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Starr MC, Griffin R, Gist KM, Segar JL, Raina R, Guillet R, et al; Neonatal Kidney Collaborative Research Committee. Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates. A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022; 5: e2248826. PMID 36580332
Reviewed By:
Brianna M. Liberio MD
Assistant Professor of Clinical Pediatrics
Department of Pediatrics, Division of Neonatal-Perinatal Medicine Indiana University School of Medicine, Indianapolis, IN, USA bliberio@iu.edu
Rebecca S. Rose MD
Assistant Professor of Clinical Pediatrics
Medical Director, Neonatal Nurse Practitioner Program
Interim Associate Medical Director, Newborn Intensive Care Unit Department of Pediatrics, Division of Neonatal-Perinatal Medicine Indiana University School of Medicine, Indianapolis, IN, USA rrose@iu.edu
Corresponding Author:
Brianna M. Liberio MD bliberio@iu.edu
TYPE OF INVESTIGATION:
Prognosis
QUESTION
Among extremely low gestational age neonates (ELGANs) (P), what is the impact of fluid balance (I/C) on invasive mechanical ventilation status (O) at postnatal day 14 (T)?
METHODS
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- Design: Secondary analysis of a randomized clinical trial (Preterm ErythropoietinNeuroprotection (PENUT) Trial)
- Allocation and Blinding: The original PENUT Trial was a phase 3, blinded, placebo-controlled, randomized controlled trial of erythropoietin in ELGANs. The present study is asecondary analysis of the PENUT Trial.
- Follow-up period: The primary outcome was assessed at postnatal day 14. The secondaryoutcome was assessed at 36 weeks’ postmenstrual age (PMA).
- Setting: The original PENUT Trial was conducted in 19 academic centers and 30 neonatalintensive care units (NICUs) in the United States, from December 1, 2013 to September 31,2016.
- Patients
- Inclusion Criteria: Gestational age (GA) 24w0d – 27w6d; Enrollment at < 24 hours of life; Arterial or venous access Exclusion Criteria: Major life-threatening anomalies; Hematologic crises; Hematocrit higher than 65%; Hydrops fetalis; Congenital infection; Death in the first 14 days of life (excluded just from this secondary analysis)
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- Intervention/Comparison
- Fluid balance: As determined by the following equation:
- Fluid balance = [(daily weight – birth weight)/(birth weight)] x 100
- Fluid balance: As determined by the following equation:
- Intervention/Comparison
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- Evaluated over the first two postnatal weeks in 5 different ways:
- Maximum percentage of weight gain (Peak positive fluid balance)
- Maximum percentage of weight loss (Peak negative fluid balance)
- Percentage weight change at postnatal day 3
- Percentage weight change at postnatal day 7
- The day the neonate returned to birth weight
- Evaluated over the first two postnatal weeks in 5 different ways:
Outcomes
o Primary Outcome: Invasive mechanical ventilation (MV) (high-frequency or conventional ventilation) on postnatal day 14
o Secondary Outcome: Composite outcome of severe bronchopulmonary dysplasia (BPD)* or death between postnatal day 14 and 36wks’ PMA * Severe BPD = receipt of 330% FiO2 or positive pressure at 36wks’ PMA
Analysis and Sample Size
Odds ratios for association between fluid balance variables and outcomes of interest were estimated from unconditional logistic regression models. Multivariable logistic regression models were used to account for confounding variables. A sensitivity analysis and best-case/worst-case analysis were performed to assess excluded infants. There was no sample size calculation for this secondary analysis of the PENUT Trial.
• 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.
COMMENTARY
With this study, Starr and colleagues add to the growing body of literature recognizing the importance of fluid status in neonates (1-3). Utilizing the weight-change method for estimating fluid balance, which is the preferred method in neonates (4), they found that fluid balance is independently associated with the need for mechanical ventilation at postnatal day 14 and the composite outcome of severe bronchopulmonary dysplasia (BPD) or death.
All neonates undergo a period of adaptation of fluid and electrolyte homeostasis after birth, with a contraction of the extracellular fluid (ECF) compartment, driven by natriuretic diuresis and transepidermal losses in preterm infants. This phase ends with maximum weight loss or negative fluid balance (5). Very low birth weight and extremely low birth weight infants can experience 10% – 15% negative fluid balance, with this phase lasting up to 8 days (5,6). Clinicians should allow for ECF contraction while maintaining intravascular fluid volume, achieving a negative sodium balance, maintaining normal serum electrolyte levels, and providing sufficient calories to meet maintenance needs (5,6). Achieving this requires close monitoring of daily intake and output, weight changes, and electrolyte concentrations, while thoughtfully adjusting prescribed fluid intake.
