What is the evidence for the safety and efficacy of using ketamine in children?

A six-year-old girl presents to the emergency department with a fracture of the right radius that needs reduction. She is otherwise healthy. Knowing that she will need short-term sedation for this painful procedure, you wonder whether ketamine is a safe and effective choice.

Ketamine, first derived from phencyclidine in 1962 (1), but in use clinically since 1970 (2), was largely unknown to emergency physicians before 1990, but has now become one of the most popular agents for procedural sedation and analgesia in children in the emergency department (3). In 1990, a landmark study by Green and Johnson (4), which was a review of 11,589 administrations of ketamine for sedation, was released, and the safety and efficacy of the drug was established. Since then, there has been considerable research on the efficacy, safety, contraindications, guidelines and dosing of ketamine (2,3,5), and it is now routinely stocked in many emergency departments across the country (6).

One of the reasons this drug has been so often studied and scrutinized is its uniqueness among sedatives. The standard definition of conscious or procedural sedation, under which most drugs used for this purpose fall, is dose-dependent alterations in consciousness that result in mild to deep sedation, preserving responsiveness to verbal or tactile stimuli (2,3). Ketamine, in contrast, exerts its effect through a functional and electrophysiological dissociation or disconnect between the thalamoneocortical and limbic areas of the brain. Therefore, it does not cause sedation along a continuum, varying with titrating doses; the dissociation is present or absent with a very narrow transition zone and, in fact, titration of dosing once dissociation is achieved is only used in prolonging the dissociative effect (2). Furthermore, dissociation is described as a ‘trance-like cataleptic state’ of ‘sensory isolation’ (2), meaning no responsiveness is present. Unlike most ‘traditional’ sedatives, ketamine preserves cardiovascular stability, spontaneous respirations and protective airway reflexes, even when exerting its full effect (2,3).

For these reasons, ketamine is often a first-line agent for short, painful procedures in the emergency department or other areas outside of the operating room (2). It can be administered via almost any route (5), although intravenous (IV) and intramuscular (IM) administrations are by far the most popular and best studied (2) for sedation purposes, partially because oral ketamine is subject to the significant first-pass effect of hepatic metabolism (3). Commonly used doses in recent studies have been IV 0.5 mg/kg to 2.0 mg/kg, and IM 4.0 mg/kg to 5.0 mg/kg, but dosing in the 1970s was typically much higher, for instance, IM 7 mg/kg to 15 mg/kg, without evidence of more adverse events (3). Currently, the dose most commonly used is IM 2 mg/kg to 4 mg/kg. Intramuscularly, ketamine is 90% to 93% absorbed and its onset of action can be up to 5 min (5); duration of effective dissociation with this route, however, is 20 min to 30 min after a single dose. When administered intravenously, the onset of action is 30 s to 40 s, and the typical duration of action is short at 5 min to 10 min. Once IV access is obtained, additional incremental doses of 0.5 mg/kg to 1.0 mg/kg may be given as necessary for longer procedures (3).

Many of ketamine’s effects and some adverse events associated with it can be linked to its sympathomimetic actions (7). These properties override its negative inotropic effects, and tend to cause an increase in blood pressure and heart rate. Also, pulmonary functions, such as minute ventilation, tidal volume and functional residual capacity remain unchanged, and pulmonary compliance and bronchodilation improve due to the release of catecholamines (2). One of the most attractive features of ketamine for clinicians is its preservation of respiratory drive and airway reflexes.

