of etomidate [73,74]. 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. In such patients, complications related to adrenal suppression have not been reported.

Benzodiazepines (midazolam) — Benzodiazepines are commonly used for minimal sedation (anxiolysis), but less often for deeper sedation due to the superior effectiveness of the ultrashort-acting agents propofol and etomidate. Benzodiazepines produce anxiolysis and amnesia, but have no analgesic properties.

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 2 to 5 minutes, and its duration of action is 30 to 60 minutes [75,76].

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 0.5 or 1 mg at a time and titrated to effect. No single dose should exceed 2.5 mg. Repeat doses may be given every two to five minutes as necessary.

With repeated doses, midazolam accumulates in adipose tissue, which can significantly prolong sedation [75]. The elderly, obese, and those with renal or hepatic disease are at greater risk of prolonged sedation. In such patients, the use of lower doses, longer dosing intervals, and smaller total amounts reduces risk.

The amount of midazolam necessary for adequate sedation varies based upon many factors, including patient size 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. For longer procedures likely to require multiple doses of a sedative, ultrashort-acting agents (eg, propofol) may be preferable. (See ‘Propofol’ above.)

Compared with ultrashort-acting agents, midazolam has a longer duration of action that makes it better suited for anxiolysis than for PSA [69]. Midazolam can cause respiratory depression in high doses or when given concomitantly with other sedatives or narcotics. For anxiolysis, a single dose of 0.02 mg/kg (approximately 1 to 2 mg) is usually sufficient.

Other benzodiazepines, such as 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 [76,77].

Short-acting opioids — Opioids are often given alone or in combination with sedatives for PSA. Short-acting agents, such as fentanyl, alfentanil, and remifentanil, are used.

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 [76].

Fentanyl is usually given by slow IV push in doses of 0.5 to 1 mcg/kg every two minutes until an appropriate level of sedation and analgesia is achieved [76]. The maximum total dose is generally 5 mcg/kg or approximately 250 mcg, but higher doses may be needed in some instances.

Fentanyl rarely causes hypotension and does not stimulate histamine release. Its primary side effect is respiratory depression, which is potentiated by the coadministration of sedatives. Patients with renal or hepatic disease and the elderly can experience more prolonged or profound effects. In such patients, the use of lower doses, longer dosing intervals, and smaller total amounts reduces risk.

Remifentanil and alfentanil are opioids similar in structure to fentanyl with a rapid onset and duration of action of approximately five minutes. 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 [78-80]. 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.

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 [79]. Subsequent doses of remifentanil 0.25 mcg/kg and propofol 0.25 mg/kg may be given approximately every one to two minutes. 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 [78].

Few studies have assessed alfentanil as a sole agent for PSA and there are no published guidelines for its use in this manner. In one prospective observational 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 [81].

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.

Coadministration of midazolam and fentanyl — In settings where ultrashort-acting agents are unavailable, the combination of midazolam and fentanyl is sometimes used for PSA [24,48,82,83]. 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 ultrashort-acting agents (eg, propofol) [24,76]. To minimize the risk of respiratory depression, some recommend that midazolam be given first and fentanyl titrated thereafter [24]. One 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 the elderly and patients with compromised hepatic or renal function
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Ketamine — Ketamine is a phencyclidine derivative that acts as a dissociative sedative. 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 action, and excellent sedative and analgesic properties, it is often used for brief, painful procedures, such as fracture reduction or laceration repair [64,84].

Ketamine is generally given IV to adults, which enables immediate onset, but it can be given intramuscularly. The duration of effect is 10 to 20 minutes. For PSA in adults, a dose of 1 to 2 mg/kg is given IV over one to two minutes. Doses of 0.25 to 0.5 mg/kg may be repeated every five to ten minutes thereafter.

According to a systematic review of 87 studies involving over 70,000 patients, significant adverse reactions rarely occur when ketamine is used for PSA in adults [85]. The authors emphasize that ketamine has proven to be an extremely safe drug despite being used frequently in “austere, poorly monitored settings.”

The reported side effects of ketamine include tachycardia, hypertension, laryngospasm, emergence reactions, nausea and vomiting, increased intracranial and intraocular pressure, and hypersalivation [64,85-87]. Ketamine can exacerbate schizophrenia and should be avoided in patients with this condition [88,89]. Tachycardia and hypertension are generally mild and transient, and significant cardiorespiratory events are rare.

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. Guidelines published by the American College of Emergency Physicians recommend preventing secretions or blood from accumulating in the posterior oropharynx and avoiding excessive stimulation of this region with suction devices or other instruments in patients receiving ketamine for PSA [87].

