Alan D. Stiles

Trial of vitamin A supplementation in very low birth weight infants at risk for bronchopulmonary dysplasia

We performed a randomized, double-blind, controlled trial to determine whether vitamin A supplementation in a group of very low birth weight infants would reduce the incidence of bronchopulmonary dysplasia. Forty-nine infants (birth weight 700 to 1100 gm) requiring mechanical ventilation and supplemental oxygen at 96 hours age were randomly assigned to receive either 2000 IU retinyl palmitate (n = 27) or saline placebo (n = 22) intramuscularly every other day for up to 14 doses. There were no differences between treatment groups in the incidences of bronchopulmonary dysplasia at 31 days of postnatal age (vitamin A group 48%, placebo group 55%; p = 0.776), supplemental oxygen requirement at 34 weeks of postconceptional age, or other complications of prematurity. The vitamin A group had higher mean plasma vitamin A concentrations than the placebo group, but mean plasma vitamin A concentrations were greater than 20 micrograms/dl (suggesting sufficiency) in both groups after the first study week. By study day 28, only one fourth of the infants in either group had plasma vitamin A concentrations less than 20 micrograms/dl. In contrast to an earlier report, we found no change in the incidence of BPD with vitamin A supplementation. Our findings may reflect a low baseline incidence of vitamin A deficiency in the study population and recent changes in the respiratory care of very low birth weight infants. The latter may have lessened the potential impact of vitamin A deficiency on lung disease.

Increased incidence of sepsis at birth in neutropenic infants of mothers with preeclampsia

Neutropenia is often found at birth in infants born to mothers with preeclampsia, and is most likely present in utero. To determine whether this neutropenia is associated with an increased incidence of early-onset sepsis, we reviewed the hospital records of 301 low birth weight infants of mothers with preeclampsia. Early-onset sepsis was proved if the result of a culture of blood or cerebrospinal fluid in the first 48 hours of life was positive, or presumed if culture results were negative but two or more clinical signs of sepsis were present and the attending neonatologist believed that an infant was infected and needed at least 7 days of antibiotic therapy. Forty-eight percent of low birth weight infants of mothers with preeclampsia had neutropenia at less than 12 hours of age. Infants with neutropenia had mothers with more severe preeclampsia, were more premature (30 weeks vs 32 weeks), weighed less (1097 gm vs 1615 gm), and were more likely to be small for gestational age. Although maternal and obstetric risk factors for infection were less common in the group with neutropenia, rates of proven or presumed early-onset sepsis were higher (14% vs 2%; p < 0.001). Sepsis was proved in 6% of infants with neutropenia and in none of the infants without neutropenia (p = 0.03). A logistic regression analysis of the relative effects of birth weight, gestational age, and absolute neutrophil count on the incidence of sepsis revealed that only a low absolute neutrophil count correlated significantly with an increased risk of early-onset sepsis in infants with neutropenia.

Effects of retinoic acid on airspace development and lung collagen in hyperoxia-exposed newborn rats

Impaired septal formation and decreased alveolarization are often caused by hyperoxic injury to the developing lung and are characteristic features of bronchopulmonary dysplasia. Dexamethasone, frequently administered to infants during oxygen exposure, also inhibits septal formation in the newborn lung. Vitamin A administration reduces the incidence of bronchopulmonary dysplasia in vitamin A-deficient premature infants, and retinoic acid improves alveolarization in newborn rats treated with dexamethasone, indicating that retinoic acid may be useful in preventing hyperoxia-induced impaired septation in bronchopulmonary dysplasia. To investigate whether treatment with retinoic acid during exposure to hyperoxia would improve septal formation, newborn rats exposed to ≥90% O2 from d 3 of life to d 14 were treated with retinoic acid (d 3–13 of life) and/or dexamethasone (d 4–13 of life). In contrast with the effects of retinoic acid on dexamethasone-induced inhibition of alveolarization, we found that retinoic acid did not improve septal formation or decrease airspace size in animals exposed to hyperoxia alone or to hyperoxia plus dexamethasone. Retinoic acid did, however, increase collagen in airspace walls as demonstrated by staining and immunohistochemistry. There was no increase in procollagen mRNA by Northern hybridization analysis, indicating that retinoic acid-associated increases in lung collagen are likely due to posttranscriptional regulation. There was a trend toward increased survival in hyperoxia in animals treated with retinoic acid to the extent that combined therapy with retinoic acid and dexamethasone resulted in the greatest improvement in animal survival. These results suggest that although retinoic acid may be of benefit in hyperoxia-induced lung injury and may have important effects on lung matrix, it does not prevent impairment of septation or induce alveolar formation during exposure to hyperoxia.

