Etomidate proves safer than ketamine for emergency intubations

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 Dec. 9 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 led the trial, along with Brian Driver, MD, and Matthew Prekker, MD, MPH, of Hennepin Healthcare, and 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., including HCMC in Minneapolis. 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.

"Ketamine and etomidate have both been around for decades and are used countless times each year during emergency intubations," explained Driver. "Despite their widespread use, no large, multi-center trial had ever directly compared the two to determine which medication leads to better outcomes for patients until the RSI trial."

"Our results show that etomidate is a safe option and that ketamine, in some situations, can trigger significant drops in blood pressure during intubation," he continues. "With this new evidence, many clinicians are likely to favor etomidate when choosing a sedative for critically ill adults. This trial highlights the importance of studying not only new drugs or technologies, but also the treatments already in routine use, so we can understand which ones truly benefit patients."

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.

Ketamine remains a valuable medication for sedation for procedures and during mechanical ventilation but may be used less often when there is a risk of low blood pressure.

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.

Finally, Hennepin Healthcare is also helping to lead 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.

The RSI trial was funded by the Patient-Centered Outcomes Research Institute (award number BPS-2022C3-30021) and the National Institutes of Health (award number K23HL153584).