The report is a product of the VA/HSR Evidence Synthesis Program.

Safety of Ketamine in the Prehospital Setting: A Systematic Review

Takeaway: Ketamine has a long history of use as a medication for procedural sedation and anesthesia in hospitals and is increasingly being used in the prehospital setting for patients with acute pain, a need for urgent sedation, and/or a need for rapid sequence intubation (RSI). Based on existing evidence, ketamine appears to be at least as effective as other medications for acute pain, sedation, and RSI and does not appear to increase the risk of serious adverse events or mortality compared to other medications used for these indications in the prehospital setting, except for a potentially higher rate of intubation and severe oxygen desaturation when ketamine is used for sedation to manage acute behavioral disturbances. However, the evidence is limited by study methodological weaknesses, variability in co-interventions and comparators, and differences in how harms were reported across studies. Evidence on mortality was limited to three studies with varying populations, comparators, and outcome definitions and should be considered preliminary. Additional studies with larger sample sizes would help confirm ketamine's safety relative to other medications administered in the prehospital setting for urgent and emergent conditions and clarify the risks of using ketamine for sedation in cases of acute behavioral disturbance.

Ketamine is a medication that has long been used for procedural sedation and anesthesia in hospitals and is increasingly being used in the prehospital setting by emergency medical services (EMS) personnel to treat patients with urgent and emergent conditions. In response to a request from the VA National Emergency Medicine Office, HSR’s Evidence Synthesis Program (ESP) Center in Portland, OR, reviewed the evidence on the safety of ketamine for acute pain management, sedation, and rapid sequence intubation (RSI) in the prehospital setting.

Through a search of Ovid Medline, CINAHL Ultimate, and other databases from inception through April 8, 2025, along with hand-searching reference lists and consulting content experts, ESP investigators identified 49 eligible studies to include in this review, with 24 prioritized as providing the most rigorous and informative evidence. Of the prioritized studies, 13 focused on the use of ketamine for acute pain management, six on sedation for acute behavioral disturbances, and four on RSI. One of the prioritized studies did not specify the indication for ketamine.

Summary of Findings

• No significant differences in mortality were reported with ketamine compared to other medications for acute pain, sedation, or RSI, but this evidence was limited to three studies with varying populations, co-interventions, comparators, and outcome definitions and should be considered preliminary.
• Overall, among studies of prehospital ketamine administration for acute pain, sedation, and RSI, the incidence of serious adverse events was generally low and did not significantly differ between ketamine and comparator medications, except for a higher rate of intubation or severe oxygen desaturation with use of prehospital ketamine vs. benzodiazepines or antipsychotics for sedation in behavioral emergencies.
• The risk of some adverse events may increase with higher ketamine doses, based on observational studies of ketamine for sedation and RSI.
• Across indications, prehospital ketamine appears to be at least as effective as other medications for pain control, sedation, and RSI.

Implications

Based on existing evidence, ketamine does not appear to increase the risk of serious adverse effects compared to other medications used for acute pain management, sedation, and RSI in the prehospital setting, except for a potentially higher rate of intubation and severe oxygen desaturation with ketamine when used for acute behavioral disturbance. Future studies designed to evaluate adverse event rates (which appear to be rare overall) would help confirm ketamine’s safety in the prehospital setting.

Limitations

Studies varied widely by ketamine indication, comparators, and outcomes, making it difficult to reach strong conclusions about ketamine’s safety. Additionally, half of the included studies lacked a comparison group or did not adequately control for baseline differences between intervention groups, limiting the investigators’ ability to understand whether benefits and harms differed due to administration of ketamine or other factors.

Future Research

Large database studies and randomized controlled trials could help confirm the safety of prehospital administration of ketamine and clarify the risks of using ketamine for sedation in cases of acute behavioral disturbance. Given the increased potential for adverse events with higher doses of ketamine, future research could focus on determining the minimum effective doses for certain indications such as sedation. Additionally, research could aim to identify best practices for accurately assessing patient weight in the prehospital setting and explore implementation approaches to ensure that existing protocols regarding ketamine dosing are followed.

Citation:

Anderson JK, Beech EH, Mackey KM. Safety of Ketamine in the Prehospital Setting: A Systematic Review. Washington, DC: Evidence Synthesis Program, Health Systems Research, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-199; 2025.

To view the full report, go to https://vaww.hsrd.research.va.gov/publications/esp/prehosp-ketamine.cfm (This report is available via intranet only.)

How can VA leadership work with the ESP? Nominations for systematic review topics may be submitted to the program at any time. When you submit a topic nomination form, ESP Coordinating Center staff will work with you to determine the appropriate research approach and ESP product to address your questions of interest. Topics are selected and assigned to an ESP Center based on program capacity and alignment with VA national goals.

This Management Brief is provided to inform you about recent HSR findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR Resource Center charged with disseminating important HSR findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers; and to disseminate these reports throughout VA.

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