Pediatric procedural sedation: Pharmacologic agents

INTRODUCTION — A wide range of short-acting sedative-hypnotic and analgesic medications are available for pediatric procedural sedation [1-3]. Many of these agents have multiple routes of administration. The choice of drug is based upon the type of procedure and the patient's underlying medical condition. Procedures that are not painful but require the child to remain still can usually be performed with sedation alone. Children undergoing painful procedures require analgesia as well as sedation.

This topic will discuss the properties of agents commonly used for procedural sedation in children.

Assessment, preparation, and proper performance of procedural sedation outside of the operating room, including selection of medications for pediatric procedural sedation, are discussed separately:

●(See "Procedural sedation in children: Preparation".)

●(See "Procedural sedation in children: Approach".)

●(See "Procedural sedation in children: Selection of medications".)

TOPIC SCOPE — This topic discusses pharmacologic agents for emergency and scheduled (elective) pediatric procedural sedation performed by sedation providers from a variety of disciplines including general and pediatric emergency medicine, pediatric critical care medicine, pediatric hospital medicine, and general pediatrics.

SEDATIVE-HYPNOTIC AGENTS — These drugs provide sedation, motion control, anxiolysis, and to varying degrees, amnesia but (with the exception of dexmedetomidine) do not provide analgesia. The properties of commonly used agents for pediatric procedural sedation are provided and summarized in the tables (table 1 and table 2).

When used for procedural sedation in children, these agents should only be administered by properly trained and experienced clinicians. All children require careful pre-sedation evaluation. The clinician should develop a sedation plan that provides appropriate targeted level of sedation (mild, moderate, dissociative, or deep) as determined by patient characteristics, anticipated degree of procedural pain, and procedural requirements. Appropriate monitoring, personnel, and equipment must also be in place during the sedation. (See "Procedural sedation in children: Preparation", section on 'Pre-sedation evaluation' and "Procedural sedation in children: Approach", section on 'Performing procedural sedation'.)

Selection of medications for pediatric procedural sedation is determined by patient factors, anticipated degree of pain, and type of procedure and is discussed in detail separately. (See "Procedural sedation in children: Selection of medications", section on 'Choice of sedative agents'.)

Propofol — Propofol is a nonopioid, nonbarbiturate sedative hypnotic that has historically been extensively used by anesthesiologists and intensivists as an induction agent for general anesthesia and as a sedative in intensive care units [4,5]. Over the past two decades, propofol has also been used extensively for procedural sedation in sedation units, emergency departments, and radiology suites [6-11]. The decision to use propofol and whether it is used with other agents (eg, ketamine or fentanyl) should depend on the duration and the nature of the procedure being performed.

Practitioners who choose to use propofol alone or in combination with other medications for brief procedural sedation outside of the operating room must vigilantly adhere to protocols that include careful monitoring with capnography as well as pulse oximetry [12] . Use must be consistent with hospital guidelines and protocols, local regulations, and the practitioner's privilege delineation. In some regions, propofol is only approved for use by physicians with special airway training, such as intensivists and emergency physicians with specialized pediatric procedural sedation training. Clinicians should check local recommendations for propofol administration.

●Dosing and administration – When used for prolonged sedation (eg, during magnetic resonance imaging), a continuous intravenous infusion of propofol at a starting dose of 150 mcg/kg per minute is frequently effective [2,13]. The infusion dose is then gradually increased as needed to achieve adequate sedation up to a maximum dose of 250 mcg/kg per minute. Administering dexmedetomidine 1 to 2 mcg/kg IV bolus prior to propofol infusion may reduce the total amount of propofol needed for sedation and has been associated with fewer adverse events [14-16].

For brief procedures, propofol may also be administered as a continuous infusion or as an initial intravenous (IV) bolus dose of 1 to 1.5 mg/kg (2 mg/kg in infants and children between six months and two years of age) [13]. When propofol is combined with other agents (eg, ketamine, fentanyl, dexmedetomidine [14], or morphine), the initial bolus dose of 0.5 to 1 mg/kg is suggested. Repeated doses of 0.5 mg/kg of IV propofol may be given every three to five minutes, up to a maximum total dose of 3 mg/kg, as needed to achieve the desired effect. Relative to a continuous infusion, bolus dosing of propofol increases the risk of exceeding the desired level of sedation and is associated with a higher likelihood of respiratory depression, bradycardia, and hypotension, especially when combined with opioid medications.

Hypovolemic patients should receive IV fluids to correct volume status prior to propofol sedation. For children with reduced cardiac output, attempts should be made to improve cardiac performance prior to sedation and dosing should be minimized. In these patients, propofol sedation should only be provided by clinicians with significant experience sedating children with heart disease

Propofol causes pain during IV administration that can be reduced by IV pretreatment with 0.5 mg/kg of systemic lidocaine injected into the vein with a tourniquet applied for one minute, or by administration of ketamine or an opioid prior to propofol [2]. Pain is also lessened by injecting into an antecubital rather than a hand vein.

●Benefits – Compared with other commonly used agents, propofol has the fastest onset of action and one of the shortest recovery times (table 1). Propofol reduces intracranial pressure, making it a good choice in hemodynamically stable patients with head trauma. Studies indicate high efficacy for successful completion of diagnostic imaging and, when combined with ketamine or fentanyl, a variety of painful procedures [17-19].

●Adverse effects – Because of the rapid onset of action and high potency of the drug, it can rapidly achieve a greater depth of sedation than intended, including general anesthesia, especially when given in bolus doses [20].

Minor adverse effects requiring routine intervention by appropriately trained providers occur in approximately 2 to 5 percent of children undergoing propofol sedation and include respiratory depression, apnea, and hypotension [6,11,21-23]. Major events such as respiratory arrest requiring endotracheal intubation, pulmonary aspiration, and cardiorespiratory arrest have all been described but occur rarely when sedation is performed by well-trained physicians as part of an organized sedation service [7,19].