Effect of L-Arginine Infusion on Infants with Persistent Pulmonary Hypertension of the Newborn

Nitric oxide (NO) is thought to be a primary mediator of the reduction in pulmonary vascular resistance which occurs in the newborn period. L-arginine is the precursor for the formation of nitric oxide in the pulmonary endothelium. Low serum arginine levels have been reported in infants with persistent pulmonary hypertension of the newborn (PPHN). We infused a single L-arginine dose of 500 mg/kg over 30 min to 5 consecutive infants with PPHN. Ninety minutes after infusion we observed an associated rise in PaO2 of 37 to 84 mm Hg and, in 4 of 5 infants, a reduction in oxygenation index (OI) of 33-50% over the 5-hour period following infusion. Infusion was not associated with adverse effects. These observations suggest that L-arginine administration may be an effective therapeutic alternative in infants with PPHN.

Tissue-Specific Developmental Regulation of the Messenger Ribonucleic Acids Encoding the Growth Hormone Receptor and the Growth Hormone Binding Protein in Rat Fetal and Postnatal Tissues

ABSTRACT: Tissue responsiveness to growth hormone is likely to be regulated by local concentrations and availability of the membrane-bound growth hormone receptor (GHR) and perhaps by the actions of the soluble growth hormone binding protein (GHBP). To determine whether the developmental regulation of the GHR and GHBP might vary among tissues, we have measured the relative abundance of the 4.3-kb GFR and 1.3-kb GHBP mRNA in rat fetal and postnatal liver, kidney, lung, and ileum by Northern hybridization of polyadenylated RNA with a 32P-labeled antisense riboprobe prepared from a rat GHR cDNA. The GHR and GHBP mRNA were both present in the four tissues studied at fetal age 19 d (E19). In postnatal liver, both transcripts increased in abundance 3− to 4-fold after 14 d to mature levels at 42 d (p = 0.0001). Similar changes were seen in postnatal kidney for GHR mRNA abundance; however, GHBP mRNA abundance increased only 2− to 3-fold to mature levels by 28 d (kidney GHR versus GHBP mRNA profile, p = 0.0001). In lung, a 2-fold linear increase in GHR mRNA abundance was observed (p = 0.0019), but the GHBP mRNA did not change (GHR versus GHBP mRNA profile, p = 0.0006). Both transcripts decreased in abundance by 2− to 3-fold from E19 to 42 d in ileum (p < 0.05). The abundance of both transcripts was three to 10 times greater in 60-d liver than in the other three tissues at 60 d. The variation in abundance and in the developmental profiles of the GHR and GHBP mRNA observed in these fetal and postnatal tissues suggests that the GHR and GHBP could mediate differences within and between tissues in the responsiveness to growth hormone. The differential regulation of the two transcripts evident in kidney and lung supports the emerging evidence that the GHBP may have a funciton distinct from that of the GHR.

Administration of granulocyte colony-stimulating factor to neutropenic low birth weight infants of mothers with preeclampsia

Nine low birth weight infants with neutropenia born to mothers with preeclampsia were treated with granulocyte-colony stimulating factor, 10 micrograms/kg intravenously, within 24 hours of birth and at 24-hour intervals for a maximum of three doses if neutropenia persisted. The absolute neutrophil count increased significantly in eight of the nine infants within 6 hours, and neutrophilia was sustained for at least 72 hours after administration of a single dose of granulocyte-colony stimulating factor.

Characterization of proteoglycans synthesized by fetal rat lung type II pneumonocytes in vitro and the effects of cortisol

The synthesis of proteoglycans by primary cultures of 19-day gestation fetal rat lung Type II pneumonocytes was studied. The cells were grown in the presence of [3H]-glucosamine and/or [35S]-Na2SO4 and the radioactive label incorporated into proteoglycans was analyzed. Proteoglycans of high molecular weight (approximately 200 Kd) were isolated by gel permeation chromatography and contained both [3H] and [35S]. The glycosaminoglycan composition of the proteoglycans was determined by electrophoresis and autoradiography. The medium contained 65-80% of the labeled proteoglycans and was enriched for hyaluronate, with lesser amounts of the sulfated glycosaminoglycans (dermatan sulfate greater than heparan sulfate greater than chondroitin sulfate). The cell layers retained 20-35% of the labeled proteoglycans and was enriched for heparan sulfate, with lesser amounts of chondroitan sulfate greater than dermatan sulfate greater than hyaluronate. The synthesis of proteoglycans was time-dependent and was stimulated by increasing concentrations of fetal bovine serum. Cortisol inhibited proteoglycan synthesis, apparently by decreasing the availability of proteoglycan core-protein.

