Objective
To determine the population pharmacokinetics of unbound hydrocortisone (HC) in critically ill neonates and infants receiving intravenous HC for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability.
Design
Prospective observational cohort study.
Setting
Level 3 neonatal intensive care unit.
Patients
Sixty-two critically ill neonates and infants receiving intravenous HC as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23 to 41), median weight 1.2 kg (range, 0.5 to 4.4), 29 females.
Interventions
None.
Measurements
Unbound baseline cortisol and post-dose HC concentrations measured from blood samples being drawn for routine laboratory tests.
Main Results
A one compartment model best described the data. Allometric weight and postmenstrual age (PMA) were significant covariates on unbound HC clearance (CL) and volume of distribution (V). Final population estimates for CL, V, and baseline cortisol concentration were 20.2 L/h, 244 L, and 1.37 ng/mL, respectively. Using the median weight and PMA of our subjects (i.e. 1.2 kg and 28 weeks) in the final model, the typical unbound HC CL and V were 1.0 L/h and 4.2 L, respectively. The typical half-life for unbound HC was 2.9 hours. A sharp and continuous increase in unbound HC CL was observed at 35 weeks PMA.
Conclusions
We report the first pharmacokinetic data for unbound HC, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound HC CL increased with body weight and was faster in children with an older PMA. Unbound HC CL increased sharply at 35 weeks PMA and continued to mature thereafter. This study lays the groundwork for evaluating unbound HC exposure-response relationships and drawing definitive conclusions about the dosing of intravenous HC in critically-ill neonates and infants with vasopressor-resistant hypotension.