title: Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial.
abstract: OBJECTIVE
  Hypotension occurs commonly among preterm neonates, but its cause and consequences remain unclear. Secondary data analyses from the NEOPAIN trial identified the clinical factors associated with hypotension and examined the contributions of morphine treatment or hypotension to severe intraventricular hemorrhage (IVH) (grades 3 and 4), any IVH (grades 1-4), or death.
  
  
  METHODS
  In the NEOPAIN trial, 898 ventilated neonates between 23 and 32 weeks of gestation were enrolled, with equal numbers randomized to receive masked morphine or placebo infusions. Additional doses of open-label morphine were administered as necessary by medical staff members. IVH was diagnosed with centralized readings of early and late cranial ultrasonograms. Hypotension was assessed before study drug infusion, during the loading dose, and at 24 and 72 hours during study drug infusion. Logistic regression analyses with stepdown elimination identified the predictor factors associated with the hypotension, severe IVH, any IVH, or death outcomes at each time point.
  
  
  RESULTS
  Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension. Severe IVH was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death.
  
  
  CONCLUSIONS
  Preemptive morphine infusions, additional morphine, and lower gestational age were associated with hypotension among preterm neonates. Severe IVH, any IVH, and death were associated with preexisting hypotension, but morphine therapy did not contribute to these outcomes. Morphine infusions, although they cause hypotension, can be used safely for most preterm neonates but should be used cautiously for 23- to 26-week neonates and those with preexisting hypotension.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Slot 512B, 4301 West Markham St, Little Rock, AR 72205, USA. hallrichardw@uams.edu
authors.forename: Richard W
authors.initials: RW
authors.lastname: Hall
authors.forename: Shari S
authors.initials: SS
authors.lastname: Kronsberg
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barton
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kaiser
authors.forename: K J S
authors.initials: KJ
authors.lastname: Anand
mesh_terms: D000367:Age Factors; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000627:therapeutic use; D002543:Cerebral Hemorrhage / Q000209:etiology*; D005865:Gestational Age; D006801:Humans; D007022:Hypotension / Q000139:chemically induced* / Q000150:complications; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000209:etiology*; D007969:Leukomalacia, Periventricular / Q000209:etiology; D016015:Logistic Models; D009020:Morphine / Q000009:adverse effects* / Q000627:therapeutic use; D012121:Respiration, Artificial; D012307:Risk Factors
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine