PEDIATRICS Vol. 106 No. 3 September 2000, pp. 561-567

Effect of Prenatal Steroids on Potassium Balance in Extremely Low Birth Weight Neonates

Said A. Omar, MD^*, , Joseph D. DeCristofaro, MD^§, Bajrang I. Agarwal, MD^¶, and Edmund F. LaGamma, MD

From the ^* Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan;  Sparrow Health System, Lansing, Michigan; ^§ Department of Pediatrics, University Hospital, Stony Brook, New York;  Department of Pediatrics, Westchester Medical Center, Valhalla, New York; and ^¶ Department of Pediatrics, Lawrence Hospital, Westchester, New York.

	ABSTRACT

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Objective.  Potassium is the most abundant intracellular cation and plays an important role in a variety of cell functions. Potassium homeostasis and regulation are important aspects of fluid and electrolyte homeostasis in extremely low birth weight (ELBW) infants. Because prenatal steroid (PNS) treatment promotes maturation of many epithelial cell systems, we sought to determine whether PNS affects potassium homeostasis in ELBW infants (<1000 g) during the first week of life.

Method.  Serum potassium (SK) concentration, potassium intake and output, and renal clearance were collected prospectively each day during the first week of life. Infants whose mothers received a full course of steroids before delivery (PNS group: n = 16) were compared with those infants whose mothers did not receive steroids (nonsteroid group [NSG]: n = 14). The decision to treat with PNS was made entirely by the obstetric staff in a nonrandomized manner. Potassium intake and excretion and serum and urine electrolytes were measured every 12 hours, and urine output was monitored every 2 to 3 hours. Hyperkalemia was defined as SK >6.5 mmol/L in a nonhemolyzed sample on at least 1 measurement from a central line.

Results.  There were no significant differences between the groups in gestational age, Apgar score, and birth weight. SK increased initially after birth in the absence of exogenous K intake in all infants, then subsequently decreased and stabilized by day 4 of life. The peak SK was significantly lower in the PNS group than in the NSG group (5.2 ± .2 mmol/L vs 6.2 ± .4 mmol/L). Moreover, the peak SK was higher than 6.5 mmol/L in 70% of the NSG infants and in none of the PNS group. Hyperkalemia occurred in the NSG infants within the first 2 days when urine output was significantly lower than in PNS infants. SK peaked in the absence of potassium intake with similar potassium excretion in both groups. PNS infants had similar cumulative potassium intake with a lower cumulative potassium excretion than did NSG infants. PNS infants had a significantly less negative potassium balance than did NSG infants by day 7 of life (1.0 mmol/kg vs 7.0 mmol/kg). There was no statistical difference in the daily serum creatinine levels, fractional excretion of potassium, and in the daily creatinine clearance between the 2 groups.

Conclusion.  We conclude that treatment with PNS prevents the nonoliguric hyperkalemia known to occur in ELBW neonates. We speculate that PNS induces upregulation of cell membrane sodium, potassium-adenosinetriphosphatase activity in the fetus. The differences in negative potassium balance may be accounted for by stabilization of cell membranes that may result in a decrease in potassium shift from intracellular to extracellular compartments.  Key words:  hyperkalemia, potassium balance, fluid homeostasis, prenatal steroids, creatinine clearance.

Potassium is the most abundant intracellular cation and plays an important role in a variety of cell functions. Potassium homeostasis and regulation are important aspects of fluid and electrolyte homeostasis in extremely low birth weight (ELBW) infants.¹ Nonoliguric hyperkalemia, defined as serum potassium (SK) >6.5 mmoL/L, affects 30% to 50% of very low birth weight infants in the absence of a decrease in urinary flow rate.^2-8 Hyperkalemia has been associated with cardiac arrhythmias, cerebral lesions, and death in ELBW infants.^3,4,9-11

Many investigators have examined mechanisms for hyperkalemia.^3,4,10 Primary renal causes have been implicated as well as potassium shifts from the intracellular to extracellular compartments.^2-4,10-12 Moreover, Stefano et al and others^7,12 have suggested that nonoliguric hyperkalemia is secondary to a decrease in sodium, potassium adenosinetriphosphatase (ATPase) activity.

