Association between positive end-expiratory pressure ventilation and midazolam metabolism in patients in intensive care unit with and without COVID-19: A retrospective observational study

Purpose To investigate association between higher positive end-expiratory pressure (PEEP) and altered midazolam (MDZ) metabolism in critically ill patients requiring mechanical ventilation in the intensive care unit (ICU) and between coronavirus disease 2019 (COVID-19) and MDZ metabolism. Methods This retrospective observational study included patients with and without COVID-19 admitted to the ICU, treated with continuous infusion of MDZ, and mechanically ventilated with PEEP. The hydroxymidazolam (1OH-MDZ)/MDZ metabolic ratio, corrected for molecular weight, was calculated for all included blood samples obtained from the residual material during steady-state MDZ infusion. Samples were categorized to low or high PEEP (PEEP ≤ 10 cmH ₂ O or > 10 cmH ₂ O, respectively). Cross-sectional multiple linear regression and generalized estimation equation (GEE) analyses, adjusted for several covariables, were conducted. Results In total, 50 patients were included, resulting in 166 samples for the GEE analysis. The cross-sectional median 1OH-MDZ/MDZ metabolic ratios were 0.058 (0.031–0.115) and 0.061 (0.022–0.135) in the low and high PEEP groups, respectively. Both analyses did not reveal any association between the PEEP and 1OH-MDZ/MDZ ratio. However, COVID-19 was associated with 42% faster MDZ metabolism. Following PEEP stratification, patients with high PEEP settings exhibited 101% faster MDZ metabolism. Conclusions PEEP was not associated with MDZ metabolism in the patients in ICU. Therefore, the MDZ dose need not be adjusted according to the PEEP settings in the ICU. However, higher doses of MDZ or other sedation strategies should be considered because of increased MDZ metabolism in patients with COVID-19 in the ICU, particularly those with high PEEP settings.