In a systematic review of 20 trials and 40 observational studies of approximately 17,000 children undergoing sedation outside of the operating room, use of propofol was associated with the following adverse events [24]:

•Respiratory events

-Oxygen desaturation: 9 percent

-Apnea: 2 percent

-Laryngospasm: 0.2 percent

-Unplanned intubation: 0.02 percent

•Hypotension: 15 percent

•Bradycardia: 0.1 percent

Hypotension was recorded as transient in the majority of cases; no adverse sequela of hypotension was documented. No patient required treatment for bradycardia.

In a separate study of almost 50,000 pediatric sedations outside of the operating room, rates of adverse events for propofol per 10,000 sedations were as follows [8]:

•Airway obstruction: 432/10,000

•Oxygen desaturation (<90 percent for >30 seconds): 154/10,000

•>30 percent change in heart rate, blood pressure, or respiratory rate: 61/10,000

•Apnea: 31/10,000

•Laryngospasm: 21/10,000

This study also documented four cases of aspiration and two cardiac arrests.

Although evidence is limited, the addition of an opioid (eg, fentanyl) to propofol sedation appears to increase the risk of respiratory events. As an example, in a trial that included 59 children undergoing fracture reduction, oxygen desaturation and requirement for respiratory maneuvers occurred more often in patients receiving propofol and fentanyl (31 percent) compared with ketamine and midazolam (7 percent) [25].

●Contraindications and precautions – Formulations of propofol contain egg lecithin, egg yolk phospholipids, and soybean oil. The manufacturer's instructions advise against the use of this agent in patients with egg allergy. However, observational evidence suggests that propofol may be used safely in patients with egg, soy, and peanut allergies (see "Management of food allergy: Avoidance", section on 'Lipid emulsions'). Thus, we do not view the history of allergy to these foods as a contraindication to the use of propofol. While no special precautions are recommended for the administration of propofol to most patients with soy or egg allergy, use of an alternate anesthetic or a small trial dose of propofol prior to full dose administration is an option for those patients with more severe soy or egg allergy.

Prolonged propofol infusions in critically ill pediatric patients have been associated with the propofol infusion syndrome, an acute refractory bradycardia that progresses to asystole in combination with metabolic acidosis, rhabdomyolysis, hyperlipidemia, and/or fatty liver. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propofol-related infusion syndrome'.)

Dexmedetomidine — Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that offers potent sedative effects along with some analgesia. Unlike most sedatives, it causes minimal respiratory depression in children. Studies in children support dexmedetomidine as an effective sedative that maintains spontaneous ventilation and preserves upper airway tone, which makes it a desirable choice for procedural sedation [26-29]. In healthy children, dexmedetomidine has been found to be generally safe and effective for nonpainful procedures (eg, neuroimaging) [13]. In some sedation services, dexmedetomidine is frequently used to sedate for diagnostic imaging [30].

●Dosing and administration

•Intravenous dose (infants >1 month old up to adolescents) – When dexmedetomidine is given intravenously for sedation in children, titration to effect is often required, and effective dosing can vary widely in individual patients. The dosing regimen typically consists of a loading dose and maintenance of sedation with a continuous infusion (table 1) [29]:

-Loading dose (dexmedetomidine as sole medication) – Initial loading dose 1 to 2 mcg/kg over 10 minutes; if child is not sedated after 10 minutes, give a repeat dose of 0.5 to 1 mcg/kg over 10 minutes (lower dose if patient has some effect but still requires more sedation; higher dose if not much effect from the initial dose). The total maximum loading dose is 3 mcg/kg.

When IV dexmedetomidine is used as the sole agent for sedation, a loading dose of 1.5 to 2 mcg/kg is effective for most children. However, some children may require doses up to 3 mcg/kg to successfully complete the procedure [31]. Of note, self-limited bradycardia commonly occurs at doses above 2 mcg/kg but usually does not require intervention.

When dexmedetomidine is given by itself for sedation during imaging or minor procedures, a loading dose of 1.5 mcg/kg over 10 minutes is effective in about two-thirds of pediatric patients (1 month to 18 years of age). Lower initial doses (eg, 0.5 to 1 mcg/kg) are associated with a lower rate of success and a requirement for repeat loading doses. Higher doses (eg, 2 mcg/kg to 3 mcg/kg over 10 minutes) increase the rate of successful sedation to >90 percent of patients [31]. Self-limited bradycardia commonly occurs at doses above 2 mcg/kg but usually does not require intervention. When administered with other medications, the effective dose of dexmedetomidine is decreased.

-Loading dose (dexmedetomidine combined with another agent [eg, midazolam, propofol, ketamine, or opioid analgesia]) – Give a loading dose of 0.5 to 1 mcg/kg over 10 minutes.

-Maintenance dose – After the loading dose start a continuous infusion of 1 to 2 mcg/kg/hour [17,31-33]. Titrate to desired clinical effect.

Alternatively, administration of midazolam (0.1 mg/kg, maximum dose 2 mg) will decrease the required dosing of dexmedetomidine (eg, initial IV bolus of 0.5 to 1 mcg/kg over 10 minutes followed by a continuous infusion of 0.5 to 1 mcg/kg per hour is often effective).

•Intranasal (IN) dose – IN dexmedetomidine doses of 2.5 to 4 mcg/kg (maximum single dose 200 mcg) have been shown to be effective for nonpainful procedures such as computed tomography or echocardiography [34-39]. In a small series of 42 children with autism, a dose of 4 mcg/kg in conjunction with desensitization and nonpharmacologic interventions has also shown efficacy for minimally invasive procedures such as blood draws, immunizations, and balloon gastrostomy button replacement [38]. However, most evidence on comparative effectiveness of IN dexmedetomidine with other commonly used agents is of low quality or is lacking [37]. In addition, further study is needed to determine the optimal dosing for IN dexmedetomidine. (See "Procedural sedation in children: Selection of medications", section on 'No intravenous access' and "Procedural sedation in children: Selection of medications", section on 'Sedation for other nonpainful procedures'.)

•Buccal dose: Based upon perioperative studies, buccal administration of 3 to 4 mcg/kg results in moderate sedation without reported respiratory complications [40-42].

