All trans-retinoic acid modulates hyperoxia-induced suppression of NF-kB-dependent Wnt signaling in alveolar A549 epithelial cells.

INTRODUCTION: Despite recent advances in perinatal medicine, bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth. Inflammation, the main cause for BPD, results in arrested alveolarization. All trans-retinoic acid (ATRA), the active metabolite of Vitamin A, facilitates recovery from hyperoxia induced cell damage. The mechanisms involved in this response, and the genes activated, however, are poorly understood. In this study, we investigated the mechanisms of action of ATRA in human lung epithelial cells exposed to hyperoxia. We hypothesized that ATRA reduces hyperoxia-induced inflammatory responses in A549 alveolar epithelial cells. METHODS: A549 cells were exposed to hyperoxia with or without treatment with ATRA, followed by RNA-seq analysis. RESULTS: Transcriptomic analysis of A549 cells revealed ~2,000 differentially expressed genes with a higher than 2-fold change. Treatment of cells with ATRA alleviated some of the hyperoxia-induced changes, including Wnt signaling, cell adhesion and cytochrome P450 genes, partially through NF-κB signaling. DISCUSSION/CONCLUSION: Our findings support the idea that ATRA supplementation may decrease hyperoxia-induced disruption of the neonatal respiratory epithelium and alleviate development of BPD.

Vitamin D deficiency and respiratory morbidity among African American very low birth weight infants.

BACKGROUND: Very low birth weight infants (VLBWI) have unexplained variation in respiratory morbidity, including respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). We examined a potential association to serum 25-hydroxyvitamin D (s-25OHD) on day one. STUDY DESIGN: Prospective, observational study on 89 VLBWI (≤1250 g). S-25OHD (day one and 21) and respiratory severity score (RSS) (day one) were examined. Other respiratory morbidities including BPD were compared between infants with s-25OHD ≤ 10 ng/ml (deficient) versus >10 ng/ml (adequate). RESULTS: Eighty one neonates (91%) were African Americans. The mean (SD) birthweight was 868 (229) g, gestational age 27 (2) weeks. On day one, mean (SD) s-25OHD was 15.48 (8.31) ng/ml, with 32 (37%) being vitamin D deficient. The deficiency and adequate VLBWI groups had similar birthweight; 860 (262) vs 873 (210) g, and gestational age; 27 (2) vs 27 (2) weeks. In 78 survivors, s-25OHD rose from 15.48 (8.31) ng/ml day one to 52.36 (22.49) ng/ml day 21 after supplementation, p < 0.001. On day one, increasing RSS was inversely related to s-25OHD, trend p = 0.054. Compared to the adequate group, the deficiency group had higher RSS (5.0 ±â€¯2.7 vs 3.6 ±â€¯1.9), required surfactant therapy more frequently (91% vs 72%), and needed home oxygen therapy more often (48% vs 26%), p ≤ 0.05 for all. Among infants with BPD, the severity of disease was inversely related to s-25OHD, trend p < 0.09. CONCLUSION: Lower levels of s-25OHD were associated with increased severity of RDS and BPD among a cohort of mostly African American VLBWI.

El rol de la hipertensión pulmonar en la displasia broncopulmonar / The role of pulmonary hypertension on bronchopulmonary dysplasia