Prenatal steroid (PNS) treatment promotes epithelial cellular differentiation and maturation of many organs systems resulting in a decreased incidence and severity of respiratory distress syndrome and reduces the incidence of intraventricular hemorrhage and necrotizing enterocolitis and decreases insensible water loss (IWL).^13-23 We have previously shown the effects of PNS treatment on sodium and water balance in ELBW infants.²⁴ The purpose of this study was to determine whether PNS affects potassium balance in ELBW infants (<1000 g) during the first week of life.

	METHODS

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Appropriate for gestational age infants weighing <1000 g at birth were cared for according to our standard protocols in the neonatal intensive care unit at University Hospital of Stony Brook, New York.^2,24,25 The data from infants admitted between July 1989 and July 1993 were collected prospectively and reviewed for accuracy retrospectively. The study was at a time before the 1995 National Institutes of Health consensus statement that recommended the use of PNS. Informed consent was deemed not necessary for this review, because all clinical protocols followed were current practice and standard of care on our clinical service.

Infants with major congenital anomalies, renal diseases, or incomplete laboratory data were excluded from review. Infants without respiratory distress syndrome or not requiring mechanical ventilation and infants without umbilical catheters were also excluded. The decision to treat mothers with a course of steroids was determined entirely by the obstetric service in a nonrandomized method. The maternal medical records were reviewed to confirm the steroid treatment. Infants were included in the PNS group if their mother was given 1 full course of dexamethasone (12 mg × 4 doses) or betamethasone (12 mg × 2 doses) within 7 days before delivery. The last dose must have been given at least 24 hours before delivery. Infants whose mother 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 course of the mothers was similar in both groups (Table 1). None of the infants received inotropic drugs or diuretic therapy in the first 7 days of life.

The infants were initially cared for under radiant warmers and then transferred to nonhumidified double-walled incubators after an initial period of stabilization. Infants were weighed on admission and every 12 hours for the first 7 days of life using the same bed scale. For consistency, birth weight was used for all calculations during the first week of life. Fluid intake and output, serum and urine electrolytes, and serum glucose and creatinine concentrations were measured approximately every 12 hours. Hyperkalemia was defined as SK >6.5 mmol/L on at least 1 nonhemolyzed sample from a central line. Serum osmolality was calculated as twice the serum sodium concentration plus serum glucose and blood urea nitrogen (BUN) in Système International units. 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 2 to 4 hours. Near the end of each collection period, the infant was observed for spontaneous voiding; the collection period ended with this void. The actual duration of the collection period and the volume of the collected urine were recorded. An aliquot of the collected urine was sent for chemical analysis. Any spilled urine was estimated by weighing the diaper as soon as possible after spontaneous voiding. Total urine output, calculated as the sum of the measured urine from the collecting device plus the spilled urine, was used for clearance calculations.

Initially, the administered fluids were electrolyte-free, and the volume of daily infusion was as previously reported.²⁴ The electrolytes were added to the intravenous fluid to maintain a normal plasma concentration of electrolytes. Potassium chloride was added to the intravenous fluid if SK was <5 mmol/L and urine output was >1 mL/kg/hour. Potassium output was calculated using the potassium concentration on spot urine samples obtained every 8 to 12 hours. Creatinine clearance (Ccr) as an index of glomerular filtration rate (GFR) and fractional excretion of potassium (FeK) were calculated daily using standard formulae. Daily weight, fluid intake, urine output, potassium intake and output, and the interval of urine 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 Wilcoxon signed-rank test if they were not. Repeated-measures data were compared by 2-way analysis of variance with repeated measures of 1 factor followed by multirange testing using the Newman-Keuls test where appropriate. All values are expressed as mean ± standard error of the mean (SEM) unless otherwise indicated. We used the Fisher exact test or ² test for comparisons of enumeration data between 2 groups.

