Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain.Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia.Doses used in this trial were based on the clearance and metabolism of morphine and midazolam in preterm neonates of 24 to 32 weeks' gestation.
Neonates were assigned to 3 groups, receiving midazolam hydrochloride (0.1 mg/m L in 10% dextrose), morphine sulfate (0.05 mg/m L in 10% dextrose), or placebo (10% dextrose) infusions.
Exclusion criteria included postnatal age greater than 72 hours, positive pressure ventilation for 8 or more hours, major congenital anomalies (defined as having surgical, medical, or cosmetic importance and requiring therapeutic interventions within 7 days after birth), severe intrapartum asphyxia (defined as a 5-minute Apgar score ≤3), and participation in other research studies that interfered with the NOPAIN study procedures or outcomes.
To monitor for clinical bias and recruitment problems, all participating centers reported eligible neonates who were not enrolled.
These doses were justified by recent clinical and pharmacokinetic studies in neonates that reported effective analgesia with morphine doses of 50 to 200 µg/kg and infusion rates of 7.5 to 50 µg/kg per hour.
These data illustrated the variability of morphine pharmacokinetics in preterm neonates, with the potential for underdosing or overdosing these patients.