THE INCIDENCE AND EFFECTS OF MOTION SICKNESS AMONG MEDICAL ATTENDANTS DURING TRANSPORT

Motion sickness is a common and often debilitating problem. The purpose of this study was to determine the incidence and effects of the motion sickness syndromes, the Nausea and Sopite Syndromes, among medical transport personnel. Members of the Transport Teams of the University of North Carolina Hospitals completed a questionnaire to identify a history of susceptibility to motion sickness. An additional questionnaire evaluated each individual for symptoms of motion sickness during transport. The Digit Span Test portion of the Mini-Mental Status Examination (DST-MMSE) was used to evaluate cognitive function after transport. Control data on each subject were obtained by testing during nontransport shifts. The Nausea Syndrome was observed during transport in 46% of subjects; 65% experienced symptoms consistent with the Sopite Syndrome. Pretransport surveys were predictive of the Nausea Syndrome, but not of the Sopite Syndrome. The Nausea Syndrome was related to subjective assessments of the severity of motion experienced; the Sopite Syndrome did not correlate with the severity of motion. The DST-MMSE scores after transport were significantly lower than scores during nontransport periods in 85% of personnel. We conclude that transport personnel are susceptible to motion sickness manifested by both the Nausea Syndrome and the Sopite Syndrome. The presence of motion sickness is associated with a significant decline in performance on tests of attention and concentration.

Effect of Initial Nitric Oxide Concentration on Outcome in Infants with Persistent Pulmonary Hypertension of the Newborn

A randomized nonblinded comparison of two treatment groups was performed to determine whether treatment of infants with persistent pulmonary hypertension of the newborn using a continuous 6-ppm dose of inhaled nitric oxide (iNO) changes the likelihood of death or utilization of extracorporeal membrane oxygenation (ECMO) when compared to infants treated with 20 ppm iNO for 4 h followed by 6 ppm. Twenty-nine infants with a gestational age ≥34 weeks and a diagnosis of persistent pulmonary hypertension of the newborn were enrolled during the 3- year study period. The relative risk (20/6 vs. 6 ppm) for treatment with ECMO was 3.11 (p = 0.02), for death it was 2.80 (p = 0.32), and for either death or ECMO it was 3.42 (p = 0.006). There was no apparent advantage of treatment with a higher dosage of iNO at the initiation of therapy in the reduction of death or utilization of ECMO. These data suggest that a continuous lower dose of iNO results in a comparable improvement in oxygenation as a short exposure of higher dose iNO at the initiation of therapy.

Relation between serum insulinlike growth factor-1, insulinlike growth factor binding protein-2, and insulinlike growth factor binding protein-3 and nutritional intake in premature infants with bronchopulmonary dysplasia.

Background The usefulness of serum insulinlike growth factor (IGF)-system–peptide measurement to assess the adequacy of nutritional intake in premature infants with chronic lung disease bronchopulmonary dysplasia (BPD) was assessed. Methods Twenty-nine premature infants had serial measurements taken of their serum IGF-1, insulinlike growth factor binding protein (IGFBP)-2, and IGFBP-3 concentrations between 2 and 6 weeks of age. Regression analyses were used to examine the relation between nutritional parameters and IGF-1, IGFBP-2, and IGFBP-3 concentrations in premature infants with and without BPD. Results The group of infants with BPD (n = 12) did not differ from infants without BPD (n = 17) in gestational age or weight at entry, but gained less weight during the study period. In infants without BPD, IGF-1 correlated positively with protein intake (r = 0.50) and caloric intake (r = 0.41) over the 3 days before sample collection and with weight change over the previous week (r = 0.46). In contrast, infants with BPD showed a significant correlation between IGF-1 and weight change (r = 0.54) only. There was a significant negative correlation between IGFBP-2 and protein intake in infants without BPD (r = −0.50) and in infants with BPD (r = −0.41). Negative correlations between IGFBP-2 and both weight change (r = −0.64) and caloric intake (r = −0.43) over the previous week were found only in the group of infants without BPD. IGFBP-3 correlated positively with weight changes and protein intake in both groups but correlated with caloric intake only in the group without BPD. Multiple regression analyses were used to determine significant independent variables associated with IGF-1, IGFBP-2, and IGFBP-3. In infants without BPD, significant independent predictors of IGFBP-2 were 7-day weight change and 2-day protein intake; 3-day caloric intake was the only significant independent predictor for IGFBP-3. For infants with BPD, 3-day weight gain was the only independent variable associated with serum IGF-1. Protein intake in the week before sample collection was an independent predictor of IGFBP-2 and 3-day weight change and 2-day protein intake were independent predictors of IGFBP-3. Conclusions These results confirm that changes in serum IGF-1, IGFBP-2, and IGFBP-3 reflect the nutritional status of premature infants and demonstrate that the relation between these proteins and nutritional intake differs in premature infants with and without BPD. Refinement of these observations by future studies may permit a more accurate determination of the protein and caloric intake sufficient for growth and repair after injury in premature infants with lung disease.