Clinical practice guideline for emergency department ketamine dissociative sedation in children

Age 

The literature is replete with anecdotal observations and reported cases of airway complications with ketamine in infants younger than 3 months, including airway obstruction, laryngospasm, and apnea.2., 50., 51., 57., 58. This propensity toward airway adverse events is not peculiar to ketamine but rather represents infant-specific differences in airway anatomy and reactivity, and laryngeal excitability.2., 50., 51., 59. Neonates and young infants requiring painful procedures are more appropriately treated with sedative-hypnotics and opioids in the ED or with general anesthesia in the operating room.

Mental state 

Ketamine has been shown to exacerbate established psychosis,60 and other procedural sedation and analgesia options should be used in such individuals.

Age 

Although historically some have recommended that ketamine be avoided in children younger than 12 months because of a presumed higher risk of airway complications,2., 50. many ED series have subsequently enrolled numerous subjects in the 3- to 12-month-old range without resultant airway difficulties. The enhanced risk, if any, would thus appear to be minimal.10., 11., 23., 26.

Laryngeal stimulation 

Ketamine is well known to preserve and exaggerate protective airway reflexes,2., 50., 51. and there is compelling evidence that stimulation of the larynx during dissociative sedation (eg, blood from pharyngeal procedures, endoscopy) will increase the risk of laryngospasm. In a large series of ketamine for pediatric gastroenterology procedures, for example, laryngospasm was encountered in 9.4% of those undergoing upper endoscopy but in none of those undergoing colonoscopy.54 Because laryngospasm occurs in only 0% to 3% of upper endoscopy patients sedated using benzodiazepines and opioids,54 it is reasonable to assume that ketamine presents additional independent risk as a sedative choice during procedures with substantial laryngeal stimulation. Several authors have reported no airway complications using ketamine for dentistry and other intraoral procedures18., 28., 31., 61.; however, others have.62., 63.

Anatomy 

Although the existing literature is insufficient to conclusively implicate a history of airway instability, tracheal surgery, tracheal stenosis, tracheomalacia, and laryngomalacia as contraindications to ketamine administration, it remains plausible that these conditions may entail a higher risk of laryngospasm and airway obstruction.2

Upper respiratory infections 

There is indirect evidence to implicate active upper respiratory infection and active asthma as relative ketamine contraindications in children but not adults. Upper respiratory infection and active asthma are well known to increase laryngospasm risk in children during inhalational anesthesia. Olsson and Hallen59 noticed that in patients with upper respiratory infection, the risk was 5.5 times higher than in those without, and when active asthma was present the risk was 3.7 times higher. No such differences were noticed in adults.59 It is uncertain whether this predisposition observed during inhalational anesthesia applies to ketamine, although presumably the laryngospastic response has similar underlying pathophysiology, regardless of drug. Because ketamine exaggerates laryngeal reflexes,2., 50., 51. whereas inhalational anesthetics depress them, it could be reasonably argued that the risk with ketamine in this setting might actually be higher than that for the anesthetics.

Anecdotal association between upper respiratory infection and laryngospasm appeared in numerous reports shortly after ketamine's release in 1970, and according to these data and the inhalational anesthesia experience discussed previously, essentially every ketamine review article or textbook chapter lists upper respiratory infection as a contraindication.2., 50., 51., 52. There is no evidence to clarify what specific magnitude of upper respiratory infection signs and symptoms should preclude ketamine administration.

Asthma 

Ketamine is not contraindicated in severe asthma with respiratory failure when it is coadministered with a neuromuscular blocker to facilitate rapid sequence intubation because concurrent paralysis effectively eliminates the possibility of laryngospasm. Indeed, ketamine is considered by many to be the sedative of choice in this setting because of its bronchodilatory properties.2., 64. Although ketamine has been administered to spontaneously breathing adults with active asthma,65 there is insufficient experience to support its safety in this setting, and indeed asthma is a known risk factor for laryngospasm in inhalational anesthesia.59 There is no evidence to support inactive asthma as a contraindication.

