Leonard I. Kleinman

Water balance in very low-birth-weight infants: Relationship to water and sodium intake and effect on outcome

The clinical effects of fluid therapy designed to maintain different degrees of negative water balance during the first five days of life were determined prospectively in 88 very low-birth-weight infants. Infants with birth weights of 750 to 1,500 gm were matched for birth weight in 250 gm increments. RDS or no RDS, asphyxiated or not, and inborn or outborn. Each infant was randomized to either Group 1--fluids managed to allow 1 to 2% loss of BW per day to a maximum loss of 8 to 10%, or Group 2--fluids managed to allow 3 to 5% loss of BW per day to a maximum loss of 13 to 15%. The mean five-day cumulative fluid input in Group 2 was 220 ml/kg less than in Group 1, yet Group 2 lost only 41 gm/kg more than did Group 1 (8.8% of BW lost in Group 1 vs 12.9% of BW lost in Group 2, P less than 0.001). There were no statistically significant differences between the groups in incidence of clinically significant patent ductus arteriosus, intracranial hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, dehydration, acute renal failure, or metabolic disturbances. There was no difference in duration of respiratory support required, in time to regain BW, or in time to discharge. There was no difference in the neonatal mortality rate. Fluid input in VLBW infants can be flexible to allow the gradual loss of 5 to 15% of birth weight during the first week of life without adversely affecting outcome.

Possible pathogenetic factors in neonatal hypocalcemia of prematurity. The role of gestation, hyperphosphatemia, hypomagnesemia, urinary calcium loss, and parathormone responsiveness

Seventy-three premature and full-term infants were studied to determine the importance of gestational age, hyperphosphatemia, hypomagnesemia, increased urinary calcium losses, and parathormone responsiveness in the pathogenesis of neonatal hypocalcemia. Serum calcium values from 12 to 72 hours of age were significantly correlated with gestational age. Birth asphyxia and hyperphosphatemia at birth were associated with subsequent hypocalcemia. Serum calcium levels were unrelated to hypomagnesemia and urinary calcium losses. Significant calcemic responses to parathormone were elicited in 24 premature infants. This calcemic response was not related to gestational age or birth asphyxia but was more marked when serum calcium concentrations were lower. The study suggests that neonatal hypocalcemia results from functionally immature or suppressed parathyroids that are unable to maintain normocalcemia in the presence of hyperphosphatemia.

Hypocalcemia in infants of diabetic mothers: Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness

Since infants of diabetic mothers are often delivered prematurely, it has been uncertain whether the hypocalcemia reported in them is related to maternal diabetes or to prematurity. In this study of 28 infants of diabetic mothers and 28 prospectively matched infants born to nondiabetic mothers, the incidence of hypocalcemia was significantly increased in the infants of diabetic mothers, even when gestational age and perinatal complications were taken into consideration. Renal studies demonstrated no differences in excretion of calcium, magnesium, and phosphorus between infants of diabetic mothers and control infants. Serum calcium levels were higher in diabetic mothers than in nondiabetic control subjects. Lower serum calcium levels and higher serum phosphate levels were present in infants of diabetic mothers postnatally. End organ responsiveness was shown by a calcemic and phosphaturic response to exogenous parathormone. It is speculated that relative maternal hyperparathyroidism leading to fetal hypoparathyroidism may be a factor in the pathogenesis of neonatal hypocalcemia in infants of diabetic mothers.

Potassium metabolism in extremely low birth weight infants in the first week of life