Resumen Hace 50 años Northway describió la Displasia Broncopulmonar (DBP), en nacidos de pretérmino expuestos a ventilación mecánica. Desde entonces, ha aumentado la sobrevida de ellos; sin embar go, ha aparecido una "nueva DBP" y la incidencia de esta no ha disminuido. Una de las caracte rísticas de esta patología es la remodelación vascular anómala, que en su expresión más severa se conoce como Hipertensión Pulmonar (HP); con una incidencia de 17%, que es proporcional a la severidad de la DBP (33% en DBP severa); y como un factor de mortalidad (hasta un 48% mortali dad a 2 años con HP por DBP). Debido a esto resulta importante conocer los métodos diagnósticos y alternativas terapéuticas, tema que se discute en esta revisión. Considerando la alta mortalidad de la asociación HP-DBP, adquiere importancia una estrategia de tamizaje en la población de riesgo. El gold standard para el diagnóstico de HP es el cateterismo cardíaco, sin embargo, el ecocardio-grama transtorácico es una herramienta útil para el tamizaje y diagnóstico de HP en pacientes dis-plásicos, con mediciones cuantitativas y cambios cualitativos en la evaluación diagnóstica. A nivel sanguíneo el péptido natriurético tipo B (BNP), ha mostrado ser útil en el seguimiento; en cuanto a imágenes, la tomografía computarizada se utiliza en casos severos. En cuanto a las terapias, se han propuesto el óxido nítrico inhalado como vasodilatador pulmonar, los inhibidores de la fosfodies-terasas -sildenafil-, los antagonistas de la endotelina -bosentán- y los análogos de prostaciclinas -iloprost-. Aún no se cuenta con evidencia de alta calidad para su uso, dosis y duración del trata miento, pero hay variadas experiencias clínicas. Además, es relevante el cuidado interdisciplinario, destacando optimizar la nutrición. El desafío es lograr una prevención efectiva de la DBP y de sus complicaciones. Un protocolo de tamizaje de HP debe asociarse a una estratificación de riesgo y directrices de tratamiento.

Abstract 50 years ago, Northway described Broncopulmonary Dysplasia (BPD) in preterm infants exposed to mechanical ventilation. Since then, their survival has increased, nevertheless a "new BPD" has appeared and its incidence has not diminished. One of the characteristics of this pathology is the the abnormal vascular remodeling, which in its most severe expression is known as Pulmonary Hyper tension (PH); with an incidence of 17% in patients with BPD, which is proportional to the severity of the disease (33% in severe BPD), and as mortality factor (up to 48% 2-year mortality in PH-BPD). Thereby, it is important to know the diagnostic methods and therapeutic alternatives, topics discus sed in this review. Considering the high mortality in BPD associated PH, screening strategies in at risk population become important. The gold standard is cardiac catheterization; however, transtho-rathic echocardiography is a useful tool for the screening and diagnosis of PH in displasic patients, using cuantitive measures and cualitative changes in the evaluation. Seric type-B natriuretic peptide has shown to be useful for follow-up; regarding images, CT scan is used in severe cases. In terms of therapy; inhaled Nitric Oxide as a pulmonary vasodilator, phosphodiesterase inhibitors -sildenafil-, endotelin antagonists -bosentan-, and prostacyclin analogues -iloprost-, have been proposed. Their use, dosis and treatment lenght still lack support of high quality evidence, but diverse clinical expe riences have been described. Interdisciplinary care is also important, highlighting to optimize nu trition. Therefore, the challenge is to effectively prevent BPD and its complications. A PH screening protocol should be associated with risk stratification and treatment guidelines.

Potential Nutrients for Preventing or Treating Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a frequent complication occurring in extremely preterm infants. Despite recent advances in newborn medicine, the incidence of BPD does not appear to have changed markedly, and specific treatments and prevention strategies are still lacking. Nutrition plays an important role in normal lung development and maturation. Malnutrition may delay somatic growth and new alveoli development, thus aggravating pulmonary injury involved in the pathogenesis of BPD. However, few nutrients have been investigated for their potential to mitigate the pathogenesis of BPD. In this article, we reviewed the recent progress in research on potential nutrients useful for the prevention or treatment of BPD, including glutamine, cysteine and N-acetylcysteine, L-arginine and L-citrulline, long chain polyunsaturated fatty acids (LCPUFAs), inositol, selenium, and some antioxidant vitamins including vitamin A. Current evidence shows that vitamin A and LCPUFA can prevent BPD, and that L-citrulline might provide a new method to treat chronic pulmonary hypertension associated with BPD in premature infants. The effects of other nutrients on BPD prevention need to be further studied.

[The role of pulmonary hypertension on bronchopulmonary dysplasia]. / El rol de la hipertensión pulmonar en la displasia broncopulmonar.

