Abstract 393: Distribution and Elimination Kinetics of Midazolam and Metabolites in Patients With Post-Cardiac Arrest Care

Abstract

Background: Administration of midazolam (MDZ) can make neuroprognostication more complex, especially in determining the safe timing for avoiding inappropriately pessimistic prognostications. This study aims to investigate the distribution and elimination kinetics of MDZ and metabolites in patients with post-resuscitation care. Methods: This was a prospectively observational study between May 2020 and April 2022. Samples for analyzing plasma concentration of MDZ and seven metabolites were obtained immediately, at 4, 8, 12, and 24 h from discontinuation of MDZ infusion. Briefly, absolute and relative concentrations of MDZ and metabolites were determined by LC-MS/MS and LC-QTOF. The area under the plasma concentration-time curve from time 0 to last measurable time point (AUC last ) and estimated half-life ( t 1/2 ) were calculated according to pharmacokinetic rules. Results: Of the 13 enrolled patients, 8 (61.5%) awakened after discontinuation of MDZ administration. MDZ, 1-hydroxylmidazolam (1-OH-MDZ), 1-hydroxylmidazolam-glucuronide (1-OH-MDZ-Glu), and midazolam-glucuronide (MDZ-Glu) were identified as the major compounds, comprising approximately 96% of the total proportion. All compounds had individual mean t 1/2 (MDZ, 1-OH-MDZ, 1-OH-MDZ-Glc, and MDZ-Glc: 6.4, 7.6, 14.3, and 10.5 h, respectively). In the subgroup analysis for the awakened patients, the significant correlation between AUC last and awakening time measured from discontinuation of MDZ infusion was demonstrated in MDZ (r 2 = 0.66) and 1-OH-MDZ (r 2 = 0.55). Conclusions: Even in the normothermia state of the patients, t 1/2 of MDZ and metabolites was prolonged compared with that reported in healthy individuals. Among all compounds, MDZ and 1-OH-MDZ concentrations may be mainly active compounds related to the sedation effect. Hence, to prevent inappropriate WLST for patients with potential for recovery, we recommend clinicians consider the prolonged t 1/2 of the main active compounds.