Richard M. Cowett

Persistent Glucose Production during Glucose Infusion in the Neonate

In adults, glucose infusion results in a decreased glucose production rate (GPR) as a mechanism for maintaining euglycemia. To document the development of glucose homeostasis, we derived the GPR in 23 preterm appropriate for gestational age infants, 14 term appropriate for gestational age infants, and in 6 adults. After a 3-h fast, the average plasma glucose and insulin concentration was measured and the GPR was derived. During glucose infusion (5.6 +/- 0.3 mg X kg-1 min-1), compared with saline controls, the preterms had a rise in plasma glucose and plasma insulin, and the GPR was 1.4 mg X kg-1 min-1 (range, 0-4.4) vs. 3.0 mg X kg-1 min-1 (range, 1.8-4.1) (saline controls). In the term infants, only the plasma insulin concentration was elevated when the glucose infused (5.7 +/- 0.3 mg X kg-1 min-1) infants were compared with the saline controls and GPR was 0.4 X kg-1 min-1 (range, 0-2.6) vs. 3.4 mg X kg-1 min-1 (range, 2.8-5.7) (saline controls). In comparison to saline infused adults, glucose infusion (3.2 +/- 0.1 mg X kg-1 min-1) resulted in a significant rise in plasma glucose and in plasma insulin; and the GPR was reduced to 0.1 mg X kg-1 min-1 (range, 0-0.3) from 2.0 mg X kg-1 min-1 (range, 1.5-2.4). 5 of 13 preterms and 2 of 7 term infants had persistent GPR during glucose infusion; in contrast, the GPR in all adults was unmeasurable. There was no correlation between the plasma glucose concentration and the GPR in the newborn or in the adult. Both newborns and adults did have a correlation between plasma insulin concentration and the GPR; however, there was considerable variability in the neonate. We conclude that there are significant developmental differences in neonatal glucose homeostasis and that insulin is important in neonatal hormonal control of glucose production.

Hypertrophic cardiomyopathy associated with dexamethasone therapy for bronchopulmonary dysplasia

The potential induction of cardiac effects by high-dose dexamethasone therapy was evaluated prospectively in 13 respirator-dependent infants with bronchopulmonary dysplasia by means of two-dimensional and M-mode echocardiography. The initial divided dose of dexamethasone was 500 micrograms/kg per day, tapered progressively for as long as 6 weeks. Evaluations were made before treatment and at 3, 7, 14, 21, 28, 35, and 42 days after the start of dexamethasone therapy. This regimen was associated with a significant (p less than 0.01) increase in thickness of the interventricular septum (2.60 +/- 0.09 to 4.00 +/- 0.16 mm), diastolic left ventricular free wall (2.80 +/- 0.13 to 4.06 +/- 0.20 mm), and diastolic right ventricular free wall (1.55 +/- 0.08 to 2.02 +/- 0.12 mm). In addition, seven dexamethasone-treated infants but no control infants had systolic anterior motion of the mitral valve (p less than 0.001). These effects were transient, reached their maximal degree by the third week of treatment, and approached pretreatment conditions by the sixth week of treatment. Ejection fraction was not affected; heart rate and mean arterial pressure were transiently increased during dexamethasone therapy. We conclude that a transient absolute myocardial hypertrophy is associated with dexamethasone therapy in infants with bronchopulmonary dysplasia. The mechanism or mechanisms through which this hypertrophy arises and the cardiopulmonary implications are unclear.

Renal functions of low birth weight infants during the first two months of life.