●Benefits – Intravenous dexmedetomidine provides effective pediatric sedation with a low potential for respiratory depression [43]. It is most effective for sedation of noninvasive, nonpainful procedures. Although onset of action is slower than other IV agents with a somewhat longer recovery time, recovery agitation is minimal (table 1). Dexmedetomidine has also achieved high efficacy for successful completion of nonpainful diagnostic studies in children with autism and other behavioral disorders [13,38,44]. In addition, dexmedetomidine is particularly useful when weaning mechanically ventilated children from ventilators since it is not associated with respiratory depression [45,46]. By contrast, respiratory depression during sedation with dexmedetomidine has been described in adults and may be more frequent in that population. (See "Monitored anesthesia care in adults", section on 'Dexmedetomidine'.)

Notably, of all the commonly used sedatives and anesthetics, dexmedetomidine is the only agent that may be neuroprotective for the development of neuroapoptosis or neurocognitive impairment in animal models, while other agents have been shown to accentuate these effects [47,48].

●Important adverse effects – In a large prospective observational study of over 13,000 children who received IV dexmedetomidine for sedation, serious adverse events, primarily laryngospasm, occurred in 0.3 percent of patients [43]. Overall adverse events (which included events that spontaneously resolved or were easily managed by the sedation provider) were seen in approximately 4 percent of patients, with the most common event being an unexpected change in heart rate or blood pressure of >30 percent from baseline, agitation, delirium, or transient oxygen desaturation.

Hypertension has been described in up to 5 percent of patients receiving IV dexmedetomidine. This adverse effect is associated with younger patient age, higher dose, and multiple boluses of the drug [33]. Hypertension is dose-related and typically resolves without specific treatment or with discontinuation of the infusion [32,33]. Hypotension during the initial bolus dose of dexmedetomidine is also dose-related and is usually reversed with a fluid bolus. By contrast, profound bradycardia has been described in patients who have conduction system pathology or who are receiving atrioventricular (AV) nodal-slowing medications such as digoxin [49,50].

In a systematic review of 19 trials (2137 patients), children receiving IN dexmedetomidine administered in doses ranging from 1 to 4 mcg/kg for nonpainful procedures had low rates of bradycardia (2.2 percent) and hypotension (1.2 percent), and no patient required resuscitative measures [37].

●Contraindications and precautions – Dexmedetomidine should be avoided in children who are receiving medicines with rate-slowing action on the AV node (eg, digoxin, nifedipine), those with cardiac conduction system pathology, and those in whom increased pulmonary artery pressure or decreased cardiac output are unlikely to be well tolerated (eg, right-sided heart failure, septic shock) unless it is provided by clinicians with training and expertise in cardiac anesthesia [49,50]. Administration of glycopyrrolate to treat bradycardia caused by dexmedetomidine has been associated with severe hypertension [51]. Thus, the use of glycopyrrolate and other anticholinergic agents (eg, atropine) should be avoided in these patients.

Etomidate — Etomidate is an imidazole, nonbarbiturate hypnotic agent with an ultra-short onset of action (5 to 30 seconds). In healthy patients (American Society of Anesthesia class I or II) (table 3), duration of effect is also short (5 to 15 minutes) and depends upon the initial dose. Rapid recovery results from drug redistribution. The duration of effect is prolonged in patients with hepatic or renal dysfunction.

●Dosing and administration – Etomidate is given as an IV bolus dose of 0.1 to 0.3 mg/kg [2]. Repeated doses of 0.05 mg/kg may be given every five minutes up to a maximum total dose of 0.6 mg/kg to achieve the desired effect.

Etomidate causes pain during IV administration that can be reduced by IV pretreatment with 0.5 mg/kg of systemic lidocaine that is injected into the vein one minute prior to etomidate with a tourniquet applied. Pain is also lessened by injecting into an antecubital rather than a hand vein.

●Benefits – Rapid onset of action and recovery with few residual effects make etomidate useful for sedation during brief nonpainful procedures, especially for children who require ongoing clinical assessment of consciousness (eg, patients with head injury) (table 1). Etomidate also reduces intracranial pressure and maintains hemodynamic stability [13]. Thus, it is a good choice for sedating patients in whom cardiovascular status is uncertain or compromised (eg, multiple system trauma patients). Etomidate is an ultra-short-acting drug that is best suited to sedation for very brief procedures [52]. (See "Procedural sedation in children: Selection of medications", section on 'Intravenous medications'.)

●Adverse effects – The frequency of adverse events when etomidate is given as a single agent for pediatric procedural sedation is approximately 1 percent. The most commonly reported adverse events include respiratory depression, vomiting, and nonepileptiform myoclonus [2,13,53]. Adverse events may be more frequent when etomidate is combined with an opioid [54].

The frequency of nonepileptiform myoclonus in children receiving etomidate as a single agent for nonpainful procedures appears to be lower than in adults (<1 percent versus up to 80 percent, respectively) [53]. In adults, small trials suggest that premedication with midazolam 0.15 mg/kg, magnesium sulfate, or etomidate 0.03 to 0.05 mg/kg significantly reduces the frequency of myoclonus. However, given the lower frequency of myoclonus in children, the routine administration of any of these drugs appears unwarranted. (See "Procedural sedation in adults in the emergency department: Medication selection, dosing, and discharge criteria", section on 'Etomidate'.)

If myoclonus occurs during pediatric procedural sedation, IV midazolam is suggested [13].

●Contraindications and precautions – Etomidate inhibits 11-beta hydroxylase, an enzyme important for adrenal steroid production, and is contraindicated in patients with known adrenal insufficiency. Adrenal suppression from single doses of etomidate has not been associated with any negative outcomes in healthy children undergoing procedural sedation. Acute adrenal insufficiency and increased mortality have been associated with single doses of etomidate in children with sepsis. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Airway and breathing'.)

Midazolam — Midazolam is a short-acting benzodiazepine with a rapid onset of action when given via IV [2]. It has good anxiolytic, amnestic, and muscle relaxant properties and has been frequently used to provide mild sedation in children or combined with fentanyl or dexmedetomidine to achieve moderate sedation [2,3,13].

