Haemodynamic effects of methoxyflurane versus fentanyl and placebo in hypovolaemia: a randomised, double-blind crossover study in healthy volunteers

Abstract

Background: Methoxyflurane is approved for relief of moderate to severe pain in conscious adult trauma patients: it may be self-administrated and is well suited for use in austere environments. Trauma patients may sustain injuries causing occult haemorrhage compromising haemodynamic stability, and it is therefore important to elucidate whether methoxyflurane may adversely affect the haemodynamic response to hypovolaemia.

Methods: In this randomised, double-blinded, placebo-controlled, three-period crossover study, inhaled methoxyflurane 3 ml, i.v. fentanyl 25 μg, and placebo were administered to 15 healthy volunteers exposed to experimental hypovolaemia in the lower body negative pressure model. The primary endpoint was the effect of treatment on changes in cardiac output, while secondary endpoints were changes in stroke volume and mean arterial pressure and time to haemodynamic decompensation during lower body negative pressure.

Results: There were no statistically significant effects of treatment on the changes in cardiac output, stroke volume, or mean arterial pressure during lower body negative pressure. The time to decompensation was longer for methoxyflurane compared with fentanyl (hazard ratio 1.9; 95% confidence interval 0.4-3.4; P=0.010), whereas there was no significant difference to placebo (hazard ratio -1.3; 95% confidence interval -2.8 to 0.23; P=0.117).

Conclusions: The present study does not indicate that methoxyflurane has significant adverse haemodynamic effects in conscious adults experiencing hypovolaemia.

Clinical trial registration: ClinicalTrials.gov (NCT04641949) and EudraCT (2019-004144-29) https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004144-29/NO.

Keywords: analgesia; cardiac output; healthy volunteers; hypovolaemia; methoxyflurane.

Fig 1

Consolidated Standards of Reporting Trials (CONSORT) diagram. F, fentanyl; P, placebo; M, methoxyflurane.

Fig 2

Timeline of the experimental setup for each visit. At baseline and each LBNP level, the first minute (marked purple) was allowed for stabilisation, and only data from the last minute were used for analyses. LBNP was interrupted after completing LBNP 80 or earlier if LBNP stop criteria occurred. Only data from completed LBNP levels were used for analyses, except for the calculations of time to decompensation. HR, heart rate; LBNP, lower body negative pressure; MAP, mean arterial pressure.

Fig 3

Primary and secondary outcomes. Primary outcome (cardiac output) and secondary outcomes (stroke volume and mean arterial pressure) through the experiment. Lines are from linear regression models (with polynomials) where LBNP is treated as a continuous variable, giving the results presented in text and tables. Circles are estimations and error bars are 95% confidence intervals for each treatment at each LBNP level when treating LBNP levels as factors. BL, baseline; LBNP, lower body negative pressure.

Fig 4

Time to haemodynamic decompensation. Kaplan–Meier plot of time to haemodynamic decompensation during LBNP for each treatment. Time starts at LBNP 0, giving 1080 s at completed LBNP 80. LBNP, lower body negative pressure.

Fig 5

Heart rate, end-tidal CO₂, and ventilatory frequency through the experiment. Lines are from linear regression models (with polynomials) where LBNP is treated as a continuous variable, giving the results presented in text and tables. Circles are estimations and error bars are 95% confidence intervals for each drug at each LBNP level when treating LBNP levels as factors. BL, baseline; LBNP, lower body negative pressure.

Fig 6

Symptoms during LBNP for each treatment. Boxes between first and third quartiles with medians marked. Whiskers to 1.5×inter-quartile range. For significant overall Friedman tests, P-values for pairwise post hoc comparisons (single-step corrections) are presented. LBNP, lower body negative pressure.