	RESULTS

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A total of 35 infants weighing <1000 g at their birth were eligible for the review. Five infants were excluded: 3 infants had transient renal failure (2 in the NSG and 1 in the PNS group) and 2 SGA infants (1 infant in each group). These 3 infants were hemodynamically unstable, had transient renal failure, and required inotropic support to maintain their blood pressure. Potassium balance during the first week of postnatal life was compared in the remaining 30 patients. All infants received phototherapy during the entire first week of life and there was no difference in their peak serum bilirubin levels. There was no difference between the 2 groups in serum glucose and the blood pressures over the entire study,²⁴ and none of the study infants received inotropic support, diuretic therapy, or indomethacin during the first week of life. The blood pressure in our study infants is similar to the blood pressure that was reported by Hegyi et al²⁶ in premature infants with similar gestational age and birth weight. In contrast, Moïse et al²⁷ reported that antenatal steroids may decrease the need for blood pressure support in ELBW infants. Eight infants in the NSG and 4 infants in the PNS group were diagnosed with a hemodynamically clinically significant patent ductus arteriosus and were treated with indomethacin or ligation during the second week of life. Each of the infants was diagnosed with hyaline membrane disease based on symptoms and confirmed by chest radiograph. Most of the infants were ventilated throughout the first 7 days of life with the exception of 2 infants in the PNS group who were placed on nasal continuous positive airway pressure by day 5 of life. There was no significant difference between the groups in gestational age, birth weight, race, or sex (Table 2).²⁴ The estimated IWL was lower in the PNS group than in the NSG during the entire study, significantly lower for each of the first 4 days (P < .01).²⁴ Infants in the PNS group had a lower estimated IWL than did the NSG (134 ± 12 mL/kg vs 176 ± 20 mL/kg; P < .01) before SK peaked.

The change in SK had a similar pattern in both groups. SK first increased after birth in the absence of exogenous potassium intake and subsequently decreased and stabilized by day 4 of life in all infants (Fig 1). The peak SK was significantly lower in the PNS group 5.2 ± .2 mmol/L than in the NSG 6.2 ± .4 mmol/L (P < .05). SK was not significantly lower in the PNS than in the NSG infants at the first measurement at 12 hours of age (Fig 1). However, SK peaked earlier in the PNS infants (24 vs 36 hours of age). None of the PNS infants and 10 of the NSG infants had hyperkalemia, defined as peak SK >6.5 mmoL/L (0/16 [0%] vs 10/14 [70%]; P < .003). When hyperkalemia was defined as a SK >6.0 mmol/L, PNS infants had significantly lower incidence of hyperkalemia than did NSG infants (2/16 [12%] vs 11/14 [78%]; P < .04; Fig 2). SK peaked in the first 2 days of life in the absence of potassium intake with similar potassium excretion in both groups. The peak SK ranged from 6.7 mmol/L to 9.7 mmol/L in the 10 NSG infants with hyperkalemia. The duration of hyperkalemia ranged from 24 hours to 72 hours. Hyperkalemia lasted for 24 hours in 5 infants, 48 hours in 4 infants, and for 72 hours in 1 infant (Fig 2). Three of the NSG infants had electrocardiographic changes associated with hyperkalemia (peaked T waves or arrhythmia). Hyperkalemia was treated with glucose and insulin in these 3 infants. Exclusion of these infants from the analysis did not significantly affect the results. In 2 of these infants, SK started to decrease even before the insulin infusion was initiated.

View larger version (25K): [in this window] [in a new window]   Fig. 1.   SK (mmol/L), cumulative K intake, and excretion (mmol/kg) at the end of each day. Error bars represent SEMs. *P < .05 versus NSG.