●Dosing and administration – Midazolam is water soluble and can be given by parenteral (IV or intramuscular), rectal (PR), intranasal, sublingual (SL), or oral (PO) routes. Doses, onset of action, and duration of effect will vary depending upon patient age and the route of administration (table 1 and table 2) [2,3,13].

When compared with PR, SL, or PO administration, intranasal midazolam has the most rapid onset of action and shortest recovery time (table 2) [3]. However, intranasal midazolam can be very irritating for some children. Pretreatment with lidocaine spray (10 mg per puff) one minute prior to intranasal administration decreases nasal mucosal irritation [55]. An atomizer device delivers midazolam as a fine mist, which results in better nasal mucosa absorption and comfort with reduction of sneezing and cough when compared with direct instillation [56,57].

●Benefits – Midazolam has strong amnestic properties and is an effective anxiolytic in most children [2,3,13]. The many potential routes of administration permit its use in children without vascular access. When used as the sole agent for sedation with proper dosing, respiratory depression is rare. Midazolam has a shorter duration of action than pentobarbital or chloral hydrate.

Flumazenil is an effective reversal agent for the few patients who develop significant respiratory depression or apnea after sedation with midazolam. Flumazenil should not be used in patients with seizure disorders or those who receive benzodiazepines on a chronic basis because of the risk of precipitating seizures or withdrawal symptoms, respectively. The use of flumazenil to reverse adverse effects of benzodiazepines, including dosing and redosing recommendations, is discussed in detail separately. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)

●Adverse effects – Midazolam can cause respiratory depression and apnea, especially when combined with opioid medications such as fentanyl or morphine [2,3]. For example, of 130 children receiving midazolam and fentanyl for orthopedic procedures in a randomized trial, hypoxia occurred in one-quarter of patients, 20 percent received supplemental oxygen, 12 percent needed breathing cues, and laryngospasm was described in one patient [58]. (See 'Fentanyl' below.)

Paradoxical reactions, including inconsolable crying, hyperactivity, and aggressive behavior may occur in approximately 1 to 3 percent of patients when midazolam is use as a single agent [59-61].

Both respiratory depression and paradoxical reactions can be reversed with flumazenil [59,62]. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)

Midazolam is inferior as a sedative agent for computed tomography when compared with short-acting barbiturates. (See "Procedural sedation in children: Selection of medications", section on 'No intravenous access'.)

●Contraindications and precautions – Midazolam has mild negative inotropic effects and should be used with caution in children with underlying myocardial depression [3].

Short-acting barbiturates — Barbiturates are central gamma-aminobutyric acid (GABA) agonists. In the past, these agents were often used to sedate children. More recently, they have been replaced by other agents with equivalent or better efficacy, shorter recovery times, and fewer adverse events. Pentobarbital, methohexital, and thiopental (not available in the United States or Canada) are the barbiturates most commonly used to sedate children [63,64]. Of these agents, pentobarbital has the best efficacy and fewest adverse effects. (See "Procedural sedation in children: Selection of medications", section on 'No intravenous access'.)

●Dosing and administration – The initial IV dose of pentobarbital is 1 to 2 mg/kg (maximum single dose 100 mg). This dose can be repeated every three to five minutes up to a maximum total dose of 6 mg/kg (maximum total dose 600 mg). Patients receiving concurrent barbiturate therapy (eg, phenobarbital) may require higher total doses up to 9 mg/kg to achieve adequate sedation.

The PO or PR dose of pentobarbital varies by age. Children younger than four years of age can receive 3 to 6 mg/kg PO or PR (maximum single dose 100 mg). Children four years of age and older are given 1.5 to 3 mg/kg PO or PR (maximum single dose 100 mg).

When used for pediatric procedural sedation, methohexital is given IV or PR and thiopental is given PR.

●Adverse effects – Respiratory depression or apnea occurs in approximately 2 to 11 percent of children who undergo sedation with short-acting barbiturates [65-70]. The risk of respiratory depression is lowest with pentobarbital and highest with rectal thiopental. The potential for airway compromise increases when barbiturates are used in combination with other sedatives and/or opioids [64]. Severe agitation during emergence and prolonged sleepiness or ataxia may occur after pentobarbital administration [71].

●Contraindications and precautions – Use of barbiturates is contraindicated in patients with porphyria. Barbiturates have myocardial depressant effects and should be avoided in patients with hemodynamic instability or heart failure.

Methohexital can cause seizures and should be avoided in children with epilepsy.

Chloral hydrate — Chloral hydrate was once the preferred sedative agent for diagnostic imaging in infants and children younger than three years of age and is efficacious for that purpose [72-74]. However, small trials and observational studies indicate that chloral hydrate is inferior to other sedation options because of its delayed onset of action, prolonged effect, and high frequency of adverse effects [73-77]. Given the availability of better alternatives, the use of chloral hydrate is no longer recommended. Also, in many regions, chloral hydrate is no longer available. (See "Procedural sedation in children: Selection of medications", section on 'No intravenous access'.)

OTHER AGENTS — Ketamine is a dissociative sedative that provides effective sedation and analgesia for moderately to severely painful procedures. Nitrous oxide (N₂O) is an inhaled anesthetic that provides mild analgesia and effective sedation.

Ketamine — Ketamine is a phencyclidine (PCP) derivative that acts as a dissociative sedative through binding of the N-methyl-D-aspartate (NMDA) receptor. There is no "sedation continuum," and the effect is either present or absent. It produces a trance-like state and provides sedation, analgesia, amnesia, and immobilization, while usually preserving upper airway muscle tone, airway protective reflexes, and spontaneous breathing [2,3,78-80]. Because of its rapid onset, relatively short duration of action and excellent sedative and analgesic properties, it often is used for brief, painful pediatric procedures such as fracture reduction or laceration repair.

Clinical practice guidelines for the use of ketamine have been developed [80,81]. When used as part of a carefully developed protocol, ketamine can provide safe and effective sedation and analgesia.

The clinical manifestations and management of ketamine toxicity (both iatrogenic and from illicit use) are discussed separately. (See "Ketamine poisoning".)