50 years ago, Northway described Broncopulmonary Dysplasia (BPD) in preterm infants exposed to mechanical ventilation. Since then, their survival has increased, nevertheless a "new BPD" has appeared and its incidence has not diminished. One of the characteristics of this pathology is the the abnormal vascular remodeling, which in its most severe expression is known as Pulmonary Hyper tension (PH); with an incidence of 17% in patients with BPD, which is proportional to the severity of the disease (33% in severe BPD), and as mortality factor (up to 48% 2-year mortality in PH-BPD). Thereby, it is important to know the diagnostic methods and therapeutic alternatives, topics discus sed in this review. Considering the high mortality in BPD associated PH, screening strategies in at risk population become important. The gold standard is cardiac catheterization; however, transtho-rathic echocardiography is a useful tool for the screening and diagnosis of PH in displasic patients, using cuantitive measures and cualitative changes in the evaluation. Seric type-B natriuretic peptide has shown to be useful for follow-up; regarding images, CT scan is used in severe cases. In terms of therapy; inhaled Nitric Oxide as a pulmonary vasodilator, phosphodiesterase inhibitors -sildenafil-, endotelin antagonists -bosentan-, and prostacyclin analogues -iloprost-, have been proposed. Their use, dosis and treatment lenght still lack support of high quality evidence, but diverse clinical expe riences have been described. Interdisciplinary care is also important, highlighting to optimize nu trition. Therefore, the challenge is to effectively prevent BPD and its complications. A PH screening protocol should be associated with risk stratification and treatment guidelines.

Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.

Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

Enteral zinc supplementation and growth in extremely-low-birth-weight infants with chronic lung disease.

OBJECTIVE: Zinc deficiency causes growth deficits. Extremely-low-birth-weight (ELBW) infants with chronic lung disease (CLD), also known as bronchopulmonary dysplasia, experience growth failure and are at risk for zinc deficiency. We hypothesized that enteral zinc supplementation would increase weight gain and linear growth. METHODS: A cohort of infants was examined retrospectively at a single center between January 2008 and December 2011. CLD was defined as the need for oxygen at 36 weeks postmenstrual age. Zinc supplementation was started in infants who had poor weight gain. Infants' weight gain and linear growth were compared before and after zinc supplementation using the paired t test. RESULTS: A total of 52 ELBW infants with CLD met entry criteria. Mean birth weight was 682 ± 183 g, and gestational age was 25.3 ± 2 weeks. Zinc supplementation started at postmenstrual age 33 ± 2 weeks. Most infants received fortified human milk. Weight gain increased from 10.9 before supplementation to 19.9 g · kg(-1) · day(-1) after supplementation (P < 0.0001). Linear growth increased from 0.7 to 1.1 cm/week (P = 0.001). CONCLUSIONS: Zinc supplementation improved growth in ELBW infants with CLD receiving human milk. Further investigation is warranted to reevaluate zinc requirements, markers, and balance.

Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country.

BACKGROUND: Zinc plays a pivotal role in the pathogenesis of many diseases and in body growth. Preterm neonates have high zinc requirements. OBJECTIVE: The objective of the study was to investigate the efficacy of zinc supplementation in reducing morbidity and mortality in preterm neonates and to promote growth. DESIGN: This was a prospective, double-blind, randomized controlled study of very-low-birth-weight preterm neonates randomly allocated on the seventh day of life to receive (zinc group) or not receive (control group) oral zinc supplementation. Total prescribed zinc intake ranged from 9.7 to 10.7 mg/d in the zinc group and from 1.3 to 1.4 mg/d in the placebo control group. The main endpoint was the rate of neonates with ≥ 1 of the following morbidities: late-onset sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leucomalacia, and retinopathy of prematurity. Secondary outcomes were mortality and body growth. RESULTS: We enrolled 97 neonates in the zinc group and 96 in the control group. Morbidities were significantly lower in the zinc group (26.8% compared with 41.7%; P = 0.030). The occurrence of necrotizing enterocolitis was significantly higher in the control group (6.3% compared with 0%; P = 0.014). Mortality risk was higher in the placebo control group (RR: 2.37; 95% CI: 1.08, 5.18; P = 0.006). Daily weight gain was similar in the zinc (18.2 ± 5.6 g · kg⁻¹ · d⁻¹) and control (17.0 ± 8.7 g · kg⁻¹ · d⁻¹) groups (P = 0.478). CONCLUSION: Oral zinc supplementation given at high doses reduces morbidities and mortality in preterm neonates. This trial was registered in the Australian New Zealand Clinical Trial Register as ACTRN12612000823875.

