A comparison of albumin-bolus therapy versus normal saline-bolus therapy for hypotension in neonates.

OBJECTIVE: We compared responses to bolus infusion of 5% albumin (ALB) or normal saline (NS) for hypotension in neonates. STUDY DESIGN: Hypotensive infants were given 10 ml kg(-1) of NS or ALB. A second bolus was given for persistent hypotension. Dopamine therapy was started for hypotension after the second bolus. The primary response was increase in arterial blood pressure toward normal range 1 h postinfusion. Secondary measures included duration of normotension, meeting criteria for second bolus, meeting criteria for vasopressor support and cost comparison. RESULT: Those receiving ALB (N=49 ALB and 52 NS) were more likely to achieve a normotensive state (ALB=57.1%, NS=32.1% P=0.01) 1 h following the initial bolus therapy. Subsequently, the NS group was also more likely to qualify for vasopressor infusion (ALB=24.5%, NS=44.2% P=0.02). Overall cost for either therapy was equivalent. CONCLUSION: In hypotensive neonates, ALB results in a greater likelihood of achieving normotension and decreased subsequent use of vasopressors when compared to NS.

Effects of hyperoxia and hypoxia on vascular prostacyclin formation in vitro.

Exposure to high oxygen (O2) concentrations, especially in the neonate, is associated with the development of pathologic syndromes characterized by vascular involvement including the retinopathy of prematurity. Some of the initial vascular changes observed appear consistent with a reduction in prostacyclin formation. Exposure of human umbilical arteries to oxygen resulted in more than 30% inhibition in the ability of the vessels to produce prostacyclin either from endogenous stores of arachidonic acid or from exogenously provided substrate. In contrast, hypoxia (which more closely approximates the fetal environment) resulted in more than 30% stimulation in the production of prostacyclin from either endogenous or exogenous arachidonic acid. When microsomes were prepared from treated arterial segments, these effects persisted. In vitro results suggest that neonates exposed to O2 after delivery may experience a marked decrease in vascular prostacyclin formation. Inhibition of the production of this potent vasodilator and antithrombotic metabolite could play an important role in the acute exudative phase of O2 toxicity.

Insulin receptors in the developing fetal lung.

Fetal lung insulin receptor numbers and affinities were studied in rat pregnancies from 15 to 22 days gestation. Insulin receptor binding capacities were found to increase six-fold from approximately 100 fmoles insulin bound/mg lung DNA at 15 days gestation to approximately 600 fmoles bound/mg DNA at 22 days gestation. However, the affinity constants of the receptors were unchanged during this same period (high affinity, 1.9 +/- 0.4 S.E. and low affinity, 0.03 +/- 0.01 S.E.). The results suggest that the lung may become increasingly more sensitive to insulin as development progresses.

A comparison of insulin receptors in the developing fetal lung in normal and in streptozotocin-induced diabetic pregnancies.

Insulin receptors from fetal rat lungs of normal and streptozotocin-induced diabetic pregnancies were examined for their binding capacities and association constants. Sprague-Dawley rats, given a single dose of streptozotocin at 7 days' gestation, became hypoinsulinemic and hyperglycemic within 48 hours, although they remained healthy enough to carry fetuses to term. The fetuses of the streptozotocin-treated pregnancies had hyperglycemia (3,750 +/- 400 micrograms glucose/ml vs 390 +/- glucose/ml for control subjects), but were not hyperinsulinemic. Insulin receptor binding capacities of fetal lungs from control pregnancies increased as a function of gestational age from 16 to 21 days. Receptor binding capacities of lungs from streptozotocin-treated pregnancies also increased with gestational age until 21 days, when they dropped to 50% of control values. It was demonstrated in organ culture that fetal lung receptors from normal pregnancies of 20 days' gestation could be down-regulated in the presence of insulin and that this down-regulation is coupled to a biologic effect of insulin, hexose transport. It was concluded that fetal lung insulin receptors can be regulated by insulin concentrations in vitro and by experimental diabetic pregnancies in vivo.