●Dosing and administration – Dosing of ketamine when used as the sole agent for pediatric sedation varies by the route of administration:

•Intravenous – The initial intravenous (IV) dose of ketamine is 1 to 1.5 mg/kg. For healthy patients without QT prolongation or receiving medications that prolong the QT interval, we suggest premedication with ondansetron (0.15 mg/kg IV, maximum single dose 4 mg) prior to ketamine to reduce vomiting.

A repeat dose of 0.5 to 1 mg/kg may be administered after 10 minutes as needed.

Intravenous dosing for ketamine when combined with propofol (sometimes called ketofol) is provided separately. (See 'Ketamine with propofol (ketofol)' below.)

•Intramuscular – Ketamine may also be given intramuscularly (IM) in an initial dose of 4 to 5 mg/kg with a repeated IM dose of 2 to 4 mg/kg after 10 minutes as needed. However, IM administration is associated with more vomiting and significantly longer recovery times compared with IV administration [82,83]. Thus, in children who are receiving procedural sedation with ketamine and have readily available vascular access, we recommend IV administration rather than IM injection. Although IM ketamine was associated with a greater risk of laryngospasm in one large observational study [80], this finding has been inconsistent and not replicated in two additional studies with larger sample sizes [84,85].

While children routinely receive IV or IM ketamine for dissociative sedation for painful procedures, intranasal (IN) ketamine alone has not been shown to reliably achieve this depth of sedation due to the high dose required for effect [86,87]. Further study is required before recommendations for IN ketamine, either alone or in combination with other sedatives, may be made. (See "Procedural sedation in children: Selection of medications", section on 'Sedation for other nonpainful procedures'.)

●Coadministration with opioid analgesia – Ketamine has powerful analgesic properties, and coadministration with opioids is not required or recommended to provide analgesia during a painful procedure. However, administration of opioids for preprocedural analgesia is not a contraindication to using ketamine sedation. In one large cohort of almost 6300 children receiving emergency department sedation, the addition of fentanyl to ketamine for procedural sedation was associated with an increased risk of serious adverse events compared with ketamine sedation alone (4.1 versus 0.4 percent, adjusted odds ratio [OR] 4.0, 95% CI 1.8-8.1) [88]. In this study, preprocedural opioid administration was associated with a significantly increased risk of vomiting, oxygen desaturation, and need for significant interventions, but not for serious adverse events. Thus, we continue to advocate for adequately treating pain in children prior to procedural sedation and emphasize that, in doing so, we must recognize that adverse events may occur more frequently.

●Premedication with other agents – Although administration of atropine or glycopyrrolate may reduce the amount of salivation, evidence suggests that these medications do not reduce the risk of laryngospasm and, thus, are not routinely necessary [89-91]. Similarly, based on the evidence, we do not recommend the routine use of midazolam premedication when ketamine alone is administered for procedural sedation.

•Anticholinergic agents – In one prospective study, only one of 947 children receiving ketamine without an anticholinergic agent experienced an adverse event that was felt to be due to hypersalivation (brief oxygen desaturation, estimated incidence 0.1 percent, 95% CI 0.0-0.6 percent) [90]. In a systematic review of 8282 ketamine sedations performed in the emergency department and reported in 32 studies, children who received no anticholinergic agent had airway and respiratory adverse events in 3 percent of sedations compared with 3 and 6 percent of patients who received atropine and glycopyrrolate, respectively [91]. No differences in laryngospasm or apnea were found among the three groups. In a prospective, multicenter, observational study of over 7000 children undergoing sedation with ketamine and propofol, the use of anticholinergic agents was associated with significant increases in adverse events, including serious adverse events (eg, airway obstruction, emergency airway, and laryngospasm) compared with ketamine and propofol alone (12 versus 4 percent, respectively; adjusted OR for serious adverse events 3.2; 95% CI 2.4-4.2) [84]. Taken together, this observational evidence indicates that anticholinergic agents do not improve the safety of ketamine sedation and may increase the risk of adverse events. However, this evidence does not preclude a benefit of anticholinergic agents for selected patients with markedly excessive secretions at baseline.

•Midazolam – Premedication with midazolam was once thought to minimize the side effects of ketamine sedation, especially vomiting and unpleasant recovery reactions (also called emergence phenomenon or agitation). However, it does not appear to be more efficacious than ondansetron for vomiting and has not been shown to impact the frequency of emergence phenomenon [3]. As an example, in one randomized trial, 266 children between the ages of 5 months and 16 years received ketamine sedation with or without midazolam [92]. Sedation was equally effective, and emergence phenomena (hallucinations, nightmares, and severe agitation) were similar with the two regimens. Although midazolam premedication was associated with decreased vomiting (9.6 versus 19.4 percent) when compared with ketamine alone, it was also associated with an increased frequency of oxygen desaturation (7.3 versus 1.6 percent, respectively), especially in children younger than 10 years of age.

In a separate large, prospective, observational study of children undergoing sedation with ketamine and propofol, coadministration of benzodiazepines was associated with fewer adverse events such as self-limited oxygen desaturation and serious adverse events (eg, airway obstruction requiring advanced airway management) [84]. These contradictory findings may be due to patient selection and the dosing regimens (as well as polypharmacy) applied in these studies.

●Adverse effects – Side effects of ketamine include vomiting, unpleasant recovery reactions, and rarely, apnea or laryngospasm [2,3,22]. Hallucinations are most common in patients older than 15 years of age. Although apnea and laryngospasm occur in <1 percent of children who receive ketamine and can generally be managed with positive pressure bag-mask ventilation, it is essential that providers be prepared to rapidly identify and manage this severe complication [85,93].

We suggest that children receiving ketamine sedation receive premedication with ondansetron or other serotonin receptor antagonists to reduce the frequency of vomiting. Ondansetron effectively reduces emesis after ketamine administration, especially in children younger than five years of age. As an example, in a blinded, randomized trial of 255 children receiving ketamine sedation, premedication with ondansetron reduced the absolute risk of vomiting in the emergency department from 13 to 5 percent (number needed to treat: 13) [94].

