Inter-center variation in death or tracheostomy placement in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born <32 weeks' gestation with sBPD. The association between center and the primary outcome of D/T was analyzed by multivariable modeling. Hypothesized diagnoses/practices were included to determine if these explained any observed ICV in D/T. RESULTS: D/T occurred in 280 (20%) of 1383 eligible infants from 21 centers. ICV was significant for D/T (range 2-46% by center, P<0.001) and tracheostomy placement (n=187, range 2-37%, P<0.001), but not death (n=93, range 0-19%, P=0.08). This association persisted in multivariable analysis (adjusted center-specific odds ratios for D/T varied 5.5-fold, P=0.009). CONCLUSIONS: ICV in D/T is apparent among infants with sBPD. These results highlight that the indications for tracheostomy (and subsequent chronic ventilation) remain uncertain.

Inhaled nitric oxide usage in preterm infants in the NICHD Neonatal Research Network: inter-site variation and propensity evaluation.

OBJECTIVE: The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, a National Institutes of Health consensus development conference cautioned against use of iNO in preterm infants. This study aims (1) to determine the prevalence and variability in use of iNO in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) before and after the consensus conference and (2) separately, to examine associations between iNO use and severe bronchopulmonary dysplasia (BPD) or death. STUDY DESIGN: The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008 to 2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO. RESULT: A total of 4885 infants were assessed between 2008 and 2011; 128 (2.6%) received iNO before day 7, 140 (2.9%) between day 7 and 28, and 47 (1.0%) at >28 days. Center-specific iNO use during 2008 to 2010 ranged from 21.9 to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6 to 1.6% (P<0.001) in 2011. The use of iNO started between day 7 and day 14 was more prevalent among younger infants with more severe courses in week 1 and associated with increased risk of severe BPD or death (odds ratio 2.24; 95% confidence interval 1.23 to 4.07). CONCLUSION: The variability and total use of iNO decreased in 2011 compared with 2008 to 2010. iNO administration started at ⩾ day 7 was associated with more severe outcomes compared with infants without iNO exposure.

Impact of intercurrent respiratory infections on lung health in infants born <29 weeks with bronchopulmonary dysplasia.

OBJECTIVE: Assess the impact of intercurrent respiratory infections in infants <29 weeks gestational age (GA). STUDY DESIGN: A retrospective cohort study of 111 infants born <29 weeks GA, controlling for bronchopulmonary dysplasia (BPD) severity and assessing pulmonary health over the first year of life through oxygen, diuretic and inhaled steroid use. RESULT: Regression analysis showed viral infections increased oxygen use (odds ratio (OR) of 15.5 (confidence interval (CI)=3.4, 71.3)). The trend test showed increasing numbers of viral infections were associated with increased oxygen (OR (95% CI)=6.4 (2.3 to 17.4), P=0.0003), diuretic (OR (95% CI)=2.4 (1.1to 5.2), P=0.02) and inhaled steroid use (OR (95% CI)=2.2 (1.003 to 5.2), P=0.049), whereas bacterial infections were not. CONCLUSION: Viral infections caused more long-term pulmonary morbidity/mortality than bacterial infections on premature lung health, even when controlling for BPD.

Infants born at <29 weeks: pulmonary outcomes from a hybrid perinatal system.

OBJECTIVE: To assess pulmonary outcomes of infants <29 weeks gestational age (GA), delivered at level I, II and III facilities, to identify potentially modifiable factors affecting bronchopulmonary dysplasia (BPD) severity and to assess the external generalizability of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) BPD Outcome Estimator. STUDY DESIGN: Outcomes for infants <29 weeks GA born during (2008-2010) and delivered either at an inborn level III center or in a level II or III metropolitan area hospital with transfer to a level IV center, or delivered in a distant level I or II center and then transported to a level IV center were assessed. BPD severity was compared with the NICHD Neonatal BPD Outcome Estimator. RESULT: Of 158 infants who comprised the cohort, 28 (17.8%) had no BPD, 39 (24.2%) had mild BPD, 45 (28.7%) had moderate BPD, 31 (19.7%) had severe BPD and 15 (9.6%) died at ≤36 weeks post menstrual age. Site of birth did not predict severe BPD or death. Receiver operator characteristic curves showed fair predictability for none/mild and severe BPD. CONCLUSION: BPD severity was not dependent on site of birth. The NICHD BPD outcome estimator provides fair prediction for extreme outcomes.

Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?

