Comparing the effect of different loading doses of phenobarbitone on serum phenobarbitone levels in babies with neonatal seizures and effect of therapeutic hypothermia on phenobarbitone levels

Abstract

Abstract Background With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. Objective To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. Design Prospective observational cohort study. Material and methods Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH—hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE − TH—hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). Results A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02–50.49) mcg/ml in HIE + TH group, 40.53 (28.66–65.09) mcg/ml in HIE − TH group and 49 (37–65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5–65.94) mcg/ml in HIE + TH group, 42.5 (34.75–48.75) mcg/ml in HIE − TH group and 42.07 (40–49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2–64.9) mcg/ml in HIE + TH group, 57.0 (49.8–60.2) mcg/ml in HIE − TH group and 48.15 (40.8–50.97) mcg/ml in non-HIE group. In babies who received >20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE − TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. Conclusion At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level