Summary: A postnatal contraction of extracellular fluid occurs in low birth weight infants. Patterns of postnatal renal maturation were assessed with the assumption that changes in body composition were mediated in part by the developing kidney. Twenty-two appropriate for gestational age, low birth weight infants (birth weight mean = 1380 g, gestational age mean 31 weeks) were studied between 12 hr and 61 days of age to evaluate simultaneously glomerular and tubular functional maturation. Since most low birth weight infants have respiratory morbidities (respiratory distress followed by chronic lung disease), the infants were grouped into: group I (13 infants), transient or absent respiratory morbidities; and group II (9 infants), persistent and severe respiratory morbidities. Sodium excretion decreased with postnatal age in both groups. Sodium intake did not vary with postnatal age. The percentage of fractional sodium excretion was inversely related to postnatal age. Creatinine clearance correlated directly with postnatal age in both groups. Increased sodium excretion and percentage of fractional sodium excretion in the first 10 days of life may reflect extracellular fluid solute losses through the kidney. The premature kidney matured in a balanced fashion and persistent respiratory morbidities did not alter this pattern.Speculation: The kidney of low birth weight infants probably plays an important role in the regulation of body fluid during the first week of life. The adjustment in renal tubular handling of sodium with greater sodium loss in the first days reflects its compensation to fit the demand of greater sodium excretion from the contraction of the extracellular fluid compartment. In an infant with a stable circulatory status, the presence of respiratory complications did not influence this adjustment process.

Neonatal Morbidities in Infants of Mothers with Glucose Intolerance in Pregnancy

Of 1839 pregnant women screened prospectively, 52 were identified to have glucose intolerance. Ten additional pregnant women identified as having glucose intolerance before the universal screening were also included in the study cohort. These 62 patients were followed in a perinatal high-risk clinic with weekly plasma glucose determinations. The patients were treated with diet and, in addition, 21 of 62 were treated with insulin therapeutically. By observational cohort design, the infants and a comparable number of matched controls were evaluated for evidence of neonatal morbidities and classified into percentile for birth weight. Compared with the control group, the operative mode of delivery, the mean birth weight, the birthweight percentile, the male/female ratio, the frequency of low Apgar score (≤ 6 at 1 min), and the number of infants with congenital anomalies were significantly higher in the infants born to the glucose-intolerant mothers. Although the mean maternal blood sugar was maintained within a reasonably euglycemic range, the usual neonatal morbidities were not eliminated entirely. Further understanding and management of glucose intolerance in pregnancy is necessary to further diminish or eliminate neonatal morbidities.

The Infant of the Diabetic Mother

Although there has been continuing improvement in outcome for infants born to diabetic mothers, they remain a high-risk population needing expert neonatal supervision preceded by meticulous medical-obstetric care. This article evaluates many of the difficulties that the infant of the diabetic mother may encounter, analyzes the pathophysiologic basis for their occurrence, and outlines specific rationale for treatment.

Effect of intrauterine growth retardation on postnatal weight change in preterm infants

To investigate the cause or causes of early postnatal weight change, we measured total body water and fluid and energy balances in 14 preterm infants who were appropriate in size for gestational age (AGA) and in 5 weight-matched, preterm, small-for-gestational-age (SGA) infants. On the first day of life, AGA and SGA infants had the same weight and total body water content. At 6 +/- 2 days (mean +/- SD), AGA infants had had significant weight loss (94 +/- 45 gm) and body water loss (67 +/- 80 ml), whereas weight and total body water content in the SGA infants at the same age (5 +/- 1 days) did not differ from the values at birth. Loss of weight and total body water in AGA infants was accompanied by a greater diuresis than in SGA infants at the same amount of fluid intake. At the end of week 1, AGA and SGA infants had the same total energy expenditure (184 +/- 33 vs 171 +/- 17 kJ.kg-1 x day-1); energy intake, which had exceeded total energy expenditure from the third day of life and beyond, already provided 188 +/- 46 (AGA) or 209 +/- 109 kJ.kg-1 x day-1 (SGA), respectively, for energy storage. Nitrogen balance was positive. Subsequent weight gain occurred at the same rate in AGA and SGA infants; both total body water and solids increased. Energy intake, total energy expenditure, and the amount of energy stored (measured during stable weight gain on a regimen of full enteral feedings) had significantly increased compared with week 1, but both groups maintained similar energy storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose kinetics in infants of diabetic mothers.

Glucose kinetic studies were performed to define the glucose turnover rate with 78% enriched D-[U-13C] glucose by the prime constant infusion technique at less than or equal to 6 hours of age in nine infants of diabetic mothers (four insulin-dependent and five chemical diabetic patients) at term. Five normal infants were studied as control subjects. All infants received 0.9% saline intravenously during the study with the tracer. Fasting plasma glucose, insulin, and glucose13/12C ratios were measured during the steady state, and the glucose turnover rate was derived. The average plasma glucose concentration was similar during the steady state in the infants of the diabetic mothers and in the control infants, and the glucose turnover rate was not significantly different among the groups: 2.3 +/- 0.6 mg . kg-1 min-1 in infants of insulin-dependent diabetic patients; 2.4 +/- 0.4 mg . kg-1 min-1 in infants of chemical diabetic patients; and 3.2 +/- 0.3 mg . kg-1 min-1 in the control subjects. Good control of maternal diabetes evidenced by the normal maternal hemoglobin A1c and plasma glucose concentration at delivery and cord plasma glucose concentration resulted in glucose kinetic values in the infants of diabetic mothers that were indistinguishable from those of control subjects. The data further support the importance of good control of the diabetic state in the pregnant woman to minimize or prevent neonatal hypoglycemia.

Endogenous glucose production during constant glucose infusion in the newborn lamb.

Summary: Prompt diminution of endogenous hepatic glucose production is characteristic of the mature (adult) response to exogenous glucose infusion. We have tested the validity of this hypothesis in the neonatal period in 26 unanesthetized mixed breed term lambs and for comparison in eight 4− to 5-month-old mixed breed sheep. After a 7-hr fast, basal plasma glucose, insulin, and glucagon concentrations were determined following which the term lambs received either no glucose or 5.7, 11.7, or 21.7 mg glucose/kg/min over a period of 6 hr, and the 5-month-old sheep received either none or 5.7 mg glucose/kg/min. Glucose turnover was determined by the prime-constant infusion technique of Steele using 3H6 radiolabeled glucose during a 50-min turnover period which followed the 6-hr infusion of 0.45% saline or varying doses of glucose following the onset of fasting by 14 hr. Both newborn and adult animals maintained a constant plasma glucose concentration and glucose specific activity during the turnover period. Endogenous glucose production persisted in the term lamb until the exogenous glucose infusion reached the rate of 21.7 mg/kg/min. In contrast, the adult lambs reduced their endogenous glucose production with an exogenous glucose infusion rate of 5.7 mg/kg/min. At the time the endogenous glucose production rates were significantly reduced, the plasma insulin level in the newborn lamb was 5-fold greater than that of the adult sheep.Under steady state conditions of plasma glucose concentration and glucose specific activity, our data suggest that there is imprecise control of endogenous glucose production in the newborn lamb in contrast to the older sheep of 4–5 months of age. The absence of precise control may be due to decreased hepatic sensitivity for insulin.

Glycemic response to lipid infusion in the premature neonate.

The effect of lipid infusion on glucose homeostasis in the preterm newborn infant was evaluated. Seven infants were given a test dose of 0.25 gm/kg/hour of lipid emulsion. Their response was characterized by :(1) a two fold increase in serum free fatty acid concentrations, (2) a small, transient rise in insulin values, and (3) a sustained increase in serum glucose concentration (mean increment in serum glucose was 24% over baseline). Nine infants received a test dose of 0.5 gm/kg/hr of lipid. Their response was similar to that in the lower infusion group, but of a greater magnitude: an eightfold increase in free fatty acids, sustained increase in serum insulin concentration, and a mean increment in serum glucose values of 65% over baseline. Increased lipid availability in the low-birth-weight newborn infant plays a significant role in promoting an increase in serum glucose concentrations.

Aberrations in Sucking Behavior of Low-birthweight Infants

The purpose of this study was to determine (1) if infants of low birthweight who had been severely stressed during the perinatal‐neonatal period had aberrant sucking behavior in contrast to low‐birthweight infants who had been mildly stressed during the same period; (2) if the mildly‐stressed infants had patterns of sucking behavior similar to infants born at term without complications; and (3) if sucking behavior at the time of discharge from hospital would differentiate those infants who showed aberrant neurological findings at one year of age.