Care of the neonate.

Surfactant administration for respiratory distress syndrome continues to make an impact on neonatal care as large controlled trials are published. Although considered safe, synthetic surfactant administration has been associated with a rare complication in the form of pulmonary hemorrhage. Despite this, significant benefits have been shown. With the approval by the FDA of two surfactant preparations, this treatment is now in widespread use. Although the mortality rate from respiratory distress syndrome and the number of ventilator days are generally decreased, surfactant effect on the incidence of bronchopulmonary dysplasia has been disappointing. Studies of steroid administration for bronchopulmonary dysplasia and steroid side effects have been published in the past year. Steroid use has become widespread for this condition, although many details of its administration and side effects have yet to be worked out. A new area of promise is the use of erythropoietin for anemia of prematurity. Natural historic data on the retinopathy of prematurity have added to our understanding of this condition and have raised new questions on its pathogenesis. Review articles and studies in the area of neonatal encephalopathy stress the need for a more accurate definition of asphyxia and discuss possible prenatal causes of this condition. An extensive review of neonatal jaundice and new recommendations for its treatment in healthy term newborns has been published but remains controversial.

Spinal-fluid procoagulant activity: a sensitive indicator of central-nervous-system damage.

Testing the procoagulant activity (P.C.A.) of cerebrospinal fluid (C.S.F.) by measuring its effect on plasma-recalcification time is a useful indicator of central-nervous-system damage. C.S.F. from 22 normal children and adolescents aged 6 months to 17 years had a mean +/- S.D. P.C.A. of 14 +/- 6%. P.C.A. in 13 children with C.N.S. infection was significantly increased to 59 +/- 13%. In 8/13 of these children activity remained high (42 +/- 11%) after therapy. In patients with acute lymphatic leukemia (A.L.L.) 12 aged greater than 2 1/2 years and diagnosis had a normal activity (17 +/- 8%) and 4 patients aged less than 2 1/2 years at diagnosis had an activity of 21 +/- 8%; during C.N.S. prophylaxis with intrathecal methotrexate and/or cranial irradiation, mean activity in these 16 patients rose significantly to 41 +/- 11%. More than 2 years after treatment P.C.A. decreased towards normal in the older children but remained high in the younger group. 5 children with neurological sequelae (including 3 with A.L.L. and the post-irradiation syndrome) had the highest activities. Ether extraction showed that the active material had lipid properties. P.C.A. did not correlate with protein, lactic dehydrogenase, or cell count in C.S.F.

The mitogenic effect of 15- and 12-hydroxyeicosatetraenoic acid on endothelial cells may be mediated via diacylglycerol kinase inhibition.

15-Hydroxyeicosatetraenoic acid (15-HETE), a major lipoxygenase metabolite of arachidonic acid in fetal bovine aortic endothelial cells, was a mitogen for these cells, stimulating both cell proliferation and DNA synthesis in the presence of serum and serum-deprived cells. In [14C]arachidonic acid-labeled confluent endothelial cell monolayers, 15-HETE (30 microM) caused an elevation of [14C]diacylglycerol (DAG) with a concomitant decrease in cellular [14C]phosphatidylinositol (PI) in both unstimulated and stimulated cells. 1-Oleoyl-2-acetylglycerol, a synthetic DAG analog, stimulated endothelial cell DNA synthesis in a concentration-dependent manner. In [3H]inositol-labeled cells, 15-HETE also caused a decrease in cellular PI content under both basal and stimulated conditions. 15-HETE, however, had no effect on either isolated phospholipase C activity or phosphoinositide turnover in lithium chloride-treated cells. In intact cells, 15-HETE (30 microM) inhibited the synthesis of [3H]PI from [3H]inositol (80% inhibition, p less than 0.001). In human red cell membranes, the production of phosphatidic acid from endogenous DAG was inhibited by 15-HETE in a concentration-dependent manner with an IC50 of 41 microM. Although 12-HETE had effects similar to those of 15-HETE, the parent compound arachidonic acid did not affect DNA synthesis or DAG kinase activity. Our study thus demonstrates that the mitogenic activity of 15- and 12-HETE on endothelial cells may be mediated via DAG kinase inhibition with the concomitant accumulation of cellular DAG.

Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis.

In a case-control study, we evaluated the effects of maternal ingestion of acetylsalicylic acid (aspirin) within 10 days of delivery on maternal and neonatal hemostasis. Only one of 34 control maternal-neonatal pairs (3 per cent) had hemostatic abnormalities. In 10 pairs, when maternal aspirin ingestion occurred within five days of delivery, 6 of 10 mothers and 9 of the 10 infants had bleeding tendencies. Seven maternal-neonatal pairs in which aspirin was ingested 6 to 10 days before delivery were free of clinical bleeding. Among seven other mothers who ingested aspirin in the immediate post-partum period four of the seven (57 per cent) also had impaired hemostasis. Neonatal hemostatic abnormalities included numerous petechiae over the presenting part, hematuria, a cephalhematoma, subconjunctival hemorrhage, and bleeding from a circumcision. Maternal bleeding was confined to excessive intrapartum or post-partum blood loss. We conclude that aspirin should be avoided during pregnancy. If ingestion has occurred within five days of delivery, the neonate should be evaluated for the presence of bleeding.

Anemia of prematurity: determinants of the erythropoietin response.

This study was undertaken to determine the factors that are important in determining the erythropoietin response in low-birth-weight infants during the period of so-called anemia of prematurity. In the first weeks of life oxygen consumption in a group of 21 infants gradually increased as hemoglobin level fell. The magnitude of the erythropoietin response inversely varied with the central venous oxygen tension (P-vO2) (r = -0.55, P less than 0.001). When the P-vO2 declined to less than 30 torr, erythropoietin values were uniformly increased above the "normal" range (defined as the values associated with P-vO2 greater than 38 torr). Erythropoietin values varied inversely with hemoglobin but in general did not exceed the values observed for normal adult men. The erythropoietin values in the infants were remarkably lower at any given hemoglobin level when compared with those of older children with anemia resulting from bone marrow failure. In general, elevations of erythropoietin were seen when the hemoglobin concentration declined to less than 10.0 gm/dl. Change in heart rate did not appear to be a reliable indicator of the presence of anemia; rather, it correlated best with oxygen consumption.

Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism.

Normal hemostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A2, measured as its stable end-product thromboxane B2 (TXB2), and vascular prostacyclin (PGI2), which inhibits platelet aggregation and is antithrombotic. Cystathionine-beta-synthase deficiency is characterized by a high frequency of thromboembolic disease. We therefore studied, in vitro, the effects of homocysteine and related compounds on platelet TXB2 and vascular PGI2 formation. In paired samples of platelet rich plasma, which had been preincubated with L-homocystine (1 mM), mean production of the two platelet cyclooxygenase products, TXB2 and 12-hydroxy-5, 8,10-heptadecatrienoic acid increased significantly from control levels [13.6% +/- 1.9 to 19.8% +/- 2.1 (P less than 0.02) TXB2 and 29.8% +/- 4.2 to 39.4% +/- 4.1 (P less than 0.01) HHT]. In the presence of D,L-homocysteine (1 mM), mean TXB2 and 12-hydroxy-5,8,10-heptadecatrienoic acid production was also significantly increased [12.7% +/- 1.5 to 16.9% +/- 1.5 (P less than 0.01) TXB2 and 27% +/- 4 to 31% +/- 4.1 (P less than 0.02) HHT]. Cystine, cysteine, or methionine (1 mM) did not have similar effects in this test system. Homocysteine and homocystine were without effect on the synthesis of vascular PGI2 by umbilical artery segments [control, 0.22 +/- 0.03 to 0.21 +/- 0.03 ng/mg with D,L-homocysteine and 0.20 +/- 0.04 control to 0.19 +/- 0.04 ng/mg with D,L-homocystine]. A homocyst(e)ine-induced increase in platelet thromboxane production in the absence of an increase in vascular prostacyclin, if present in vivo, may contribute to the vascular thromboses characteristic of human homocystinemias (homocystinurias).

