John R. Raye

Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures

There is controversy in the literature regarding the prognostic value of the EEG following neonatal seizures. This report reviews the results of a prospective study comparing EEG findings and outcome in 74 term and preterm infants following neonatal seizures. EEGs were evaluated for both background rhythms and epileptiform activity. Outcome was evaluated at an average age of 33 months. Background rhythms were highly correlated with outcome. Low voltage, electrocerebral inactivity and burst suppression EEGs were associated with poor outcomes while normal EEGs were associated with favorable outcomes. Slow, maturationally delayed and asymmetrical EEGs were associated with variable outcomes. The presence of epileptiform activity on the EEG was correlated with adverse outcomes but was not as highly significant as background rhythms. Electroencephalographic seizures, whether associated with clinical manifestations or not, were highly correlated with poor outcomes. The significance of these EEG findings was similar in both term and preterm infants. The study demonstrates that the EEG is predictive of outcome following neonatal seizures.

Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus.

Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (11.9 +/- 0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial O2 content difference by 24 h of infusion (P less than 0.01). Calculated fetal O2 consumption increased from 8.1 +/- 0.4 ml/kg per min in the control period to a maximum value of 10.6 +/- 0.3 ml/kg per min by third infusion day (P less than 0.01), which is an increase of approximately 30%. The degree of stimulation of fetal O2 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal O2 consumption was accompanied by a significant increase in fetal O2 extraction with no change in either fetal O2 delivery or fetal blood O2 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial PCO2 was linearly related (P less than 0.001) to the magnitude of increase in fetal O2 consumption. These studies suggest that chronic fetal hyperglycemia induces a state of accelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

Hypophosphatemia and hypercalciuria in small premature infants fed human milk: evidence for inadequate dietary phosphorus.

Phosphorus and calcium balance was measured prospectively in stable premature infants (less than or equal to 1600 gm) fed human milk or a standard commercial formula. Throughout the study, the P and Ca intakes of the infants fed human milk were two to three times less than those of infants fed formula. Infants fed human milk showed low serum P and normal serum Ca concentrations, complete renal reabsorption of P, and elevated renal Ca excretion. The net effect in infants fed human milk was a 50% reduction in the P and Ca retention, compared with the formula-fed group. Despite the unfavorable P and Ca balance in the group fed human milk, the only evidence of rickets was elevated alkaline phosphatase activity. Nevertheless, based on the biochemical changes in these infants, low serum P values, and excess urinary calcium losses, we conclude that the stable small premature infant fed human milk exclusively is deficient in phosphorus and only slightly more sufficient in calcium.

Arterial Hypoxemia and Hyperinsulinemia in the Chronically Hyperglycemic Fetal Lamb

Summary: Sustained fetal hyperglycemia was produced in eight chronically catheterized fetal lambs (seven twins, one singleton) by means of direct fetal glucose infusion. In twin preparations, only one twin was infused, the noninfused twin serving as a simultaneous in utero control. Glucose infusions lasted 7.6 ± 118 days and resulted in significant fetal hyperglycemia (from 20.3 ± 1.1 mg/dl to 58.2 ± 4.7 mg/dl, P < 0.001). The magnitude of the hyperglycemia was linearly related to the glucose infusion rate. Elevations of fetal plasma glucose and glucose infusion rate were associated with a significant fall in fetal arterial oxygen content (P < 0.001). In twin preparations studied, these relationships remained when the simultaneously sampled, noninfused twin was used as control. The fetal glucose-induced hypoxemia was not associated with fetal acidosis (tissue hypoxia) until the arterial oxygen content fell below 30% of baseline (mean base deficit in acidotic fetuses = 11.2 ± 2.2 meq/liter). Although Pao2 fell in hypoxemic fetuses (from 13.5 ±1.2 mmHg to 9.7 ±1.2 mmHg), the difference was not significant. Fetal plasma insulin rose during hyperglycemia from 10.2 ±3.1 μU/ml to a peak concentration of 26.2 ± 3.3 μU/ml, but this response was blunted in markedly hypoxemic fetuses. Neither fetal anemia nor hemoconcentration were evident in these preparations to account for the fall in fetal oxygen content.Speculation: Glucose-induced hypoxemia may be the result of accelerated fetal and/or uteroplacental oxygen consumption. In utero hypoxemia in the fetus of the pregnant diabetic may present a unifying hypothesis linking the known clinical findings of increased fetal red blood cell production, polycythemia, and late fetal demise in fetuses of diabetic mothers.

Furosemide pharmacokinetics in very low birth weight infants

The pharmacokinetics of furosemide were studied longitudinally during long-term administration in 10 very low birth weight infants with bronchopulmonary dysplasia. Mean birth weight of the infants was 829 +/- 217 g, mean gestational age at birth was 26.6 +/- 2.9 weeks, and mean postnatal age at the start of therapy was 2.4 +/- 1.0 weeks. Serial determinations of furosemide pharmacokinetic parameters were performed during 2 weeks to 3 months of long-term therapy. Plasma half-life was prolonged in infants less than 31 weeks postconceptional age (gestational + postnatal age), frequently exceeding 24 hours. All infants less than 29 weeks postconceptional age whose dosing schedule was once every 12 hours accumulated furosemide to potentially ototoxic levels. Furosemide renal clearance increased and plasma half-life decreased in association with increasing postconceptional age. Furosemide secretory clearance was very low in patients less than 31 weeks postconceptional age, resulting in a reliance on glomerular filtration to deliver drug to its main site of action within the lumen of the loop of Henle. Thus elevated plasma levels may be required to ensure adequate luminal delivery and adequate diuresis in these infants with low secretory clearance. Nevertheless, the current dosing schedule (once every 12 hours) of furosemide should be modified to once every 24 hours in infants of low postconceptional age to avoid possible toxic effects.

