• Patient follow-up: 874 neonates were included in this secondary analysis. Weight was recorded on 96.7% of possible patient-days. The primary outcome was known for all 874 neonates.

MAIN RESULTS

• The original PENUT Trial included 941 neonates, with 923 infants having sufficient data for analysis. Of these, 49 infants were excluded from this secondary analysis due to death prior to 14 days. Thus, 874 infants were included in this secondary analysis.
• In the total cohort, the mean birth weight (BW) was 801g (SD 188g), and 51.4% were males. Various gestational ages among ELGANs were well-represented, with 23.7% being 24wk GA, 25.8% being 25wk GA, 24.3% being 26wk GA, and 26.2% being 27wk GA. Neonates requiring MV at postnatal day 14 were more likely to have a lower birth weight and length, lower GA, lower APGAR scores. They were more likely to be SGA, require vasopressors, receive treatment for a patent ductus arteriosus (PDA), have intraventricular hemorrhage (IVH), and experience an episode of acute kidney injury (AKI). Exposure to one dose of antenatal steroids was no different among those requiring MV compared to those without MV at postnatal day 14.
• Primary Outcome: 458 neonates (52.4%) received mechanical ventilation on postnatal day 14. Compared to infants not requiring MV on postnatal day 14, infants requiring MV were more likely to have a less negative fluid balance on postnatal day 3, a higher peak positive fluid balance on postnatal day 14, and a shorter time to regain their BW. Utilizing logistic regression, neonates with peak positive fluid balance >5%, >10%, and >16% had similar increased odds of requiring MV on postnatal day 14 (~75% increased odds). When adjusting for multiple factors (GA, 5-min APGAR score, receipt of vasopressors, occurrence of AKI in first 14 days of life, treated PDA, IVH, study site), the peak positive fluid balance in the first 14 days and fluid balance on postnatal day 3 and 7 remained independently associated with need for MV on postnatal day 14. Upon multivariable analysis, for every 10% increase in peak positive fluid balance, there was a 103% increased odds of MV at postnatal day 14. For every 10% increase in fluid balance at postnatal day 3, there was a 66% increased odds of MV at postnatal day 14. Finally, infants were more likely to require MV on postnatal day 14 if their daily weight never decreased below BW.
• Secondary Outcome: A total of 291 infants (33.3%) had severe BPD (at 36wks’ PMA) or death (after postnatal day 14 but before 36wks’ PMA). Compared to surviving infants with mild/no BPD, infants with severe BPD or death were more likely to have a higher peak positive fluid balance, a less negative fluid balance on postnatal days 3 and 7, and a shorter time to regain their BW. Utilizing logistic regression, neonates with peak positive fluid balance >5%, >10%, and >16% had increased odds of severe BPD or death. Upon multivariable analysis, there was no significant change in odds of severe BPD or death for every 10% increase in peak positive fluid balance.
  

  CONCLUSION

  This secondary analysis of a large, prospective, multicenter, placebo-controlled randomized control trial of extremely premature neonates reports on the epidemiology of fluid balance in the first two postnatal weeks and its association with short- and long-term respiratory outcomes. Fluid balance in the first 2 postnatal weeks is independently associated with the need for MV at postnatal day 14, as well as the composite outcome of severe BPD or death. Fluid balance on postnatal day 3, time to regain BW, and a peak positive fluid balance of even >5% in the first two postnatal weeks were identified as clinically important targets warranting further study.