Comparing the Effects of Low-Dose Ketamine, Fentanyl, and Morphine on Hemorrhagic Tolerance and Analgesia in Humans

Abstract

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73–139], fentanyl (n = 28): 95 [68–130], morphine (n = 30): 62 [35–85]; values expressed as a % of the respective placebo trial’s CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R²=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Acknowledgments

We thank all participants as well as Naomi Kennedy, Ileana Hill, Courtney Hakes, Margot Morris, Caitlin Jarrard, Frank Cimino III, Elias Johnson, Bonnie Orth, Mayah Benning, Manall Jaffery, Sarah Bailey, Qi Fu, Jeung-Ki Yoo, Mark Badrov, Mads Fischer, Jan Petric, Kelly Lenz, Zaid Mohammad, and Laasya Madana for their contributions to this project.

Data Availability Statement

Data are available upon reasonable request to the principal investigator after institutional data transfer agreement approvals.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was supported by the Department of Defense - US Army W81XWH1820012 (CGC), American Physiology Society Postdoctoral Fellowship (JCW), National Institutes of Health F32HL154559 & K01HL160772 (JCW), National Institutes of Health F32HL154565 (LNB), National Institutes of Health Administrative Supplement to Promote Diversity in Health-Related Research (GM), and Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship (MNC).