Denver Health has taken part in a national clinical trial comparing two sedatives, etomidate and ketamine, used during intubation for critically ill patients. The procedure involves inserting a breathing tube into the patient’s windpipe to connect them to a ventilator. Sedatives are required to keep patients comfortable during this process. Since most patients who need emergency intubation cannot give consent due to their condition, it is important for clinicians to have clear evidence when choosing medications.
The results of the Randomized Trial of Sedative Choice for Intubation (RSI) were published on December 9, 2025, in the New England Journal of Medicine. The study included 2,365 patients across 14 emergency departments and intensive care units in the United States. According to the findings, etomidate does not increase the risk of death compared with ketamine. However, ketamine was associated with higher cardiovascular risks such as low blood pressure and arrhythmias—side effects that had not been thoroughly studied before.
“Etomidate and ketamine are both FDA approved and have been used for intubation for almost as long as I have been alive,” said Stacy Trent, MD, MPH, an emergency physician and the lead RSI investigator at Denver Health. “When I started practicing emergency medicine, etomidate was the most used sedative for intubation, but over time, ketamine has been increasingly used and sometimes favored without good data to support one drug over the other. The RSI trial is the first large, multicenter study to examine which of these two sedatives results in the best outcomes for patients. While both drugs are similar in terms of the risk of death, the increased cardiovascular risks of ketamine may make clinicians prefer etomidate again.”
Previous concerns about etomidate’s effect on cortisol production led some countries to remove it from use. The new findings regarding ketamine’s cardiovascular risks may prompt reconsideration about making etomidate available again in those countries.
“Patients receive treatments every day that have never been rigorously evaluated and may be ineffective or even harmful,” said lead author Jonathan Casey, MD, of Vanderbilt University Medical Center. “Studies like RSI are critically important to understand the treatments patients are already receiving and to ensure patients receive the treatments that lead to the best outcomes.”
Researchers will continue studying whether either sedative affects long-term outcomes such as post-traumatic stress symptoms after one year. They are also conducting another trial called BREATHE to see if smaller breathing tubes can reduce vocal-cord injury and long-term issues with speaking or swallowing.
The RSI trial received funding from both the Patient-Centered Outcomes Research Institute and the National Institutes of Health.
