Joseph A Carcillo1,2,3, Lesley Doughty4, Danny Kofos4, Reginald F Frye5,6, Sandra S Kaplan7, Howell Sasser8, Gilbert J Burckart5,6. 1. Division of Critical Care Medicine, Children's Hospital of Pittsburgh, 3705 5th Ave, Pittsburgh, PA, 15123, USA. carcilloja@ccm.upmc.edu. 2. Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. carcilloja@ccm.upmc.edu. 3. Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. carcilloja@ccm.upmc.edu. 4. Department of Anesthesiology and Critical Care Medicine and Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. 5. Center for Clinical Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. 6. School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA. 7. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. 8. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Abstract
OBJECTIVE: Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population. METHODS: Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis. RESULTS: Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures. CONCLUSIONS: Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population
OBJECTIVE:Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population. METHODS: Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis. RESULTS:Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures. CONCLUSIONS: Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population
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