Fetal growth retardation following maternal morphine administration: nutritional or drug effect?

The effects of maternal morphine administration on maternal nutrition and on fetal growth have been systematically examined in a rabbit model. Significant alterations in maternal food intake occurred morphine exposure. These nutrition changes did not result in fetal growth retardation. Fetal morphine exposure was associated with significant reductions in fetal weight, length, placental weight and in the weights of most organs including the brain. When organ weight was considered as a fraction of total fetal weight morphine exposure was associated with a significant increase in the relative weight of the brain and a significant decrease in the relative weight of liver and kidneys. These narcotic effects were dose dependent.

Effects of surfactant therapy on outcome of infants with birth weights of 600 to 750 grams

Replacement therapy with exogenous surfactant has been studied for both prevention and treatment of respiratory distress syndrome. Although reports demonstrate improved survival rates for surfactant-treated infants with RDS, the impact of this therapy on outcome of extremely low birth weight infants is unknown. TM Previous studies have not reported outcome after surfactant treatment for the subset of premature infants who are born at ELBWs and who are at the highest risk for complications of prematurity. We report the outcome of infants born with birth weights between 600 and 750 gm who underwent prospective random selection to receive either surfactant or placebo as part of a multidose prevention study.

Simultaneous infusion of calcium and phosphorus in parenteral nutrition for premature infants: Use of physiologic calcium/phosphorus ratio

We hypothesized that parenteral delivery of calcium and phosphorus in a ratio of 1.7:1 would promote retention of these minerals and decrease urinary phosphorus excretion, and that delivery of increased amounts of this ratio would result in higher retentions. Serum levels and retention of calcium and phosphorus were measured as calcium intake was increased from 36 to 76 mg/kg/day in 10 mg increments and as phosphorus intake was adjusted to maintain the 1.7:1 ratio. Five different infants were studied at each of the five levels. The amounts of calcium and phosphorus retained increased steadily and at level 5 were 71.8 +/- 1.2 mg/kg/day and 40.9 +/- 1.7 mg/kg/day, respectively. Over the five levels the average percent calcium retention was 91.4 +/- 4.2 and the average percent phosphorus retention was 89.1 +/- 7.7. The provision of parenteral calcium and phosphorus in a 1.7:1 ratio resulted in a balanced retention of both minerals over the range studied. The use of this calcium/phosphorus ratio appears to be appropriate for the preterm infant receiving total parenteral nutrition.

Effects of Fetal Insulin Deficiency on Growth in Fetal Lambs

Insulin may be an important regulator of growth in late fetal life. To assess the importance of endogenous insulin release in regulation of normal fetal growth, eight fetal lamb pairs were given either an intravenous injection of streptozocin (STZ), a nitrosourea that selectively damages pancreatic β-cells, or buffer infusion (controls). In six preparations, twins were used, and in two cases, triplets, thus allowing for comparison between treated and control fetuses residing in the same intrauterine environment. Fetal STZ injection was associated with relative fetal hyperglycemia, hypoinsulinemia, and a decrease in the fetal plasma insulin-glucose ratio. Fetal lambs exposed to STZ also developed a mild nonprogressive metabolic acidosis compared with controls. Fetal body weight was depressed by 21% overall, the magnitude of reduction related to length of time in utero after STZ injection. Similar reductions in organ weights (liver, heart, and kidney) were also observed in STZ-administered fetuses compared with controls. Protein accretion in carcass, liver, and kidney after STZ was also depressed, but no significant changes in fetal lipid accretion were observed. Skeletal growth, as measured by tail and tibial lengths, was also depressed after STZ but to a lesser extent than body weight or protein accretion. Thus, in a stable maternal environment, isolated fetal insulin deficiency is associated with significant retardation of somatic and skeletal growth and protein deposition.

Fetal metabolic response to endogenous insulin release

The fetal metabolic response to tolbutamide-induced insulin release was evaluated in nine chronically catheterized fetal lambs. Tolbutamide produced an elevation in fetal insulin that persisted throughout the 1-hour experimental period (peak insulin concentration achieved was 76.1 +/- 9.5 micro U/ml). Fetal hyperinsulinemia was associated with a fall by 30 minutes in both fetal arterial and umbilical venous glucose concentrations as well as an increase in the umbilical glucose venous-arterial difference. This increase was associated with an elevation of fetal glucose uptake 65.6% +/- 29.6% above control at 30 minutes after infusion. Fetal arterial oxygen content fell after tolbutamide administration and was accompanied by an increase in the umbilical venous-arterial oxygen content difference (13.0% +/- 5.0% above the basal level.) Despite the increased venous-arterial difference, however, no change in umbilical oxygen consumption was noted. Isolated endogenous fetal insulin release is thus associated with a relatively rapid increase in umbilical glucose uptake as well as concomitant fetal hypoglycemia. The etiology of the mild fetal hypoxemia produced is unclear. The alterations in fetal glucose uptake in the ovine fetus after tolbutamide mimic those changes occurring after fetal exogenous insulin infusion. These alterations strongly suggest a significant role for insulin in the modulation of fetal carbohydrate metabolism and perhaps oxygen utilization.