Efectos protectores del aceite de Nigella sativa en la lesión pulmonar inducida por hiperoxia / Protective Effects of Nigella sativa Oil in Hyperoxia-Induced Lung Injury

Antecedentes: Se cree que la lesión pulmonar inducida por el oxígeno conduce al desarrollo de una displasia broncopulmonar en los recién nacidos prematuros. Hemos evaluado los efectos favorables del aceite de Nigella sativa (NSO) en ratas con lesión pulmonar inducida por hiperoxia. Métodos: Se utilizaron 30 ratas Sprague-Dawley recién nacidas a las que se dividió aleatoriamente en 3 grupos para aplicarles hiperoxia (O2 al 95%), hiperoxia+NSO o el grupo de control (O2 al 21%). A las crías del grupo de hiperoxia+NSO se les administró NSO a una dosis de 4ml/kg al día por vía intraperitoneal durante el periodo de estudio. Se realizó una evaluación histopatológica, inmunoquímica y bioquímica (superóxido dismutasa [SOD], glutatión peroxidasa [GSH-Px], malonilaldehído [MDA] y mieloperoxidasa [MPO]). Resultados: En la evaluación histopatológica e inmunoquímica, la gravedad de la lesión pulmonar fue significativamente inferior en el grupo de hiperoxia+NOS (p<0,05). Los niveles tisulares de GSH-Px y SOD se mantuvieron significativamente preservados, y los niveles de MDA y MPO fueron significativamente inferiores en el grupo de hiperoxia+NSO (p<0,05). Conclusión: El NSO redujo significativamente la gravedad de la lesión pulmonar debida a la hiperoxia(AU)

Background: Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia in premature infants. We have evaluated the beneficial effects of Nigella sativa oil (NSO) on rats with hyperoxia-induced lung injury. Methods: Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups as hyperoxia (95% O2), hyperoxia+NSO and control (21% O2). Pups in the hyperoxia+NSO group were administered intraperitoneal NSO at a dose of 4ml/kg daily during the study period. Histopathologic, immunochemical, and biochemical evaluations (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], malonaldehyde [MDA] and myeloperoxidase [MPO]) were performed. Results: In the histopathologic and immunochemical evaluation, severity of lung damage was significantly lower in the hyperoxia+NOS group (P<0.05). Tissue GSH-Px and SOD levels were significantly preserved, and MDA, MPO levels were significantly lower in the hyperoxia+NSO group (P<0.05). Conclusion: NSO significantly reduced the severity of lung damage due to hyperoxia(AU)

Calcium absorption in very low birth weight infants with and without bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the effects of early bronchopulmonary dysplasia (BPD) on calcium (Ca) metabolism and growth in very low birth weight (VLBW) infants. STUDY DESIGN: A dual-tracer, stable isotope method was used to assess Ca absorption in VLBW infants. Infants with early BPD received energy-dense feedings and mild fluid restriction. RESULTS: Sixteen of 41 preterm infants were classified as having early BPD. Fractional Ca absorption (early BPD, 58.4 ± 4.6% versus no early BPD, 50.3 ± 4.0%, P = .2), total Ca absorption (early BPD, 127 ± 14 mg/kg/d versus no early BPD, 104 ± 9 mg/kg/d, P = .9), and Ca retention (early BPD, 99.6 ± 10.0 mg/kg/d versus no early BPD, 91.0 ± 9.8 mg/kg/d, P = .2) were similar among groups. There was no significant difference in weight gain, linear growth, or head circumference growth between groups. CONCLUSIONS: The ability of VLBW infants with early BPD and fluid restriction to grow and accrete calcium is similar to those without early BPD. The use of high caloric density feedings in VLBW infants with early BPD can help achieve bone and overall growth outcomes close to those achievable in utero.

