Procedural Sedation

The American College of Emergency Physicians (ACEP) defines procedural sedation as "a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. Procedural sedation and analgesia (PSA) is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently." ^[1]

The number of noninvasive and minimally invasive procedures performed outside of the operating room has grown exponentially over the last several decades. Sedation, analgesia, or both may be needed for many of these interventional or diagnostic procedures. Sedation and analgesia introduces an independent risk factor for morbidity and mortality in addition to the procedure itself. Medications that elicit pharmacologic effects, such as anxiolysis, amnesia, or analgesia, provide patient comfort during various procedures. 

Guidelines for procedural sedation have been available since 1985 for dentists and pediatricians through their societies. ^{[2, 3]} They have since expanded to other specialties including emergency medicine. ^[4] In October 2014, the American Society of Anesthesiologists (ASA) Committee on Standards and Practice Parameters recommended new guidelines for moderate sedation to guide various practitioners and encourage education and training. The guidelines cover core sedation principles and should be customized to address specific specialty needs. ^[5] An ongoing quality improvement review and implementation of these guidelines are necessary. Hospitals should establish these guidelines for their providers in accordance to their available resources. ^[6]

The information described in this article does NOT apply to the following types of patients:

• Patients receiving inhaled anesthetics

• Patients receiving analgesia for pain control without sedation

• Patients receiving sedation to manage behavioral emergencies

• Patients who are intubated

Understanding the various depths of sedation is essential to provide safe and effective procedural sedation and analgesia. The ASA has defined the various sedation depths. As defined below, minimal sedation or moderate sedation is used for PSA. ^[1]

Minimal sedation (anxiolysis) is as follows:

• Response to verbal stimulation is normal.

• Cognitive function and coordination may be impaired.

• Ventilatory and cardiovascular functions are unaffected.

Moderate sedation/analgesia (formerly called conscious sedation) is as follows:

• Depression of consciousness is drug-induced.

• Patient responds purposefully to verbal commands.

• Airway is patent, and spontaneous ventilation is adequate.

• Cardiovascular function is usually unaffected.

Deep sedation/analgesia is as follows:

• Depression of consciousness is drug-induced.

• Patient is not easily aroused but responds purposefully following repeated or painful stimulation.

• Independent maintenance of ventilatory function may be impaired.

• Patient may require assistance in maintaining a patent airway.

• Spontaneous ventilation may be inadequate.

• Cardiovascular function is usually maintained.

General anesthesia is as follows:

• Loss of consciousness is drug-induced, where the patient is not able to be aroused, even by painful stimulation.

• Patient's ability to maintain ventilatory function independently is impaired.

• Patient requires assistance to maintain patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function.

• Cardiovascular function may be impaired.

Additionally, clinicians must recognize procedures performed outside of the operating room that may require monitored anesthesia care (MAC) with an anesthesia provider overseeing the sedation and monitoring of the patient. ^[7]

Various drugs are available to provide procedural sedation; their pharmacodynamic descriptions are described below. ^[8] A short-acting benzodiazepine (eg, midazolam), either alone or in combination with an opioid analgesic (eg, fentanyl, morphine, hydromorphone [Dilaudid]), is commonly selected for procedural sedation. ^[9] Combining use of a benzodiazepine and an opiate may be preferable for longer procedures but increases the risk of oxygen desaturation and cardiorespiratory complications. Specific reversal agents for opiates (naloxone [Narcan]) and benzodiazepines (flumazenil [Mazicon]) must be readily available during the procedure.

The use of other sedatives that are not respiratory depressants are gaining favor. ^[10] Etomidate can be used because it elicits minimal hemodynamic effects and has a very reliable onset of action. Ketamine results in a dissociative state, and patients may not be able to speak or respond purposefully to verbal commands and is a good analgesic. Ketamine is being used more but it does have frequent association with emergence delirium especially in adults. The addition of a benzodiazepine has been shown to reduce postprocedure delirium in adults. Dexmedetomidine is another recent addition that provides a level of sedation similar to previously mentioned agents but lacks both respiratory depression and major cardiac depression. ^[11]  A concern with dexmedetomidine is severe bradycardia. Comparative trials comparing a mixture of ketamine and propofol, referred to as ketofol, have also been reported. ^{[12, 13, 14]}

Nitrous oxide (N2O) for analgesia and sedation has been used for years in pediatric patients and is currently used for adult colonoscopy, in labor and other nonoperating room procedures. The short half-life of N2O allows a quicker recovery than most sedative/analgesics. N2O has been shown to be as effective as other sedatives with little pulmonary or cardiovascular risk compared with other sedative/analgesics.

Benzodiazepines

Benzodiazepines elicit beneficial effects for PSA that include amnesia, anticonvulsant, anxiolysis, and sedation. Benzodiazepines potentiate gamma-aminobutyric acid (GABA) inhibitory action in the CNS by binding to benzodiazepine-specific receptors on the GABA_A -benzodiazepine receptor complex. Binding of this complex potentiates GABA-mediated chloride influx that results in sedation, amnesia, anxiolysis, and anticonvulsant effects and respiratory depression.

Midazolam is the benzodiazepine most commonly used for PSA, since it produces a faster onset of sedation, more complete amnesia, less pain on injection, and improved awakening when compared with diazepam. Midazolam possesses a relatively high volume of distribution (V_d) compared with other benzodiazepines because of its lipophilicity. The V_d is greatly amplified in obese patients, resulting in an increased half-life from 2.7 hours to 8.4 hours. Midazolam is cleared by hepatic hydroxylation to 1-hydroxymidazolam (elicits about 10% of the pharmacologic activity as parent compound). In comparison, diazepam has an extremely long half-life (0.8-2.25 d) that is markedly increased in obese or elderly patients (3.9 d and 3.29 d, respectively). Additionally, its active metabolites have long half-lives (ie, N -desmethyldiazepam[1.6-4.2 d]; nordazepam [about 8 d]).

Remimazolam is a very rapid onset/offset intravenous (IV) benzodiazepine indicated for induction and maintenance of procedural sedation during invasive medical procedures in adults lasting 30 minutes or less (eg, colonoscopy, bronchoscopy).

Lorazepam (Ativan) is another benzodiazepine that may be used for mild-to-moderate sedation; however, unlike midazolam, its onset of action does not peak until 15-20 minutes after administration. The duration of action of lorazepam is longer (ie, 6-8 h) than that of midazolam (30-60 min). In addition, lorazepam has roughly double the potency of midazolam and lack of metabolite activity. Because of this, lorazepam is typically used for long-term sedation, such as in an ICU setting.

When combined with alcohol or opioids, the sedative and respiratory-depressant effects of benzodiazepines are greatly increased, as is the risk for cardiovascular depression.

Opiates

Opiates provide analgesia and sedation during painful procedures. Fentanyl is favored because of its prompt onset and short duration of action. Unlike morphine, fentanyl has minimal cardiovascular depressive effects and hypotension rarely occurs. Fentanyl binds with stereospecific receptors at many sites within the CNS and increases pain threshold, alters pain reception, and inhibits ascending pain pathways. In addition to analgesia, opioid agonists suppress the cough reflex and cause respiratory depression, drowsiness, and sedation. The half-life is 2-4 hours.

Ketamine

Ketamine (Ketalar) elicits profound dissociative and amnestic actions. In doses typically used for PSA it does not affect pharyngeal-laryngeal reflexes and, thus, allows a patent airway as well as spontaneous respiration to maintain intact. This characteristic of the medication is particularly useful for emergency procedures when fasting is not assured. It should be mentioned, though, that reflexes may remain intact but cannot be assumed to be protective. ^[15] Cardiovascular and respiratory stimulation and normal or slightly enhanced skeletal muscle tone are observed following administration, although transient respiratory depression may occur if administered too rapidly or in high doses. The unique dissociative action and partial agonist at opiate mu-receptors permits painful procedures to be performed in a consistent state of sedation and patient comfort. Ketamine is contraindicated in patients who have underlying conditions in which increased blood pressure or heart rate would pose risk of complications. An increase in oropharyngeal secretions is often triggered and this can be prevented by premedication with glycopyrrolate. 

Onset of action for intravenous (IV) administration of ketamine is within 1 minute, and duration of action lasts about 10-15 minutes. The context sensitive half-life after administration is roughly 45 minutes and it does have an active metabolite with approximately 1/3 the activity of the parent compound. If administered intramuscularly (IM), the onset of action is observed in 3-5 minutes, and duration of procedural conditions lasts about 20-30 minutes.

Ketamine results in a dissociative state, and patients may not be able to speak or respond purposefully to verbal commands. Ketamine can cause vivid imagination, hallucinations, confusion, excitement, irrational behavior and severe anxiety. Emergence reactions are estimated to occur in approximately 12% of patients. Strayer and Nelson have estimated emergence phenomena to occur in between 10% and 20% of adults who have received ketamine. ^[16] Symptoms can be expected to last from 1-3 hours.