Laryngospasm 

For the relative contraindications described above that are based on an increased potential for laryngospasm, it is expected that practitioners will weigh this risk according to their relative comfort with managing this complication. Although laryngospasm is relatively uncommon in the literature (0.4% incidence in the largest ED series),10 essentially all ketamine-associated laryngospasm has been transient and responded quickly to assisted ventilation and oxygen. In fact, in a systematic review of all ketamine series in children before 1990, totaling 11,589 ketamine administrations, there were only 2 reported cases in which ketamine-associated laryngospasm led to intubation (0.02% incidence, 95% confidence interval 0.002% to 0.06%).57., 66. In both cases, it is unclear whether the intubation was required or rather used for anesthesiologist convenience. There is currently no evidence to suggest that practitioners skilled in dissociative sedation and advanced airway management cannot consistently manage laryngospasm without a greater-than-minimal risk of adverse outcome.

Cardiac disease 

It is widely recommended according to circumstantial evidence that ketamine be avoided in patients with known or possible coronary artery disease, congestive heart failure, or hypertension.50., 51., 52., 67. Ketamine exerts sympathomimetic activity by inhibiting reuptake of catecholamines and produces mild to moderate increases in blood pressure, pulse rate, cardiac output, and myocardial oxygen consumption. It is unclear whether the increased coronary perfusion associated with this hyperdynamic state parallels increases in oxygen demand.2., 51., 68., 69., 70. Although ketamine has been widely administered to elderly patients in the developing world,57., 71. the baseline incidence of coronary artery disease in these populations is substantially lower than that in developed countries, and safety in this setting cannot be extrapolated.

Increased intracranial pressure 

On the basis of inconclusive evidence, it is widely believed that ketamine elevates intracranial pressure.2., 50., 51., 72., 73., 74., 75. Accordingly, central nervous system masses, abnormalities, or hydrocephalus must be assumed to present an increased risk for neurologic deterioration during dissociative sedation.73., 74., 75. Similarly, patients with significant head injury (eg, associated with loss of consciousness, altered mental status, or emesis) must also be considered at risk. Sedation using other agents would appear preferable in most such cases unless neurologic imaging has excluded abnormality.

Seizure disorder 

Seizure disorder has not been identified as a contraindication to ketamine, and indeed ketamine demonstrates anticonvulsant properties.2., 50., 51.

Increased intraocular pressure 

There is inconclusive and conflicting evidence of elevated intraocular pressure with ketamine.76., 77., 78., 79., 80. Accordingly, dissociative sedation may represent risk in patients with glaucoma or acute globe injury.

Porphyria and thyroid disease 

There is anecdotal and inconclusive evidence of enhanced sympathomimetic responses in patients with porphyria,81., 82. thyroid disorder,83 or thyroid medication.83 Ketamine should be used with caution in these patients.

Fasting state 

There is no evidence that a specific fasting duration is necessary before dissociative sedation. Preprocedural fasting is intended to minimize the risk of pulmonary aspiration, and in 34 years of continual use, there are no documented reports of clinically significant ketamine-associated aspiration, except in ill neonates.2., 41., 42., 50., 51. Indeed, several series from non-ED settings report no adverse effects from administering ketamine to nonfasted children,2., 7., 84., 85., 86., 87. and a systematic review of this research revealed no apparent association of fasting state with emesis, laryngospasm, or any other complication.2 Two large, prospective ED series have also failed to shown any association between fasting and adverse effects.29., 88. The unique protection of airway reflexes with ketamine would appear to make it preferable to alternative sedatives in situations of incomplete fasting.41., 42.

