The influence of haemorrhagic shock on the pharmacokinetic and pharmacodynamic effects of remimazolam in a swine model: A laboratory study.

Abstract

Background: Haemorrhagic shock enhances the potency of several intravenous anaesthetics.

Objective: To assess the influence of haemorrhagic shock on the pharmacokinetic and pharmacodynamic effects of remimazolam, a new short-acting benzodiazepine.

Design: An animal observational study.

Setting: An animal laboratory in Hamamatsu University School of Medicine, Hamamatsu, Japan, from 3 April to 7 June 2021.

Animals: Ten pigs, 24.5 ± 0.5 (mean ± standard deviation) kg.

Interventions: Pigs were anaesthetised with isoflurane, and raw electroencephalographic waveforms, bispectral index (BIS) and 95% spectral edge frequency (SEF) were recorded throughout the study. After isoflurane was stopped, remimazolam was administered at a rate of 150 mg h^-1 for 10 min and arterial blood was collected 16 times until 180 min to measure the remimazolam concentration (baseline condition). After the baseline measurements, haemorrhagic shock was induced by 750 ml bleeding and maintained for 40 min. The same dose of remimazolam was administered again (4 h after the first remimazolam infusion) and blood samples were collected.

Main outcome measures: Pharmacokinetic variables were quantified using a three-compartment model and the pharmacodynamic variables were estimated using an inhibitory sigmoid maximal effect model.

Results: The peak remimazolam concentration increased from 1.0 ± 0.3 to 1.5 ± 0.4 μg ml^-1. Haemorrhagic shock decreased the central compartment volume, elimination clearance, and fast distribution clearance by 30 to 50%. The effect-site concentration producing 50% of the maximal BIS effect was 0.10 ± 0.09 μg ml^-1 at baseline and 0.11 ± 0.09 μg ml^-1 during haemorrhagic shock (P = 0.78), and that of SEF was 0.09 ± 0.03 and 0.11 ± 0.04 μg ml^-1, respectively (P = 0.28).

Conclusion: Haemorrhagic shock alters the pharmacokinetics of remimazolam, but does not enhance the end-organ sensitivity. Because the impact of haemorrhagic shock is small, remimazolam might be a suitable sedative/hypnotic for the management of patients who have massive bleeding.