Association between Sedation-Analgesia and Neurodevelopment Outcomes in Neonatal Hypoxic-ischemic Encephalopathy

OBJECTIVE: To evaluate the association between sedation-analgesia (SA) during initial 72 hours and death/disability at 18 months of age in neonatal hypoxic-ischemic encephalopathy (HIE). DESIGN: This was a secondary analysis of the NICHD therapeutic hypothermia (TH) randomized controlled trial in moderate or severe HIE. Receipt of SA and anticonvulsant medications at 5 time points were considered: prior to and at baseline, 24, 48 and 72 hours of TH or normothermia. Disability was defined as mental developmental index <85, cerebral palsy, blindness, hearing impairment or Gross Motor Function Classification System 2-5. RESULTS: Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the 5 time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only and 69 (33%) received both SA and anticonvulsants. SA category drugs were not administered in 57% of infants while 18% received SA at ≥3 time points; 72% infants received anticonvulsants during 72 hours of intervention. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with (48 and 65%) or without (37 and 58%) SA, compared to groups with no exposure (14 and 34%) or SA (13 and 32%) alone. Severe HIE (aOR 3.60; 1.59-8.13), anticonvulsant receipt (aOR 2.48; 1.05-5.88) and mechanical ventilation (aOR 7.36; 3.15-17.20) were independently associated with 18-month death/disability whereas TH (aOR 0.28; 0.13-0.60) was protective. SA exposure showed no association with outcome. CONCLUSIONS: The risk-benefits of SA in HIE needs further investigation.