Effect of polyclonal anti-TNFalpha antibody on endotoxic shock in suckling rats.

The aim of this study was to evaluate the effect of anti-tumor necrosis factor alpha (TNFalpha) antibodies on the TNFalpha gene expression in a neonatal septic shock model. Ten-day-old Sprague-Dawley rats were divided into four groups and given intraperitoneal (ip) injection as follows: group 1: 0.1 ml saline; group 2: 0.1 mg/kg Salmonella enteritidis lipopolysaccharide (LPS); group 3: 1 mg/kg of anti-TNFalpha antibodies (Ab); group 4: 0.1 mg/kg of LPS and 1 mg/kg of Ab. We found that in group 2, LPS induced shock, demonstrating hypoglycemia and lactacidemia (p < 0. 05) and death (81.8%). Ab decreased the mortality significantly (35%) and attenuated the hypoglycemia (35 +/- 8 mg/dl in group 2 vs. 53 +/- 3 mg/dl in group 4) and lactacidemia (5.40 +/- 0.63 vs. 2.35 +/- 0.45 mmol) at 8 h in group 4 when compared to group 2. Northern blot demonstrated a significant decrease in TNFalpha mRNA expression in group 4 as compared to group 2, at 2 h after LPS injection. We conclude that the beneficial effects of anti-TNFalpha antibodies on LPS-induced shock may be due to decreased TNFalpha gene expression.

Prophylactic treatment of endotoxic shock with monophosphoryl lipid A in newborn rats.

Mortality due to gram-negative septic shock remains high despite advances in medical care. Induction of endotoxin tolerance might be a new treatment strategy to prevent septic shock in the newborn. The present study was performed to show that an injection in pregnant rats of monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS), induces tolerance to Salmonella enteritidis LPS and tumor necrosis factor alpha (TNF-alpha) in their offspring. MPL at a dose of 2 mg/kg was injected into pregnant rats on the 19th day of gestation. Their 0-day-old offspring later received an intraperitoneal injection of S. enteritidis LPS or TNF-alpha. Newborn rats of MPL-treated dams exhibited a higher survival rate, absence of lactacidemia and lower plasma TNF-alpha concentration in response to S. enteritidis LPS when compared to the newborn rats of saline-treated dams. Newborn rats of MPL-treated dams were more tolerant to TNF-alpha than those of saline-treated dams. MPL injection into pregnant rats did not increase plasma endotoxin concentration in the fetuses, suggesting no placental passage took place, but it did increase plasma TNF-alpha concentration. We concluded that an injection of MPL into pregnant rats induced tolerance to LPS in their offspring, which might be due to TNF-alpha-induced TNF-alpha tolerance.

Reduced capacity of neonatal lymphocytes to inhibit the growth of Candida albicans.

Opportunistic microorganisms produce significant morbidity and mortality in preterm and term infants. Because of the heightened susceptibility of infants to opportunistic fungal infections, neonatal lymphocytes were assessed for their capacity to inhibit the growth of Candida albicans. Lymphocytes from both preterm and term cord blood demonstrated significantly less effect upon C. albicans than did lymphocytes from adults. Neonatal lymphocytes of infants <32 weeks of gestation showed a marked reduction in growth inhibitory capacity compared to infants >32 weeks of gestation. Lymphocytes from female infants had a significantly greater fungal growth inhibitory capacity than did lymphocytes from male infants. These results show that neonatal lymphocytes have a reduced capacity to inhibit the growth of C. albicans. This reduced antifungal capacity may underlie the increased susceptibility of such infants to opportunistic microorganisms, like C. albicans.

Computer-enhanced neonatology practice evolution in an academic medical center. NICU Clinical Effectiveness Task Force.

The U.S. health care system is evolving as a result of market-place forces that demand optimal medical outcomes, cost effectiveness, and improved customer service. These demands may be in conflict with the mission of an academic neonatal intensive care unit (NICU). For more than 5 years, we have used computer-enhanced clinical practice evolution to improve quality while reducing costs. The multidisciplinary NICU Clinical Effectiveness Task Force used the Quality/Cost Improvement Cycle in an evidenced-based, data-driven approach to clinical practice change. Merger of the Neonatal Clinical Database permitted birth weight-specific cost reporting. Specific practice patterns in the Pharmacy, Clinical Laboratory, Respiratory Therapy, and Radiology cost centers were targeted for improvement based on the medical literature. Customized interactive physician order-entry pathways were created within the existing medical ordering module of the Medical Information System. Birth weight-specific neonatal survival rates were unchanged. A dramatic reduction in neonatal medication errors from 3.2 to 0.6 errors per 1000 patient days occurred. Changes in targeted clinical practices were documented. A substantial decrease in average total hospital cost per infant and average length of stay was demonstrated for infants whose birth weights were less than 1001 gm. In conclusion, clinical practices can be changed while outcomes are improved and cost is reduced in an academic NICU through implementation of computer-enhanced clinical practice evolution. There are many remaining questions regarding the best neonatal practices to optimize outcome and minimize cost.