A relative contraindication of a “full meal within 3 hours of procedure” has been widely used in emergency medicine for more than a decade; however, there is no specific evidence to support this recommendation.1., 2., 10., 33. A case-by-case risk-benefit assessment is more consistent with the current literature than setting an arbitrary fasting period.41

Comorbidity 

Patients with underlying illness are believed to exhibit greater susceptibility to the cardiopulmonary depressant effects characteristic of nondissociative sedatives and anesthetics and accordingly are believed to be at greater risk of respiratory adverse events with these agents.43., 44., 48., 89. Such an association has not been similarly observed with dissociative sedation,35., 53. and indeed the cardiopulmonary support characteristic of ketamine may make this agent preferable to other procedural sedation and analgesia agents in patients with substantial underlying illness.2., 35., 53., 54.

Dosing and adverse events 

Clinicians are highly accustomed to the concept of a continuum of sedation and dose-dependent adverse events with nondissociative procedural sedation and analgesia agents. However, there is no evidence that ketamine exhibits any dose-related adverse events within the range of clinically administered doses using standard administration techniques.2., 34., 35. During the 1970s, the ketamine dose administered by anesthesiologists was typically 7 to 15 mg/kg intramuscularly2 compared with 4 to 5 mg/kg intramuscularly today.10., 23., 43. Adverse event profiles are similar between these reports using such different dosing ranges. There is no evidence to suggest that doses lower than in current use (ie, “subdissociative” doses) provide a decreased incidence of adverse effects or any clinical advantage, and indeed sedation is clearly less effective with lower doses.34

Route of administration 

Ketamine may be safely and effectively administered by either the intramuscular or intravenous route,2., 10., 11., 43. and the choice should be based on practical considerations. Although some physicians may prefer having intravenous access as a precaution in case of an adverse event, there is no evidence to support the contention that intramuscular administration is any less safe than intravenous administration,10., 11. and there are no reported cases in which intravenous access averted or would have averted an adverse outcome.2., 50., 51. However, the expertise to promptly initiate such access should be immediately available, as is typical in any ED.2 Although recovery appears approximately 20 minutes faster after intravenous administration,11 in the ED setting this relatively small difference will in many circumstances be of limited clinical importance. Intramuscular administration averts the cost, time, and discomfort associated with the initiation of intravenous access in a frightened child, and the duration of optimal operational conditions from a single injection alone (20 to 30 minutes) permits the completion of many common procedures. Ketamine should be administered intravenously, however, if such access is already in place for an unrelated reason, simply to spare a further injection. The intravenous route may also be advantageous for lengthy procedures (>20 minutes) in which intravenous access allows more convenient repeated dosing. A preferred strategy at some institutions is to administer the first dose intramuscularly and then painlessly initiate intravenous access for subsequent doses while the procedure is under way. Intravenous access is also preferred for adults so that midazolam can be promptly administered in the event of a clinically important unpleasant recovery reaction. Occasional combativeness in adults has been reported.67., 71.

Pulse oximetry 

Continuous pulse oximetry effectively detects hypoxemia associated with airway complications during procedural sedation and analgesia and is universally recommended.36., 43., 44., 45., 47. Although there is no evidence that continuous cardiac monitoring is beneficial in patients without underlying heart disease, such monitoring provides a simple, inexpensive, and readily available backup to pulse oximetry and is strongly recommended.43

Capnography 

Capnography permits continuous assessment of ventilatory status and provides the earliest indication of respiratory compromise.17., 99. Potentially significant airway events—apnea (flatline waveform with no chest wall movement), upper airway obstruction (flatline waveform with chest wall movement responsive to chin lift/jaw thrust), and laryngospasm (flatline waveform with chest wall movement not responsive to chin lift/jaw thrust)—can all be immediately detected by capnography.99., 100.

Supplemental oxygen 

Although routine oxygen supplementation is strongly recommended in patients receiving sedatives with a relatively high risk of respiratory depression (eg, propofol),101 the safety of ketamine in patients breathing room air is well documented.2., 10., 23. Oxygen supplementation is not harmful in and of itself; however, it may delay the detection of respiratory depression by pulse oximetry43 and is recommended only when capnography is present. Regardless of operator preference about routine supplementation, oxygen should be immediately available should hypoxemia occur.

