Koch G (1), Corminboeuf F (2), Eugster N (2), Pfister M (1), Gerull R (3)
(1) University of Basel, Children’s Hospital (UKBB), Pediatric Pharmacology and Pharmacometrics Research, 4056 Basel, Switzerland, (2) University of Bern, Children’s Hospital Inselspital Bern, Department of Pediatrics, 3010 Bern, Switzerland, (3) University of Basel, Children’s Hospital (UKBB), Department of Neonatology, 4056 Basel, Switzerland
Objectives: It is well know that severely ill patients experience substantial fluctuations of serum sodium. Several studies show that large variations of sodium are associated with increased morbidity and mortality in adults [1]. Interpretation of available studies allows the conclusion that serum fluctuations are not only a marker of illness severity, but cause increased morbidity and mortality itself. The situation in the pediatric population and even more in preterm neonates is less clear. However, some studies associate hypernatremia, hyponatremia or sodium variations with increased risk of serious complications such as intracerebral hemorrhage in preterm infants [2-3]. After birth, neonates experience loss of water and can develop hypernatremia, i.e. a rise of serum sodium to a value exceeding 145 mmol/l during the first days of life. Hypernatremia seems to be more frequent in preterm neonates with low gestational age (GA) due to increased water loss. Hyponatremia, i.e. values below 135 mmol/l, may also occur due to renal salt wasting as a result of the inability of immature kidneys to produce adequate urine tonicity. The purpose of this study is to identify factors that influence sodium fluctuations during the first 28 days of life in preterm neonates with GA < 32 weeks.
Methods: This retrospective study included all preterm neonates with GA < 32 weeks, born between 2007 and 2014 at the neonatal unit of the University Children’s Hospital in Bern, Switzerland. A descriptive modeling approach based on an indirect response model with a stimulatory effect on sodium production was used to characterize data. Delayed increase of sodium after birth was modeled with a tlag parameter. Initial value of sodium at birth was allowed to be different from steady state value after 28 days. Non-linear mixed modeling in The Monolix Suite 2016 (Lixoft, Orsay, France) was applied to fit data and to characterize covariate effects on model parameters. Continuous covariates were described by non-linear power functions. Secondary parameters, such as predicted sodium peak concentration, were accessed via simulations from the estimated individual model parameters in R (R Foundation for Statistical Computing). Normally distributed values are reported as mean (sd) and others as median [IQR].
Results: A total of 901 preterm neonates with GA of 29.4 [27.4, 30.9] weeks and a total of 20714 sodium measurements were eligible to be included in the study. Inclusion criteria were (i) at least one sodium measurement within the first 24 hours, and (ii) at least two measurements in total. Sodium at birth was predicted to be 133.1 (1.9) mmol/l and similar across GA. Sodium increase started at post-natal age (PNA) of 1.2 (0.6) days and a sodium peak of 143.0 (2.7) mmol/l was observed at PNA of 3.2 (1.5) days. GA and delivery mode (DM) had a significant impact on sodium peak concentration. More precisely, lower GA caused higher sodium peaks (e.g. 145 mmol/l for GA = 24 weeks and 142 mmol/l for GA = 30 weeks) and neonates with spontaneous birth had higher peaks compared to neonates with caesarean section. Approximately after 10-15 days mean sodium concentration become constant around 134 mmol/l. Neither sodium at birth nor peak sodium were different between male and female neonates.
Conclusions: Modeling and simulation allows to characterize individual serum sodium profiles and to identify risk factors in this vulnerable population. Consistent with immature regulation of sodium and water balance, maximum fluctuation increases with decreasing gestational age. Interestingly, also delivery mode seems to have an impact on sodium peak concentration.
References:
[1] Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PloS one 2013;8:e80451
[2] Dalton J, Dechert RE, Sarkar S. Assessment of association between rapid fluctuations in serum sodium and intraventricular hemorrhage in hypernatremic preterm infants. Am J Perinatol 2015;32:795-802
[3] Baraton L, Ancel PY, Flamant C, Orsonneau JL, Darmaun D, Roze JC. Impact of changes in serum sodium levels on 2-year neurologic outcomes for very preterm neonates. Pediatrics 2009;124:e655-61
Reference: PAGE 27 (2018) Abstr 8728 [www.page-meeting.org/?abstract=8728]
Poster: Drug/Disease Modelling - Paediatrics