CU Anschutz researchers help lead largest U.S. randomized trial highlighting ketamine's cardiovascular risks while guiding emergency and critical care practice
A nationwide study by researchers at CU Anschutz, Vanderbilt University Medical Center and four other academic medical centers found that ketamine, a sedative for critically ill patients, does not improve survival compared with the drug etomidate and carries a higher risk of heart-related complications during emergency intubation. The findings provide long-awaited evidence to guide one of the most critical decisions emergency clinicians make.
The study was published today in the New England Journal of Medicine.
"Sedating critically ill patients for emergency intubation is a high-stakes decision that clinicians make every day," said study co-author Adit Ginde, MD, MPH, professor of emergency medicine and senior associate dean for clinical research at the University of Colorado Anschutz School of Medicine. "This trial finally provides the rigorous evidence needed to guide those decisions and improve patient safety."
New evidence clarifies risks and benefits of ketamine vs. etomidate
Historically, etomidate was the main sedative for emergency intubation but concerns it could impair cortisol production and increase mortality led some countries to remove it from the market. Ketamine then became the primary sedative in many settings and is increasingly used for pain, depression and PTSD, despite limited evidence on safety and effectiveness. Public attention to ketamine's risks rose in 2023 after autopsy findings linked it to actor Matthew Perry's death.
The new Randomized Trial of Sedative Choice for Intubation (RSI) addressed decades of uncertainty, finding that ketamine did not improve survival over etomidate and caused critically low blood pressure in more patients during the procedure.
"Emergency and critical care teams make split-second decisions about which drug will best stabilize a patient," said Daniel Resnick-Ault, MD, co-author and an assistant professor of emergency medicine at CU Anschutz. "Many physicians have long-held preferences and opinions about these medications. They have always been based on individual experience, anecdote and culture. Now, decisions can be grounded in high-quality scientific evidence instead."
More than 13 million critically ill patients worldwide require emergency tracheal intubation each year yet clinicians have disagreed on whether ketamine or etomidate is safer. To provide definitive evidence, the RSI trial was conducted across 14 emergency departments and ICUs nationwide, including the emergency department and three ICUs at UCHealth. Vanderbilt served as the coordinating center, with CU Anschutz and clinical partners in six cities working closely with investigators and patients to ensure real-world relevance.
Similar mortality but higher cardiovascular risks with ketamine
The trial enrolled 2,365 adults, randomly assigning them to ketamine or etomidate before intubation. Mortality was nearly identical, 28.1% for ketamine and 29.1% for etomidate, showing etomidate does not significantly increase death risk even among the sickest patients, challenging concerns that prompted restrictions in some countries.
The study also revealed an important safety difference. Patients who received ketamine experienced significantly more cardiovascular collapse, particularly severe drops in blood pressure.
"For unstable patients, including those at risk of a severe drop in blood pressure due to septic or hypovolemic shock, these additional risks matter," said study co-author Neil Aggarwal, MD, MHSC, associate professor of medicine and director of critical care research for the Division of Pulmonary, Allergy and Critical Care Medicine. "This evidence will influence bedside decision-making prior to intubation immediately"
Co-author Jason Brainard, MD, associate professor of anesthesiology at CU Anschutz and section chief of critical care, emphasized the significance of evaluating treatments already in widespread use.
"We often lack definitive evidence to compare two commonly used treatment strategies," he said. "Large, multicenter randomized controlled trials like RSI provide the crucial outcomes data we need to ensure we are delivering the very best care to our patients."
Etomidate and ketamine were both FDA-approved more than four decades ago, yet the lack of large, multicenter randomized evidence left major gaps in understanding. This study, nearly as large as all previous trials combined, provided long-needed clarity.
"Our goal was to give clinicians definitive, actionable evidence," said Ginde. "And now they have it."
Long-term outcomes and future intubation research
The RSI research team is now evaluating the effect of these sedative medications on long-term, patient-centered outcomes like symptoms of PTSD.
It 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.
Other institutions involved in the study included Denver Health Medical Center, Hennepin Healthcare in Minnesota, Wake Forest University and the University of Alabama at Birmingham.
The RSI trial was funded by the Patient-Centered Outcomes Research Institute and the National Institutes of Health.