OBJECTIVE Nonoliguric hyperkalemia has been reported to occur in the first week of life in as many as 50% of extremely low birth weight (ELBW) infants. We studied potassium balance and renal function in the first 5 days of life to characterize potassium metabolism during the three phases of fluid and electrolyte homeostasis that we have described in ELBW infants and to elucidate the factors that contribute to the development of nonoliguric hyperkalemia. STUDY DESIGN Plasma potassium concentration (PK), potassium intake and output, and renal clearances were obtained for the first 6 days of life in 31 infants with a birth weight of 1000 gm or less. Collection periods in which urine flow rate was greater than or equal to 3 ml/kg per hour and weight loss was greater than or equal to 0.8 gm/kg per hour were denoted to be diuretic. Prediuresis includes all collection periods before the first diuretic period; diuresis includes all collection periods between the first and last diuretic periods; postdiuresis includes all collection periods after the last diuretic period. Infants with a PK greater than 6.7 mmol/L on at least one measurement were denoted to have hyperkalemia. RESULTS PK increased initially after birth--despite the absence of potassium intake- and then decreased and stabilized by the fourth day of life. Diuresis occurred in 27 of 31 infants. The age at which PK peaked was closely related to the onset of diuresis. PK decreased significantly during diuresis as the result of a more negative potassium balance, despite a significant increase in potassium intake. In fact, PK fell to less than 4 mmol/L in 13 of 27 infants during diuresis. After the cessation of diuresis, potassium excretion decreased even though there was a significant increase in potassium intake, potassium balance was zero, and PK stabilized. Hyperkalemia developed in 11 of 31 infants. The pattern of change in PK with age was similar in infants with normokalemia and hyperkalemia: PK initially increased (essentially in the absence of potassium intake) and then decreased and stabilized by the fourth day of life. However, the rise in PK after birth was greater in infants with hyperkalemia than in those with normokalemia: 0.7 +/- 0.2 versus 1.8 +/- 0.2 mmol/L (p < 0.001). No differences in fluid and electrolyte homeostasis or renal function were identified as associated with hyperkalemia. CONCLUSIONS PK increases in most ELBW infants in the first few days after birth as a result of a shift of potassium from the intracellular to the extracellular compartment. The increase in the glomerular filtration rate and in the fractional excretion of sodium, with the onset of diuresis, facilitates potassium excretion, and PK almost invariably decreases. Hyperkalemia seems to be principally the result of a greater intracellular to extracellular potassium shift immediately after birth in some ELBW infants.

Factors affecting the maturation of glomerular filtration rate and renal plasma flow in the new‐born dog

1. The maturation of glomerular filtration rate was studied by comparison of thirty‐six new‐born mongrel dogs aged 1–35 days with six adult dogs.

Maturation of glomerular blood flow distribution in the new‐born dog

1. Glomerular blood flow distribution was studied in seventy‐eight new‐born mongrel dogs aged 1–40 days by measuring the distribution of radioactive labelled microspheres within the kidney.

Serum anion gap in the differential diagnosis of metabolic acidosis in critically ill newborns

OBJECTIVES To determine in critically ill newborn infants (1) the range of the serum anion gap without metabolic acidosis and (2) whether the serum anion gap can be used to distinguish newborns with lactic acidosis from those with hyperchloremic metabolic acidosis. STUDY DESIGN Umbilical arterial blood gases and serum electrolyte and lactate concentrations were measured simultaneously in 210 samples from 63 infants over the first week of life. Metabolic acidosis was defined as a blood base deficit (BD) >4 mmol/L. The anion gap was calculated as [Na(+)] - [C1(-)] - [TCO (2)]. Lactic acidosis was defined as a serum lactate concentration >2 SD above the mean serum lactate concentration in samples without metabolic acidosis. RESULTS In 89 blood samples with BD <4 mmol/L, serum lactate concentration decreased with postnatal age (r = 0.51). The upper limit of serum lactate concentration was 3.8 mmol/L at less than 48 hours, 2.4 mmol/L between 48 and 96 hours, and 1.5 mmol/L for infants greater than 96 hours of age. The mean serum anion gap +/- 2 SD in 174 samples without lactic acidosis was 8 +/- 4 mmol/L; in 36 samples with lactic acidosis it was 16 +/- 9 mmol/L (P <.0001). Serum anion gap and lactate concentration were poorly correlated for samples without lactic acidosis (r = 0.04) but highly correlated in those with lactic acidosis (r = 0.81, P <.0001). None of the 85 samples with metabolic acidosis but without lactic acidosis had an anion gap >16 mmol/L; only 4 of 36 samples with lactic acidosis had an anion gap <8 meq/L. However, 25 of 36 samples with lactic acidosis had serum anion gaps of 8 to 16 mmol/L. CONCLUSION In the presence of metabolic acidosis, a serum anion gap >16 mmol/L is highly predictive of lactic acidosis; a serum anion gap <8 is highly predictive of the absence of lactic acidosis; an anion gap = 8 - 16 mmol/L has no use in the differential diagnosis of metabolic acidosis in the critically ill newborn.

Segmental Nephron Sodium and Potassium Reabsorption in Newborn and Adult Dogs during Saline Expansion

