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PEDIATRICS Vol. 104 No. 3 September 1999, pp. 482-488
,,
From the * Department of Pediatrics, Westchester Medical Center,
Valhalla, New York; the Departments of Pediatrics, University
Hospital, Stony Brook, New York; and the § Department of Pediatrics,
Lawrence Hospital, Brownsville, New York.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Objective. We sought to determine if prenatal steroid (PNS) treatment affects water and sodium (Na) balance in extremely low birth weight infants (<1000 g).
Methods. PNS treatment enhances lung maturation in preterm
infants and induces maturation of renal tubular function and adenylate
cyclase activity in animals. We compared water and Na homeostasis for the first week of life in those infants whose mothers received steroids
before delivery (PNS: n = 16) to those who did not
(nonsteroid group [NSG]: n = 14). The data were
collected prospectively, but PNS treatment was not given in a
randomized manner. Fluids were initiated at 100 to 125 mL/kg/d and
adjusted every 8 to 12 hours to allow a daily weight loss of 
4% of
birth weight and to maintain normal serum electrolytes. Weight, serum
and urine electrolytes, and urine output were frequently measured and
fluid intake was adjusted by increasing the amount of free water to
achieve these goals.
Results. When using our fluid management protocol, the
percent weight loss in both groups was equivalent during each of the 7 days (15% PNS vs 17% NSG maximum loss) as well as the cumulative
urine output at 1 week of age (663 mL/kg/wk PNS vs 681 mL/kg/wk NSG). PNS infants had a higher urine output on the first 2 days of
life and a lower daily fluid intake for the first week. PNS
infants also had significantly less insensible water loss for
each of the first 4 days of life. The PNS group had a significantly
lower mean peak serum Na of 138 ± 1 mmol/L vs 144 ± 2 mmol/L and none had a peak serum Na >150 mmol/L compared with 36% of
the NSG infants. PNS infants had a higher cumulative Na excretion at
day 2 of life (10 ± 2 mmol/kg vs 6 ± 1 mmol/kg) but a less
negative cumulative Na balance at 1 week (
10 mmol/kg vs 14
mmol/kg).
Conclusion. PNS treatment was associated with lower estimated insensible water loss, a decreased incidence of hypernatremia, and an earlier diuresis and natriuresis in extremely low birth weight neonates. We speculate that PNS effects these changes through enhancement of epithelial cell maturation improving skin barrier function. PNS treatment may also enhance lung Na,K-ATPase activity leading to an earlier postnatal reabsorption of fetal lung fluid increasing extracellular volume expansion to help prevent hypernatremia. Key words: insensible water loss, fluid homeostasis, hypernatremia, dexamethasone, creatinine clearance, sodium balance, extremely low birth weight neonate.
In the first week of postnatal life, fluid and electrolyte
management in extremely low birth weight (ELBW) infants (<1000 g birth
weight) has become a difficult challenge. Insensible water loss (IWL)
in these infants may be as high as 200 mL/kg/d. Failure to keep up with
these losses in the first few days of life may result in dehydration,
hypernatremia, and hyperkalemia, and may contribute to the
complications of intraventricular hemorrhage and
arrhythmia.1 To compensate for this high evaporative fluid
loss, body fluids must often be maintained at high infusion rates. The
attendant excess infusion of glucose to maintain an isoosmotic
intravenous solution often results in a secondary hyperglycemia and
glycosuria. Glycosuria may contribute to the problem of dehydration when an osmotic diuresis ensues, necessitating the use of exogenous insulin. Indeed, prevention of dehydration, hypernatremia, and hyperglycemia has increasingly become one of the greatest challenges in
neonatology in the treatment of the ELBW infant.
Survival of ELBW infants <1000 g has increased dramatically during the
last several years concomitant with an increased use of prenatal
steroid (PNS) treatment and surfactant replacement therapy.2,3 PNS have been shown to be of significant benefit to the ELBW infant, reducing the severity of pulmonary disease,
intraventricular hemorrhage, and necrotizing
enterocolitis.4-12 In addition to these effects, PNS has
a maturational effect on the skin epidermis.13,14 In this
capacity, PNS are thought to have a major effect on epithelial cell
differentiation and maturation as well as an improvement in function of
multiple body organs.
