Ketamine is a Class III controlled substance approved by the Food and Drug Administration (FDA) for induction and maintenance of anesthesia.[29, 39] Ketamine is also used off-label in medical settings for procedural sedation and management of severe/extreme agitation as well as an antidepressant, analgesic, and anticonvulsant for refractory seizures. Ketamine is a fast-acting (IM, 3-5 min) dissociative anesthetic that can disconnect the cognitive from external stimuli, producing amnesia, analgesia, relative immobility, and an altered state of consciousness. In controlled settings - the relatively calm patient in a healthcare setting and with adequate personnel support - incremental low doses (0.25 - 0.5 mg/kg IV) are frequently combined with benzodiazepines for procedural sedation. However, low doses do carry the risk of causing agitation, dysphoria, and paranoia. At higher doses (>1 mg/kg IV), ketamine rapidly reaches a threshold effect that produces dissociative anesthesia: this is not dose-related, that is, dissociation does not increase with increasing dose – dissociation is either present or absent.
Ketamine has been identified as useful in the prehospital setting for several reasons: high bioavailability (>90%) when administered intramuscularly, rapid and predictable onset of 3-5 minutes, a quick peak effect, and duration of 20-30 minutes. (See, e.g., https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf). In contrast with other sedatives given at high doses, ketamine frequently preserves airway reflexes, ventilation, and hemodynamics (blood pressure). Its rapid onset and moderate duration when administered IM allow most patients to be safely transported to the hospital with a single dose.
Ketamine Safety:
In general, sedative medications do not cause organ damage to humans at high doses, but instead lead to prolonged sedation and a risk of respiratory or cardiac depression. For example, drugs like acetaminophen and lithium, are safe for humans at the recommended dosage, but can cause damage to organs such as the liver and kidney at higher doses.
Studies of the safety of a drug begin with animal studies to determine if the compound may be toxic at various doses. Pertinent here, a publication using rodents found that the median lethal dose (LD50)[40] of oral ketamine is 600 mg/kg.[41] A second study,[42] using cats, found that the safety of ketamine is broad: cats were given intentional overdoses of 50-100 mg/kg IM ketamine to evaluate toxicity and found only to suffer from a prolonged recovery.
In humans, intramuscular doses of ketamine in the recommended range of 3-5 mg/kg are considered safe;[43] a dose of 5 mg/kg usually achieves the desired dissociative state (~90% success rate) to allow for EMS evaluation.[43,44] According to the FDA prescribing information, “Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of [Ketamine] (up to ten times that usually required) have been followed by prolonged but complete recovery.”[45] The panel’s toxicologist and anesthesiologists agreed that the dose can be doubled for the majority of people with a low likelihood of adverse effects when qualified personnel are monitoring the patient. The panel’s toxicologist advised the panel that a large dose of ketamine will impact the patient by increasing the duration of its effectiveness, as seen in pediatric overdose cases.[46]
Nonetheless, ketamine is known to have adverse effects in the prehospital setting. The most common complications are hypoventilation, airway obstruction, hypoxia, hypertension, and hypersalivation. Respiratory compromise may be of sufficient magnitude to require endotracheal intubation of the patient. The data are conflicting as to whether there is an association between higher IM ketamine doses and incidence of intubation and hospital admissions.[47, 48] As noted previously, the 2019 Colorado experience found no difference in the median ketamine dose given to patients who did or did not require intubation. Variations in published intubation rates as a function of ketamine dose may be biased by the low number of publications on the use of prehospital ketamine and by their lower quality.
Differences across institutions in their familiarity with ketamine use in the prehospital setting may also be a factor. Paramedics or hospital staff lacking experience with dissociative anesthesia – the state produced by ketamine – may be more inclined to intubate due to the patient being non-responsive, even though the patient maintains airway reflexes, blood pressure, and ventilation. Given the multiple factors contributing to the decision to intubate a patient, the intubation rate associated with ketamine use is considered a “poor surrogate marker to understand the effect of various doses of ketamine on respiratory depression.”[27(p. 31)]
Ketamine, with its rapid onset and its lower risk for respiratory suppression, may be the drug of choice for extremely agitated patients[49] or individuals at higher risk for shock or cardiopulmonary decompensation. In these circumstances, EMS providers may need to administer ketamine as the most appropriate drug to individuals who have a higher chance of a bad outcome. Such selection effects can make ketamine appear to have higher rates of complications than other sedatives. The panel took all these considerations into account when formulating its dosing, monitoring, indications, and paramedic training recommendations.