15-Hydroxyeicosatetraenoic acid stimulates migration of human retinal microvessel endothelium in vitro and neovascularization in vivo.

We evaluated 15-hydroxyeicosatetraenoic acid (15-HETE), a major arachidonic acid product of vascular endothelium and leukocytes, for its effect on neovascularization. In a modified Boyden chamber assay, 15-HETE (10-7 M) stimulated human retinal microvessel endothelial cell migration by 42 +/- 10% (mean +/- S.E.M., p less than 0.01). 12-HETE, a major arachidonic acid metabolite of platelets, had no such effect. Further studies in the rabbit corneal pocket assay revealed that 15-HETE stimulated neovascularization in vivo. Concentrations at which the in vivo effects were observed are within the range generated by several cell types and are achievable in human serum. 15-HETE stimulation of human endothelial cell migration in vitro and neovascularization in vivo suggests that it may play a role in vasoproliferative disorders.

A multicenter randomized, masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome.

OBJECTIVE: To compare the efficacy and safety of two surfactant preparations in the treatment of respiratory distress syndrome (RDS). METHODS: We conducted a randomized, masked comparison trial at 21 centers. Infants with RDS who were undergoing mechanical ventilation were eligible for treatment with two doses of either a synthetic (Exosurf) or natural (Infasurf) surfactant if the ratio of arterial to alveolar partial pressure of oxygen was less than or equal to 0.22. Crossover treatment was allowed within 96 hours of age if severe respiratory failure (defined as two consecutive arterial/alveolar oxygen tension ratios < or = 0.10) persisted after two doses of the randomly assigned surfactant. Four primary outcome measures of efficacy (the incidence of pulmonary air leak (< or = 7 days); the severity of RDS; the incidence of death from RDS; and the incidence of survival without bronchopulmonary dysplasia (BPD) at 28 days after birth) were compared by means of linear regression techniques. RESULTS: The primary analysis of efficacy was performed in 1033 eligible infants and an analysis of safety outcomes in the 1126 infants who received study surfactant. Preentry demographic characteristics and respiratory status were similar for the two treatment groups, except for a small but significant difference in mean gestational age (0.5 week) that favored the infasurf treatment group. Pulmonary air leak (< or = 7 days) occurred in 21% of Exosurf- and 11% of infasurf-treated infants (adjusted relative risk, 0.53; 95% confidence interval, 0.40 to 0.71; p < or = 0.0001). During the 72 hours after the initial surfactant treatment, the average fraction of inspired oxygen (+/-SEM) was 0.47 +/- 0.01 for Exosurf- and 0.39 +/- 0.01 for infasurf-treated infants (difference, 0.08; 95% confidence interval, 0.06 to 0.10; p < 0.0001); the average mean airway pressure (+/-SEM) was 8.6 +/- 0.1 cm H2O; for Exosurf- and 7.2 +/- 0.1 cm H2O for Infasurf-treated infants (difference, 1.4 cm H2O; 95% confidence interval, 1.0 to 1.8 cm H2O; p < 0.0001). The incidences of RDS-related death, total respiratory death, death to discharge, and survival without bronchopulmonary dysplasia at 28 days after birth did not differ. The number of days of more than 30% inspired oxygen and of assisted ventilation, but not the duration of hospitalization, were significantly lower in Infasurf-treated infants. CONCLUSION: Compared with Exosurf, Infasurf provided more effective therapy for RDS as assessed by significant reductions in the severity of respiratory disease and in the incidence of air leak complications.