Ketamine vs Etomidate: No Difference in 28-Day Mortality in critically ill adults requiring tracheal intubation: NEJM

Doctors treating seriously ill patients in an emergency setting may want to give the sedative etomidate, rather than ketamine, while placing a breathing tube, according to a randomized trial published in the New England Journal of Medicine.

The Randomized Trial of Sedative Choice for Intubation (RSI) is the first multicenter trial to demonstrate significant cardiovascular risks of high doses of ketamine (low blood pressure, arrhythmia), side effects that have not been well studied in the past.

“We know that patients receive treatments every day in hospitals around the world that have never been evaluated in a rigorous study and may be ineffective or even harmful,” said lead author Jonathan Casey, MD, associate professor of Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University Medical Center.

“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,” he said.

Casey co-led the trial with Matthew Semler, MD, MSCI, associate professor of Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at VUMC, along with a team of patients, clinicians and researchers from six cities across the U.S.

The RSI trial compared the use of ketamine and etomidate during tracheal intubation of 2,365 patients in 14 emergency departments and intensive care units in the U.S. The trial found that etomidate is safe to use, meaning it did not increase the risk of death, and that etomidate significantly decreased the risk of dangerously low blood pressures during the procedure, 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 said.

Historically, etomidate was the more commonly used sedative, but it was found to impair production of cortisol, which raised concerns that it could increase the risk of death following intubation. Based on these concerns, some countries removed etomidate from the market.

In many settings, ketamine replaced etomidate as the primary sedative during emergency tracheal intubation. This has been part of a movement by clinicians and patients to use ketamine for an increasing number of problems, including acute and chronic pain, depression and post-traumatic stress disorder, despite limited data on its effectiveness and safety. The potential risks of ketamine were brought to public attention in 2023 when the drug was thought to be a cause of “Friends” actor Matthew Perry's death.

Casey said that 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. Coinciding with the paper’s release, the RSI trial was presented at the Critical Care Reviews conference in Melbourne, Australia — one of the countries in which etomidate has been removed from the market.

For next steps, the researchers are evaluating the effect of sedative medications on long-term patient-centered outcomes like symptoms of post-traumatic stress disorder at 12 months.

They are also conducting the INSPIRE trial, evaluating the use of the neuromuscular relaxing medications that are given along with a sedative during emergency tracheal intubation to relax patient’s muscles for breathing tube placement.

“Whether the benefit of giving neuromuscular relaxing medication outweighs the risk remains unknown and is important to evaluate in a rigorous study,” Casey said.

Finally, VUMC is also leading a large, multicenter randomized trial (BREATHE) that seeks to understand whether using a smaller size of breathing tube can prevent injury to patients’ vocal cords and long-term problems with breathing, speaking and swallowing.

Reference:

Jonathan D. Casey, Kevin P. Seitz, Brian E. Driver, Kevin W. Gibbs, Adit A. Ginde, Ketamine or Etomidate for Tracheal Intubation of Critically Ill Adults, New England Journal of Medicine, DOI: 10.1056/NEJMoa2511420