Several studies of ketamine sedation in children best inform our understanding of associated adverse events and risks. In an individual patient data meta-analysis of 32 studies consisting of over 8000 patients who received sedation in the emergency department, primarily for fracture reduction or wound repair, use of ketamine was associated with the following adverse events [95,96]:

•Respiratory events

-Apnea: 0.8 percent

-Laryngospasm: 0.8 percent

-Aspiration: None reported (estimated upper limit of the 95% CI 0.04 percent)

-Oxygen desaturation ≤90 percent or upper airway obstruction: 2.8 percent

Airway and respiratory events were independently associated with age younger than 2 years or older than 12 years, high IV dosing (≥2.5 mg/kg initial dose or total dose ≥5 mg/kg), and coadministration of a benzodiazepine (eg, midazolam) or an anticholinergic agent (eg, atropine) [96]. Thus, attention to dosing and avoidance of coadministration of midazolam or atropine may result in a lower risk of respiratory events.

•Vomiting: 8 percent

Vomiting was independently associated with high IV dosing (≥2.5 mg/kg or total dose ≥5 mg/kg), IM administration, and older age [95].

•Recovery agitation requiring specific treatment or described as severe: 1.4 percent

In an observational study from the Pediatric Sedation Research Consortium, which prospectively examined ketamine use for mostly elective procedural sedation in over 22,600 children, the overall incidence of severe adverse events was low. Risk factors found to be associated with increased odds of adverse events were cardiac and gastrointestinal disease, lower respiratory tract infection, and the coadministration of propofol and anticholinergics [97]. In a multicenter, prospective, observational study of ketamine sedation of almost 6300 children in six Canadian pediatric emergency departments, serious adverse events and significant interventions were associated with adding propofol or fentanyl to ketamine. In addition, preprocedural antiemetics were associated with a 50 percent reduction in the odds of vomiting [88].

Although data are limited in children, the combination of propofol and ketamine for procedural sedation appears to provide effective sedation and less vomiting than reported for ketamine alone and less hypotension than described with propofol alone. For example, based on a small observational study and one trial, propofol combined with ketamine was associated with vomiting in 0 to 2 percent of patients and no episodes of hypotension [18,98]. However, adverse respiratory events including laryngospasm can still occur.

●Contraindications and precautions – Ketamine is contraindicated in patients younger than three months of age, those with psychosis, and those who have had severe adverse reactions in the past (table 1).

Ketamine is relatively contraindicated in other patients with the following conditions [81]:

•Airway instability

•Hypertension

•Angina or heart failure

•Increased intracranial pressure caused by obstructive brain lesions that cause hydrocephalus

•Increased intraocular pressure (IOP), such as glaucoma or eye injury

•Porphyria

•Thyroid disease

Evidence for restricting ketamine use in children with possible increased intraocular pressure (IOP) has been conflicting. For example, in two small observational studies of children with healthy eyes undergoing procedural sedation with ketamine, the mean increase in IOP associated with ketamine administration at total doses <4 mg/kg was approximately 1 mmHg [99,100]. However, another series of 60 children with healthy eyes undergoing ketamine sedation with similar dosing found transient increases in IOP >5 mmHg occurring in 25 percent of patients, although the median increase in IOP was modest (3 mmHg [range 0 to 8 mmHg]) [101]. Thus, options other than ketamine are still best for patients with a strong likelihood of increased IOP whenever possible.

Ketamine with propofol (ketofol) — Ketamine and propofol (also called "ketofol"), with or without an opioid, are commonly used for procedural sedation and analgesia for children outside of the operating room [84,88]. Ketofol has been proposed as an alternative to either ketamine or propofol alone, which benefits from the positive properties of each drug while mitigating their adverse events [81,102]. The proposed benefit of ketofol is that sub-dissociative dosing of ketamine provides analgesia and sympathomimetic effects, while propofol provides deep sedation and antiemetic effects with a more rapid recovery [102].

●Dosing and administration – The optimal dosing for ketofol has not been established. One regimen consists of 0.5 mg/kg ketamine IV followed by a bolus dose of 0.5 mg/kg of propofol. If needed, additional doses of 0.5 mg/kg of propofol may be given every two minutes [18].

In a systematic review of 11 randomized controlled trials, the dosing of ketofol varied and included IV ketamine bolus doses of 0.2 to 1 mg/kg and IV propofol initial bolus doses of 0.5 to 2 mg/kg followed by subsequent propofol IV boluses of 0.5 to 1 mg/kg. In some cases, ketamine and propofol were administered individually and in others simultaneously at ketamine to propofol ratios of 1:1, 1:2, 2:1, 1:4 and 1:6 [103].

●Adverse effects – Risk of adverse events including apnea, laryngospasm, hypotension, and bradycardia may be higher for patients receiving ketofol compared with ketamine alone. In a large, multicenter surveillance study of emergency department procedural sedation, serious adverse events, apnea, laryngospasm, hypotension, and bradycardia were found to be associated with administration of propofol or a combination of ketamine and propofol as compared with ketamine alone [88]. The incidence of serious adverse events in this observational study of 6295 children was low in all groups (ketamine 0.4, propofol 3.7, and ketofol 2.1 percent).

By contrast, in an unblinded trial of 139 children with cancer undergoing sedation for a lumbar puncture or bone marrow aspiration, the risk of hypotension was lower in patients assigned to ketofol (11 percent) compared with those receiving propofol alone (39 percent) and recovery time was shorter (mean time 8 versus 20 minutes) [103].

●Contraindications and precautions – Contraindications and precautions for ketofol are the same as for both ketamine and propofol as described separately. (See 'Ketamine' above and 'Propofol' above.)

●Efficacy – Although evidence is limited, when used by experienced providers, ketofol appears to be safe and effective and may result in less vomiting than sedation with ketamine alone and less hypotension and a shorter recovery time than sedation with propofol alone [104].

•Ketofol versus ketamine alone – In one randomized controlled trial of 136 children comparing ketofol 1:1 to ketamine alone for emergency department orthopedic reduction, no difference in efficacy or airway complications was detected [18]. Patients who received ketofol demonstrated slightly faster recoveries (10 versus 12 minutes, difference -2 minutes; 95% CI -4 to -1 minute) and less vomiting (2 versus 12 percent, difference -10 percent; 95% CI -18 to -2 percent). No significant differences in cardiovascular or respiratory adverse events or unpleasant emergency reactions were found between 96 children who received either ketamine alone or ketofol in a second randomized controlled trial [105]. Median recovery time was the same, and although satisfaction scores for providers and nurses were higher in the ketamine alone group, parents or caregivers were equally satisfied with both sedation regimens.

