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The administration of etomidate for rapid sequence induction (RSI) has been linked to subsequent adrenocortical insufficiency in nontrauma patients. However, etomidate-related adrenocortical insufficiency has not been well studied in the trauma population.We performed a prospective, randomized, controlled study to assess the effect of one dose of etomidate for RSI on adrenal function and its clinical significance during and after resuscitation in trauma patients.Adult trauma patients admitted to our Level I trauma center requiring RSI were randomized to receive etomidate 0.3 mg/kg and succinylcholine 1 mg/kg (E group) or fentanyl 100 μg, midazolam 5 mg, and succinylcholine 1 mg/kg (FM group) for induction. A baseline serum cortisol level was drawn before RSI. Four to six hours after RSI, a postintubation serum cortisol level was drawn. An ACTH stimulation test was performed.Thirty patients were enrolled: 18 E group patients and 12 FM group patients. No statistical difference was detected between the two groups with respect to age, injury severity score, and baseline serum cortisol. Mean serum cortisol levels were significantly lower in E group patients than in FM group patients 4 to 6 hours after intubation (18.2 vs. 27.8 μg/dL, p < 0.05). Change in serum cortisol between baseline and postintubation levels was different (−12.8 μg/dL ± 9.6 μg/dL vs. 1.1 μg/dL ± 7.6 μg/dL, p < 0.01). Patients in the E group had an average increase in cortisol after ACTH administration of 4.2 μg/dL ± 4.9 μg/dL vs. 11.2 μg/dL ± 6.1 μg/dL in the FM group, p < 0.001. Patients in the E group required longer ICU lengths of stay (mean, 6.3 days vs. 1.5 days, p < 0.05), more ventilator days (mean, 28 days vs. 17 days, p < 0.01), and longer hospital lengths of stay (mean, 11.6 days vs. 6.4 days, p < 0.01).The use of etomidate for RSI in trauma patients led to chemical evidence of adrenocortical insufficiency and may have contributed to increased hospital and ICU lengths of stay and increased ventilator days. Further studies should be considered to evaluate the safety profile of this drug in trauma patients.