title: Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy.
abstract: OBJECTIVE
  Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants.
  
  
  METHODS
  Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33 degrees C to 34 degrees C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth.
  
  
  RESULTS
  Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137-767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88-327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58-1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65-1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 microg/kg per h.
  
  
  CONCLUSIONS
  Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 microg/kg per h.
authors.affiliation: First Department of Paediatrics, Semmelweis University, 1083 Budapest Bókay Str 53, Hungary. aniko.roka@gmail.com
authors.forename: Anikó
authors.initials: A
authors.lastname: Róka
authors.forename: Kis Tamas
authors.initials: KT
authors.lastname: Melinda
authors.forename: Barna
authors.initials: B
authors.lastname: Vásárhelyi
authors.forename: Tamás
authors.initials: T
authors.lastname: Machay
authors.forename: Denis
authors.initials: D
authors.lastname: Azzopardi
authors.forename: Miklós
authors.initials: M
authors.lastname: Szabó
mesh_terms: D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000175:diagnosis / Q000401:mortality* / Q000628:therapy*; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D007363:Intensive Care Units, Neonatal; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood*; D015999:Multivariate Analysis; D011336:Probability; D012044:Regression Analysis; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D009020:Morphine