Decreasing blood donor exposure in the neonates by using dedicated donor transfusions.

Critically ill infants receive frequent red cell transfusions for replacement of blood drawn for laboratory analysis and in treatment of symptomatic anemia. Since blood for multiple transfusions on a given day is typically obtained from one fresh RBC unit, each multiply transfused neonate is exposed to many donors increasing the risk of transfusion transmitted disease. We hypothesized that the number of donor exposures per infant would decrease by instituting DDTP and that more infants will be exposed to only a single donor. We started a Dedicated Donor Transfusion Program (DDTP) in our NICU. One unit of red cells is dedicated to each baby for the life of the unit (35 days). We compared the donor exposure in infants for one year, before and after DDTP. The infants were divided into three birth weight groups. Group I were infants < 1000 g; Group II infants were 1000-1500 g; Group III infants were > 1500g. The average number of transfusions per patient decreased significantly from 7.5 +/- 6.0 to 4.7 +/- 4.2 (P < 0.001) in Group I while it remained unchanged in Groups II and III. The Dedicated Donor Transfusion Program significantly reduced the donor exposure in NICU infants. The program also facilitated the reduction of the number of transfusions in the infants under 1000 g.

Dexamethasone-induced myocardial hypertrophy in neonatal rats.

Clinical trials have shown dexamethasone's beneficial effects on the pulmonary status of infants with bronchopulmonary dysplasia; however, hypertrophic cardiomyopathy has been a reported complication of this therapy with no known mechanism. Our study was designed to test the hypothesis that therapeutic dexamethasone doses would induce myocardial hypertrophy. Newborn Sprague-Dawley rats were randomly assigned to receive dexamethasone 0.125 mg/kg/day, while paired littermate controls received saline placebo. The daily body weights were recorded and pups were sacrificed after 5 or 7 days of treatment. The heart weight to body weight ratio was used as a gross index of myocardial mass. Myocardial protein content, total protein to total DNA ratio, actin content and myosin heavy chain content were used as biochemical indices of hypertrophy. Our results included an increased heart weight to body weight ratio with elevation of the total protein content, actin content and total protein to total DNA ratio after both 5 and 7 days. We conclude that dexamethasone induces myocardial hypertrophy in neonatal rats.

Perinatal nutrition enriched with omega-3 polyunsaturated fatty acids attenuates endotoxic shock in newborn rats.

Sepsis and septic shock continue to have a high mortality and morbidity in the newborn. Eicosanoids are important mediators in Gram negative septic shock. Omega-3 polyunsaturated fatty acids (omega-3) decrease production of biologically active 2-series eicosanoids. Therefore, we hypothesized that omega-3-enriched diet could decrease 2-series eicosanoids and attenuate endotoxic shock in newborn rats. Sprague-Dawley rat dams were fed with either omega-3 polyunsaturated fatty acid-enriched diet (omega-3 PURA) or omega-6 polyunsaturated fatty acid enriched diet (omega-6PUFA; controls) from the 16th day of gestation until 10 days after parturition. In 10 day old rats, shock was induced by an intraperitoneal injection of Salmonella enteritidis lipopolysaccharide. The omega-3PUFA decreased the mortality of endotoxic shock. In omega-6PUFA, lipopolysaccharide induced hyperglycemia at 2 h and hypoglycemia thereafter without an elevation in plasma insulin concentration, omega-3PUFA attenuated the hyperglycemia and hypoglycemia. omega-3PUFA attenuated the decrease of liver phosphoenolpyruvate ca-boxykinase mRNA abundance, suggesting preserved gluconeogenesis. Therefore, perinatal feeding with omega-3PUFA was beneficial in attenuating glucose dyshomeostasis in newborn rats with endotoxic shock and may be a novel approach to the prevention of endotoxic shock in the newborn.

Disseminated herpes simplex virus infection presenting as fever in the newborn--a lethal outcome.

The clinical course of a neonate who presented with fever and tachypnea on day 6 of life is described. He developed disseminated intravascular coagulopathy, hepatic failure, coma and expired at 14 days of age. The post mortem viral cultures from liver, adrenal and lungs were positive for HSV type 2. The fatal outcome of this case of fever, due to HSV infection, emphasizes the need for early treatment of suspicious cases of HSV infection. HSV should be considered in the differential diagnosis of the newborn with persistent fever unresponsive to antibiotics.