The incidence of emergence delirium may be reduced by decreasing the recommended dose of ketamine and using it in conjunction with a benzodiazepine. A small hypnotic dose of a short-acting benzodiazepine is recommended to terminate severe emergence reactions. Emergence delirium is not typical in children younger than 15 years. In a randomized controlled study of adult ED patients, Sener et al found that the incidence of recovery agitation was significantly reduced when midazolam was coadministered with ketamine for procedural sedation. ^[17]

A 1:1 mixture of ketamine with propofol can be used for procedural sedation and analgesia. This mixture has been associated with a reduced incidence of emergence delirium and may negate the need for concomitant benzodiazepine use. In a prospective case series study of 728 adults presenting to a trauma center for orthopedic procedures, the median dose of ketamine and propofol was 0.7 mg/kg. Bag-mask ventilation occurred in 21%, and recovery agitation occurred in 3.6% (50% of these patients required treatment for agitation). ^[18]

A double-blind, randomized trial compared ketamine (0.5 mg/kg) plus propofol with placebo plus propofol in 193 adults and children. Respiratory depression was similar between the groups but less propofol was needed when ketamine was administered, and there was trend toward better sedation quality. ^[12]

A prospective trial comparing ketamine plus propofol (ketofol) to midazolam plus fentanyl (MF) was conducted in the emergency setting by Nejati et al. Patients (n=62) requiring procedural sedation and analgesia for deep traumatic lacerations and reduction of bone fractures were included. No significant differences were observed for sedation time or physician satisfaction between the groups. Pain was significantly lower in the ketofol group compared with the MF group (p < 0.001). ^[13]

The use of ketamine and propofol is a potential alternative in adults requiring procedural sedation.

Propofol

Propofol (Diprivan) provides potent, ultra–short-acting sedation and anesthesia. It is a phenolic compound, and its mechanism of action is unknown, but it is thought to mediate GABA activity. Propofol has no analgesic properties. It is associated with rapid deepening of a sedation level to that of general anesthesia. Because of this, an anesthesiologist or sedation team often administers it and monitors its use outside the operating room. ^{[19, 20]}

Propofol is rapidly metabolized by the liver; though duration of action when continuous infusion is not used is related to redistribution away from its site of action - therefore renal and hepatic dysfunction typically do not affect its duration of action. Onset of action is very rapid with peak affect seen at 90 - 100 seconds. Duration of action is dose dependant and ranges from 5-10min after bolus administration. Propofol leads to a dose dependant decrease in arterial blood pressure and cardiac output. Therefore, it must be used with caution in those that may be hemodynamically unstable or reliant on sympathetic tone.

Increasing use of propofol for emergency department procedural sedation has been described. ^{[21, 22, 23, 24, 25]} Hohl et al described propofol as slightly more cost-effective than midazolam because of shorter recovery times with propofol. ^[21] A prospective study using propofol in a standard protocol in 113 patients in an emergency department concluded propofol as safe and effective for procedural sedation with high patient and physician satisfaction. ^[22] Other studies have confirmed the safety of propofol in the emergency department setting. ^{[23, 24]} One randomized clinical trial indicated that, while ketamine and propofol are both safe and effective agents for procedural sedation in the ED, patients who received ketamine had less rates respiratory depression, higher rates of recovery agitation, and longer times to regain baseline mental status than patients who received propofol. ^[26]

A consideration for the use of propofol is the relatively high rate of discomfort, including severe or excruciating pain, with injection. Propofol is known to cause injection site burning, stinging, and pain. Up to 28-90% of adults ^{[27, 28]} and 28-85% of children ^{[29, 30]} may experience this. There are many publications that have examined methods to reduce this and none of them are completely effective except the tourniquet method. ^[28] The prescribing information describes that when a small vein in the hand is used in children to administer propofol, pain was frequently reported (45%). Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used.

A systematic review and meta-analysis in 2011 concluded that the incidence of discomfort could be significantly reduced by simple interventions such as selection of an antecubital vein for injection instead of a hand vein (relative risk [RR], 0.14; 95% confidence interval [CI], 0.07-0.30), pretreatment with lidocaine in conjunction with venous occlusion (RR, 0.29; CI, 0.22-0.38), or the use of admixtures containing lidocaine (RR, 0.40; CI, 0.33-0.48) or ketamine (RR, 0.52; CI, 0.46-0.57). ^[31]

Etomidate

Etomidate (Amidate) is an ultra–short-acting nonbarbiturate hypnotic used for anesthesia. It produces rapid induction without histamine release and with minimal cardiovascular and respiratory effects. As with ketamine or barbiturates, etomidate transiently lowers cerebral blood flow by 20-30% and slightly reduces intracranial and intraocular pressure. It has no analgesic properties. Onset of action is 5-30 seconds with peak action at 1 minute. Etomidate has a duration of 2-10 minutes depending on the dose. The major adverse effect is transient adrenal suppression secondary to inhibition of 11-ß-hydroxylase and 17-alpha-hydroxylase enzymes which are important in cortisol synthesis. There is also a high incidence of pain on injection and nausea and vomiting associated with bolus administration.

