The effect of critical illness and inflammation on midazolam therapy in children

OBJECTIVE:: To determine the effect of inflammation and disease severity on midazolam pharmacokinetics (as surrogate marker of cytochrome 3A activity) and pharmacodynamics in critically ill children. DESIGN:: Analysis of prospectively collected pharmacokinetic and pharmacodynamic data from a midazolam study in critically ill children. SETTING:: Pediatric intensive care unit of a university hospital. PATIENTS:: Twenty-one critically ill children who needed midazolam for sedation. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We determined the relationship between inflammation (using C-reactive protein and leukocyte count as surrogate markers) and disease severity (Pediatric Logistic Organ Dysfunction and Pediatric Risk of Mortality scores) vs. the pharmacokinetics (clearance) and pharmacodynamics (COMFORT score, dose requirement) of midazolam. We found a significant negative correlation between disease severity and midazolam clearance corrected for body weight (r =-0.49, p = .02). Midazolam clearance was significantly lower in children with multiple organ failure (defined as Pediatric Logistic Organ Dysfunction ≥10, n = 11) compared with children without multiple organ failure (Pediatric Logistic Organ Dysfunction <10, n = 10) (median 0.14 [interquartile range, 0.11-0.23] vs. 0.28 [interquartile range, 0.14-0.43]) L/kg/h, p = .035). No other significant correlations were found. CONCLUSIONS:: Results from this pilot study suggest that increased disease severity is associated with reduced midazolam clearance in critically ill children, most likely as a result of reduced cytochrome 3A activity. In contrast, reduced midazolam clearance does not seem to result in decreased midazolam dose requirements.

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