Cecal perforation associated with sodium polystyrene sulfonate-sorbitol enemas in a 650 gram infant with hyperkalemia.

We report a 650 g, 24 week hyperkalemic newborn who developed both cecal impaction and perforation after treatment with sodium polystyrene sulfonate enemas. Flat plate abdominal radiographs revealed impacted resin as a radiodense material outlining the bowel. Pathological examination showed sodium polystyrene sulfonate crystals contained in the cecal abscess. Review of the literature in both adults and children leads us to conclude that the use of this sodium-potassium exchange resin for the treatment of hyperkalemia in this gestational age group is probably not helpful for decreasing serum potassium and may be detrimental to the infant.

How accurate is glucose analysis in the presence of multiple interfering substances in the neonate? (glucose analysis and interfering substances).

Whole blood glucose testing by reagent sticks is inaccurate at low plasma glucose concentrations and with varying hematocrit. Both conditions are frequently seen in newborn infants. Therefore plasma glucose analysis is the preferred method for newborn glucose monitoring. We encountered unanticipated difficulties in plasma glucose measurement by the automated hexokinase method caused by the combinations of plasma free hemoglobin, bilirubin, and plasma triglycerides, which are frequently elevated in newborn plasma. We determined the adverse effects of various combinations of these interfering substances on glucose analysis by the hexokinase method and demonstrated that accurate analysis is possible by a 1:1 plasma dilution only at high plasma glucose levels but not at the more critical low plasma glucose concentration. The dilution reduced the number of repeat specimens required in newborns. But 1:1 plasma dilution overestimated the glucose levels at low plasma glucose values, and therefore this automated hexokinase method is not suitable for glucose analysis in the newborn. Glucose-oxidase remains the method of choice for plasma glucose analysis in neonates. This information is important because using this hexokinase methodology, one might miss hypoglycemia in the newborn.

Morphine use and adverse effects in a neonatal intensive care unit.

Prescribing patterns and appropriateness of morphine use in a neonatal intensive care unit (NICU) were evaluated in a concurrent drug-use evaluation (DUE). Data were collected for 99 infants who received morphine over a six-month period. Patient charts were reviewed to collect the following data: patient's age, weight, dosage schedule, concurrent sedatives, ventilatory status, whether adequacy of analgesia was documented, and descriptions of adverse drug reactions (ADRs). The physicians' orders were reviewed to determine whether NICU morphine dosage guidelines were followed and whether the indication for use was noted. Seven ADRs occurred in six of the patients; three of the ADRs occurred after ophthalmic cryosurgery. Indications for use were noted in 79 of 285 physician orders (27.7%). The adequacy of sedation or analgesia was documented on 60 of the 360 patient days (16.7%). The DUE results prompted several changes: physicians were asked to select indications from a list in the computerized order-entry system, an analgesia or sedation assessment scale was added to nursing flow sheets, and endotracheal intubation became a requirement before ophthalmic cryosurgery. A follow-up DUE showed nearly complete compliance with the new guidelines for morphine use and a reduction in the number of adverse reactions to morphine. A DUE prompted policy changes that improved documentation of indications for and efficacy of morphine use and reduced adverse reactions to the drug in an NICU.

Transient central hypothyroidism as a cause of failure to thrive in newborns and infants.

The course of two neonates and one 4-month-old infant with laboratory and clinical evidence of central hypothyroidism is described. All three presented with failure to thrive and improved after L-T4 therapy. Early recognition and treatment of newborns and infants with central hypothyroidism is important to maximize the potential for growth and development. Two of the three infants have been documented to have transient central hypothyroidism of hypothalamic origin, not previously reported.

Meta-analysis of phenobarbital usage for prevention of intraventricular hemorrhage in premature infants: factors related to variation in outcome.

PURPOSE: To assess the efficacy of phenobarbital for the prevention of intraventricular hemorrhage (IVH) in premature infants and to identify study characteristics that were associated with beneficial or adverse effects. DATA IDENTIFICATION: Studies published from 1981 to 1994 were identified through a computerized search, and by searching the bibliographies of all identified articles. STUDY SELECTION: Ten randomized, controlled clinical trials were selected. DATA EXTRACTION: Data were extracted from each article, including the percentage of patients in the control and treatment groups with IVH, and key patient and study characteristics. RESULTS OF DATA ANALYSIS: Seven studies showed no statistically significant effects, two studies showed a beneficial effect of phenobarbital, and one study showed an adverse effect. The meta-analysis showed no significant difference in the percentage of IVH in treated and untreated infants when treatment effects were combined across all studies. However, prenatal administration of phenobarbital in two studies was associated with a beneficial effect. CONCLUSIONS: Overall, we did not find a significant beneficial effect of postnatal phenobarbital administration. The data suggests that prenatal phenobarbital is beneficial. Further evaluations of the efficacy of prenatal phenobarbital are warranted.