Dexmedetomidine

Dexmedetomidine (Precedex) is utilized for procedural sedation in pediatric and adult patients. ^[32] It is an alpha2-adrenergic agonist that provides sedation, anxiolysis, hypnosis, analgesia, and sympatholysis. Clonidine, another alpha2 agonist, has been shown to decrease anesthetic requirements and thus prompted the study and creation of this drug. ^{[33, 34]}  Clonidine, however, is not used for sedation, Dexmedetomidine is gaining favor for procedural and ICU sedation as well as in the operating room for short procedures and awake fiberoptic intubations.(ref 58)

Dexmedetomidine has several characteristics that make its use for procedural sedation very appealing. First, it provides little to no respiratory depression. ^[35] Also, patients are able to follow commands and respond to verbal and tactile stimulus but fall quickly asleep when not stimulated. It does provide some pain relief, like ketamine, but not to the same degree. This makes the use of other analgesics necessary for the more painful procedures. Minimal cardiovascular effects are seen and include a decrease in systemic vascular resistance. Severe bradycardia has been reported.  ^[36]

Onset of action is relatively rapid and the context-sensitive half-time is approximately 4 minutes after a 10-minute infusion. ^[37] Dexmedetomidine is 1600 times more selective for alpha2 than alpha1 receptors and therefore has very few side effects and provides predictable results. ^[38]

Clinical practice guidelines by the Society for Critical Care Medicine that include recommendations on sedation in adult patients in the ICU urge the use of light sedation (vs deep sedation) in critically ill, mechanically ventilated adults. The guidelines also recommend the use of either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults. ^[39]

Question the patient or caregiver regarding the following ^{[40, 5]} :

• Abnormalities of major organ systems

• History of adverse events with sedation or analgesia, or regional or general anesthesia

• Drug allergies

• Current medications or herbal products

• Description and time of last oral intake (for elective procedures requiring deep sedation, should be fasting)

• Tobacco, alcohol, or substance abuse

• Vital signs

• Heart and lung assessment

• Airway evaluation history of difficult airway and any loose teeth

Note the following equipment and supplies ^[5] :

• Oxygen

• Suction

• Airway management equipment

• Reversal agents for opioids or benzodiazepines (eg, naloxone, flumazenil)

• Resuscitation medications and equipment

• Intravenous access (when intravenous sedation is administered and anytime more than very light sedation is planned)

See the list below:

Practitioners must be skilled in providing procedural sedation, must be proficient in airway management and cardiovascular support, and must possess the skills required to rescue a patient from sedation deeper than intended. Continually evaluating and monitoring respiratory and circulatory requirements prior to, during, and following the procedure is essential. Practitioners must be competent in managing reversal of sedation. Patients should have recovery care. 

Note the following ^[5] :

• Monitor vital signs before, during, and after the procedure.

• Blood pressure

• Heart rate

• Pulse oximetry

• ECG monitoring should be continuous for high-risk patients, during prolonged procedures, or during deep sedation.

• Observe the patient's appearance.

• Monitor airway patency.

• Monitor response to physical stimuli and verbal command.

• Measurement of blood gas level may be required.

• Capnography are part of the new ASA recommendations. ^[5] According to a 2010 randomized controlled trial that included 132 adult patients receiving propofol sedation in the ED, adding capnography to standard monitoring resulted in a decrease in hypoxia and identified all hypoxic events before onset. ^[41]

 

   Table 1. Commonly Used Drugs for Procedural Sedation and Analgesia in Adults (Open Table in a new window)

The selection of sedative and analgesic agents differs slightly when these agents are used in children. Benzodiazepines, chloral hydrate, and barbiturates have been used for decades to provide sedation for pediatric procedures. ^{[42, 43, 44, 45, 46]} Propofol is also readily being used outside the operating room to induce anesthesia for pediatric procedures (mostly by pediatric anesthesiologists or a sedation team). Data suggest greater variability in children younger than 1 year for the loading dose, whereas more variability is seen with the maintenance dose in children older than 7 years. ^[47]

Data are limited for the use of etomidate for procedural sedation in children. A review by den Brinker et al summarizes the information currently available. The potential for etomidate to inhibit cortisol production may make its use in children limited. ^[48]

For painful procedures, an opioid analgesic (eg, fentanyl) is required; ketamine, which provides sedation and analgesia, may be considered instead. ^[45]

Midazolam is the most commonly prescribed benzodiazepine for pediatrics and can be administered via various routes (eg, oral, intranasal, rectal, intramuscular, intravenous). It provides excellent amnesia and anxiolytic effect. Chloral hydrate has been used for routine sedation for many years; however, the development of safer and more effective agents have largely replaced it. 