In the same patient cohort as the present study, Valentine and colleagues analyzed weight loss and fluid administration (7). They found that a maximum weight loss of 5-15% within the first postnatal week was associated with a decreased odds of developing necrotizing enterocolitis (NEC), while an average total fluid administration of >150ml/kg BW/day over the first postnatal week was associated with increased risk of NEC and patent ductus arteriosus (PDA) requiring surgery. They suggested cautious limitation of total fluid administration and allowing for moderate weight loss in the first postnatal week (7). A 2014 Cochrane review recommended careful restriction of fluid intake in preterm neonates to meet physiological needs without causing dehydration rather than a practice of liberal fluid intake, citing that restricted fluid intake significantly reduced the risks of PDA and NEC, with trends toward reduced risk of BPD, intraventricular hemorrhage, and death (8).
No discussion about fluid status is complete without addressing electrolytes, specifically sodium. Dysnatremias are common in critically ill patients and are associated with mortality and hospital length of stay (9). Preterm infants are at particular risk for dysnatremias given immature renal tubules, fluid shifts, insensible losses, and exposure to parenteral nutrition. In an analysis of a contemporary large neonatal cohort, dysnatremias were common in the first week of life, occurring in half of the cohort (9). In adjusted models, the occurrence of hypernatremia and combined hypo- and hypernatremia in the first week of life was associated with increased risk of mortality in neonates with normal renal function (9).
Weight changes, fluid intake, electrolyte status—this is quite the fine balance. When does physiologic weight loss become pathologic? Clearly, there are many variables and outcomes to consider. Starr and colleagues provide potential targets of this complex problem. In efforts to reduce rates of BPD and other neonatal morbidities, fluid balance is emerging as a critical factor.
REFERENCES
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Starr MC, Griffin R, Gist KM, Segar JL, Raina R, Guillet R, et al; Neonatal Kidney Collaborative Research Committee. Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates. A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022; 5: e2248826. PMID 36580332
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Selewski DT, Gist KM, Nathan AT, Goldstein SL, Boohaker LJ, Akcan-Arikan A, et al; Neonatal Kidney Collaborative. The impact of fluid balance on outcomes in premature neonates: a report from the AWAKEN study group. Pediatr Res. 2020 Feb; 87: 550-557
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Selewski DT, Akcan-Arikan A, Bonachea EM, Gist KM, Goldstein SL, Hanna M, et al; Neonatal Kidney Collaborative. The impact of fluid balance on outcomes in critically ill near-term/term neonates: a report from the AWAKEN study group. Pediatr Res. 2019 Jan; 85: 79-85
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Goldstein SL, Akcan-Arikan A, Alobaidi R, Aseknazi DJ, Bagshaw SM, Barhight M, et al; Pediatric ADQI Collaborative. Consensus-Based Recommendations on Priority Activities to Address Acute Kidney Injury in Children: A Modified Delphi Consensus Statement. JAMA Netw Open. 2022 Sep 1; 5: e2229442
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Fusch C and Jochum F. (2014). Water, Sodium, Potassium and Chloride. In Koletzko B, Poindexter B, & Uauy R (Eds), Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. (Vol. 110, pp 99-120). Karger.
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Oh W. (2019). Body Composition in the Fetus and Newborn: Effects of Intrauterine Growth Aberration. In W. Oh & M. Baum (Eds), Neonatal Questions and Controversies: Nephrology and Fluid/Electrolyte Physiology (3rd ed, pp 19-28). Elsevier.
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Valentine GC, Perez KM, Wood TR, Maycock DE, Comstock BA, Puia-Dumitrescu M, et al. Postnatal maximal weight loss, fluid administration, and outcomes in extremely preterm newborns. J Perinatol. 2022 Aug; 42: 1008-1016.
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Bell EF and Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2014. Epub. Art. No.: CD000503
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Basalely AM, Griffin R, Gist KM, Guillet R, Askenazi DJ, Charlton JR, et al; AWAKEN Study Group. Association of early dysnatremia with mortality in the neonatal intensive care unit: results from the AWAKEN study. J Perinatol. 2022 Oct; 42: 1353-1360
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