Research Article

Variables Which Impact Fluid and Electrolyte Management in The Neonatal Intensive Care Unit and Associations with Neonatal Outcomes

Tara Beck¹*, Deborah Tuttle², Keshab Subedi³, Amy Mackley RN² and Kelley ZK²

¹Department of Pediatrics, Nemours/ Alfred I DuPont Hospital for Children, Wilmington, (DE,) USA

²Department of Pediatrics, Division of Neonatology, ChristianaCare, Newark, (DE,) USA

³Institute for Research on Equity and Community Health (iREACH), ChristianaCare, Newark, DE, USA

Submission: June 26, 2024; Published: September 24, 2024

*Corresponding author: Tara Beck, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh Penn Avenue, USA

How to cite this article: Tara Beck*, Deborah Tuttle, Keshab Subedi, Amy Mackley RN and Kelley ZK. Variables Which Impact Fluid and Electrolyte Management in The Neonatal Intensive Care Unit and Associations with Neonatal Outcomes. Acad J Ped Neonatol 2024; 14(3): 555943. 10.19080/AJPN.2024.14.555943

Abstract

Objective: Managing fluids in extremely premature infants is challenging due to the delicate balance required between nutrition, organ perfusion, and avoiding fluid overload. This study aims to evaluate how early fluid management strategies affect morbidity and mortality outcomes in these neonates.

Study Design: This retrospective observational study focused on infants born at ≤28 weeks gestation at a level 3 neonatal intensive care unit (NICU). We analyzed demographic, clinical, and laboratory data from the first two weeks of life to assess current fluid management practices. The study examined correlations between total daily fluid intake and morbidities such as bronchopulmonary dysplasia (BPD), hemodynamically significant patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and mortality. Additionally, we explored the impact of early postnatal weight loss on these outcomes.

Results: The study included 184 infants with a mean gestational age of approximately 26 weeks. Daily fluid intake was consistent across gestational ages and various clinical parameters, including blood urea nitrogen (BUN), creatinine, and signs of diuresis. Correlations were noted between serum sodium levels and fluid intake on specific days. Infants diagnosed with a hemodynamically significant PDA received lower fluid volumes during the first two weeks. Percent weight loss by day 5 significantly correlated with lower rates of BPD and PDA.

Conclusion: Fluid intake was uniformly prescribed across our cohort, irrespective of hydration markers. Early weight loss in the first five days of life appears to influence morbidity, suggesting a need for personalized fluid management strategies in extremely premature infants.

Keywords: Neonatal Fluid Balance; Early Volume Status; Neonatal Fluid Overload; Neonatal Weight Loss

Abbreviation: NICU: Neonatal Intensive Care Unit; BPD: Bronchopulmonary Dysplasia; NEC : Necrotizing Enterocolitis; NEC: Necrotizing Enterocolitis; IVH: Intraventricular Hemorrhage; BUN: Blood Urea Nitrogen

Introduction

Fluid and electrolyte management is essential in the care of critically ill neonates but presents a unique challenge for clinicians. Premature infants are susceptible to fluid and electrolyte imbalances from postnatal changes in body water compartments, immature kidneys that inefficiently respond to fluid and electrolytes and increased insensible water losses across the skin and respiratory tract [1]. Extreme fluid and electrolyte dysfunction may be associated with increased morbidity and mortality, including bronchopulmonary dysplasia (BPD), persistent patent ductus arteriosus (PDA) and necrotizing enterocolitis (NEC) [2-4]. However, when fluid restriction is prescribed, providers may inadvertently decrease the amount of nutrition, including sodium, a neonate receives which could be detrimental to growth and neurodevelopmental outcomes [5-9].

The ideal fluid strategy for premature infants is unknown. Fluid balance is a continuum and may vary between patients, making application of standard total daily fluid guidelines challenging [10-12]. Clinicians often use physical exam, serum electrolytes, weight change, and urine output to determine individual fluid goals, but an absolute standard has not been established and practice variation exists. To address this dilemma, we first aimed to summarize the daily fluid intake trajectories and delineate variability in fluid intake between extremely premature patients born ≤28 weeks in our Level 3 neonatal intensive care unit (NICU). Next, we aimed to determine clinical variables that impact fluid management in extremely premature infants, mainly daily sodium, BUN and creatinine values. Then, we assessed how early fluid management impacts morbidities, including BPD, hemodynamically significant PDA, NEC development and mortality. We hypothesized that there would be limited variability in daily fluid intake among our cohort, as no guideline exists for extreme premature neonatal fluid management; we suspected this would result in close adherence to our institutional nutrition protocol for uniform daily fluid advancement. We also surmised those with increased daily fluid intake would have higher rates of BPD, PDA and NEC due to inappropriate fluid accumulation disrupting physiologic hemodynamics throughout the body.