View larger version (17K): [in this window] [in a new window]   Fig. 2.   All SK (mmol/L) measurements during each day of the first 7 days of life.

PNS infants had a significantly less negative cumulative potassium balance than did NSG infants (.9 ± .9 mmoL/kg vs 6.7 ± 2.5 mmoL/kg; P < .05) by day 7 of life (Fig 1). There was similar cumulative potassium intake but higher cumulative potassium excretion in NSG infants (P < .05; Fig 1). This higher potassium excretion was the result of a significant kaluresis in the NSG infants that started on day 4 of life and coincided with marked increase in urine output. In both groups, the urinary potassium excretion was highly variable and did not correlate with SK.

Total body potassium, urinary potassium excretion, and the intracellular-extracellular distribution of potassium are the dynamic forces that affect SK.²⁸ The factors that may affect distribution of potassium between intracellular and extracellular water compartments (internal potassium balance)^9-11,28-30 before SK peaked were examined (Table 3). The occurrence of low Apgar scores, glucose intake, arterial pH, and incidence or severity of intraventricular hemorrhage was similar between the 2 groups before peak SK. The calculated plasma osmolality was significantly lower in PNS than in NSG infants before the peak SK, which could be accounted for by a significantly lower serum sodium in the PNS infants (136 ± 1 mmol/L vs 144 ± 2 mmol/L; P < .01).²⁴

The factors that may influence external potassium balance^9-11,28-30 were examined before SK peak (Table 4). We found no difference between the groups in the percentage of daily weight loss, fluid intake, sodium intake, or sodium excretion. PNS infants had a higher daily urine output than did NSG infants before SK peak (56 ± 8 mL/kg/day vs 33 ± 4 mL/kg/day; P < .03) with no difference in potassium intake and excretion. Urine flow rate was not significantly different between the PNS and NSG infants at 72 hours to 7 days of age.²⁴ There was no difference between the 2 groups in the number or volume of packed erythrocyte transfusions before SK peaked, and there was no relationship between blood transfusion and SK peak in the hyperkalemic infants. In addition, there was no difference between the groups in Ccr, fractional excretion of sodium, FeK, and urine sodium to urine potassium ratio. PNS infants had a significantly lower BUN and BUN/creatinine ratio than did NSG infants.

The daily serum creatinine levels, FeK, and Ccr were not different between the 2 groups (Fig 3). In both groups, the Ccr was low initially, doubled by day 3, and subsequently decreased to an intermediate level (Fig 3).

View larger version (18K): [in this window] [in a new window]   Fig. 3.   FeK, serum creatinine (mmol/L), and Ccr (mL/minute). Error bars represent SEMs. *P < .05 versus NSG.

	DISCUSSION

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Previously we have shown that PNS treatment has a beneficial effect on sodium and water balance in ELBW infants during the first week of life.²⁴ PNS infants had a decreased IWL, early diuresis and natriuresis, less hypernatremia, and less negative sodium balance.²⁴ Our findings in this report indicated that PNS treatment has a significant effect in potassium balance in ELBW infants during the first week of life. Infants whose mothers received a full course of PNS had no hyperkalemia >6.5 mmol/L and a less negative potassium balance at the end of the first week of life. The PNS group had a similar Ccr as the NSG infants.

The postnatal changes in potassium homeostasis in our study infants are similar to the findings of Lorenz et al and others.^2,12 Also, Ervin et al³¹ have reported similar results to our findings and showed that PNS treatment was associated with lower SK in premature rats. Hyperkalemia in the absence of oliguria has been reported in 32% to 50% of very low birth weight and ELBW infants.^2-8 Indeed, despite our aggressive fluid management strategy, we still found nonoliguric hyperkalemia (SK: >6.5 mmol/L) in 37% of all infants. However, this occurred only in the NSG infants, who all had a lower urine output and had a similar weight loss and fluid intake compared with PNS infants. This is consistent with previous reports that showed an inverse relationship between SK concentration and urine flow rate in the first 2 days of life in low birth weight infants.^4,6,32 The decrease in urine output in the NSG infants does not explain the higher incidence of hyperkalemia because the cumulative potassium excretion in the first 3 days of life was similar in both groups.