OBJECTIVE: The objective of this study is to determine the effects that sildenafil citrate has on gas exchange in infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). STUDY DESIGN: A retrospective review was performed from 2005 to 2009. Infants treated with sildenafil citrate for greater than 48 h were included. Standard patient data was collected, including echocardiogram, inspired oxygen and systemic blood pressure, before and during administration of sildenafil citrate. RESULT: Sildenafil citrate was used in 21 preterm infants with BPD-associated PH. A significant reduction in estimated right ventricular peak systolic pressure was seen after initiation of sildenafil citrate, with the majority of infants showing no improvement in gas exchange at 48 h of treatment. Four infants died during treatment. CONCLUSION: Sildenafil citrate reduced estimated pulmonary artery pressures, but this reduction was not reflected in improved gas exchange within the first 48 h.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites.

OBJECTIVE: Inhaled nitric oxide (iNO) is a potential new therapy for prevention of bronchopulmonary dysplasia and brain injury in premature infants. This study examined dose-related effects of iNO on NO metabolites as evidence of NO delivery. STUDY DESIGN: A subset of 102 premature infants in the NO CLD trial, receiving 24 days of iNO (20 p.p.m. decreasing to 2 p.p.m.) or placebo, were analyzed. Tracheal aspirate (TA) and plasma samples collected at enrollment and at intervals during study gas were analyzed for NO metabolites. RESULT: iNO treatment increased NO metabolites in TA at 20 and 10 p.p.m. (1.7- to 2.3-fold vs control) and in plasma at 20, 10, and 5 p.p.m. (1.6- to 2.3-fold). In post hoc analysis, treated infants with lower metabolite levels at entry had an improved clinical outcome. CONCLUSION: iNO causes dose-related increases in NO metabolites in the circulation as well as lung fluid, as evidenced by TA analysis, showing NO delivery to these compartments.

Monocyte chemoattractant protein-1 and its receptor CCR-2 in piglet lungs exposed to inhaled nitric oxide and hyperoxia.

Monocyte chemoattractant protein-1 (MCP-1), acting through its C-C chemokine receptor 2 (CCR-2), has important roles in inflammation, angiogenesis, and wound repair. The individual and combined effects of inhaled nitric oxide (NO) and hyperoxia on lung MCP-1 and CCR-2 in relation to lung leukocyte dynamics are unknown. Because MCP-1 gene is up-regulated by oxidants, we hypothesized that inhaled NO with hyperoxia will increase MCP-1 production and CCR-2 expression more than either gas alone. We randomly assigned young piglets to breathe room air (RA), RA+50 ppm NO (RA+NO), O(2), or O(2)+NO for 1 or 5 d before sacrifice. Lungs were lavaged and tissues preserved for hybridization studies, Western blotting, histology, and immunohistochemistry. The results show that lung MCP-1 production and alveolar macrophage count were significantly elevated in the 5-d O(2) and O(2)+NO groups relative to the RA group (p < or = 0.05). In contrast, lung CCR-2 abundance was diminished in the O(2) group (p

High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets.

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.

Effects of surfactant treatment on gas-exchange and clinical course in near-term newborns with RDS.

OBJECTIVE: To determine if there is a relationship between acute improvement in pulmonary gas exchange and surfactant use in near-term (35-39 weeks' gestation) infants with respiratory distress syndrome (RDS). METHODS: We examined retrospectively the records of 54 infants admitted during a 15 month period who were 35 or more weeks of gestation, and who demonstrated all the diagnostic features of RDS. Data analyzed included: birth weight; gestational age; Apgar scores; calculated alveolar to arterial oxygen gradient (AaDO2) and oxygenation index (0I); hours of life at intubation; surfactant administration; complications with surfactant administration; use of inotropic medications. RESULTS: A total of 30 of infants were treated with intubation and surfactant administration. Mean FiO2 at the time of surfactant administration was 0.96. The AaDO2 decreased from 64.0 +/- 14.8 kPa to 41.8 +/- 22.5 kPa by 6 hrs (p < 0.0001). There was no relationship between age at treatment (6-89 hr) and response to treatment as measured by changes in AaDO2, FiO2, or oxygenation index (OI). CONCLUSIONS: Near-term infants with severe RDS often respond to exogenous surfactant, suggesting a functional deficiency of endogenous surfactant at a "late" stage in their disease process. We speculate that delayed treatment may still be effective in these patients.

Influence of inhaled nitric oxide and hyperoxia on Na,K-ATPase expression and lung edema in newborn piglets.