•Ketofol compared with propofol alone – As previously mentioned, children with cancer receiving ketofol had less hypotension and shorter recovery times in one unblinded trial [103].

Nitrous oxide — Inhaled N₂O is an anesthetic gas that provides mild analgesia, sedation, amnesia, and anxiolysis [106-108]. Spontaneous respirations, airway protective reflexes, and hemodynamic status are generally preserved at concentrations typically used for sedation and analgesia (50 to 70 percent N₂O).

●Dosing and administration – Onset of sedation and recovery is very rapid with N₂O. N₂O is mixed with 30 to 50 percent oxygen and delivered through a demand-valve mask or continuous flow system [109]. Because the demand-valve mask requires cooperation and may be difficult to activate by smaller children, N₂O is used primarily in patients older than four years of age. Continuous delivery systems (a mask strapped over the nose and/or mouth) have been used in younger children with variable success [110,111]. This system is more frequently associated with emesis than the demand-valve technique [2].

Delivery systems include those that provide a fixed concentration of N₂O with oxygen (typically 50 percent of each) or wall-mounted piped N₂O and oxygen that permits increasing concentrations of N₂O from 0 to 70 percent [112,113]. Essential safety features include the following [109,113]:

•Automatic cutoff of N₂O if oxygen delivery fails

•Emergency oxygen override

•Maximum N₂O delivery limit of 70 percent

•Color-coded tanks with different pin assemblies to attach to the delivery system so that practitioners cannot mistake an N₂O tank for an oxygen tank

•Proportional delivery of N₂O with oxygen

•Recovery of patients with a high concentration of oxygen (oxygen washout) to prevent diffusion hypoxia

•Adequate scavenger systems to prevent excessive occupational exposure to medical personnel

●Adverse effects – N₂O has an excellent safety profile for sedation in children with no major cardiopulmonary events (eg, apnea, significant hypoxia, bradycardia, or hypotension) reported in several large observational studies [109]. Minor adverse effects include nausea, vomiting, and dysphoria. Of these, vomiting (up to 7 percent of patients) is most frequently reported [112].

Deaths have been rarely associated with mechanical failure of the delivery system and inadvertent administration of 100 percent N₂O [109]. Thus, clinicians must know how to test and use the equipment in use in their facility. In addition, equipment must be carefully maintained and periodically tested to ensure adequate safety.

●Contraindications and precautions – Contraindications to N₂O include nausea and vomiting; trapped gas within body cavities (eg, bowel obstruction, pneumothorax, middle ear infection), especially with the use of concentrations >50 percent; and pregnancy (increased risk of spontaneous abortion) [2,3].

Furthermore, potentially pregnant medical personnel should not participate in N₂O administration [109].

Deeper sedation than anticipated can occur with prolonged inhalation and when N₂O is combined with opioids or benzodiazepines [112].

ANALGESIC AGENTS

Indications — Appropriate analgesia can often lower the amount of sedative agent needed to provide adequate sedation and thus increase the safety of the procedure. The need for supplementary analgesia varies by the agents used:

●Ketamine has both sedative and analgesic properties and can thus be used alone to provide sedation for painful procedures. (See "Procedural sedation in children: Selection of medications", section on 'Approach'.)

●Dexmedetomidine and nitrous oxide (N₂O) have limited analgesic properties that may be inadequate and warrant additional analgesic medications for moderately or severely painful procedures.

●Midazolam, etomidate, and propofol, do not have analgesic properties and need to be combined with other analgesic agents.

Topical, local, and regional anesthesia — Local anesthetics can be delivered topically or by direct infiltration to diminish or abolish the pain associated with many procedures including intravenous (IV) cannula insertion, lumbar puncture, abscess drainage, or laceration repair. The topical anesthetic most frequently used for laceration repair is the combination of lidocaine, epinephrine, and tetracaine (LET), which becomes effective in approximately 30 minutes. For intact skin, EMLA (a eutectic mixture of lidocaine-prilocaine in a cream base) and LMX 4 (a nonprescription 4 percent liposomal lidocaine preparation) are also effective topical agents. They are discussed in more detail separately. (See "Clinical use of topical anesthetics in children", section on 'Lidocaine-prilocaine'.)

Local infiltration is typically performed using lidocaine. A variety of techniques may be used to decrease the pain of infiltration. (See "Subcutaneous infiltration of local anesthetics", section on 'Methods to decrease injection pain'.)

Regional anesthesia is also an effective means of procedural analgesia and includes techniques such as digital (picture 1), dorsal penile (figure 1), facial nerve (figure 2 and figure 3), and Bier blocks. The procedures for performing these blocks are discussed in detail separately. (See "Digital nerve block" and "Assessment and management of facial lacerations", section on 'Facial nerve blocks' and "Overview of anesthesia", section on 'Intravenous regional anesthesia' and "Management of zipper entrapment injuries", section on 'Dorsal penile block'.)

When local or regional anesthesia is used, sedation may also be provided to reduce pain and anxiety associated with performing local or regional anesthetic infiltration. Once successful pain control is achieved by local or regional anesthesia, requirements for additional procedural sedation (eg, additional doses or increased depth of sedation) are usually markedly reduced when compared with performing procedural sedation alone.

Oral sucrose — Much of the research that has evaluated oral sucrose for pain relief has occurred in preterm and term neonates. In this population, oral sucrose and other sweet-tasting liquids, such as glucose or saccharin, appear to be effective analgesics for minor procedures (eg, heel lancing). (See "Management and prevention of pain in neonates", section on 'Oral sucrose and other sweet liquids'.)