The vulnerability of ELBW infants to hyperkalemia may be the result of at least 2 mechanisms. The first mechanism is a shift of potassium from the intracellular to extracellular space.^2,12 Such a shift could explain the postnatal rise in SK in most of the study infants in the absence of potassium intake. PNS helps to stabilize cell membranes and may help to prevent this shift.

A second mechanism for hyperkalemia is related to a limited renal potassium excretory capacity known to occur in ELBW infants because of the anatomic and functional immaturity of cortical collecting tubules.^3,33 This limited capacity is associated with low GFR and limited water and sodium delivery to the collecting tubules.^2,34 We found no difference in serum creatinine levels and Ccr, an assessment of glomerular function, between the PNS and NSG infants. Slotkin et al³⁵ reported similar results to ours, whereby prenatal dexamethasone given to pregnant rats had no effect on GFR in the offspring. The subsequent decrease in SK maybe accounted for by a decrease or cessation of intracellular to extracellular potassium shift coupled with a physiologic diuresis and natriuresis that leads to a marked kaluresis.^6,12,25

In the PNS infants the mobilization of potassium was uniform over the first 7 days of life. The NSG infants had a similar trend in the first 3 days but potassium excretion increased by day 4 of life and was associated with marked diuresis and ultimately a more negative potassium balance by day 7 of life. This increase in potassium excretion may be attributable to a greater potassium load moving from the intracellular to the extracellular compartment in NSG infants. Increased potassium delivery to the kidney would result in an increase in potassium excretion in these infants. Kaluresis was observed even if SK was low. This necessitated potassium supplementation to avoid hypokalemia. Potassium stabilized with the cessation of kaluresis and homeostasis was achieved where potassium intake approximates potassium excretion.

Sato et al⁵ and Stefano et al⁷ have suggested that the difference in the magnitude of the internal potassium shift may be related to differences in cell membrane sodium, potassium-ATPase activity. In addition, Stefano et al⁷ showed that sodium, potassium-ATPase activity from erythrocyte membranes was lower in hyperkalemic than in normokalemic ELBW infants. Moreover, several studies have shown that antenatal or postnatal administration of glucocorticoids in a rat model accelerated sodium, potassium-ATPase expression and maturation in multiple organs including the lung, heart, and renal cortex.^36-38 We speculate that PNS infants had no hyperkalemia attributable to upregulation of sodium, potassium-ATPase activity with stabilization of cell membrane and a decrease in intracellular to extracellular potassium shift.

The factors that may affect internal potassium balance were examined in both groups (Table 3). Gestational age is inversely related to the magnitude of intracellular to extracellular potassium shift.^5,12 However, we found no difference in the gestational age between PNS and NSG infants. Potassium is predominantly an intracellular cation and factors that cause cations to move out of the cells, such as acidosis, will result in increased SK concentration. The effect of metabolic acidosis on potassium balance also depends on the duration of acidosis.²⁸ The change in SK concentration per unit change in pH is initially very small but increases progressively with time. In addition changes in external potassium balance may influence the magnitude of the effect of acid-base balance disturbance on SK concentration. Persistence of metabolic acidosis can lead to an increase in the delivery of fluid to the distal tubules and can lead ultimately to renal potassium loss and hypokalemia.²⁸ In contrast, Santos and Chan³⁹ reported normokalemia or hyperkalemia rather than hypokalemia in children with renal tubular acidosis. Previous studies have suggested that neonatal hyperkalemia may occur in sick newborn infants with metabolic acidosis.^4,6 In this report, arterial pH was not different between the PNS and NSG infants before SK peak. There was no evidence of asphyxia, increased tissue damage, or continuing acidosis among the infants in either group. In addition, there was no difference in erythrocyte transfusions received by the infants in either group. It is also evident from our findings and other prospective studies that intracranial hemorrhage in very low birth weight infants is not necessarily related to the occurrence of hyperkalemia.^2,3,7,30,32 A moderate increase in serum osmolality can cause a moderate rise in SK in normal adults.²⁸ This is thought to be attributable to the osmotic shift of water out of cells resulting in an increase of intracellular potassium concentration that will then tend to shift outward.²⁸ Serum osmolality was not measured in our infants, but serum sodium is a major determinant of serum osmolality and can be used to calculate serum osmolality. The peak serum sodium and the calculated peak serum osmolality were significantly higher in NSG than in PNS infants. We doubt that hyperkalemia was related to hypernatremia or hyperosmolality because we found no correlation between the change in SK from the first value to the peak value and the change in serum sodium or serum osmolality in the same interval in either group. A glucose-induced hyperkalemia is reportedly attributable to a combination of hypertonicity and insulin deficiency, with a potassium efflux from the cells.²⁸ However, glucose intake was no different between NSG and PNS infants.