Palivizumab: a review of its use as prophylaxis for serious respiratory syncytial virus infection.

Palivizumab (Synagi) is a humanized monoclonal antibody that provides immunoprophylaxis against serious lower respiratory tract infections (LRTIs) caused by respiratory syncytial virus (RSV). RSV is the leading cause of hospitalization for LRTIs in infants, causing winter- or wet-season epidemics. In two double-blind, placebo-controlled trials, intramuscular palivizumab 15 mg/kg every 30 days for 5 months significantly reduced RSV-related hospitalizations by 55% in 1502 infants with prematurity and/or bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) and by 45% in 1287 infants with hemodynamically significant congenital heart disease (HSCHD). Reductions were statistically significant versus placebo in infants with BPD/CLD, with all degrees of prematurity, and with acyanotic/other heart disease. Palivizumab was generally well tolerated, with < or =1.9% of recipients discontinuing treatment for tolerability reasons. In placebo-controlled trials, the most common potentially drug-related adverse events were fever, nervousness, injection-site reactions, and diarrhea. Drug-related events occurred in 7.2-11% of palivizumab recipients in controlled trials (vs 6.9-10% with placebo) and 0-7.9% in open-label trials. Very few serious potentially drug-related adverse events occurred in clinical trials; four occurred in 2 of 285 patients in one open-label trial. No significant anti-palivizumab antibodies developed during palivizumab use. Palivizumab trough serum concentrations were below the recommended 40 microg/mL in about 33% and up to 14% of children prior to their second and third palivizumab injections. In pharmacoeconomic studies, the cost of palivizumab per hospitalization averted was generally lowest in the highest-risk infants. Drug cost was generally the most influential factor in sensitivity analyses. In conclusion, prophylaxis with palivizumab significantly reduces the incidence of RSV-related hospitalization relative to placebo and is generally well tolerated in high-risk infants aged <2 years, including those with prematurity and BPD/CLD or HSCHD, which are risk factors for early or serious RSV infection. Palivizumab is approved for use in these patients. Other high-risk infants in whom palivizumab has not been formally assessed, such as those with immunodeficiency, cystic fibrosis, or location-specific risk factors (including extended hospital stays) might potentially benefit from palivizumab. The use of palivizumab in these other high-risk populations is likely to be determined as much by pharmacoeconomic considerations as by efficacy outcomes.

[Nutrition and bronchopulmonary dysplasia]. / Nutrition et dysplasie bronchopulmonaire.

Bronchopulmonary dysplasia remains a frequent complication of extreme prematurity. In preterm neonates catch-up and pulmonary alveolar growth occur during the first two years of life. However 10 to 25% of preterm infants with bronchopulmonary dysplasia are under-nourished after two years of age, and 30 to 60% of them also suffer from persistent airway obstruction, hyperinflation and bronchial hyperreactivity. Recommendations on nutritional requirements in this population are not yet clearly defined, but an adequate nutritional status in prenatal and early postnatal period can have long-term consequences on brain and lung development. There are a few randomised trial of nutrition for preterm infants with bronchopulmonary dysplasia after discharge. Caloric and protein requirements in this population are probably higher than in full-term infants. Moreover there are potential benefits in using specific nutrients: supplementation with long chain polyunsaturated fatty acids could decrease lung inflammation injuries, glutamine is the main source of energy of pneumocyte, vitamin A is essential for lung development, inositol is necessary for surfactant synthesis, vitamin E and selenium have anti-oxidant effects. Controlled nutritional trial are needed with a long term follow-up in late childhood in order to test their effects on growth and pulmonary status.

Growth and body composition in infants with bronchopulmonary dysplasia up to 3 months corrected age: a randomized trial of a high-energy nutrient-enriched formula fed after hospital discharge.