The influence of factors such as age, type of painful procedure, location in which the procedure is performed, and intercurrent illness on the analgesic effect of sucrose is uncertain. Nevertheless, sucrose appears to be safe and is easy to administer. A procedure for the administration of sucrose analgesia is described in the table (table 4). The dosing of oral sucrose in term and preterm neonates is discussed in detail separately. (See "Management and prevention of pain in neonates", section on 'Oral sucrose and other sweet liquids'.)

In older infants, oral sucrose also appears effective:

●A meta-analysis of randomized controlled trials that studied the use of sucrose or glucose for control of pain prior to immunization in infants 1 to 12 months of age found significant reductions in the incidence and duration of crying [114].

●A randomized trial in a pediatric emergency department described infants younger than 90 days who received sucrose prior to bladder catheterization [115]. The analgesic effect of sucrose was only significant among infants 30 days of age or younger.

Fentanyl — Fentanyl is a synthetic opioid that has 75 to 125 times the potency of morphine and provides analgesia for procedures with moderate to severe pain [64,116]. Its rapid onset (within two to three minutes), relatively short duration of action (30 to 60 minutes), and lack of histamine release render it preferable for procedural sedation when compared with longer-acting opioids such as morphine [2,116]. Morphine is an acceptable alternative if fentanyl is not available but has a longer onset and duration of action (20 minutes and 4 hours, respectively). (See "Pain in children: Approach to pain assessment and overview of management principles", section on 'Opioids'.)

Initial dosing of fentanyl and morphine may need to be adjusted for patients who have tolerance to opioids (eg, patients receiving chronic opioid analgesia). (See "Pain in children: Approach to pain assessment and overview of management principles", section on 'Initial dosing'.)

Hypoxemia, respiratory depression, and apnea may occur when fentanyl is combined with other sedatives (eg, propofol, etomidate, or midazolam) [25,52,58]. Chest wall and glottic rigidity is a rare but life-threatening adverse effect of fentanyl [117,118]. This muscle rigidity results in inability to ventilate the patient, even after endotracheal intubation. Although widely thought to primarily occur when large doses (eg, >4 mcg/kg) of fentanyl are given rapidly, perioperative chest wall rigidity has been reported in neonates, infants, and young children with single doses of fentanyl as low as 1 mcg/kg [118]. In addition to naloxone administration, neuromuscular blockade and endotracheal intubation may be needed to alleviate these symptoms.

Although typically administered parenterally, fentanyl also can be effective when used intranasally or via nebulizer, as demonstrated in the following reports:

●In a randomized trial, intranasal fentanyl (as compared with IV morphine) provided effective analgesia for children with long bone fractures [119]. Initial pain control in patients with moderate to severe pain can be achieved within one to two minutes with intranasal fentanyl delivered by an atomizer (2 mcg/kg; maximum single dose 100 mcg) [57,120-122]

●In a small randomized trial, nebulized fentanyl was as effective as IV fentanyl for pain relief among children who presented to an emergency department with painful conditions [123].

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 children".)

SUMMARY AND RECOMMENDATIONS

●Agents and dosing – The properties of commonly used agents for pediatric procedural sedation are discussed in this topic and summarized in the tables (table 1 and table 2). Assessment, preparation, and proper performance of pediatric procedural sedation outside of the operating room, including selection of medications for pediatric procedural sedation, are discussed separately. (See "Procedural sedation in children: Preparation" and "Procedural sedation in children: Approach" and "Procedural sedation in children: Selection of medications".)

●Sedative-hypnotic agents – Propofol, etomidate, midazolam, and short-acting barbiturates (eg, pentobarbital, methohexital) provide sedation but do not provide analgesia. Chloral hydrate is inferior to other sedation options because of its delayed onset of action, prolonged effect, and high frequency of adverse effects. (See 'Sedative-hypnotic agents' above and 'Chloral hydrate' above.)

●Ketamine – Ketamine is a phencyclidine (PCP) derivative that acts as a dissociative sedative through binding of the N-methyl-D-aspartate (NMDA) receptor and is an effective single agent for sedation of children undergoing moderately to severely painful procedures. In children who are receiving procedural sedation with ketamine, intravenous (IV) administration is preferred. (See 'Ketamine' above and "Procedural sedation in children: Selection of medications", section on 'Moderately or severely painful procedures'.)

Side effects of ketamine include increased vomiting, unpleasant recovery reactions, and rarely, apnea or laryngospasm. For healthy patients without QT prolongation or receiving medications that prolong the QT interval and undergoing sedation with ketamine as the sole agent, we suggest premedication with ondansetron to reduce the frequency of vomiting rather than no premedication (Grade 2B). (See 'Ketamine' above.)

●Analgesia – When providing sedation for painful procedures, addition of analgesia lowers the amount of sedative agent needed to provide adequate sedation and thus increases the safety of the procedure. The need for supplementary analgesia varies by the agents used (see 'Analgesic agents' above):

•Ketamine – Ketamine has both sedative and analgesic properties and can thus be used alone to provide sedation for painful procedures. (See 'Ketamine' above and "Procedural sedation in children: Selection of medications", section on 'Approach'.)

•Dexmedetomidine or nitrous oxide – Dexmedetomidine or nitrous oxide (N₂O) have limited analgesic properties that may be inadequate and warrant additional analgesic medications for moderately or severely painful procedures. (See 'Dexmedetomidine' above and 'Nitrous oxide' above.)

•Propofol, etomidate, or midazolam – Propofol, etomidate, and midazolam do not have analgesic properties and need to be combined with other analgesic agents (eg, local or regional anesthesia or fentanyl) to provide effective sedation for painful procedures. (See 'Propofol' above and 'Etomidate' above and 'Midazolam' above.)

Topical, local, and regional anesthesia or systemic opioids (eg, fentanyl) are the medications most commonly combined with sedative-hypnotic agents to provide procedural sedation for moderately to severely painful procedures. (See 'Analgesic agents' above.)

Oral sucrose is suggested to decrease the pain response to minor procedures (eg, heel lancing or immunization administration) in infants younger than one year of age. (See 'Analgesic agents' above and "Management and prevention of pain in neonates", section on 'Oral sucrose and other sweet liquids'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Deborah C Hsu, MD, MEd, who contributed to earlier versions of this topic review.