Analgesia and sedation in preterm neonates who require ventilatory support- Results from the NOPAIN trial

Background: Preterm neonates are exposed to multiple painful procedures aft er birth and exhibit acute physiological responses to pain. Occurrence of e arly intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intrav entricular hemorrhage and periventricular leukomalacia. We proposed that su ch neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo. Objectives: To define the incidence of clinical outcomes in the target stud y population, to estimate the effect size and adverse effects associated wi th analgesia and sedation, and to calculate the sample size for a definitiv e test of this hypothesis. Methods: Sixty-seven preterm neonates were randomized in a pilot clinical t rial from 9 centers. Neonates of 24 to 32 weeks' gestation were eligible if they had been intubated and required ventilatory support for less than 8 h ours and if they were enrolled within 72 hours after birth. Exclusion crite ria included major congenital anomalies, severe intrapartum asphyxia, and p articipation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receiv e continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as cli nically necessary, then weaned and stopped according to predefined criteria . Levels of sedation (COMFORT scores) and responses to pain (Premature Infa nt Pain Profile scores) were measured be-fore, during, and 12 hours after d iscontinuation of drug infusion. Cranial ultrasound examinations were perfo rmed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), o r periventricular leukomalacia. Results: No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the m idazolam group died; no deaths occurred in the morphine group. Poor neurolo gic outcomes occurred in 24% of neonates in the placebo group, 32% in the m idazolam group, and 4% in the morphine group (likelihood ratio chi(2) = 7.0 4, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicit ed by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (P < .001) and midazolam (P = .0 02) infusions compared with the placebo group. Conclusions: This pilot trial suggests that preemptive analgesia given by c ontinuous low-dose morphine infusion may reduce the incidence of poor neuro logic outcomes in preterm neonates who require ventilatory support. Limitat ions in the sample size of this pilot study suggest that these results shou ld be confirmed in a large multicenter randomized trial.