The panel spent an extensive amount of time considering and discussing the topic of ketamine dosing. The panel reviewed the published medical articles assessing the effectiveness and safety of ketamine use in the prehospital setting using doses of 3-5 mg/kg IM. The panel also reviewed a recent ACEP report on treating extreme agitation in the field, which included a literature review of ketamine use. The panel considered the accuracy of weight estimation in the field and its impact on delivered dose and whether using a standard dose might be a better approach to care. Further, the panel discussed the issue of single versus multiple dosing of ketamine and the effectiveness and safety of this approach. The panel also considered why, in the opinion of some medical providers, the administration of ketamine should be limited to clinical settings. Finally, the panel spent substantial time discussing and determining the monitoring and resuscitation protocol paramedics should employ in the prehospital setting to avoid and counteract ketamine’s possible adverse effects.
FDA Prescribing Information:
According to the FDA prescribing information for ketamine, a dose of 10 mg/kg IM will usually produce 12-25 minutes of surgical anesthesia.[45] Doses of 4-5 mg/kg IM are used for procedural sedation in the emergency room when brief painful procedures, such as reducing a fracture or repairing a laceration, are required.[50] The decades-long experience of using 4-5 mg/kg of ketamine for procedural sedation in the emergency department evolved over time to using this dose in the prehospital setting for extreme agitation, a dose considered effective for sedation and below that used for surgical anesthesia. The dose to produce sedation in the prehospital setting varies depending on the patient: a young agitated patient on cocaine requires a larger dose than an elderly patient on no illicit drugs who is agitated after a car accident. The increased anesthetic requirement seen with acute illicit drug ingestion (i.e., cocaine) has been previously published.[51],[52] The FDA prescribing information reflects this variability in appropriate dosing: “as with other general anesthetic agents, the individual response to [ketamine] is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed.”[45]
Literature Review and ACEP Report:
The panel reviewed various published studies on the use of ketamine in the prehospital setting as well as the 2021 ACEP Report that summarized the research on ketamine dosages used for severe agitation.[27(pp. 117-132)] In general, the quality of published studies on dosing was low: rather than a series of prospective, well defined studies, the research to date involves looking back at the experience of medical centers with EMS protocols in place for ketamine use in the field. Doses studied reflect the variation in mg/kg used by medical centers and medical directors, which range from 3-5 mg/kg. The studies focus on the time to sedation as a primary outcome, as well as the success with achieving sedation with one dose in order to avoid repeat dosing. The studies vary in their approach of defining these two outcomes, and do not have a uniform measure of level of agitation prior to ketamine administration. The outcome successes may be greater in a study that enrolled persons only moderately agitated - that is to say, time to sedation may be shorter and the need for second dosing lesser - than in a study of extremely agitated persons. The panel concluded that it could not appropriately compare outcomes across studies without standardized agitation measurements.
In general, ketamine is typically found to have a shorter time to achieve sedation than the comparison drugs (e.g., benzodiazepines, antipsychotics). At doses of 4-5 mg/kg of estimated body weight, failure of single dose treatment occurred regularly (10-30%). Whether a higher dose of ketamine would reduce the first treatment sedation failure rate or increase the risk of respiratory depression is unclear, as these studies have not been done. The authors of the 2021 ACEP Report conclude that there are insufficient data to determine the proper dose of IM ketamine to treat severe agitation:
- No prospective studies have been performed to examine appropriate dosing in this specific patient population. It is therefore possible that a dose lower than 4 mg/kg IM would be effective with fewer respiratory events. However, an improved safety profile with lower dosing must be balanced with the risk of inadequate severe agitation management leading to prolonged time to effective treatment due to the need for redosing or adjunctive agents. This question warrants further study and emergency physicians should consider this void in the literature when making current decisions in EMS protocols specifying treatment regimens and/or in the ED on the IM ketamine dose when managing patients with hyperactive delirium with severe agitation.[27(p. 32)]
In Colorado, the EMPAC Waiver Guidance that was in place before ketamine waivers for excited delirium and/or extreme agitation were suspended stated that ketamine should be administered in a maximum single dose of 5mg/kg IM in the prehospital setting for a profoundly agitated patient. (See Appendix G) Multiple doses could be authorized by the agency’s direct (online) medical control. This guidance was advisory but not mandated; paramedics who could administer ketamine pursuant to a waiver were required to follow the ketamine protocol formulated by their EMS medical directors.
