Landmark RSI Trial Reveals Etomidate Safer Than Ketamine for Emergency Intubation
Key Insights
A nationwide randomized trial of 2,365 critically ill patients found that etomidate does not increase mortality risk compared to ketamine during emergency intubation, challenging decades-old safety concerns.
Ketamine caused significantly more cardiovascular complications, particularly severe drops in blood pressure, without providing any survival advantage over etomidate.
The findings may prompt countries that removed etomidate from the market to reconsider its availability and influence clinical practice guidelines for emergency airway management.
A landmark randomized trial has overturned decades of clinical assumptions about sedative selection for emergency intubation, finding that etomidate is safer than ketamine for critically ill patients requiring emergency airway management. The Randomized Trial of Sedative Choice for Intubation (RSI), published in the New England Journal of Medicine, represents the first large multicenter study to definitively compare these two widely-used sedatives.
The trial enrolled 2,365 adults across 14 emergency departments and intensive care units in the United States, randomly assigning patients to receive either ketamine or etomidate before tracheal intubation. The results challenge long-held clinical beliefs and may reshape emergency medicine practice worldwide.
Mortality Outcomes Dispel Safety Concerns
The study found nearly identical mortality rates between the two drugs: 28.1% for ketamine versus 29.1% for etomidate. This finding directly contradicts historical concerns that etomidate increases death risk by impairing cortisol production - concerns that led some countries to remove the drug from their markets entirely.
"We found that etomidate is safe and that ketamine can cause severely low blood pressure during intubation," said Matthew Semler, MD, MSCI, associate professor of Medicine at Vanderbilt University Medical Center and co-lead investigator. "Going forward, many clinicians will choose to use etomidate rather than ketamine."
Ketamine Shows Higher Cardiovascular Risk Profile
While mortality rates were similar, the trial revealed significant safety differences between the medications. Patients receiving ketamine experienced substantially more cardiovascular collapse, particularly severe drops in blood pressure during the intubation procedure.
"For unstable patients, including those at risk of a severe drop in blood pressure due to septic or hypovolemic shock (search), these additional risks matter," said Neil Aggarwal, MD, MHSC, associate professor of medicine at the University of Colorado Anschutz School of Medicine (search) and study co-author.
The cardiovascular risks associated with ketamine represent a critical finding, as emergency intubation often occurs in patients who are already hemodynamically unstable. The study's results suggest that etomidate may be the safer choice for these vulnerable populations.
Addressing Decades of Clinical Uncertainty
The RSI trial fills a significant evidence gap that has persisted for more than 40 years since both medications received FDA approval. Despite being administered to millions of critically ill adults annually, this represents the first large, multicenter trial to examine which drug produces better patient outcomes.
"These two medicines, ketamine and etomidate, were approved by the FDA before I was born," Semler noted. "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."
The historical shift from etomidate to ketamine occurred when concerns about cortisol suppression emerged, leading to etomidate's removal from some international markets. In many settings, ketamine became the primary sedative for emergency intubation, part of a broader trend toward expanded ketamine use for conditions including acute and chronic pain, depression (search), and post-traumatic stress disorder (search).
Clinical Practice Implications
The trial's findings may have immediate implications for clinical practice and drug availability. Lead author Jonathan Casey, MD, associate professor at Vanderbilt University Medical Center, suggested that countries which removed etomidate from the market may reconsider its availability based on these safety data.
"Sedating critically ill patients for emergency intubation is a high-stakes decision that clinicians make every day," said Adit Ginde, MD, MPH, professor of emergency medicine at the University of Colorado Anschutz School of Medicine (search). "This trial finally provides the rigorous evidence needed to guide those decisions and improve patient safety."
The study's presentation at the Critical Care Reviews conference in Melbourne, Australia - one of the countries where etomidate has been removed from the market - coincided with the paper's publication, potentially influencing international regulatory decisions.
Ongoing Research Initiatives
The RSI research team is expanding their investigation to examine long-term patient outcomes, including symptoms of post-traumatic stress disorder (search) at 12 months following intubation. They are also conducting the INSPIRE trial, which evaluates neuromuscular relaxing medications given alongside sedatives during emergency intubation.
Additionally, researchers are leading the BREATHE trial, a large multicenter study investigating whether smaller breathing tubes can prevent vocal cord injury and long-term complications affecting breathing, speaking, and swallowing.
"Whether the benefit of giving neuromuscular relaxing medication outweighs the risk remains unknown and is important to evaluate in a rigorous study," Casey said.
The RSI trial was funded by the Patient-Centered Outcomes Research Institute and the National Institutes of Health, reflecting the critical importance of comparative effectiveness research for treatments already in widespread clinical use.