Laryngospasm 

Laryngospasm in ED procedural sedation and analgesia is a rare complication that appears unrelated to age, sex, underlying medical conditions, or dose in children.35 However, procedures that stimulate the hyperactive gag reflex through either direct instrumentation or secretions appear to represent higher risk.2., 50., 51., 54. In a study of children undergoing gastrointestinal procedures using dissociative sedation, laryngospasm was noted in 9.5% of those receiving upper endoscopy and in 0% of those receiving colonoscopy. In an analysis of this endoscopy subset, the sole risk factor for laryngospasm was age, with the risk being 3 times higher in preschool-aged children compared with school-aged children.54 As discussed in the contraindications section, additional risk factors for laryngospasm (upper respiratory infection, age between 3 and 12 months, and active pulmonary disease, including asthma) have been extrapolated from large studies of inhalational anesthesia.2., 50., 51., 59.

Respiratory depression 

Respiratory depression and apnea are unusual with ketamine and are transient when they do occur. Although most commonly associated with rapid intravenous administration, they can rarely occur with intramuscular administration. When respiratory depression is noticed, it is invariably at the time of peak central nervous system levels (ie, 1 to 2 minutes after intravenous administration or 4 to 5 minutes after intramuscular administration).2., 10., 11., 17., 35., 50., 51.

Emesis 

When emesis occurs, it is typically late during the recovery phase when the patient is alert and can clear the airway without assistance.10., 23. It occurs more frequently in older children (12.1% in those aged ≥5 years) compared with younger children (3.5% in those <5 years).35

Recovery reactions 

Ketamine is legendary for its unique ability to stimulate hallucinatory reactions during recovery, which may be either pleasant or unpleasant. Although these so-called “emergence reactions” are rarely unpleasant in children (1.6% incidence of reactions judged greater than “mild”),10 their incidence in adults is highly variable, with reported incidences ranging from 0% to 30%.2., 50., 51. When ketamine is administered in adults, clinicians should be aware of the rare potential for pronounced reactions, including nightmares, delirium, excitation, and physical combativeness.2., 50., 51., 65., 67., 71. Titrated benzodiazepines appear to consistently and rapidly pacify such reactions.2., 30., 50., 51., 71. Transient diplopia commonly occurs during emergence from dissociative sedation, and although well tolerated in toddlers, it can be disconcerting to older children.

Recovery agitation without an apparent hallucinatory component is not uncommon after dissociative sedation. It appears to be a separate entity from the ketamine-specific hallucinatory reactions30 because it occurs at a similar frequency as with midazolam alone.16., 20., 102. A recent study demonstrated that recovery agitation is not clinically significant in children.30 Physicians graded ketamine recovery agitation using a 100-mm visual analog scale, with the median rating being 5 mm, low enough to lack clinical significance. Such mild recovery agitation occurs more frequently in younger children (22.5% in those <5 years) compared with older children (12.5% in those ≥5 years) and in those with underlying medical problems (33.3% in those with American Society of Anesthesiologists class 2 or greater compared with 17.9% in those with American Society of Anesthesiologists class 1).35 It is associated with the degree of preprocedural agitation but not the degree of external stimulation during recovery.30

Age 

In 1990, it was recommended that ketamine be avoided in ED children older than 10 years, under the assumption that this group would demonstrate a propensity toward unpleasant recovery reactions more similar to those of adults than to younger children.2 Subsequently, however, ketamine has been widely administered to children between 10 and 15 years of age without adverse effects,10., 11., 13., 16., 30., 32. and there now appears to be no reason to avoid ketamine in this age group.

Delayed effects 

There is no compelling evidence to support anecdotal reports of delayed psychic effects or personality changes.2., 30., 103.