Transition to the extrauterine environment is associated with major changes of body water and salt composition in the premature baby [
To our knowledge, no study has explored the chloride balance during the first week of life or the impact of changes in plasma chloride levels on perinatal morbidity and neurological outcome in preterm infants. The present investigation was carried out to enlighten these two points.
From January 2007 to May 2008 all consecutive infants born below 33 weeks of gestational age (GA) and admitted to the neonatal intensive care unit (NICU) of Dijon University Hospital within 6 hours after birth were eligible. Noninclusion criteria were major congenital anomalies. A criterion for secondary exclusion was death within the first week.
The research protocol was authorized by the Ethics Committee of the Hospital. Informed, signed parental consent was obtained.
Parenteral nutrition (PN) was administered by eight different PN bags commercially batch produced with increasing nutrient intake for day 1 to day 7 of life in infants with central venous line [
In the purpose to assess short- and middle-term neurological outcome in this population, cerebral ultrasounds were realized during the infant hospital stay and neurological examination at 18 months of corrected age.
Cranial ultrasounds were performed by experienced examiners (neonatologists or radiologists) according to the following protocol: day 1, 3, 7, 10, 15, and then at least every 2 weeks or more often as clinically indicated, until discharge.
Severe abnormal cerebral ultrasound was defined as severe (grade 3 or 4) intraventricular hemorrhage (IVH) and/or cystic periventricular leukomalacia (c-PVL) occurring before infants discharge from hospital. IVH was graded at cerebral ultrasound according to Papile et al. [
Children were subjected to a detailed physical and neurological examination at 18 months of corrected age, in order to assess tone, reflexes, posture, and movements. We used the definition of cerebral palsy proposed by the European Cerebral Palsy Network [
For the 7 days after birth, plasma sodium, potassium, chloride, phosphate, and total carbon dioxide (tCO2) were determined daily. We daily calculated the plasma SID as the difference between sodium and chloride. Base excess (BE), bicarbonate (
Day 1 data were obtained on a blood sample taken at 12 hours of life. Day 2 blood sample was taken 24 hours later.
Sodium, potassium, and chloride intake from intravenous, oral fluids and drugs administration during the study period was recorded from the infant chart. Intravenous flushes and sodium and chloride administration by drugs, or transfusions were taken into account when calculating fluid and electrolyte intake.
Daily, consecutive 8-hour urine collection starting 4 hours before the blood sampling was performed by using a plastic bag. Urine was analyzed for sodium and chloride concentrations. Plasma and urine sodium and chloride, plasma potassium, phosphate, and tCO2 concentrations were measured by an Ortho Clinical Diagnostic analyzer (Rochester, USA), which uses direct potentiometry. Blood gas was analyzed on the Radiometer ABL 700 blood gas analyzer.
Chloride and sodium balance were defined, respectively, as the difference between chloride intake and urinary excretion and sodium intake and urinary excretion was expressed as mmol/kg/day.
Data from categorical variables were analyzed using
We measured the relationship between both plasma chloride concentration and plasma SID with plasma sodium, phosphate, tCO2, pH, BE, and
Furthermore, we realized for each of the following parameters (plasma chloride concentration, plasma SID, and tCO2) a univariate analysis of variance in order to explore their association with water, energy, amino acids, phosphate, sodium, potassium, and chloride intakes and also their association with all the perinatal variables summarized in Table
Characteristics of 107 infants <33 weeks of GA hospitalized in NICU.
Characteristics at birth | % |
---|---|
Male gender | 54.2 |
BW | |
GA | |
SGA | 25.4 |
Apgar score <3 at 1 minute of life | 11.2 |
Prenatal characteristics | |
Antenatal steroids | 77.6 |
Caesarean section | 79.4 |
Postnatal characteristics | |
Central venous line | 62.6 |
Acute anaemia at birth | 13.2 |
Body weight loss >15% of BW | 11.2 |
RDS-requiring surfactant | 66.4 |
Early onset sepsis | 6.5 |
Hypotension-requiring treatment | 13.1 |
Acute renal failure* | 11.2 |
HsPDA | 36.4 |
Oxygen dependency beyond 36 wks PCA | 12.3 |
Necrotizing enterocolitis | 2.8 |
Severe abnormal cerebral ultrasound† | 1.8 |
Death after the first week of life | 0 |
Cerebral palsy at 18 months of PCA | 2.1 |
(NICU) Neonatal Intensive Care Unit; (BW) birth weight; (GA) gestational age; (SGA) small for gestational age; (RDS) respiratory distress syndrome; (HsPDA) hemodynamically significant patent ductus arteriosus; (PCA) postconceptional age.
