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Thiopentone elimination in newborn infants: exploring Michaelis–Menten kinetics
Author(s) -
LARSSON P.,
ANDERSON B. J.,
NORMAN E.,
WESTRIN P.,
FELLMAN V.
Publication year - 2011
Publication title -
acta anaesthesiologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.738
H-Index - 107
eISSN - 1399-6576
pISSN - 0001-5172
DOI - 10.1111/j.1399-6576.2010.02380.x
Subject(s) - medicine , pharmacokinetics , volume of distribution , elimination rate constant , metabolic clearance rate , bolus (digestion) , confidence interval , anesthesia , intravenous bolus , plasma clearance , zoology , endocrinology , biology
Background: Thiopentone elimination has been described using Michaelis–Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates. Methods: Time–concentration profiles for neonates ( n =37) given single‐dose thiopentone were examined using both first‐order (constant clearance) and mixed‐order (Michaelis–Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33‐week post‐menstrual age (PMA) neonate given an overdose. A two‐compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models. Results: There were 197 observations available for analysis from neonates with a mean post‐menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination ( V max ) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant ( K m ) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49–99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27–0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7–59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3–128) l/70 kg. Conclusions: Both first‐order and mixed‐order processes satisfactorily described elimination. First‐order elimination adequately described the time–concentration profile in the premature neonate given an overdose. Clearance is immature in the pre‐term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post‐natal age.