Emergence reactions are the most commonly reported side effect [85]. These reactions vary in their intensity and have been described as disorientation, dream-like experiences, or hallucinations that may be frightening. They occur in up to 20 percent of adults but can be prevented or treated by giving a small dose of midazolam [2,85,90-93]. For prevention, midazolam, approximately 0.05 mg/kg (typical adult dose 2 to 4 mg), may be given slowly (over about two minutes) by IV prior to administering ketamine.

Nausea and vomiting associated with ketamine administration occur in approximately four percent of adults. They usually occur when the patient is awake and alert and do not appear to predispose the patient to aspiration. Prophylactic treatment with midazolam has met with mixed results in pediatric populations [51,94,95], but pretreatment with ondansetron or comparable agents may be helpful. In one randomized trial involving PSA with ketamine, 16 of 127 children managed without antiemetics experienced post-procedural vomiting versus 6 of 128 children pretreated with ondansetron, a 7.9 percent reduction in absolute risk (95% CI 1.1-14.7) [52].

Ketamine can lead to hypersalivation, which can be reduced by pretreating with glycopyrrolate or atropine, although the benefit of such pretreatment is unclear [76].

Barbiturates — Barbiturates suppress the reticular activating center in the brainstem and cerebral cortex, thereby causing sedation. Methohexital is the most commonly used barbiturate for PSA, but has largely been supplanted by etomidate and propofol.

Methohexital has immediate onset, a duration of action less than 10 minutes, and provides sedation and amnesia but no analgesia. It is often given in combination with opiates, which can potentiate respiratory depression. The initial dose of methohexital is 0.75 to 1 mg/kg given intravenously; repeat doses of 0.5 mg/kg IV can be given every two minutes.

Methohexital causes myocardial depression, which can lead to hypotension and tachycardia. Unlike other barbiturates, methohexital can precipitate or exacerbate seizures and should be avoided in patients with a seizure disorder [96]. One small randomized trial found methohexital and propofol to have comparable safety and efficacy when used for fracture and dislocation reduction [97].

Thiopental is a barbiturate 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.

Ketamine and propofol (ketofol) — “Ketofol” is a combination of ketamine and propofol being studied for use in PSA. The concept of ketofol is that the benefits of the two medications are synergistic and allow lower doses of each to be used. Lower doses reduce the risk for potential side effects (ie, propofol-induced hypotension and ketamine-induced vomiting and emergence reactions) [98,99]. Studies of ketofol are limited and to date have not shown this combination therapy to be more efficacious or safer than propofol or ketamine alone when performing PSA in adults [100-104].

As an example, a trial performed in the emergency department of a university teaching hospital reported no significant difference in the overall incidence of respiratory depression (the primary endpoint) between patients randomly assigned to treatment with a combination of ketamine and propofol for PSA (21/97; 22 percent) or propofol alone (27/96; 28 percent) [103]. The authors report that the group given the combination of ketamine and propofol exhibited fewer episodes of apnea and oxygen desaturation and more consistent sedation, and required smaller cumulative doses of propofol. However, these differences did not achieve statistical significance and their clinical importance remains uncertain.

Nitrous oxide — Nitrous oxide (N2O) is an ultra-short acting agent used for PSA that is inhaled as a 30 to 50 percent mixture, with 30 percent oxygen to avoid hypoxemia. N2O has an immediate onset of action and provides analgesia, anxiolysis, and sedation. The use of N2O also obviates the need for an intravenous line. The major disadvantage to N2O is that it must be administered in a well-ventilated room with a scavenging system to prevent clinician exposure [76].

Little evidence is available about the use of N2O in adults. Studies in children have generally found it to be safe, but it may not provide adequate analgesia for more painful procedures, such as fracture reduction [105].

Future medications — New drugs are being developed that may have a future role in PSA. Fospropofol is a propofol prodrug that may provide more sustained and consistent clinical effects at lower plasma levels than equivalent doses of propofol. Dexmedetomidine is an alpha 2 agonist similar to clonidine that has sedative and analgesic effects. Further clinical study of these medications is needed before recommendations can be made.

MEDICATION SELECTION

Patients without increased risk — Procedural sedation and analgesia (PSA) is generally performed in relatively healthy patients who are hemodynamically stable. In such patients, we suggest that ultrashort-acting sedatives, such as propofol or etomidate, be used for PSA. The relative advantages and disadvantages of each are discussed immediately below (table 2).