PNS has been shown to affect epithelial surfaces other than the lung,
including renal epithelium and skin. Previous animal and human studies
have demonstrated an effect of PNS on renal cell differentiation with
an increase in renal adenylate cyclase activity and tubular
function.15 The glomerular filtration rate (GFR)
has been reported to increase in lambs and humans but not
rats.17-20 In this article we sought to determine the
effect of PNS on sodium (Na) and water balance during the first week of
life. We hypothesized that PNS treatment enhances maturation of the
barrier functions of the epidermis of ELBW infants resulting in a
decrease in IWL as well as an enhancement of postnatal fluid and
electrolyte homeostasis.
Patient Population
Appropriate-for-gestational age neonates weighing <1000 g at
birth were cared for according to the standard protocols in the neonatal intensive care unit at the University Hospital of Stony Brook,
New York.21,22 Data were collected prospectively between
July 1989 and July 1993. Infants with complete laboratory data
consecutively admitted to the intensive care were eligible for the
study. Other inclusion criteria were mechanical ventilation for
respiratory distress syndrome and umbilical artery catheterization.
Informed consent was deemed not necessary to carry out this review
because no additional laboratory tests were ordered solely for the
purpose of this tabulation and the clinical protocols followed were
current practice in our clinical unit. Infants with major congenital
anomalies, renal diseases, and incomplete laboratory data were excluded
from review. The decision to treat with PNS was determined entirely by
the obstetrical staff at a time before widespread use of PNS and the
1994 National Institutes of Health consensus statement. Patients were
included in the PNS group if their mother was given one full course of
dexamethasone (12 mg × 4 doses) or betamethasone (12 mg × 2 doses) within 7 days before delivery with the last dose given at least
24 hours before delivery. Infants whose mothers did not receive PNS
constituted the nonsteroid group (NSG). NSG infants were matched with
the PNS group for birth weight and gestational age. The prenatal
maternal course was similar in both groups regarding their duration of hospitalization, and tocolytic and antibiotic use.
Weight
Body weight was measured on admission to the unit and then every
8 to 12 hours for the first week of life using the same bed scale. This
scale is accurate to 5 g and was periodically checked for accuracy
by the biomedical engineering division. As much equipment as possible
was removed from the infant and tubing was suspended during each
weight. Weight was corrected for dressing, arm boards, tubes, and other
equipment that could not be removed. Weights that differed >5% of the
previous one were repeated for accuracy.
Fluid Therapy
Infants were admitted to a radiant warmer and after insertion of
umbilical arterial and venous catheters, an intravenous infusion of
D5W at a rate of 100 to 125 mL/kg/d was started. The fluids were adjusted to allow for a gradual weight loss of TABLE 1
METHODS
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Abstract
Methods
Results
Discussion
References
4% per day (40
g/kg/d) with an anticipated overall maximum weight loss of 15% to 20%
by 7 days when the weight plateaus. Serum and urine electrolytes were
measured every 12 hours. Fluid intake and output were recorded every 8 to 12 hours. The infants were transferred to nonhumidified
double-walled incubators after an initial period of stabilization
(Table 1). Estimated IWL was calculated as: total fluid intake fluid output + weight loss in g.
Demographic Characteristics of the Study Infants
During the first week of life, fluids were increased (or decreased) in increments (or decrements) of 25 to 50 mL/kg/d every 12 hours depending on the weight and serum Na changes to achieve targets. When the infant reached the homeostatic phase,21 the daily fluid intake was reduced gradually by 25 to 50 mL/kg/d to maintain a targeted urine output at or around 50 mL/kg/d. Fluid intake included intravenous fluids, medications, and flushes. Fluid output included urine output and phlebotomy blood drawn for lab work.
