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Little is known about the safety of intravenous fentanyl for adult trauma patients in the prehospital setting. Our objective was to study the hemodynamic effect of prehospital intravenous fentanyl in initially normotensive adult trauma patients.A quasi-experimental design was used to compare adult trauma patients who received intravenous fentanyl and those who did not receive fentanyl in a large regional prehospital system and its affiliated Level I trauma center. Emergent adult trauma patients were included with an initial prehospital Glasgow Coma Scale score of ≥13 and systolic blood pressure >90 mm Hg. Patients were stratified into two groups, those who received a single dose of intravenous fentanyl (100 μg) and those who did not. The outcome was initial emergency department (ED) shock index (heart rate divided by systolic blood pressure). Multivariable linear regression was used to estimate the effect of fentanyl on ED shock index while adjusting for prehospital shock index, age, gender, Trauma Injury Severity Score, and the propensity for receiving fentanyl.Seven hundred sixty-three patients were included, of whom 217 (28%) received fentanyl. The groups had comparable demographics (age, gender, and race/ethnicity) but different clinical characteristics (ED vital signs, Injury Severity Score, mechanism, and ED disposition). The adjusted ED shock index of fentanyl patients improved (-0.03; 95% confidence interval: −0.05 to 0.00; p = 0.02) compared with no fentanyl.Prehospital intravenous fentanyl did not adversely affect the initial ED shock index in adult trauma patients. Additional research should be performed to confirm and extend our findings.III.