Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Abstract

Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUClast) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUClast: R2 = 0.59, p = 0.03; AUCinf: R2 = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time.

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“…In this study, kinetic analyses were conducted by measuring only the primary metabolite of MDZ, 1′-OH MDZ. However, it is also known that 1′-OH MDZ can undergo further glucuronidation, as well as MDZ undergoing n -glucuronidation. , In a preliminary experiment, the effluent samples were thus divided and treated with glucuronidase to assess the increase in intact and 1′-OH MDZ compared to untreated samples (Figure S1). As a result, there was little observed increase in their amount thought to be due to deconjugation, suggesting the contribution of glucuronide conjugation be minimal in this experimental system.…”