Michael F. Epstein

Heparin Use as a Risk Factor for Intraventricular Hemorrhage in Low-Birth-Weight Infants

In a systematic review of data on drug use and adverse clinical events in infants with birth weights under 2000 g, we observed an association between germinal matrix-intraventricular hemorrhage and the use of heparin to maintain the patency of vascular catheters. Sixty-six infants with germinal-matrix (periventricular) or intraventricular hemorrhage or both (cases) were matched with 254 infants with other conditions (controls), and analysis, taking the matching factors into account, yielded an odds ratio of 14.0 (95 percent confidence interval, 5.4 to 34). When potential confounding factors were taken into account, the odds ratio was 3.9 (1.4 to 11). The association did not appear to vary according to the severity of hemorrhage or to the method of administration or dose of heparin. The data suggest that the routine use of heparin in neonatal intensive care units is associated with a four-fold increase in the risk of germinal matrix-intraventricular hemorrhage. Because of the possibility that confounding may have been incompletely controlled for, the true risk cannot be determined from these data, and a controlled clinical trial of heparin use in low-birth-weight infants is recommended.

Neonatal hypoglycemia after beta-sympathomimetic tocolytic therapy

The effect of oral beta-sympathomimetic tocolytic therapy on neonatal serum glucose concentrations in the first several hours after delivery was examined in 12 babies. Hypoglycemia was noted in eight babies, and was sustained over at least a 30-minute period in five. The group with sustained hypoglycemia had a higher cord serum insulin concentration, a lower serum glucose nadir, and a more rapid initial rate of serum glucose disappearance than those babies with normoglycemia or transient hypoglycemia. Sustained hypoglycemia was observed in five of six babies delivered within two days of the termination of tocolytic therapy, but was not present in any of six babies delivered five or more days after the end of tocolytic therapy. Speculations as to the interaction between beta-sympathomimetic tocolytic drugs administered to the mother and fetal and neonatal glucose metabolism are made.

Estimation of PaCO2 by two noninvasive methods in the critically ill newborn infant.

Simultaneous measurements of arterial, transcutaneous, and peak expired carbon dioxide were obtained in 24 newborn infants receiving mechanical ventilation during the first week after birth. Two calibration algorithms designed to estimate PaCO2 from the noninvasive measurements were then examined. Both approaches entailed finding a statistical relationship by which future noninvasive measurement could be used to estimate the arterial value rather then measuring it directly. The first utilized the difference between the initial paired measurements (an in vivo calibration); the second used the mean difference between all measurements in the population. Adjusted tcPCO2 measurements by either the in vivo calibration or by the population-based factor led to estimates of PaCO2 with 95% confidence limits of +/- 6 to +/- 8 torr. In contrast, this degree of precision for the peak expired CO2 measurement was only possible using the in vivo calibration method. The use of an airway adaptor for PCO2 measurement led to CO2 retention in more than half of the infants. Transcutaneous monitoring had no significant effects on the infants, but was hampered by excessive drift and erratic sensitivity of the electrodes.

Effect of Isoxsuprine on Fetal Lung Surfactant in Rabbits

Summary: To examine the effect of beta adrenergic drugs on fetal lung development, we administered isoxsuprine to pregnant rabbits for 24 hr and measured indices of pulmonary surfactant synthesis, storage, and release in rabbit fetuses at 26 days gestation. Incorporation of radiolabeled choline into total and disaturated phosphatidylcholine was measured in vitro in fetal lung slices. There was a significant increase in the rate of choline incorporation into disaturated phosphatidylcholine in the isoxsuprine-treated group and a tendency toward an increased incorporation into total phosphatidylcholine as well. We also observed an increase in the pulmonary phospholipid reservoir as evidenced by a significant increase in total lung disaturated phosphatidylcholine and a trend toward higher total lung phosphatidylcholine in the isoxsuprine group. In addition, there was a significant increase in lung lavage L/S ratio in the treated fetuses and in lung deflation stability determined by pressure volume curve. We conclude that isoxsuprine increases synthesis, storage, and release of surfactant in rabbit fetuses at 26 days gestation.Speculation: The effect of isoxsuprine to increase lung disaturated phosphatidylcholine synthesis which leads to an increase in total lung disaturated phosphatidylcholine is probably mediated through an increase in intracellular cyclic adenosine monophosphate. It is possible that cyclic adenosine monophosphate can activate inactive forms of the enzymes of the choline incorporation and/or remodelling pathways within the fetal lung cells and enhance disaturated phosphatidylcholine synthesis.