Unfortunately, although ketamine has an excellent safety profile (2–5,7), it is not without adverse events or controversy. It is contraindicated in children younger than three months of age due to concerns about airway complications in that age group. There is also some controversy surrounding its use in infants up to 12 months of age, but it has been used on numerous children in that age range without resultant increases in adverse events (3). Laryngospasm has been a concern in all patients and, as a result, procedures involving stimulation of the upper airway were at one time thought to be a contraindication. Subsequent studies have been performed successfully using ketamine for incision and drainage of peritonsillar abscesses and upper gastrointestinal procedures; however, this concern appears to be significantly overstated in the initial papers (8,9). Some physicians prefer to avoid using ketamine when a child has an upper respiratory tract infection because of the potential risk of laryngospasm, but there are no data supporting this approach. There has also been discussion and reports on the use of atropine or glycopyrrolate to prevent hypersalivation, a known effect of ketamine and one that is thought to contribute to laryngospasm risk; however, a study of prophylactic antisialogogues by Brown et al (10) suggested that they were ineffective (10). A more recent randomized clinical trial (11) suggested that the use of 0.01 mg/kg of atropine reduced hypersalivation and vomiting associated with IM ketamine; there are no data on this strategy when used with IV ketamine. It should also be noted that in the largest reported emergency department series (4) on ketamine, the incidence of laryngospasm was 0.4%, and that when it did occur, it was easily treated; of 11,589 patients studied before 1990, only two cases of ketamine-associated laryngospasm led to intubation (4).

Other possible adverse effects include jerky nonpurposeful movements, nystagmus and increased intracranial pressure (research is ongoing on this often believed, but possibly unfounded, claim [1,3]). Nausea and vomiting is also a common effect, with incidence increasing with age and most events occuring late in recovery (3); no documented cases of ketamine-induced aspiration have been reported. It would be important, however, to alert parents to the possibility of this common event because very often the child will become nauseous or vomit on the way back home or at home (3,7). The last, and perhaps the most well known of ketamine’s adverse effects, is the emergence reaction. These reactions, unpleasant dreams or hallucinations when emerging from the dissociative state, are mainly found to be transient and mild in children. The precise rate is not known, but appears to be less than 5%. Although it was once believed that benzodiazepines, such as midazolam, would curb the incidence of these reactions, this is controversial. Several studies (2,3,7,12) have refuted this claim and argued that the concurrent use of these medications in children should be discouraged. A recent study (13) has suggested that the use of midazolam in addition to ketamine reduces complications in the postoperative period, but this study was conducted using the drugs for anesthesia in an operating room, not within the setting of procedural sedation. The incidence of postoperative complications was higher than what may have normally been expected (90%). The incidence of these phenomena increases with age and with psychiatric comorbidities and, in fact, ketamine has been known to exacerbate established psychosis and, thus, is contraindicated in those patients. For healthy children, however, emergence reactions are generally mild, infrequent and easily treated (2,3).

It should be noted that ketamine is a nonreversible agent. As noted above, it is thought that ketamine is contraindicated in the presence of glaucoma and increased intracranial pressure and, thus, should be used with caution, if at all, in children with suspected head injury or other conditions that raise intracranial pressure.

There are limited data on the comparison of ketamine versus the other options available for procedural sedation, but a well-performed recent systematic review (14) of sedation and analgesia for fracture reduction in children has suggested that ketamine (in this context, the combination of ketamine and midazolam) is effective and safe for this indication, and appeared to have a superior efficacy and safety profile than the combination of fentanyl and midazolam, or the combination of propofol and midazolam.

Overall, ketamine has been proven over the past 35 years to be a safe and effective choice for sedation in children. Its wide range of safe dosing makes it an attractive option, and its cardiovascular support characteristic and properties of preservation of respiratory function and airway reflexes makes it preferable to other modes of sedation and analgesia in patients with significant underlying illness (3,5). However, the possible side effects and adverse effects of ketamine support the need for dedicated health care professionals to observe patients until they are fully awake, ensuring patent airway, chest wall motion and providing physical immobilization if needed. Mechanical monitoring, such as pulse oximetry and capnography, should always be used to ensure patient safety. It should be noted that, while pulse oximetry is commonly available, the use of capnography is not universal and, because the incidence of hypoventilation is very low, the utility of capnography in montoring strategies for procedural sedation remains uncertain. If such measures are taken and guidelines (3) are adhered to, ketamine can and will continue to be an excellent choice for sedation in children.