Abstract Studies were carried out in 23 anesthetized neonatal dogs aged 2 to 20 days and in 16 adult dogs to compare the effects of saline volume expansion on renal tubular Na and K reabsorption between newborn and adult animals. Proximal- and distal-tubule function was estimated by the distal-nephron-blockade technique using ethacrynic acid and amiloride. During saline infusion, which increased extracellular volume by approximately 30% for both age groups, total nephron fractional Na reabsorption was 0.91 for the adult but 0.98 for the puppy (P < 0.01). However, proximal tubule fractional Na reabsorption was greater in the adult (0.64) than in the puppy (0.48, P < 0.01) whereas distal nephron fractional Na reabsorption was much greater in the newborn (0.51) than in the adult (0.26, P < 0.01). Sodium reabsorption normalized to kidney weight was lower in all segments of the neonatal kidney than in the adult kidney. The filtered sodium load was lower in the newborn (27.0 μeq min–1g–1) than in the adult (105.0, P < 0.01), and the Na load to the distal nephron was also lower in the newborn (14.0 μeq min–1g–1) than in the adult (37.2, P < 0.01). Fractional K excretion was similar in both age groups even though the fraction of filtered K escaping proximal-tubule reabsorption was greater in the newborn than in the adult, indicating greater net K fractional reabsorption in the distal nephron of the newborn than in the adult kidney. These results indicate that in response to saline expansion there is a greater proximal tubule natriuresis in the neonate than in the adult but overall renal Na excretion is less in the newborn animal due to enhanced fractional Na reabsorption in the neonatal distal nephron, particularly in Henles Loop.

Cerebrovascular hemodynamics during and after recovery from acute asphyxia in the newborn dog.

ABSTRACT: Cerebrovascular volume and transmural pressure loads accompanying acute increases in cerebral blood flow are implicated in the pathogenesis of periventricular-intraventricular hemorrhage in preterm infants. An acute increase in cerebral blood flow would be expected during acute recovery from asphyxia. Therefore, cerebrovascular hemodynamics, including flow (microspheres), were studied during and after acute recovery from asphyxia in seven newborn dogs in order to study the determinants of these volume and pressure loads. During the acute recovery phase, cerebral hemispheric blood flow was 69.6 ± 10 ml/100 g/min (mean ± SEM) representing a 250% increase from baseline values of 19.9 ± 1.8 ml/100 g/min (p < 0.005), while combined cerebellar-brainstem flow was 204.3 ± 19.3 ml/100 g/min representing a 536% increase from baseline values of 32.0 ± 1.5 ml/100 g/min (p < 0.005). Blood flow to both areas had returned to baseline levels 20 min after the onset of recovery. Associated with this cerebral hyperemia was an acute increase in mean arterial pressure from 21.3 ± 4.5 mm Hg at end asphyxia to 69.5 ± 6.0 mm Hg at peak recovery (p < 0.01), and parallel acute increases in sagittal sinus pressure (from 4.0 ± 0.4 to 14.6 ± 1.9 mm Hg, p ±.01) and cerebrospinal fluid pressure (from 3.8 ± 0.4 to 14.3 ± mm Hg, p <1). Central venous pressure fell from 4.3 ± 6 mm Hg at end asphyxia to 1.6 ± 0.5 mm Hg, and thus is not a determinant of the elevation in sagittal sinus pressure. AH of these pressure changes were attained within 20–30 s of the onset of recovery. Assuming that acute changes in cerebrospinal fluid pressure reflect acute changes in cerebrovascular volume via the cranial compliance (volume/pressure) relationship, then the acute (<30s) elevation of cerebrospinal fluid pressure reflects an acute cerebrovascular volume load. Also, the elevated cerebrospinal fluid pressure considerably modifies both the cerebral arterial and venous transmural pressures. The cranial compliance relationship thus plays a key role in determining both volume and transmural pressure loads. We propose that the combination of a high cranial compliance and frequent acute cerebral flow/volume loads may be involved in the pathogenesis of periventricular-intraventricular hemorrhage in premature newborn infants.

The effect of metabolic acidosis upon autoregulation of cerebral blood flow in newborn dogs

The radioactive microsphere technique was used in 13 newborn dogs to determine the effect of a metabolic (lactic)acidosis upon cardiac output (CO), cerebral blood flow (CBF), and autoregulation of cerebral blood flow. The animals were mechanically ventilated with supplemental oxygen to ensure normocarbia and hyperoxia throughout the experiments. Baseline cardiac output and cerebral blood flow measurements were made, followed by a lactic acid infusion to maintain pH less than 7.25. Metabolic acidosis produced a 27% fall in cardiac output and no change in cerebral blood flow (19 ml/100 g/min). Autoregulation was tested in 6 of the acidemic puppies by acute volume depletion to reduce blood pressure by 30% of baseline, followed by rapid volume re-expansion of the withdrawn blood. With volume depletion, CO decreased by 38%, and with volume re-expansion CO returned to baseline. The CBF remained at baseline levels with volume depletion but was slightly increased after rapid volume re-expansion. Five acidemic controls maintained CO and CBF constant with time. Thus cerebral autoregulation is preserved in the newborn dogs during metabolic acidosis, although cerebral blood flow was slightly increased following volume re-expansion.