This study was undertaken to examine the combined effect of nitric oxide (NO) and hyperoxia on lung edema and Na,K-ATPase expression. Newborn piglets were exposed to room air (FiO2 = 0.21), room air plus 50 ppm NO, hyperoxia (FiO2 >/= 0.96) or to hyperoxia plus 50 ppm NO for 4-5 days. Animals exposed to NO in room air experienced only a slight decrease in Na,K-ATPase alpha subunit protein level. Hyperoxia, in the absence of NO, induced both the mRNA and the protein level of Na,K-ATP-ase alpha subunit and significantly increased wet lung weight, extravascular lung water, and alveolar permeability. NO in hyperoxia decreased the hyperoxic-mediated induction of Na,K-ATPase alpha subunit mRNA and protein while wet lung weight, extravascular lung water, and alveolar permeability remained elevated. These results suggest that 50 ppm of inhaled NO may not improve hyperoxic-induced lung injury and may interfere with the expression of Na,K-ATPase which constitutes a part of the cellular defense mechanism against oxygen toxicity.

Airway muscle in infants with congenital diaphragmatic hernia: response to treatment.

BACKGROUND/PURPOSE: Airway muscle hyperactivity and chronic lung disease frequently follow congenital diaphragmatic hernia (CDH) treatment. The aim of this study was to compare the quantity of airway muscle and alveolar ductal artery muscle in CDH infants after various treatments. METHODS: Five groups were studied postmortem: CDH, died within 24 hours, without high ventilatory assistance (n = 3); CDH, various extracorporeal membrane oxgenation (ECMO) durations, without high ventilatory assistance (n = 4); CDH, various ECMO durations, with high ventilatory assistance (n = 7); no CDH, without high ventilatory assistance (n = 12); and no CDH, with high ventilatory assistance and bronchopulmonary dysplasia (BPD) (n = 5). Sections from standardized fixed lungs were immunohistochemically stained for alpha-smooth muscle actin. Muscle surrounding conducting airways from small preterminal bronchioles to bronchi was quantitated in both the ipsilateral and contralateral lungs with computerized image analysis. Similarly, muscle mass was quantitated in alveolar ductal arteries. RESULTS: CDH infants with low ventilatory assistance, regardless of postnatal age, had the same quantity of airway muscle as low ventilatory assistance controls. Infants with CDH and prolonged high ventilatory assistance had significantly more muscle throughout the conducting airways, similar to BPD infants without CDH, even though the CDH infants had significantly less exposure to high ventilatory assistance. With both low and high ventilatory assistance, the quantity of muscle in both the ipsilateral and contralateral lungs was similar. In contrast, small acinar arteries in CDH infants have increased muscle mass at birth. This muscle is decreased by ECMO but persists in CDH infants with high ventilatory assistance. CONCLUSIONS: The authors show that postnatally, CDH infants acquire increased muscle quantity throughout the conducting airways, in both the ipsilateral and contralateral lungs, with relatively short exposure to high ventilatory assistance. The normal decrease in acinar arterial mass that occurs postnatally is delayed in CDH infants with high ventilatory assistance.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn.

BACKGROUND: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed. METHODS: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. RESULTS: Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%). CONCLUSIONS: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

Reduction in lung injury after combined surfactant and high-frequency ventilation.

Previous studies demonstrated that high-frequency oscillatory ventilation (HFOV) begun at birth limits the development of alveolar proteinaceous edema in premature monkeys at risk for hyaline membrane disease (HMD). We hypothesized that exogenous surfactant combined with HFOV would lead to even further reductions in edema. Twenty Macaca nemestrina monkeys were delivered at 134 d gestation (term = 168 d) and treated with either HFOV or conventional mechanical ventilation (CMV) from the first breath; modified bovine surfactant (Survanta [beractant]) was introduced into the trachea over the first few minutes of life. These animals were compared with 20 animals treated with either CMV or HFOV but without surfactant. At 6 h the lung was rapidly frozen in situ during inflation for determination of the volume fraction of alveolar edema. The combined use of surfactant and HFOV from the first breath reduced alveolar proteinaceous edema (3 +/- 1%; mean +/- SEM) from that seen with CMV alone (27 +/- 3%, p < 0.0001), CMV after surfactant (21 +/- 3%, p < 0.0001), and HFOV alone (13 +/- 3%, p < 0.015). We conclude that the use of surfactant with HFOV after premature birth is superior to either surfactant or HFOV alone in reducing lung injury during the first few hours of life. We speculate that this reduction in lung injury may reduce the incidence or severity of bronchopulmonary dysplasia.

Changes in hyaluronan deposition during early respiratory distress syndrome in premature monkeys.