Methods

Study Design

This is a retrospective observational study of premature infants with a gestational age of ≤28 weeks admitted to Christiana Care NICU, a large single center level 3 unit, from January 2017 to December 2019. Infants admitted after 24 hours of life were excluded. The Institutional Review Board of ChristianaCare approved this study. We have followed the STROBE guidelines for reporting our study aims and results11.

Data and Data Preparation

Demographic, clinical and outcome variables were collected from the electronic medical record. Demographic variables included birth weight, gestational age, sex, singleton or multiple birth and race. Clinical variables were tracked daily over the first 14 days of life and included total fluid intake (ml/kg/day), highest serum sodium (mEq/L), blood urea nitrogen (BUN, mg/dL) and serum creatinine (mg/dL), weight (grams) and urine output (ml/ kg/hr). Intake and output measurements were calculated using birthweight for the first seven days of life.

Fluid management was determined at the discretion of the medical team. The outcome variables in this study included diagnosis of BPD, PDA, NEC and mortality. BPD was defined per the 2000 National Institute of Health consensus statement definition12. PDA was considered hemodynamically significant if documented in the discharge summary or problem list and confirmed on echocardiogram, as echocardiograms are not routinely performed in our unit unless there is high suspicion for a persistent, hemodynamically significant PDA that may require medical intervention. NEC was considered present if infant received bowel rest and targeted antibiotic treatment for >48 hours and the diagnosis was listed in the discharge summary.

Statistical Analysis

The demographic and baseline clinical characteristics of the infants were summarized using means (± standard deviation, SD) for continuous variable and count (percent) for categorical variables. We compared baseline characteristic differences in neonates with and without BPD, PDA, IVH and NEC using chi-squared or Fisher’s exact test for categorical variables, as appropriate, and t-tests or Wilcoxon rank sum tests for continuous variables, as appropriate. We fit separate multivariable logistic regression models of BPD, PDA, NEC and mortality to estimate the adjusted effect of total fluid intake when factoring gestational age, gender, race, and antenatal steroid exposure.

We summarized fluid intake trajectories for the first 14 days of life to determine variability in fluid intake amongst our cohort. This was done using a latent growth model that analyzes longitudinal data and estimates changes over time. The model was fit using lavaan package in R, and the predicted trajectories were visualized using ggplot2. Next, we aimed to determine whether total fluid intake was influenced by daily sodium, BUN and creatinine using Pearson correlation coefficients. We plotted the scatter plot of total fluid intake against sodium, creatinine and BUN for each day of life then fitted separate linear regression models of total fluid intake as a function of sodium, creatinine and BUN value for each day of life. The resultant R-squared value represents the proportion of variability in the daily fluid intake explained by sodium, creatinine and BUN values. We used a boxplot model to determine the differences in percent weight loss on BPD, PDA and NEC development. To handle missing outcomes, we performed pairwise deletion, resulting in an available case analysis, where cases were excluded only if data were missing on a required value. All data manipulation and analysis were done using R.

Results

Characteristics of the Study Population

We identified 184 neonates who met the inclusion criteria within our study period. We excluded 15 neonates who died during the 14-day follow-up period and 1 infant for whom the survival data was missing, resulting in an analysis population of 168 (Figure 1). Our cohort was composed of primarily Black male infants with a mean gestational age of 26.1±1.5 weeks and mean birthweight of 875.7±232.2 grams (Table 1).

Variability of Fluid Intake in Our Cohort

Results from the latent growth model showed an average total fluid intake at day 0 of 218.3ml/kg with an estimated variance in slope of 3.9 ml/kg, indicating a higher variability of fluid intake on day 0 (Figure 2). This variability changed from day of life 1-14; day of life 1 data showed average expected total fluid intake was 138.7 ml/kg/day with an overall slope of 0.38ml/kg (Figure 2). This indicates, on average, fluid intake increases by 0.38ml/kg with each day of life over the first 14 days of life with little variance within the cohort. This data is clearly depicted in a box-scatter plot in Figure 2, showing greatest variability in fluid intake on day of life 0 and minimal variability in fluid intake on days of life 1-14 (Figure 3).

Effect of Electrolytes on Fluid Intake

When investigating potential correlations between electrolyte concentrations and total fluid intake, we detected positive correlations between elevated sodium levels and increased fluid intake on DOL 0 (r=0.37, p<0.001), DOL 1 (r=0.49, p<0.001), DOL 2 (r=0.49, p<0.001), and DOL 5 (r=0.23, p=0.004). No correlation between daily maximum serum sodium and fluid intake was detected on the remainder of the analyzed days. We did not detect any correlations between serum BUN or creatinine and fluid intake on any DOL 0 through 14.