Plasma beta-endorphin concentrations and analgesia-muscle relaxation in the newborn infant supported by mechanical ventilation.

We evaluated the effects of pancuronium and opiates on plasma beta-endorphin concentrations in 25 infants supported by mechanical ventilation. Infants receiving opiate were randomly assigned to receive either fentanyl or morphine. There was no change in beta-endorphin concentrations after administration of pancuronium, whereas both fentanyl and morphine reduced beta-endorphin concentrations by approximately 60%.

Randomized clinical trial of surfactant prophylaxis in retinopathy of prematurity.

Prophylactic lung surfactant is commonly used to reduce the severity of neonatal respiratory distress syndrome in premature infants. There is disagreement in the literature regarding the effect of prophylactic lung surfactant on the incidence of retinopathy of prematurity (ROP). Sixty-four infants, gestational age 23 to 32 weeks, birth weight 610 to 1250 g, were randomized to receive either intratracheal bovine surfactant prophylaxis or air control, at our institution, as part of a national double-masked multicenter trial. Forty-eight of these infants survived and underwent complete ophthalmologic examinations by a single masked examiner. ROP data were gathered retrospectively. ROP developed in 19 of the 23 (83%) who received surfactant and 15 of the 25 (60%) controls (P = .1). Analysis of the worst stage of ROP for each infant also revealed no difference between the surfactant and control groups (P = .4). Our retrospective analysis of ROP data in a prospective double-masked randomized study revealed no significant effect of surfactant on the incidence or severity of ROP.

An association of pulmonary hypoplasia with unilateral agenesis of the diaphragm.

During a period of 5 years, 33 newborns with congenital diaphragmatic hernia were treated. Three groups presenting with respiratory distress in the delivery room were identified. These included 8 newborns with agenesis (group 1) and 4 newborns with nonagenesis (group 2), all of whom died. There were 19 nonagenesis survivors (group 3), giving an overall survival rate of 61%. Two newborns who presented beyond 6 hours of life were excluded. No one specific arterial blood gas value or ventilation parameter obtained preoperatively could predict survival. Postmortem right and left lung weights, lung/body weight ratio, and radial alveolar counts demonstrate that agenesis is a unique subgroup with profound pulmonary hypoplasia and a dismal prognosis.

Early metabolic effects of sepsis in the preterm infant: lactic acidosis and increased glucose requirement.

The effects of sepsis on carbohydrate metabolism were studied in preterm newborn infants (weight > 1.2 kg, appropriate for gestational age) without maternal endocrine problems who were being examined for infection. Plasma glucose, lactate, and insulin concentrations were measured at initial evaluation and then every 8 hours for a total of 48 hours. Blood, urine, and spinal fluid were obtained for culture and counterimmunoelectrophoresis. Dextrose was administered to each patient to maintain glucose levels in the normal range. Dextrose infusion rates were calculated in milligrams per kilogram per minute. Of the 29 infants, 6 had sepsis (positive culture and counterimmunoelectrophoresis results). Infants with sepsis had significant elevations of plasma lactate concentration (p < 0.003) but normal pH. The dextrose infusion rate was also significantly elevated in the infected infants (p < 0.01). No hypoglycemia or hyperglycemia was observed in either group. No significant difference in plasma insulin concentration was observed. We conclude that significant elevations in plasma lactate concentrations and dextrose infusion rate may be early clinical markers of neonatal sepsis in the first 48 hours of life.

Intact survival of a 280-g infant: an extreme case of growth retardation with normal cognitive development at two years of age.

The care of infants born weighing less then 500 g is not only controversial but is also associated with medical uncertainties. We report the management of a growth retarded infant who weighed 280 g at birth after 26.9 weeks' gestation. The child not only survived but appears developmentally normal at two years of age. Although the infant is the smallest survivor reported, the case demonstrates the importance of gestational assessment in deciding delivery room management.

Effects of dexamethasone on the hypothalamic-pituitary-adrenal axis in preterm infants.

The effects of dexamethasone therapy on the hypothalamic-pituitary-adrenal axis were tested in 10 premature infants with bronchopulmonary dysplasia by means of the corticotropin-releasing hormone stimulation test before therapy and on the seventh day of therapy. Adrenocorticotropic hormone and cortisol levels were determined by radioimmunoassay. There was significant suppression of the hypothalamic-pituitary-adrenal axis after 7 days of a currently used dexamethasone treatment regimen. A site of suppression was located at the level of the pituitary gland.