Recent patterns of drug use in newborn intensive care

To better understand patterns of medication use in neonatal intensive care, we examined data collected prospectively over a recent 9-year period in the newborn intensive care units of two large teaching hospitals. Among 2690 infants studied, 91% received at least one drug; 99% of infants weighing less than 1500 gm were exposed to drugs, compared with 90% of infants weighing more than 1500 gm. Among treated infants, the median number of drugs received was eight; the number of drugs administered was inversely related to birth weight and directly related to both length of hospital stay and the complexity of the infants clinical condition. Within categories of length of hospital stay, the number of drugs received per day was greatest during the first week in the neonatal intensive care unit and fell to a relatively stable lower level during the second week. The most commonly used single drug was gentamicin (71% exposed), followed by sodium chloride (60%), potassium chloride (59%), heparin (58%), and packed erythrocytes (45%). Between 1978-1979 and 1985-1986 the prevalence of use increased substantially for some drugs (ampicillin, morphine, calcium salts, and acetates of sodium and potassium) and decreased for others (kanamycin, sodium bicarbonate, and blood products). These data document the dynamic nature of drug therapy in the neonatal intensive care unit and provide information that can guide cost-benefit assessments in this setting.

Vancomycin-associated shock and rash in newborn infants

Vancomycin, an antibiotic isolated from Streptomyces ~rientalis, was developed to treat staphylococcal infections resistant to the penicillins. However, because intravenous administration was associated with venous irritation, vancomycin was largely replaced by semisynthetic penicillins. Recently, intravenously administered vancomycin has come into increasing use, and its indications now include infections caused by Staphylococcus epidermidis and resistant Staphylococcus aureus.1 Vancomycin has become an important antibiotic for use in premature newborn infants, because S. epidermidis is the most common nosocomial infection in the neonatal intensive care unit. 2,3 Adverse reactions attributed to vaneomycin have been described in adults and children, but not in newborn infants. We report two newborn infants who had shock and rash after receiving vancomycin; these reactions were identified by tt~e Pediatric Drug Surveillance (PeDS) Program at the Childrens Hospital, Boston. 4

Elevated Levels of α2-Macroglobulin-Protease Complexes in Infants

Proteases form stable complexes with α2-macroglobin (α2-MG) in human plasma. We previously showed that the intestine of newborn rabbits takes up greater amounts of proteases than

Lung lecithin synthesis in primates as related to respiratory distress syndrome.

Lecithin is synthesized de novo in the lung by two biochemical pathways, choline incorporation and phosphatidylethanolamine methylation. These studies in the Macaca mulatta fetus and neonate have demonstrated the relative contributions of the two pathways and the timing in monkey gestation of increased pulmonary lecithin production.

Vitamin E concentrations in serum of newborn infants after topical use of vitamin E by nursing mothers

Presented is a study that examined the effect of topical application of vitamin E by nursing mothers.

1508 WEIGHT GAIN AND SERUM BILIRUBIN IN NEWBORNS WITH RDS TREATED WITH PANCURONIUM BROMIDE

In order to examine the effect of pancuronium bromide (PBr) on body weight and serum bilirubin, we retrospectively reviewed the charts of 100 infants with RDS treated with mechanical ventilation. PBr was ordered according to each physicians judgment and was used in 51 infants. Both groups were similar in gestational age, (30.5±3.5 (PBr) vs. 30.1±2.8wk), male/female distribution, and survival, but patients in the PBr group had higher birth weight (1680±80 Vs. 1400±50g. p<.05). Infants treated with PBr gained weight during the first three days and showed a larger Δ wt (daily - birth weight) than the control group during the first week (PBr, +42±14g vs. noPBr, -35±12g, p<0.01). Edema was present in 27 PBr treated infants and in 13 of those not treated with PBr (p<0, 05). In addition, hyperbilirubinemia was more severe and more prolonged in patients treated with PBr. The two groups had similar serum bilirubin on days 1 to 5 but serum bilirubin was significantly greater in the treated group on days 6 to 10 (d.6 PBr 10.5±0.6 vs. noPBr 8.6±0.4 mg/dl, p<.02).The use of PBr was associated with edema, excessive weight gain in the first week of life, and a higher, more prolonged peak of serum bilirubin. These findings remained valid when subgroups matched for severity of hypoxia on day one were examined in order to control for severity of underlying lung disease.