Effect of Fluid Intake on BPD, PDA, NEC and Mortality

Table 2 depicts baseline characteristics between those with and without BPD, PDA, and NEC. Sixteen neonates were excluded from the BPD analysis due to death or transfer prior to 36 weeks’ gestation. BPD, PDA, and NEC were diagnosed in 52%, 52%, and 10% of patients, respectively. Average daily fluid intake was lower for patients with PDA (PDA: 133±8.7 ml/kg/day vs. no PDA: 136±8.0 ml/kg/day; p=0.03) compared to those without PDA, but average fluid intake did not differ between infants with and without BPD or NEC. There were no significant associations between fluid intake and mortality in our cohort.

Effect of Weight Loss on BPD, PDA and NEC Development

We assessed the effect of post-natal weight loss on morbidity and found infants with less weight loss from birth to DOL 5 had greater rates of both BPD (BPD: 7.3±7.57% vs. no BPD: 9.91±5.39%; p=0.024) and hemodynamically significant PDA (PDA: 6.7±7.37% vs. No PDA: 9.7±6.07%, p=0.006) (Figure 3). The effect of weight loss on PDA was modified by gestational age; the odds of PDA decreased by 13% for each percent increase in weight loss for infants 27.1-28.9 weeks. This effect was not significant for infants born at a gestational age GA <27 weeks. Percent weight loss did not impact the diagnosis of NEC.

Discussion

Our cohort of neonates born ≤28 weeks had greatest variability in fluid intake on day of life zero, or day of birth. This accounts for both varying times of birth (i.e.: a baby born earlier in the day will have greater fluid intake than a baby born late in the evening) and different resuscitation requirements. However, there was minimal variability in fluid intake across our cohort from days of life 1-14, regardless of serum sodium, BUN, creatinine or percent weight loss. This suggests that adjustments in fluid intake did not reflect individual hydration and electrolyte needs in our population and that providers follow a similar fluid management plan for all extremely preterm infants. Perhaps a reason for this is the development of feeding advancement protocols which have become common practice in the NICU to guide enteral nutritional volume advancement to reduce the rate of NEC [13]. It is possible that some providers use the prescribed volume advancements in these protocols to guide fluid management in all patients. However, uncoupling fluid goals with clinical data used to assess fluid balance places preterm infants at risk for inappropriate fluid management and related complications.

Our data also showed insufficient weight loss in the first 5 days of life was associated with a diagnosis of PDA and BPD, adding to the growing literature that early fluid management impacts long term morbidity. Multiple studies have found increased risk of BPD in infants who received higher total fluid intakes [3,14,15] and less post-natal weight loss through the first 10 days of life [2,15]. Soullane et al evaluated the impact cumulative fluid balance, median serum sodium concentration and maximum percentage weight loss on death and/or BPD and found that only cumulative fluid balance was different between BPD-free survivors and infants with death/BPD [14]. In an adjusted analysis, there was an association between higher cumulative fluid balance and higher odds of death/BPD [14]. While our data did not show a difference in total fluid intake and BPD diagnosis, it showed a greater risk of BPD development with decreased post-natal weight loss in the first 5 days of life, highlighting that fluid balance is key to preventing BPD.

Additional studies have highlighted the importance of postnatal diuresis; a meta-analysis of 5 randomized controlled trials assessing the impact of liberal versus restricted fluid intake in premature infants demonstrated that increased postnatal weight loss significantly reduced the risk of significant PDA and NEC, while there were trends toward decreased risk of BPD, IVH and death [4]. Askoy et al demonstrated increased mortality for infants <1000 grams birth weight with weight loss of 0-3% from birth weight or greater than 12% [16]. Further, in a recently published secondary analysis of the PENUT trial, neonates with increased fluid balance were associated with increased odds of receiving mechanical ventilation on postnatal day 14, severe BPD, or death [15].

Our data supports the growing body of literature that the allowance of increased diuresis, defined by percent weight loss during the first week of life, may be a more important clinical variable to improve morbidity [2,3,13-15]. A recent quality improvement study by Havinga et al suggested that by simply decreasing starting fluid volumes, a goal weight loss of >6% of birthweight by the end of the first week of life can be accomplished [17]. This, in conjunction with our results, could warrant revision of the unit’s fluid management protocol and allow for greater diuresis.

Limitations and Strengths

This study included a comprehensive collection of data regarding fluids goals in the first two weeks of life and clinical outcomes for a large group of extremely premature infants which contributes to its strength. However, many of the outcome variables are gestational age dependent, making it difficult to differentiate if the measured clinical variables, such as BPD and PDA of clinical concern, are due to degree of prematurity versus fluid status. Additionally, extremely premature infants are often not weighed daily, making actual fluid status and postnatal weight loss difficult to assess.