Dexmedetomidine is widely used for procedural sedation in pediatric patients with minimal side effects. ^[49]  In December 2022, the FDA approved dexmedetomidine for sedation in nonintubated pediatric patients aged 1 month to 18 years prior to and/or during surgical and other procedures. ^[50]

A prospective, multicenter, observational cohort study from 6 pediatric emergency departments that examined 6295 cases of pediatric sedation reported that the use of ketamine alone resulted in the lowest incidence of serious adverse events (17 [0.4%]) and significant interventions (37 [0.9%]) compared to just propofol or a combination of ketamine with propofol or fentanyl. ^[51]

A prospective, nonblinded, interventional trial by Saunders et al investigated the use of intranasal fentanyl as analgesia for painful orthopedic injuries among children aged 3-18 years. ^[52] The trial determined that intranasal fentanyl at 2 μ g/kg was effective in alleviating pain caused by orthopedic trauma in pediatric patients within 10 minutes of administration.

A study by Tsze et al investigating the optimal intranasal volume of administration for pediatric sedation found that the clinical outcomes for children undergoing laceration repair were comparable for volumes of administration for intranasal midazolam (0.5 mg/kg) of 0.2, 0.5, and 1 mL. However, with regard to ease of administration, more clinicians were unsatisfied with the 2-mL volume of administration. The study’s patients were aged 1-7 years. ^[53]

Leroy et al state that procedural sedation for children should only be provided by well-trained and credentialed professionals and that professionals with the needed expertise are available at all times. ^[54] Ideally, procedural sedation should be performed in the fasted state, but this is not always possible in an emergency setting. A survey of Canadian pediatric emergency physicians by Bhatt et al suggest that fasting guidelines are not strictly adhered to in Canadian pediatric emergency departments. Additionally, the survey found some willingness of physicians to change their sedation practice in light of evidence from hypothetical surveillance data about risks. Years in practice affected the decision, with those in practice for 6-10 years more likely to perform immediate procedural sedation and analgesia than those in practice for shorter or longer. ^[55]

A study that evaluated the impact of obesity on adverse events and required interventions during pediatric procedural sedation reported that obesity is an independent risk factor for adverse respiratory events during procedural sedation and is associated with an increased frequency of airway interventions. ^[56]

  Table 2. Commonly Used Drugs for Procedural Sedation and Analgesia in Pediatric Patients (Open Table in a new window)

 

Drug dosages for sedation and analgesia are highly variable, and other factors such as concurrent medications, medical conditions, and age contribute to this variability. Drugs for mild-to-moderate sedation should only be used in settings that provide for continuous monitoring of respiratory and cardiac function. Availability of resuscitative drugs, equipment, and health care personnel experienced with the use of these drugs must be guaranteed. Reversal agents for opioids (ie, naloxone) and benzodiazepines (ie, flumazenil) must also be available.

Table 3. Commonly Used Reversal Agents (Open Table in a new window)

 

Consent should be obtained from the patient or family member. ^{[57, 58]} The reason the procedure is being performed (suspected diagnosis); the risks, benefits, and alternatives of the procedure; the risks and benefits of the alternative procedure; and the risks and benefits of not undergoing the procedure. Allow the patient the opportunity to ask any questions and address any concerns they may have. Make sure that they have an understanding about the procedure so they can make an informed decision.

The patient should be counseled about the risks of hypotension, hypoxia, bradycardia, cardiac dysrhythmias, respiratory depression, need for assisted ventilation, intubation, allergic reaction (swelling, rash, nausea, vomiting), or achieving deeper sedation than intended. Reassure the patient that many of the side effects are minor and can resolve spontaneously or with the use of adjunctive agents.

The patient should also be counseled that the procedure may not be successful (inadequate analgesia).

Discuss how these risks can be avoided or prevented (eg, monitoring, preoxygenation, having appropriate airway management, and equipment and resuscitation medications available, having reversal agents for opioids or benzodiazepines readily available).