OBJECTIVES: (1) To determine whether nutrient malabsorption or inadequate nutrient intake were involved in the cause of growth delay in patients with bronchopulmonary dysplasia, and (2) to determine whether a nutrient-enriched formula given to infants with bronchopulmonary dysplasia to 3 months corrected age improves the rate of growth with greater lean and bone mass accretion when compared with infants fed an isoenergetic standard infant formula. STUDY DESIGN: A blinded, nutrition intervention trial of 60 preterm infants with bronchopulmonary dysplasia (birth weight, 866 +/- 169 g, gestational age, 26 +/- 1.5 weeks) randomized to either nutrient-enriched formula or standard formula. Growth, body composition, and nutrient retention were compared between groups by Student's t tests and analysis of covariance. RESULTS: Infants fed the enriched formula had significantly greater nitrogen and mineral retention at 38 weeks' postmenstrual age, and only the infants fed enriched formula had zinc retention similar to the intrauterine accretion. At 3 months corrected age infants fed enriched formula attained greater length (P < .05), greater radial bone mineral content (P < .01), and greater lean mass (P < .01). The male infants in the enriched formula group had greater whole body bone mineral content than did male infants in the standard formula group (P = .02). CONCLUSIONS: Greater linear growth and lean and bone mass in the enriched formula group suggests that infants with bronchopulmonary dysplasia attain faster "catch-up" growth when fed higher intakes of protein, calcium, phosphorus, and zinc than provided in standard proprietary formulas.

Subependymal caudothalamic groove hyperechogenicity and neonatal chronic lung disease.

Chronic lung disease is associated with several poorly defined risk factors for impaired cerebral development. Late neonatal onset of subependymal hyperechogenic areas in the caudothalamic groove has been reported in association with dexamethasone treatment and postnatal cytomegalovirus infection. We reviewed charts of 18 patients who developed subependymal hyperechogenicity beyond the first week of life, as well as charts of 79 patients belonging to a prospective surfactant study group. Thirteen of the 18 patients with subependymal hyperdensities had been treated with surfactant and were all found in the subgroup with chronic lung disease. In the surfactant-treated patients who did not develop chronic lung disease, we could not find any patient with subependymal hyperdensities. From the remaining five patients with ultrasound lesions, but who were not treated with surfactant, three had developed chronic lung disease. There was no evident association with dexamethasone treatment or cytomegalovirus infection. Our results support the idea of an association between chronic lung disease and the described echographic lesions in the caudothalamic groove, but the nature of the link between them is still unclear.

Vitamin A deficiency and severe bronchopulmonary dysplasia in very low birthweight infants.

Preterm infants often have abnormally low serum vitamin A concentrations. Persistence of vitamin A deficiency for a prolonged postnatal period may contribute to the development of bronchopulmonary dysplasia. We retrospectively analyzed data from 22 infants with birthweight < or = 1250 g who had hyaline membrane disease requiring mechanical ventilation with oxygen and in whom serum vitamin A concentrations had been measured at the onset of enteral feeding and every 2 weeks thereafter. Thirteen infants (low serum vitamin A group) had one or more serum vitamin A concentrations < or = 11 mcg/dL at > 10 days of age. In 9 infants (higher serum vitamin A group) all serum vitamin A concentrations were > 11 mcg/dL at > 10 days of age. Mean birthweight, mean gestational age, sex, race, incidence of antenatal maternal glucocorticoid treatment and ventilatory support on the first day of life were similar for the two groups. Severe bronchopulmonary dysplasia was as defined as characteristic radiographic changes and either discharge from the hospital with supplemental oxygen or death from respiratory failure at > 28 days of age following mechanical ventilation with oxygen since birth. The incidence of severe bronchopulmonary dysplasia was significantly higher in the low serum vitamin A group (11/13, 3 deaths vs. 1/9, no deaths; p=0.001). The incidence of pulmonary air leak, the number of ventilator days, the number of days of postnatal glucocorticoid treatment for chronic lung disease, the number of episodes of suspected sepsis and the number of days of antibiotic treatment also were higher in the low serum vitamin A group. Low serum vitamin A group infants were older at the onset of enteral feeding (21 days vs. 8 days; p = 0.001) and during feeding their average daily enteral intake of vitamin A was lower (713 IU vs. 1255 IU; p = 0.001) when compared with infants in the higher serum vitamin A group. Our retrospective analysis of data from these infants confirms earlier reports from other workers that persistent marked vitamin A deficiency in very low birthweight infants is associated with a high incidence of severe bronchopulmonary dysplasia, delayed onset of enteral feeding and low enteral intake of vitamin A.