Since the clinical impact of the PDA and the need for treatment is controversial and without consensus, the relationship between fluid intake and impact on the PDA may have less clinical importance in patient management. Our study found a statistical but unlikely clinically significant difference in fluid intake for infants diagnosed with a PDA of clinical concern versus infants without a PDA. Additionally, there is practice variation for obtaining echocardiograms and treating hemodynamically stable PDAs, which could alter the number of patients who were diagnosed with PDA of clinical concern. Strict fluid management may have a greater impact on the PDA in certain groups within the extremely premature infant population. Infants <27 weeks are likely to be diagnosed with PDA regardless of fluid status but strict monitoring of percent weight loss and fluid infant for infants >27 weeks gestation may result in improved outcomes. Additionally, our unit does not routinely use humidity unless a neonate shows signs of refractory hypothermia despite thermal padding and heated isolette, which means insensible losses could have a larger impact than a unit who standardly uses humidity.

Conclusion

Fluid management in extremely premature infants is challenging. Our data revealed fluid intake was uniform across our cohort regardless of serum sodium, BUN or creatinine values or evidence of diuresis. This could be due to lack of guidance on extremely premature neonatal fluid management in conjunction with strict adherence to the unit’s nutritional protocol which uniformly guides nutritional advancements without considering electrolyte balance or diuresis. Our study suggests that a higher percent weight loss within the first week of life is associated with a reduction in BPD and PDA diagnosis and thus should be considered an important variable for targeting fluid management.

References

1. Oh W (2019) Nephrology and Fluid/Electrolyte Physiology In: Oh W, Baum M, eds. Neonatal Questions and Controversies (3^rd edition). Elsevier, New York, NY, United States, pp. 19-28.
2. Oh W, Poindexter BB, Perritt R, Lemons JA, Bauer CR, et. Al (2005) Neonatal Research Network: Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. J Pediatr 147(6): 786-790.
3. Rocha G, Ribeiro O, Guimarães H (2010) Fluid, and electrolyte balance during the first week of life and risk of bronchopulmonary dysplasia in the preterm neonate. Clinics (Sao Paulo) 65(7): 663-674.
4. Bell EF, Acarregui MJ (2014) Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 14(12): CD000503.
5. Araya B, Ziegler A, Grobe C, Grobe J, Segar J (2023) Sodium and Growth in Preterm Infants: A Review. Newborn (Clarksville) 2(2): 142-147.
6. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, et al. (2006) Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 117(4): 1253-1261.
7. Schneider J, Fischer Fumeaux CJ, Duerden EG, Guo T, Foong J, et. al. (2018) Nutrient Intake in the First Two Weeks of Life and Brain Growth in Preterm Neonates. Pediatrics 141(3): e20172169.
8. Moyses HE, Johnson MJ, Leaf AA, Cornelius VR (2013) Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 97(4): 816-826.
9. Al-Dahhan J, Jannoun L, Haycock GB (2002) Effect of salt supplementation of newborn premature infants on neurodevelopmental outcome at 10-13 years of age. Arch Dis Child Fetal Neonatal Ed. 86(2): F120-F123.
10. Askenazi D (2023) The AWAKEN Study [Summarizing findings of the AWAKEN Study]. Neonatal and Infant Course for Kidney Support. Birmingham, AL, USA.
11. Von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, et al. (2007) The Strengthening the Reporting of Observation Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. BMJ 335(7624): 806-808.
12. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, et. al. (2005) National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116(6): 1353-1360.
13. Patole SK, de Klerk N (2005) Impact of standardized feeding regimens on incidence of neonatal necrotizing enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal 90(2): 147-151.
14. Soullane S, Patel S, Claveau M, Wazneh L, Sant'Anna G, et. al. (2021) Fluid status in the first 10 days of life and death/bronchopulmonary dysplasia among preterm infants. Pediatr Res 90(2): 353-358.
15. Starr MC, Griffin R, Gist KM, Segar J, Raina R, et al. (2022) 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. 5(12).
16. Aksoy HT, Güzoğlu N, Eras Z, Gökçe İK, Canpolat FE, et al. (2019) The association of early postnatal weight loss with outcome in extremely low birth weight infants. Pediatr Neonatol 60(2): 192-196.
17. Havinga J, Williams A, Hassan N, Moore S, Dollhopf E, et. al. (2021) Individualized fluid management in extremely preterm neonates to ensure adequate diuresis without increasing complications. J Perinatology 41(2): 240-246.