Plasma levels of catecholamine, aldosterone, atrial natriurtic factor, and renin, which can affect potassium balance,^28,34,40 were not measured in this study. Previous studies have reported that plasma concentrations of these hormones were not different between the normokalemic and hyperkalemic infants.^6,7,40

There was no difference in the factors that affect external potassium balance between the PNS and NSG infants (Table 4). The infants in both groups had a similar amount of potassium intake and excretion before SK peaked. This suggested that in the PNS infants mobilization of potassium and its excretion into the urine began before birth or that there was less potassium shift from the intracellular to extracellular space or both. The first possibility cannot be excluded because SK was lower in PNS infants by 12 hours of age. The high BUN level and BUN/creatinine ratio and a higher IWL (176 ± 20 vs 134 mL/kg ± 12 mL/kg; P < .01) before SK peaked suggests that extracellular volume may be contracted in NSG infants. However, there was no significant difference in weight loss between groups.²⁴ Other studies have shown that ELBW infants with nonoliguric hyperkalemia have azotemia, a condition that can result from a catabolic state with cellular breakdown and loss of potassium into the extracellular space.^3,4,7,10 However, Stefano and Norman⁸ have shown that catabolism is unlikely to contribute to the development of nonoliguric hyperkalemia in ELBW infants.

There are important clinical implications of this study in fluid and electrolyte management of ELBW infants. Hyperkalemia is a frequent complication in ELBW infants during the first 2 days of life and is more likely to occur in infants whose mothers receive PNS. Early and frequent monitoring of SK is important for detecting and treating hyperkalemia. PNS can prevent nonoliguric hyperkalemia in ELBW infants, a life-threatening electrolyte imbalance.

	ACKNOWLEDGMENTS

We acknowledge the professionalism of our neonatal intensive care unit nursing personnel for diligently, meticulously, and consistently measuring fluid and electrolyte balance as part of our routine medical management of ELBW neonates.

We thank Dr John Lorenz for his constructive criticism during the preparation of this review.

	FOOTNOTES

Received for publication Apr 13, 1999; accepted Dec 22, 1999.

This work was presented, in part, at the Society for Pediatric Research meeting; May 1-5, 1998; New Orleans, LA.

Reprint requests to (S.A.O.) Sparrow Hospital, Neonatology, 1215 E Michigan Ave, Lansing, MI 48909-7980. E-mail: omar{at}pilot.msu.edu

	ABBREVIATIONS

ELBW, extremely low birth weight; SK, serum potassium; ATPase, adenosinetriphosphatase; PNS, prenatal steroid; IWL, insensible water loss; NSG, nonsteroid group; BUN, blood urea nitrogen; Ccr, creatinine clearance; GFR, glomerular filtration rate; FeK, fractional excretion of potassium; SEM, standard error of the mean.

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