Acetaminophen in cerebrospinal fluid in children

Abstract

Background: There are few studies describing acetaminophen (APAP) cerebrospinal fluid (CSF) concentrations in children. This current study was undertaken in children - from neonates to adolescents - in order to investigate age-related changes in the plasma to CSF equilibration half-time (Teq) of APAP. Methods: Children (n=41) 1 week to 18 years of age undergoing (semi) elective surgery for placement or revision of a ventriculo-peritoneal shunt or insertion of a temporary external ventricular drain received a loading dose of 30-40 mg/ kg APAP 1 h before scheduled surgery. Blood and CSF samples for APAP concentration analysis were collected during surgery. In those children with a temporary external drain, blood and CSF sampling were extended into the postoperative period. APAP and CSF pharmacokinetics were estimated using non-linear mixed-effects models. Size was standardized to a 70-kg person using allometric "1/4 power models". Results: Median (25-75th percentile) age and weight of the patients included in this study were 12 months (3-62 months) and 10.0 kg (5.8-20.0 kg). Median (25-75th percentile) time between APAP loading dose administration and collection of blood samples and median time (25-75th percentile) between APAP loading dose and collection of CSF were, respectively, 125 min (95-210 min) and 133 min (33-202 min). The population mean Teq, standardized to a 70-kg person, was 1.93 h (CV 43%), an estimate similar to that described in adults (2.1 h). There was no relationship between age and Teq other than that predicted by size. APAP plasma concentrations ranged from 0.0 mg/l to 33.0 mg/l, APAP CSF concentrations ranged from 0.0 mg/l to 21.0 mg/l. Conclusion: Size rather than blood-brain-barrier maturation determines Teq changes with age in children. We predict a neonate (3.5 kg), 1-year-old child (10 kg), 5-year-old child (20 kg), 10-year-old child (30 kg) and adult (70 kg) to have Teq values of 0.9, 1, 1.4, 1.6, and 1.93 h, respectively.