Urine was collected using an external device attached to the genitalia (finger cots in males and plastic boats for females) and its volume was measured every 3 to 6 hours. Near the end of each collection period, the infant was observed for spontaneous voiding, and the collection period ended with this void. The time period of urine collection and the urine volume were recorded. Every 8 to 12 hours, an aliquot of the collected urine was analyzed for electrolytes and creatinine. The spilled urine was measured by weighing the diapers. Diapers were weighed as soon as possible after spontaneous voiding. Total urine output, calculated as the sum of the measured urine from the collecting device and the spilled urine into the diaper, was used for clearance calculations. To obtain consistency with derived data, birth weight was used for all calculations during the first week of postnatal life.
Electrolyte Therapy
Na and potassium salts were not added to the initial intravenous dextrose water solutions. Sodium chloride (or acetate) was introduced into the intravenous solution after 24 hours if the serum Na concentration was low in the absence of weight gain or normal (130-145 mmol/L) and not increasing. Potassium chloride was introduced once the serum potassium levels were normal and the urine output was >1 mL/kg/h. Values for creatinine clearance (Ccr) and fractional excretion of sodium (FeNa) were calculated using standard formulae. Daily weight, fluid intake, urine output, Na intake and output, and the interval of collections were obtained from the bedside nursing notes.
Statistics
Group mean values were compared by Student's t test
if the data were normally distributed or by the Wilcox signed ranks
test if they were not. Repeated measures data were compared by two-way analysis of variance with repeated measures of one factor followed by
multirange testing using the Neuman Keul's test where appropriate. All
values are expressed as mean plus/minus standard error of the mean
unless otherwise indicated. We used the Fisher's exact test or
2 test for comparisons of enumeration data between two
groups.
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RESULTS |
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Abstract
Methods
Results
Discussion
References
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A total of 40 infants weighing <1000 g at their birth weight were eligible for the review. Ten infants were excluded: 5 infants with incomplete laboratory data (3 in the NSG and 2 in the PNS group), 3 infants had transient renal failure (2 in the NSG and 1 in the PNS group), and 2 infants were small-for-gestational age (1 in each group). The water and Na balance for the remaining 30 patients were reviewed during the first week of postnatal life. There was no significant difference between the groups in gestational age, birth weight, sex, 1 and 5 minute Apgar scores, or duration of phototherapy (Table 1). There was no difference between the two groups in serum glucose throughout the entire study period (Fig 1). We found no difference in the systolic and diastolic blood pressures between the groups (Fig 1). None of the infants received inotropic support, diuretic therapy, or indomethacin during the first week of life. During the second week of life, 8 infants in the NSG and 4 infants in the PNS group had a hemodynamically clinically significant patent ductus arteriosus that was treated with indomethacin or ligation. All infants had hyaline membrane disease based on their symptoms and confirmed by chest radiograph and most were ventilated during the first 7 days with the exception of 2 infants in the PNS group in nasal CPAP by day 5 of life. The PNS group did have a milder respiratory course from birth as assessed by the mean peak inspiratory pressure and fractional inspiratory oxygen as shown in Fig 2.
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Weight Loss
There was no significant difference in the percentage of weight loss in both groups throughout each of the 7 days with a 15% ± 2 maximum weight loss in the PNS group and a 17% ± 1 in the NSG by day 7 (Fig 3).
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Fluid Intake (Fig 4)
The PNS group had a significantly higher urine output (P < .01) on days 1 and 2 with a similar fluid intake. The highest fluid intake in the PNS group occurred on day 6 (183 ± 10 mL/kg), whereas the highest in the NSG was 239 ± 15 mL/kg that occurred on day 4 (Fig 4; P < .01 at days 3, 4, 5, and 6). At the end of 7 days, the cumulative mean fluid intake was significantly lower in the PNS group (1175 ± 54 mL/kg/wk [PNS group] vs 1454 ± 94 mL/kg/wk [NSG]; P < .02) with no difference in cumulative mean urine output (663 ± 66 mL/kg/wk [PNS group] vs 681 ± 79 mL/kg/wk [NSG], P = ns). There was no difference between the groups in caloric intake, phlebotomy losses, and red blood cell transfusion (data not shown).
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Urine Output (Fig 4)
By 12 hours of postnatal age, urine output was >1.5 mL/kg/h in 15 out of 16 neonates in the PNS group, but none of the NSG infants. All of the NSG infants achieved this urine output only after the first 24 hours of life. The total urine output throughout the 7 days was not different between the groups (see above).
