Doctors treating critically ill patients in emergency situations may want to consider using the sedative etomidate instead of ketamine during intubation, according to new research published in the New England Journal of Medicine. The Randomized Trial of Sedative Choice for Intubation (RSI) is the first multicenter study to show that high doses of ketamine are linked to significant cardiovascular risks, such as low blood pressure and arrhythmia. These side effects have not been well studied before.
"Studies like RSI are critically important to understand the treatments that patients are already receiving and to ensure that patients receive the treatments that will result in the best outcomes," said one of the trial's leaders.
The trial was co-led by Matthew Semler, MD, MSCI, associate professor at Vanderbilt University Medical Center (VUMC), along with a team from six U.S. cities. The RSI trial compared ketamine and etomidate during tracheal intubation in 2,365 patients across 14 emergency departments and intensive care units in the United States. Results showed that etomidate did not increase the risk of death and significantly reduced instances of dangerously low blood pressure compared with ketamine.
"These two medicines, ketamine and etomidate, were approved by the FDA (Food and Drug Administration) before I was born," Semler said. "For more than 40 years, they've been administered to millions of critically ill adults each year. Yet, our RSI trial is the first large, multicenter trial to examine which of the two medicines results in best outcomes for patients.
"We found that etomidate is safe and that ketamine can cause severely low blood pressure during intubation. Going forward, many clinicians will choose to use etomidate rather than ketamine. These findings emphasize why more research must focus not just on the development of new drugs and devices, but also on understanding which treatments patients are already receiving produce the best outcomes," he added.
Etomidate was once commonly used as a sedative but concerns over its effect on cortisol production led some countries to remove it from their markets due to fears it could raise mortality after intubation. As a result, ketamine became more widely used for emergency tracheal intubation despite limited data about its safety or effectiveness. Interest in ketamine has also grown for other uses such as pain management and mental health conditions like depression and PTSD.
Public attention turned toward potential risks associated with ketamine after it was suspected as a factor in actor Matthew Perry's death in 2023.
Casey noted that these latest findings might prompt countries that had removed etomidate from clinical use to reconsider its availability: "The results of the RSI trial, showing that etomidate does not increase the risk of death and causes less hypotension than ketamine, may convince countries that had removed etomidate from the market to make it available again." The study’s results were also presented at a major critical care conference in Melbourne—one country where etomidate remains unavailable.
Researchers plan further studies examining how sedatives affect long-term patient outcomes like post-traumatic stress disorder symptoms at one year post-intubation. They are also conducting another study called INSPIRE focused on neuromuscular relaxing medications given alongside sedatives during emergency airway procedures.
"Whether the benefit of giving neuromuscular relaxing medication outweighs the risk remains unknown and is important to evaluate in a rigorous study," Casey said.
Additionally, VUMC is leading another randomized trial named BREATHE investigating whether smaller breathing tubes can help prevent injuries affecting vocal cords or long-term problems with breathing or swallowing after intubation.
Funding for this research came from grants provided by both the Patient-Centered Outcomes Research Institute (BPS-2024C1-37478) and National Institutes of Health (K23HL153584).
