Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study

Crit Care Med. 2019 Apr;47(4):e301-e309. doi: 10.1097/CCM.0000000000003638.


Objectives: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure.

Design: Prospective pharmacokinetic-pharmacogenomic observational study.

Setting: Thirteen PICUs across the United States.

Patients: Pediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.

Interventions: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation.

Measurements and main results: Concentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele.

Conclusions: This work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Critical Illness / therapy*
  • Dose-Response Relationship, Drug
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / pharmacokinetics*
  • Male
  • Midazolam / administration & dosage
  • Midazolam / pharmacokinetics*
  • Pharmacogenomic Testing
  • Prospective Studies
  • Respiration, Artificial
  • Respiratory Distress Syndrome / drug therapy*
  • Respiratory Distress Syndrome / physiopathology


  • Hypnotics and Sedatives
  • Midazolam