With this EMPAC guidance in mind, the panel considered different options that might improve dosing and patient outcomes. Among other things, it discussed: 1) modifying the current weight-based dosing of 5 mg/kg to a different static number; 2) allowing multiple doses; and 3) discarding weight-based dosing entirely and setting a standard dose amount.
The panel first considered whether weight-based dosing is appropriate in the field. Weight-based dosing in the prehospital setting is “fraught with errors.”[53] Ambulances are not equipped with scales, and emergency scenes where a highly agitated person is struggling decreases the EMS provider’s ability to accurately estimate the person’s weight and calculate the appropriate dose. A recent study that reviewed weight and height estimates by emergency department physicians, residents, and registered nurses found that their accuracy was “unacceptably low.”[54] Coupling the inaccuracies of weight estimation with the time and effort required to calculate and draw up the appropriate dose, the panel concluded the paramedic should use a standard dose for the sake of simplicity and safety. In so doing, the attention of the paramedic can focus on patient monitoring and management even prior to administering the dose, which the panel believes to be critical for the safe use of chemical restraint with ketamine. The panel recommends that Colorado EMS agencies eliminate strictly weight-based dosing for ketamine administration and instead use three fixed, standard doses, determined by patient body size.
KIRP members initially expressed concerns about underdosing - possibly exacerbating profound agitation, or failing to adequately restrain the patient with one dose - and overdosing - which can lead to respiratory depression and a need for ventilatory assistance. In order to balance the need for successful sedation, minimize the risk for respiratory depression, and simplify the dosing by using a standard dose strategy, the panel recommends classifying individuals as small, average and large size, with an assigned standard dose of 300/400/500 milligrams of ketamine for males, respectively. “Small” size for males is defined as being in the bottom quartile of weight percentile for a US male (< 165 lbs.); “average” size represents the 25th to 75th weight percentile (165-220 lbs.); “large” size would be adults estimated to weigh more than 220 lbs, in the top quartile. Such an approach simplifies weight estimation into three categories and would assure that the majority of doses given would be in the range of 4-5 mg/kg, the current practice standard. Almost 8 of 10 patients with severe agitation in Colorado in 2019 were men. Standard dosing for women could be reduced to 250/350/450 mg for “small” (< 137 lbs.), “average” (137-195 lbs.), and “large” (more than 195 lbs.) size, mimicking the dose range of 4-5 mg/kg, using the same percentile ranges as used for men. Further research is needed to determine if a single standard dose (vs. a three-level standard dose) would be safe and effective across all body sizes. The panel expressed a preference for simplifying to a single standard dose when such evidence is available.
Also, the panel recognized that a single IM ketamine dose should be calibrated to restrain the patient adequately to avoid repeat, or multiple, doses that can lead to patient complications. Panel members expressed concern that patients receiving more than one dose of ketamine may have higher rates of complications. It is unclear from existing studies, however, whether complications arise from repeated dosing or from the underlying conditions of the patient which led to the need for more than one dose for restraint. Nevertheless, in the panel’s experience, repeat dosing can often result in complications that do not typically occur with patients who only receive a single dose of ketamine. To avoid the risk of repeat dosing complications, the panel recommends that EMS medical directors comply with the recommended single dose regime. If a second ketamine dose might be required, the panel recommends that the paramedic must contact the on-line medical control physician gto discuss the plan and receive a verbal order to do so.