Low-dose fentanyl does not alter muscle sympathetic nerve activity, blood pressure, or tolerance during progressive central hypovolemia

Abstract

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Keywords: cerebral tissue oxygenation; opioids; respiration; sympathoexcitatory.

Figure 1.

Experimental protocol timeline of each experimental day. After instrumentation, participants rested quietly for 10 min for baseline data collection and then assessments of pain (via algometer and the cold pressor test). Participants then received the drug (fentanyl)/placebo for that specific trial, followed 1 min later by lower body negative pressure (LBNP) testing and recovery. Thirty minutes after first administration, the same medication (or placebo) was again administered followed by pain assessments. Afterward, the subject was monitored for a minimum of 60 min to allow for the effects of the drug to subside.

Figure 2.

Group mean (±SD) comparison of lower body negative pressure tolerance capacity expressed as cumulative stress index (CSI) following fentanyl vs. placebo administration (n = 28; paired, two-tailed t test analysis).

Figure 3.

Comparisons of cumulative stress index (CSI) partitioned by sex. Data expressed as group means ± SD (female n = 13, male n = 15; paired, two-tailed t test analysis).

Figure 4.

Group mean (±SD) data showing heart rate responses during fentanyl vs. placebo administration [baseline n = 28, T1 n = 28, T2 n = 27, T3 n = 25, T4 n = 28; mixed-effect model analysis with post hoc Holm-Bonferroni corrected paired t test, baseline data were not included in analysis]. *Significant differences.

Figure 5.

Group mean (±SD) data showing Finometer-derived mean arterial pressure during fentanyl vs. placebo administration. Baseline n = 28, T1 n = 28, T2 n = 27, T3 n = 25, T4 n = 28; mixed-effect model ANOVA, baseline data were not included in analysis.

Figure 6.

Group mean (±SD) data showing muscle sympathetic nerve activity (A: burst incidence; B: burst frequency) during fentanyl vs. placebo administration. Baseline n = 21, T1 n = 20, T2 n = 16, T3 n = 15, T4 n = 16; mixed-effect model ANOVA, baseline data were not included in analysis.