During the study period, 147 neonates born below 33 weeks of gestation were hospitalized in our NICU. Of these, 129 were admitted within the 6th hour of life. Among them, 12 were not enrolled in the study: 1 due to major congenital anomalies, 9 due to omission of the attending physician, and 2 due to refused parental consent. So, 117 infants were entered into the study. Among them, 10 were excluded secondary: 2 because they died during the first week, 2 as they were transferred to other units, and 6 due to difficulties of blood sampling. Finally, 107 infants were entered into the study. Table
Chloride concentration values were available for 95, 96, 98, 98, 91, 92, and 88% of infants, and sodium concentration values were available for 98, 100, 99, 99, 95, 95, and 92% from day 1 to 7. tCO2 values were available for 87, 83, 86, 87, 83, 83, and 77% of infants from day 1 to 7. Arterial blood gas was performed in 37% of the blood samples; when these data were available, the analysis showed that plasma chloride and SID were significantly associated with tCO2, BE, and
Figure
Chloride and sodium intake and balance during the first week of life in 107 infants <33 weeks of GA hospitalized in NICU.
Plasma chloride percentiles during the first week of life in 107 infants <33 weeks of GA hospitalized in NICU (
Plasma chloride and sodium profiles were similar, while urinary chloride concentration did not parallel urinary sodium excretion (Figure
Figure
Strong ion difference (SID) during the first week of life in 107 infants <33 weeks of GA hospitalized in NICU (
Plasma chloride concentration was strongly positively associated with plasma sodium concentration (
Clinical factors associated with plasma chloride concentration at the univariate analysis were weight loss % of birth weight (BW), GA, acute anaemia at birth, respiratory distress syndrome (RDS) requiring surfactant, hypotension requiring treatment, hemodynamically significant patent ductus arteriosus (hsPDA), acute renal failure, intraventricular haemorrhage (IVH) grade 3-4, necrotizing enterocolitis (stage 2 or more of the Bell classification), chloride, sodium, phosphate, amino acid, and water intakes and day of life (data not shown). Among them, chloride intake, hsPDA, weight loss % of BW, sodium intake, and GA remained independent factors associated with plasma chloride at the multivariate analysis (Table
Factors associated with plasma chloride (mmol/L), SID, and tCO2 levels (mmol/L) at multivariate analysis in 107 infants <33 weeks of GA.
Incremental | Beta coefficient | ||
---|---|---|---|
Plasma chloride* | |||
Chloride intake | <0.001 | 0.14 | + |
HsPDA | <0.01 | 0.03 | + |
Sodium intake | <0.01 | 0.02 | − |
Weight loss % of BW | <0.01 | 0.02 | + |
GA | <0.05 | 0.01 | − |
SID** | |||
Chloride intake | <0.001 | 0.09 | − |
HsPDA | <0.01 | 0.04 | − |
Sodium intake | <0.05 | 0.01 | + |
Phosphate intake | <0.05 | 0.01 | + |
GA | <0.05 | 0.01 | + |
tCO2*** | |||
Chloride intake | <0.001 | 0.13 | − |
GA | <0.01 | 0.02 | + |
Sodium intake | <0.05 | 0.01 | + |
(SID) strong ion difference; (tCO2) total carbon dioxide; (hsPDA) hemodynamically significant patent ductus arteriosus; (BW) Birth weight; (GA) gestational age;
*General
Factors associated with lower plasma tCO2 at the univariate analysis were GA, RDS requiring surfactant, hypotension requiring treatment, hsPDA, low Apgar score at 1 minute of life, sodium, chloride, phosphate and amino acid intake and day of life (data not shown). Among them, chloride and sodium intakes and GA remained independent factors associated with plasma tCO2 at the multivariate analysis (Table
To our knowledge this is the first prospective study showing the chloride balance in very preterm infants during the first week of life. Our data found a strong link between chloride and sodium metabolism. These results are consistent with others; Day et al. [
Our study also disclosed a wide variability of chloride levels during the first week of life with mean plasma concentrations much higher when compared to the range usually considered as normal for preterm babies [
Even if no previous studies have specifically explored the association of changes in plasma chloride levels and neonatal neurological morbidities, concerns have been expressed about the finding that blood chloride concentration had a significant linear correlation with metabolic acidosis, which is thought to be a causative factor in intraventricular haemorrhage in preterm [
This cohort of very preterm infants provided important additional information, as in our study the only clinical variable associated with both high chloride levels and low SID was hsPDA, and this could be explained as infants with this pathological condition may exhibit metabolic acidosis [
Finally it is interesting to remind that chloride depletion too may represent a contributing cause of morbidity and mortality in preterm populations, as proven by human and animals studies [
The low incidence of electrolyte disturbance-related morbidity in our population was probably due to careful management of fluid and electrolyte balance advocated by the unit guidelines and based on the strict monitoring of infants hydroelectrolytic status.
This study allowed describing the postnatal chloride balance in preterm infants hospitalized in NICU. Plasma chloride levels during the first week are higher in infants born at lower GA, and they are correlated with plasma sodium levels and biological markers of metabolic acidosis. In this carefully monitored population, changes in plasma chloride levels were not associated to poor neurological outcome in the short and middle term.