Propofol versus etomidate — Both propofol and etomidate have gained popularity as medications for procedural sedation and analgesia (PSA). Both medications are safe and effective in the performance of PSA, and both possess similar times to onset and recovery [63,106]. Propofol may result in a higher procedural success rate [63,100].

Factors to consider when choosing between propofol and etomidate include the following:

  • Etomidate provides greater hemodynamic stability, as propofol can cause hypotension. The fall in blood pressure from propofol is generally small and transient, but this difference may be of importance in patients with hypovolemia or hypotension who undergo PSA [107-109].
  • Etomidate can cause myoclonus, which appears to reduce the rate of procedural success [63,64,110,111].
  • Etomidate causes dose-dependent adrenal suppression, which may be harmful in patients with severe disease (eg, sepsis, multiple trauma). Such patients may not be suitable for PSA. This effect is unlikely to be important in otherwise healthy patients.
  • Respiratory depression occurs at comparable rates during PSA with both drugs, although this rarely causes harm to the patient.

Few studies have directly compared propofol and etomidate for PSA. In the largest such trial, 214 patients undergoing painful procedures in the emergency department were randomly assigned to sedation with either medication [63]. Myoclonus was more frequent with etomidate (20 versus less than 2 percent with propofol). This likely accounts for the lower rate of procedural success in the etomidate group (89 versus 97 percent). No clinically significant complications (eg, prolonged hypoxia) occurred in either group.

Propofol versus ketamine — Ketamine is more commonly used to sedate children and few studies of its role in adult procedural sedation have been performed. One small, unblinded randomized trial in adults reported higher rates of subclinical respiratory depression (as determined by changes in end-tidal CO2 or oxygen saturation), longer median times for return to baseline mental status (14 minutes versus 5 minutes), and increased agitation during recovery among patients treated with ketamine for procedural sedation compared to those treated with propofol [112]. The rates for clinical intervention for respiratory problems, duration of the procedure, and successful completion of the procedure did not differ between the two groups.

Patients at increased risk — In some circumstances, clinicians, after carefully considering the relative risks and benefits, may elect to perform PSA in patients at increased risk of complications. Suggestions for drug selection in several common scenarios are provided here; contraindications to PSA are reviewed above (table 2) and (see ‘Contraindications and precautions’ above).

Patients at risk of hypotension — In patients at risk of hypotension due to recent illness and dehydration, cardiac disease, or some other condition, we suggest that either etomidate or ketamine be used for PSA; in contrast, propofol has a greater blood pressure lowering effect [63]. Either agent will maintain hemodynamic stability. (See ‘Etomidate’ above and ‘Ketamine’ above.)

Patient at risk for airway or respiratory complications — In patients who may have a potentially difficult airway to manage or have compromised respiratory function, we suggest that ketamine be used for PSA. Ketamine allows the patient to maintain protective airway reflexes and does not cause respiratory depression.

Elderly patients — Older patients are at increased risk of complications during PSA [9]. As a result, sedatives administered to older patients for PSA, regardless of the agent, should be given at a lower starting dose with slower rates of administration and less frequent dosing intervals. In elderly patients without major comorbidities or hemodynamic instability, it may be best to perform PSA using an ultrashort-acting sedative, such as propofol. Procedures in elderly patients with major comorbidities are probably best performed in the operating room. (See ‘Propofol’ above.)

Ketamine versus short-acting opioids for analgesia — Ultra short-acting opioids (eg, fentanyl) provide analgesia during PSA but can contribute to respiratory depression. Some researchers hypothesize that a subdissociative dose of ketamine can provide adequate analgesia without the risk of respiratory depression.

One small randomized trial found that patients given ketamine (0.3 mg/kg IV) and propofol during PSA achieved similar analgesia but experienced fewer complications compared with patients given fentanyl (1.5 mcg/kg IV) and propofol, who had five times the risk of experiencing a serious adverse event (eg, hypoxia) (95% CI 1.9-13.6) [99]. A smaller, nonrandomized trial found that the addition of ketamine reduced pain and the need for post-procedural analgesics [113]. Further studies are needed to confirm these preliminary findings.

DISCHARGE CRITERIA — There is little evidence to guide decisions about discharge following procedural sedation and analgesia (PSA). Some guidelines suggest that patients are ready for discharge when they have reached their “neuromuscular and cognitive pre-procedure baseline” [114].

Certain conditions should be met before a patient can be considered safe for discharge following PSA:

  • The procedure should be of sufficiently low risk that additional monitoring for complications is unnecessary.
  • 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 himself or herself 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.