Use of the intramuscular relative-dose-response test to predict bronchopulmonary dysplasia in premature infants.

We tested the hypothesis that an intramuscular relative dose response (IM-RDR) on day 1 of life would more accurately predict which premature infants would develop bronchopulmonary dysplasia (BPD) than single measurements of retinol, retinyl palmitate (RP), or retinol binding protein (RBP). Seventy-five premature infants < or = 32 wk gestation had the IM-RDR on day 1 of life. An RDR > or = 25% occurred in 6 of 37 infants who did not develop BPD compared with 15 of 38 infants who developed BPD (P = 0.025). Retinol, RP, and RBP on day 1 were not different between the groups. BPD infants who received postnatal dexamethasone during their hospital course had a higher day-28 baseline retinol concentration (1.19 +/- 0.15 mumol/L) than did the group with no BPD (0.82 +/- 0.06 mumol/L) (P = 0.03). However, the effect of postnatal dexamethasone on serum retinol was biphasic, rising initially, and then declining after 8-12 d. RP values at time 0 and 5 h on day 28 were higher than day 1 values in both infants without BPD and infants with BPD who did not receive dexamethasone. Retrospective analysis also revealed a significant correlation between a day-1 RDR > or = 25% and the incidence of intraventricular hemorrhage in these premature infants. Because the IM-RDR is more helpful in predicting the development of BPD than single serum retinol and RP analyses, this test could be useful in determining which premature infants might benefit from supplemental vitamin A for BPD.

Rickets of prematurity: a case report.

A case report is given, and an attempt made to summarize our knowledge about this disorder. An extremely premature infant (birth weight 750 grammes) developed progressive rickets resulting in fractures despite phosphate, calcium and calciferol (vitamin D) supplementation. The patient had mild respiratory distress syndrome but later developed broncopulmonary dysplasia. Initial biochemical evidence of rickets occurred by the 6th week of post-natal life (or 31 weeks post-conceptional age). Although the serum levels of vitamin D or 1-alphahydroxy vitamin D were not determined, it is assumed that the levels of the active metabolite was probably low since clinical, biochemical and radiologic cure of the rickets occurred following its usage.

Treatment of pulmonary hypertension with diltiazem in a child with bronchopulmonary dysplasia.

A two-year-old child dying of pulmonary hypertension and cor pulmonale secondary to bronchopulmonary dysplasia, was demonstrated to have reactive pulmonary hypertension in response to 100% oxygen and isoproterenol infusion. In an attempt to find an oral medication to maintain pulmonary vasodilatation, experimental trials were done using hydralazine, salbutamol, nifedipine and diltiazem. Cardiac index, pulmonary and systemic vascular resistances and intrapulmonary shunts were monitored during the trials. Hydralazine, salbutamol and nifedipine were ineffective. Diltiazem 2.0 mg given every 6 h resulted in a profound and sustained decrease in pulmonary pressures and resistance, and a reversal of the cor pulmonale.

Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease.

Aerosolized ribavirin was evaluated in the treatment of respiratory syncytial virus lower respiratory tract disease in 53 infants, 36 of whom had underlying diseases. Of the total infants, 26 were studied in a double-blind, placebo-controlled manner; 14 received ribavirin and 12 received placebo, a water aerosol, for an average of five days. When the infants with bronchopulmonary dysplasia and congenital heart disease treated with ribavirin were compared with those receiving placebo, the treated infants showed a significantly faster rate of improvement in their illness severity score. The degree of improvement in the total group of infants receiving ribavirin compared with those receiving placebo was similarly greater, and at the end of therapy significantly greater improvement was also demonstrated in their arterial blood gas values and in the amount of virus shed from their nasal washes. No toxic or adverse effects of the aerosol therapy were observed in any of the 53 infants studied, and resistance to ribavirin did not develop in any of the respiratory syncytial virus strains isolated, despite prolonged treatment in some of the more ill infants.