Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort

Abstract

To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2years in very premature infants who were ventilated. This national observational study included premature infants born before 32weeks of gestation intubated within 1hour after birth and still intubated at 24hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n=450) vs naive (n=472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age2 years. Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P=.037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P=.063). These results were confirmed by sensitivity analyses using 5 alternative models. Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2years.