IWL (Fig 3)
Estimated IWL was quite variable among the infants during the first 7 days, however it gradually decreased in both groups. The estimated IWL was lower in the PNS group than the NSG during the entire study period, significantly lower for each of the first 4 days (P < .01). The highest estimated IWL occurred on day 1: 131 ± 14 mL/kg/d for the PNS group and 187 ± 15 mL/kg/d for the NSG (P < .01). There was no sudden decrease in estimated IWL in any of the infants after they were transferred from a radiant warmer to an incubator. We found no correlation between birth weight and estimated IWL.
Na Balance
The mean serum Na concentrations tended to be higher in the NSG
infants during the first 7 days after birth despite a higher fluid
intake, an equivalent urine output, and less Na intake (Fig
5). The mean serum Na was significantly
lower in the PNS group for the first 2 days after birth
(P < .01). The peak serum Na was also lower in the PNS
group (138 ± 1 mmol/L vs 144 ± 2 mmol/L; P < .01). Hypernatremia of >145 mmol/L occurred in 50% of the NSG and
25% of the PNS group (Fig 6).
Hypernatremia >150 mmol/L was seen in 36% of the NSG infants but in
none of the PNS group (P < .001). There was no
difference in the incidence of hyponatremia (Na < 130) between
the two groups. Two infants (14%) of each group had early (4th day
of life) hyponatremia and 4 infants in each group (30%) had late (day
5 to 7 of life) hyponatremia (Fig 6).
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The urinary Na excretion was highly variable in both groups and
followed no predictable pattern in conjunction with serum electrolytes.
The maximum urinary Na concentration observed was 162 mmol/L with a
concomitant serum Na of 155 mmol/L in the NSG. In comparison, the
maximum urinary Na concentration in the PNS group was 150 mmol/L during
a concomitant serum Na of 140 mmol/L. In both groups, the lowest
urinary Na concentration observed was 20 mmol/L (Fig 6). PNS infants
had a higher Na excretion (10 ± 2 mmol/kg vs 6 ± 1 mmol/kg;
P < .03) in the first 2 days of life. However, by 1 week of life, the PNS group had a less negative cumulative Na balance
(cumulative Na intake minus cumulative urinary Na output), 10 mmol/kg
vs 14 mmol/kg (Fig 5).
There was no statistical difference in either the daily Ccr or in the daily serum creatinine between the two groups. In both groups, the Ccr was initially low, doubled by day 3, and subsequently decreased to an intermediate level (Fig 7). The PNS group had a statistically significantly higher FeNa during the first 2 days postnatal life (P < .05; Fig 7).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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PNS have been shown to be of significant benefit to the ELBW preterm infant.3-14 In this report we identify another beneficial effect of PNS on salt and water balance. In this series, infants whose mothers received a full course of PNS had lower estimated IWL, lower incidence of hypernatremia, an earlier diuresis and natriuresis, and a lower fluid intake. The PNS group had a less negative Na balance with a similar Ccr compared with the NSG patients. These observations suggest that PNS resulted in a maturation of the skin epithelial barrier function as well as a maturation of postnatal fluid and electrolytes homeostasis.
The lower estimated IWL in the PNS group is likely to be secondary to a maturational effect in the skin epithelial barrier. Azterbaum et al13 have shown that daily prenatal administration of high doses of steroids accelerated the rate of maturation of the stratum corneum and diminished transepidermal water loss in rats. Okah et al14 confirmed these findings and further showed that PNS in prematurely born rats (using doses similar to those currently used in humans) accelerated maturation of the epidermal/peridermal complex resulting in less hydrated skin.
The lower estimated IWL in PNS infants may also be a result of differences in plasma oncotic pressure or in skin blood flow. These parameters were not measured in our study. In addition, differences in the humidification and subsequently, in the ambient water vapor pressures16 can have significant effects on IWL. We do not think this played a significant role in this study because all the infants were placed into the incubator around the same time of life and the humidification to the isolettes were similar between groups. However, our use of nonhumidified isolettes probably contributed to the large estimated IWL in our infants.