Clear written discharge instructions should be given and explained to the patient and to the family member or friend 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.

One important issue is to determine a period of observation after which adverse events are sufficiently unlikely that even a patient who has not entirely returned to baseline (eg, exhibits mild drowsiness) can be discharged safely. The only study to examine the timing of significant adverse events associated with PSA was performed in a sample of 1341 children and found that 92 percent of such events occurred during the procedure, while only 8 percent occurred afterwards [114]. Significant adverse events rarely occurred more than 25 minutes after the last dose of medication was administered, provided that no adverse events had occurred up to that point. Rarely, episodes of hypoxia developed up to 40 minutes after the last medication dose. In all such cases, prior episodes of hypoxia had occurred.

Based on these data, some clinicians believe that patients can be safely discharged within 30 minutes of receiving their last dose of sedative provided that no significant adverse events occurred during the procedure and the patient did not receive a reversal agent (eg, naloxone). Of note, only relatively long acting agents, such as ketamine, midazolam and fentanyl were used in this study (ie, neither etomidate nor propofol were used). It is unlikely that a longer period of observation would be necessary following PSA with ultra-short acting agents [12].

Although serious adverse events, such as hypoxia, rarely occur after discharge, it is not uncommon for patients to experience mild symptoms, such as nausea, lightheadedness, fatigue, or unsteadiness, for up to 24 hours [5,115,116]. This should be made clear to the patient.

SUMMARY AND RECOMMENDATIONS

  • Procedural sedation and analgesia (PSA) involves the use of short-acting analgesic and sedative medications to enable clinicians to perform procedures, while monitoring the patient closely for potential adverse effects. This process was previously (and inappropriately) termed “conscious sedation.” (see ‘Definitions’ above).
  • PSA may be used for any procedure in which a patient’s pain or anxiety may be excessive and may impede performance. There are no absolute contraindications to PSA. Relative contraindications include: older age, significant medical comorbidities, and signs of a difficult airway. Whether the patient recently ate should be considered before performing PSA, although this may not increase aspiration risk. (See ‘Indications’ above and ‘Contraindications and precautions’ above.)
  • The number of clinicians needed to perform PSA and the procedure safely may vary according to the patient and the procedure. In most cases, one clinician performs the procedure while another (usually a nurse) administers the sedative agents and monitors and records the patient’s vital signs and clinical status. Whenever possible, we suggest that this minimum standard be met. (See ‘Prerequisites and personnel’ above.)
  • Proper monitoring during PSA is crucial. The patient’s blood pressure, heart rate, and respiratory rate should be measured at frequent, regular intervals; oxygen saturation (SpO2), end-tidal carbon dioxide level (EtCO2), and cardiac rhythm should be monitored continuously. We suggest that high flow oxygen (15 L by face mask) be provided to patients receiving PSA. (See ‘Monitoring and preoxygenation’ above.)
  • Serious complications attributable to PSA rarely occur. Significant respiratory compromise develops in less than one percent of cases. Adverse outcomes may include respiratory depression with hypoxia or hypercarbia, cardiovascular instability, vomiting and aspiration, and inadequate sedation preventing completion of the procedure. All equipment and medications necessary for airway management should be at the bedside during PSA. (See ‘Complications’ above and ‘Equipment’ above.)
  • Ideal drugs for PSA have a rapid onset and short duration of action, maintain hemodynamic stability, and do not cause major side effects. Several medications are commonly used and no single drug is ideal for all situations (table 2). Medications used for PSA are discussed in the text. (See ‘Medications’ above.)
  • PSA is most often performed in patients without major comorbidities or hemodynamic instability. In such patients, we suggest that PSA be performed using propofol (Grade 2B). Etomidate may also be used. The relative advantages and disadvantages of each drug are discussed in the text. (See ‘Patients without increased risk’ above.)
  • Older patients are at increased risk of complications during PSA. Therefore, sedatives administered to older patients for PSA, regardless of the agent, should be given using a lower starting dose, slower rates of administration, and less frequent dosing intervals. (See ‘Elderly patients’ above.)
  • In some circumstances, clinicians, after carefully considering the relative risks and benefits, may elect to perform PSA in patients at some increased risk of complications. In patients at risk of hypotension, we suggest that either etomidate or ketamine be used for PSA (Grade 2C). In patients who may have a potentially difficult airway or have compromised respiratory function, we suggest that ketamine be used for PSA (Grade 2C). (See ‘Patients at increased risk’ above.)
  • Criteria for safe discharge following PSA are described in the text. (See ‘Discharge criteria’ above.)
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