Namasivayam Ambalavanan

Early CPAP versus surfactant in extremely preterm infants

BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

Target ranges of oxygen saturation in extremely preterm infants.

BACKGROUND Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. CONCLUSIONS A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants

OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.

Acute kidney injury in critically ill newborns: What do we know? What do we need to learn?

Outcomes in critically ill neonates have improved over the past three decades, yet high residual mortality and morbidity rates exist. Acute kidney injury (AKI) is not just an innocent by-stander in the critically ill patient. Research on incidence and outcomes of AKI in the critically ill neonatal population is scarce. The objective of this publication is to (a) review original articles on the short- and long-term outcomes after neonatal AKI, (b) highlight key articles on adults and children with AKI in order to demonstrate how such insights might be applied to neonates, and (c) suggest clinical research studies to fill the gaps in our understanding of neonatal AKI. To date, observational studies suggest high rates of AKI and poor outcomes in critically ill neonates. Neonates with AKI are at risk of developing chronic kidney disease and hypertension. Large prospective studies are needed to test definitions and to better understand risk factors, incidence, independent outcomes, and mechanisms that lead to poor short- and long-term outcomes. Early biomarkers of AKI need to be explored in critically ill neonates. Infants with AKI need to be followed for sequelae after AKI.

Prospective Analysis of Pulmonary Hypertension in Extremely Low Birth Weight Infants

OBJECTIVES: Pulmonary hypertension is associated with bronchopulmonary dysplasia in extremely low birth weight (ELBW) infants and contributes to morbidity and mortality. The objective was to determine the prevalence of pulmonary hypertension among ELBW infants by screening echocardiography and evaluate subsequent outcomes. METHODS: All ELBW infants admitted to a regional perinatal center were evaluated for pulmonary hypertension with echocardiography at 4 weeks of age and subsequently if clinical signs suggestive of right-sided heart failure or severe lung disease were evident. Management was at discretion of the clinician, and infants were evaluated until discharge from the hospital or pre-discharge death occurred. RESULTS: One hundred forty-five ELBW infants (birth weight: 755 ± 144 g; median gestational age: 26 weeks [interquartile range: 24–27]) were screened from December 2008 to February 2011. Overall, 26 (17.9%) were diagnosed with pulmonary hypertension at any time during hospitalization (birth weight: 665 ± 140 g; median gestational age: 26 weeks [interquartile range: 24–27]): 9 (6.2%) by initial screening (early pulmonary hypertension) and 17 (11.7%) who were identified later (late pulmonary hypertension). Infants with pulmonary hypertension were more likely to receive oxygen treatment on day 28 compared with those without pulmonary hypertension (96% vs 75%, P < .05). Of the 26 infants, 3 died (all in the late group because of cor pulmonale) before being discharged from the hospital. CONCLUSIONS: Pulmonary hypertension is relatively common, affecting at least 1 in 6 ELBW infants, and persists to discharge in most survivors. Routine screening of ELBW infants with echocardiography at 4 weeks of age identifies only one-third of the infants diagnosed with pulmonary hypertension. Further research is required to determine optimal detection and intervention strategies.

Acute Kidney Injury Reduces Survival in Very Low Birth Weight Infants

Acute kidney injury (AKI) independently predicts mortality in children and adults. Our understanding of the epidemiology of AKI in very LBW (VLBW) infants is limited to retrospective studies. After adjustment for demographics, comorbidities, and interventions, infants with AKI have decreased survival compared with those without AKI. The study was conducted in regional quaternary care NICU of the University of Alabama at Birmingham. VLBW infants were followed prospectively and were classified into a serum creatinine (SCr)-based classification for AKI. Forty-one of 229 (18%) VLBW infants developed AKI. Those with AKI were more likely to have umbilical artery catheters, assisted ventilation, blood pressure medications, and lower 1- and 5-min Apgar scores. Of the infants with AKI, 17 of 41 (42%) died compared with 9 of 188 (5%) of those without AKI (p < 0.001). AKI was associated with mortality with a crude hazard ratio (HR) of 9.3 (95% CI, 4.1–21.0). After adjusting for potential confounders, those with AKI had higher chance of death as the adjusted HR was 2.4 (95% CI 0.95–6.04). AKI is associated with mortality in VLBW infants. Efforts to prevent and ameliorate the impact of AKI may improve the outcomes in this vulnerable population.

Both Extremes of Arterial Carbon Dioxide Pressure and the Magnitude of Fluctuations in Arterial Carbon Dioxide Pressure Are Associated With Severe Intraventricular Hemorrhage in Preterm Infants

OBJECTIVE. The goal was to test the hypothesis that extremes of Paco2 during the first 4 days after birth are associated with severe intraventricular hemorrhage (grades 3 and 4). METHODS. A single-center retrospective review of clinical and blood gas data in the first 4 postnatal days for 849 infants with birth weights of 401 to 1250 g was performed. The univariate and multivariate relationships of severe intraventricular hemorrhage with maximal and minimal Paco2, Paco2 averaged over time (time-weighted Paco2), and measures of Paco2 fluctuation (SD of Paco2 and difference in Paco2 [maximum minus minimum]) were assessed. RESULTS. Birth weight (mean ± SD) was 848 ± 212 g, and the median gestational age was 26 weeks. Infants with severe intraventricular hemorrhage had higher maximal Paco2 (median: 72 vs 59 mm Hg) and time-weighted Paco2 (mean: 49 vs 47 mm Hg) values but lower minimal Paco2 values (32 vs 37 mm Hg). High Paco2, low Paco2, SD of Paco2, and difference in Paco2 predicted severe intraventricular hemorrhage, but time-weighted average Paco2 was not as predictive. CONCLUSIONS. Both extremes and fluctuations of Paco2 are associated with severe intraventricular hemorrhage. It may be prudent to avoid extreme hypocapnia and hypercapnia during the period of risk for intraventricular hemorrhage.

Cytokines Associated With Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants

OBJECTIVE. The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days. METHODS. For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21. RESULTS. Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1β, 6, 8, and 10 and interferon γ and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor β. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude. CONCLUSIONS. The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation

The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing–NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin β-chain (βCys93) and, specifically, for S-nitrosation of βCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the βCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell–mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of βCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell–dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.

Altered DNA Methylation Profile in Idiopathic Pulmonary Fibrosis

RATIONALE DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF). OBJECTIVES To determine the DNA methylation changes in IPF and their effects on gene expression. METHODS Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels. MEASUREMENTS AND MAIN RESULTS DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression. CONCLUSIONS Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.