In contrast to other methods of fluid administration which use the day
of life or serum Na alone as the primary determinant, we used a fluid
strategy whereby body weight, urine output (fluid homeostasis) and
serum Na were the primary determinants for defining the volume of fluid
administration.21,23 Specifically, we targeted a weight
loss of 4% of birth weight per day (40 g/kg/d) by calculating
fluid balance two to three times daily and adjusted the fluid and Na
intake to help hit that target. In a previous study in larger preterm
infants 1500 g receiving standard fluid and electrolyte treatment,
the incidence of hypernatremia >145 mmol/L was 35% and more than 15%
had a serum Na >150 mmol/L (n = 266 infants; personal
communication Joseph D. DeCristofaro, Edmund F. La
Gamma).24 The infants in our current report are much smaller and the incidence of hypernatremia >145 mmol/L was
similar, 37% overall (25% of the PNS infants and 50% of the NSG
infants; P = ns). None of the PNS infants, but 36% of
the NSG, had serum Na >150 mmol/L (P < .001). We
interpret the lower incidence of hypernatremia in PNS infants to
indicate a smaller contraction of extracellular space that may be
secondary to the lower IWL and/or enhanced reabsorption of the fetal
lung fluid.
Lorenz et al21 described three phases of fluid and electrolyte homeostasis in ELBW infants: prediuretic, diuretic, and homeostatic phase. The major renal physiologic correlates of diuresis are natriuresis, increase in FeNa, and increased GFR.23 Our study infants showed a similar postnatal change in fluid and Na homeostasis but occurred more rapidly in PNS infants.
In addition to surfactant induction, PNS may contribute to improved respiratory function through earlier clearance of the fetal lung fluid. Indeed, the reabsorption of the fetal lung fluid is through the active transport of Na across the pulmonary epithelium.25-27 Na,K-ATPase provides energy for vectorial transport of fluid and electrolytes from the lumen to the perialveolar space across the alveolar membrane.28 In rabbit alveolar type II cells, involved in fluid reabsorption, Na,K-ATPase-mediated ion transport increases threefold postnatally.28 Celsi et al29 showed that glucocorticoids can up-regulate Na,K-ATPase mRNA expression in the immature mouse lung. An expanded extracellular fluid volume may result in inhibition of the birth-associated enhanced sympathetic activity30,31 would result in a decrease in renal vascular resistance32 and a concomitant increase in renal blood flow, FeNa, and urine output.21,31 This facilitates the excretion of the reabsorbed fetal lung fluid and prevents further expansion of the extrapulmonary extracellular space.21 Alternatively, PNS may have a direct effect on lowering the plasma catecholamines at birth.40
PNS also increases renal cell differentiation and maturation of the renal autoregulatory mechanisms resulting in an increase in the tubular excretory capacity to handle excess solutes.15 Thus, the kidney responds to the increased extracellular space by increasing Na excretion, leading to an earlier natriuresis, and lowering the extracellular fluid volume.33 Once a normal extracellular space is achieved, renal Na excretion decreases. Maturation of this response would result in a less negative Na balance. On the other hand, an up-regulation of tubular Na,K-ATPase expression leading to increased renal tubular function and increased renal Na reabsorption may also contribute to this less negative Na balance.29
The contribution of the angiotensin II and arginine vasopressin (AVP) systems must also be considered as a possible mechanism for the earlier diuresis and natriuresis observed in PNS infants. Ervin et al17 have shown that postnatal plasma angiotensin II and AVP are significantly lower in betamethasone-treated animals by ~3 hours of life. This was associated with a consistent increase in urine output and Na excretion in betamethasone-treated animals.17 They attributed the lower AVP in these animals to an improved cardiovascular status rather than a PNS-induced suppression of AVP secretion. Moreover, NSG infants in our report had low urine output with a high urine Na concentration in the first 2 days of life, consistent with a higher AVP level in these infants.