Increased deposition of hyaluronan (HA) is part of the early response to fibrogenic stimulus in the lung exposed to bleomycin injury and has been associated with increased lung water in adult animals. Early respiratory distress syndrome (RDS) in premature infants is characterized by increased lung water, and late sequelae include fibrosis or bronchopulmonary dysplasia. We hypothesized that increased HA in the alveolar interstitium would be associated with increasingly severe RDS in prematurely delivered monkeys and that modes of therapy that affect severity of disease such as treatment with high-frequency oscillatory ventilation or exogenous surfactant would decrease this response. Thirty-four Macaca nemestrina monkeys were delivered at 134 +/- 1 d (term = 168 d) and randomized to high-frequency oscillatory ventilation or conventional mechanical ventilation from birth. Sixteen of these animals received surfactant. At 6 h of age, the right lower lung was frozen in situ during inflation to 30 cm H2O (approximately 2940 Pa) and then dehydrated and processed for microscopy. The presence and severity of RDS were evaluated by clinical and morphologic criteria. HA concentrations in lung extracts increased with progressively severe RDS (p = 0.0003). Treatment with high-frequency oscillatory ventilation decreased the lung injury score (1.69 +/- 0.7 compared with 2.5 +/- 0.9, p = 0.05), but changes in lung HA concentration did not reach significance (37.9 +/- 22.7 compared with 44.8 +/- 22.6). Surfactant treatment decreased lung HA concentration (29.6 +/- 19.0 micrograms/wet lung) compared with non-surfactant-treated animals (54.7 +/- 20.2 micrograms/g wet lung, p = 0.0009).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of amrinone during group B Streptococcus-induced pulmonary hypertension in piglets.

Intravenous infusion of group B Streptococcus (GBS) into neonatal animals produces pulmonary hypertension, ventilation/perfusion (VA/Q) mismatch, and an increase in serum levels of thromboxane B2 (TxB2) and tumor necrosis factor (TNF) alpha. The vasodilator amrinone (amr) is a cGMP-inhibited phosphodiesterase inhibitor and is reported to inhibit thromboxane A2 and TNF production. We hypothesized that infusion of amr would cause pulmonary vasodilation and reduce serum TxB2 and TNF levels in piglets with late phase GBS-induced pulmonary hypertension. The effect of amr on gas exchange was also determined. A continuous infusion of GBS was administered for 5 hr to 4 groups of anesthetized, mechanically ventilated neonatal piglets. An amr bolus of 8 mg/kg was given at 4 hr followed by a 1 hr continuous infusion of either 10 or 20 micrograms/kg/min of amr (amr 10 and amr 20, respectively). Control piglets received a bolus and 1 hr infusion of amr carrier. The infusion of amr, but not of carrier reversed late phase GBS-induced pulmonary hypertension. Piglets infused with amr 20 showed transient selective pulmonary vasodilation, based on a reduced ratio of pulmonary to systemic vascular resistance (PVR/SVR ratio) value at 30 min but not at 1 hr, compared to pre-amr treatment values. The PVR/SVR ratio values for amr 10 and control group did not change after treatment with either amr or carrier. Treatment with amr 10 or 20 did not decrease serum TxB2 or TNF levels or increase VA/Q mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased expression of human leukocyte antigen-DR on pulmonary macrophages in bronchopulmonary dysplasia.

We used an immunoperoxidase method to examine the expression of the immune activation marker HLA-DR on pulmonary tissue obtained at autopsy from 14 patients dying of bronchopulmonary dysplasia. Controls consisted of 16 age-matched, sex-matched children dying of noncardiac, nonrespiratory, noninfectious illnesses or as a result of motor vehicle accidents. We did not observe aberrant expression of HLA-DR on pulmonary endothelial cells. Positive staining appeared exclusively on macrophages. We quantitated the expression of antigen by counting the number of positive macrophages and total macrophages/monocytes per high power field. Bronchopulmonary dysplasia patients displayed significantly greater numbers of both positive and total macrophages compared with the control group (p < 0.05). The percent positive macrophages also was significantly higher in the bronchopulmonary dysplasia patients (p < 0.005). We also examined a group of patients dying with infant respiratory distress syndrome. There was no significant difference in number of total macrophages in this group compared with age-matched controls.

Alternative modes of ventilation in the prevention and treatment of bronchopulmonary dysplasia.

Recent technologic innovations and refinements have increased and enhanced the armamentarium that potentially can prevent or ameliorate bronchopulmonary dysplasia. Short of altering the most important factor in the development of BPD--premature delivery--these new tools should allow individualization of ventilator treatment plans with a degree of sophistication not previously possible. By so doing, these techniques may shorten the often prolonged and uncertain course of recovery from BPD, and by so doing, limit the ongoing injury associated with BPD. The results of studies designed to test the utility of this new technology in the management of BPD are eagerly awaited.