Wilkins34 has suggested that high osmolar excretion will lead to high urine flow. For example, if the maximum urine osmolality is 600 and the osmolar excretion rate is as high as 60 mOsm/kg/d, then a urine volume of at least 100 mL/kg/d is required to excrete this obligatory solute.34 Thus, we have used this relationship to generate a series of fluid isopleths that enable the calculation of a targeted urine output based on a desired Na excretion rate.22 Interestingly, we observed that the spot urine Na concentration does not exceed serum Na concentration suggesting that neonatal tubular function is limited in its capacity to excrete excess salt to levels at or around the serum Na concentration. Therefore, determination of an adequate fluid intake becomes entirely dependent on the calculated IWL plus minimum urine output as defined by renal solute load and the maximum excreting capacity which, in turn, is limited by the maximal urine concentration of solute.22
The postnatal changes in Ccr seen in our infants are consistent with those of previous studies.21,23,35,36 The tubular function of preterm infants is more immature than the glomerular function resulting in a higher urinary Na loss and a greater fractional Na excretion rate.26 Other groups have reported no effect of PNS on GFR.15,18,19,37,38 Animal studies using micropuncture technique found GFR to be higher in rats chronically treated with methylprednisolone.20,39 Additionally, fetal lambs injected with betamethasone also have a higher GFR than controls.39
We found a significant amount of hyponatremia in our patients. We speculate that this was a result of an excess of free water administration. We aggressively increased the fluid intake but failed to decrease it as rapidly once infants had reached the homeostatic phase.21 Since the completion of this study, our clinical practices have been altered where we now aggressively decrease the free water intake as aggressively as we increased it and our incidence of hyponatremia has decreased.
In summary, we conclude that PNS treatment results in clinically important changes in epithelial cell functions in the ELBW neonates directly effecting fluid homeostasis, salt, and water balance. Administration of PNS had no effect on GFR but the estimated IWL was lower (presumably as a result of earlier maturation of the skin as a barrier surface), with less hypernatremia, and lower overall fluid requirements.
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ACKNOWLEDGMENTS |
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We would like to acknowledge the professionalism of our neonatal intensive care unit nursing personnel for diligently, meticulously, and consistently measuring fluid balance as part of our routine medical management of extremely low birth weight neonates. We also thank Dr John Lorenz for his constructive criticism and review.
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FOOTNOTES |
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Received for publication Sep 2, 1998; accepted Mar 10, 1999.
Presented in part at the Society for Pediatric Research meeting; May 1995; San Diego, CA.
Address correspondence to Joseph D. DeCristofaro, MD, Department of Pediatrics, University Hospital and Medical Center, Stony Brook, NY 11794-8111. E-mail: jdecrist{at}mail.som.sunysb.edu
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ABBREVIATIONS |
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ELBW, extremely low birth weight; IWL, insensible water loss; PNS, prenatal steroids; GFR, glomerular filtration rate; Na, sodium; NSG, nonsteroid group; FeNa, fractional excretion of sodium; Ccr, creatinine clearance; AVP, arginine vasopressin.
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REFERENCES |
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This article has been cited by other articles:
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  G Dimitriou, V Kavvadia, M Marcou, and A Greenough Antenatal steroids and fluid balance in very low birthweight infants Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2005; 90(6): F509 - F513. [Abstract] [Full Text] [PDF]
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 M. P. Meyer, M. J. Payton, A. Salmon, C. Hutchinson, and A. de Klerk A Clinical Comparison of Radiant Warmer and Incubator Care for Preterm Infants From Birth to 1800 Grams Pediatrics, August 1, 2001; 108(2): 395 - 401. [Abstract] [Full Text] [PDF]
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 G. D. Sysyn, K. H. Petersson, C. S. Patlak, G. B. Sadowska, and B. S. Stonestreet Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R547 - R553. [Abstract] [Full Text] [PDF]
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S. A. Omar, J. D. DeCristofaro, B. I. Agarwal, and E. F. LaGamma Effect of Prenatal Steroids on Potassium Balance in Extremely Low Birth Weight Neonates Pediatrics, September 1, 2000; 106(3): 561 - 567. [Abstract] [Full Text]
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 J. D. Merrill and R. A. Ballard Clinical Use of Antenatal Corticosteroids: Benefits and Risks NeoReviews, May 1, 2000; 1(5): e91 - 98. [Full Text]
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