Higher Incidence Of Bronchopulmonary Dysplasia Research Articles

Serum surfactant protein D as a marker for bronchopulmonary dysplasia

Background: Lung epithelial cells express surfactant protein D (SP-D), a calcium-dependent lectin that plays an important role in antibody-independent pulmonary host defense. Previous studies have shown that it is found in the peripheral circulation in patients with pulmonary disease, likely because of translocation into the blood when lung epithelial barriers are disrupted by inflammation or acute injury. In adults, serum SP-D levels are biomarkers for the progression and severity of chronic lung disease. In neonates, elevated SP-D levels in cord blood and on day 1 have been associated with prenatal risk factors and with an increased risk of respiratory distress syndrome and infections. It is not known whether serum SP-D during the first week of life is a marker for bronchopulmonary dysplasia (BPD), a form of chronic lung disease of prematurity that is associated with lung parenchymal maldevelopment and injury.Objective: The goal of this study is to determine whether serum SP-D on days 3 and 7 of life are associated with the development of BPD in preterm infants.Design/methods: Serum samples were obtained on postnatal days 3 and 7 from 106 preterm infants (500–2000 g birth weight, 23–32-week gestation). SP-D was quantified by Western blot. BPD was determined at 36 weeks PMA using NICHD criteria.Results: The mean birth weight was 1145 ± 347 g and gestational age 29.2 ± 7.4 weeks. BPD was diagnosed in 7 and “BPD or death” in 16 infants. Days 3 and 7 values tracked significantly (r = 0.648), and did not correlate with birth weight or gestational age. Contrary to expectations, serum SP-D was not associated with BPD. Significant gender differences were noted, with SP-D dropping from day 3 to day 7 in males, while increasing in females (p < .05).Conclusion: Elevated serum SP-D does not appear to be a useful marker for BPD. Decreasing serum SP-D levels in males, as compared to females, during the first week of life are likely related to gender differences in lung maturation, consistent with the higher incidence of BPD in males.

Extracorporeal Membrane Oxygenation Incidence, Characteristics, and Outcomes in Neonatal Down Syndrome Patients.

Practice patterns for extracorporeal membrane oxygenation (ECMO) use in newborns with Trisomy 21 (T21) have not been fully reported. The goals of this study were to 1) determine the incidence of ECMO use in T21 neonates; 2) identify clinical and demographic characteristics associated with ECMO use in this population; 3) describe outcomes of neonates with T21 supported with ECMO. This was a retrospective cohort study using the Pediatric Health Information System database (January 2000 to January 2014). Given the exploratory nature, only descriptive statistics were used. p < 0.05 was considered significant. Within 43 pediatric hospitals, the incidence of ECMO use in neonates with T21 was 2.3% (131/5,737). Neonates with T21 supported with ECMO were more likely to be admitted earlier; have higher birth weight, gestational age, and longer hospitalization; and have congenital diaphragmatic hernia or select cardiac anomalies versus those who did not require ECMO. T21 neonates supported with ECMO also had higher incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, and mortality (unadjusted odds ratio 12.3 [95% confidence interval: 8.6-17.6]) compared with T21 neonates not exposed to ECMO. Compared with T21 neonates not requiring ECMO, those supported with ECMO had increased morbidity and mortality. Additional investigation on timing, indications, and risk/benefit profiles, for ECMO use in T21 neonates is needed.

Health status evaluation in extremely premature infants

The health status was analyzed in extremely preterm infants at a postconceptual age of 38–40 weeks and in the first year of life. All the infants in the analyzed group were shown to have respiratory disorders, severe perinatal CNS lesions, and the high incidence of bronchopulmonary dysplasia and infectious and inflammatory diseases. In the first year of life, these children belonged to a group of the frequently ill. Dysfunction of the digestive system and intestinal microflora and residual signs of rickets were detected in the majority of the patients; the manifestations of bronchopulmonary dysplasia persisted in 50%. 40% of the infants had disabling complications.

Association between Hemodynamically Significant Patent Ductus Arteriosus and Bronchopulmonary Dysplasia

To assess whether the duration and magnitude of the shunt with patent ductus arteriosus (PDA) are related to a higher incidence of bronchopulmonary dysplasia (BPD) or death. A total of 242 infants ≤ 28 weeks gestational age were evaluated retrospectively between 2007 and 2012; 105 (43.3%) developed BPD or died (group 1) and 137 (56.6%) did not (group 2). A review of all echocardiographic evaluations performed from birth up to 36 weeks of postconceptional age or final ductal closure was carried out, to detect the presence of PDA, and estimate the severity of ductal shunt through the "PDA staging system" proposed by McNamara and Sehgal. Group 1 presented with a hemodynamically significant ductus arteriosus (DA) (E3 and/or E4-PDA) for a longer period of time vs group 2: 4.8 vs 2.3 days, respectively (P < .001). Persistence of a nonsignificant DA (E2) was not associated with development of BPD (P = .16). Each week of a hemodynamically significant DA represented an added risk for BPD (OR 1.7), and the duration of a small, nonsignificant DA (E2) did not. Surgical ligation of PDA itself was not found to be an independent risk factor for BPD. In the subgroup of patients who received ligation, a later ligation (33 vs 23 days) and a prolonged PDA were the only factors associated to BPD or death. A shared scoring system of the severity of ductal shunt is helpful to correctly evaluate the association between PDA morbidities, to compare scientific studies, and to guide treatment.

Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants.

Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age.Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin.Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = −.322, p = .009; r= −.381, p= .002), lower mean albumin (r = −.276, p= .029; r= −.385, p= .002), and lower mean bilirubin (r = −.293, p= .020; r= −.337 p= .007).Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.

Adverse cardiorespiratory events following primary vaccination of very low birth weight infants

To examine the relationship between primary vaccination of preterm infants and prevalence ratios of associated factors for unwanted cardiorespiratory events, following the recommendation of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices for immunization of preterm infants at 2 months of chronological age. Two-year retrospective study of very low birth weight infants receiving their primary vaccination. Major cardiorespiratory events, such as apnea, bradycardia, SpO(2) desaturation, and minor adverse events, such as temperature instability, poor handling and local reactions, were recorded. Prevalence ratio with 95% confidence interval for associated factors between infants with and without cardiorespiratory events was calculated. Eighty neonates were studied (median [range] birth weight 970 g [428-1,490]), gestational age of 27.4 weeks (23.3-33). Adverse reactions occurred in 35 (44%): minor events in 19 (24%) patients, major events in 28 (35%). Infants with major events had significantly lower gestational age (p = 0.008) and a higher incidence of bronchopulmonary dysplasia (71% vs. 48%; p < 0.05). In very low birth weight infants with major events, O(2) desaturations before vaccination were 3.40 (1.41-8.23) times higher and treatment with methylxanthines for apnea and bradycardia syndrome was 8.05 (2.50-25.89) times higher compared to infants without major events. Major cardiorespiratory events occurred in over 1/3 of all very low birth weight infants after vaccination. Associated factors were low gestational age, bronchopulmonary dysplasia, methylxanthine treatment, and persisting O(2) desaturations before vaccination. Primary vaccination of very low birth weight infants should be performed under continuous monitoring of vital parameters.

513 Timing of Surfactant Treatment in Extremely Premature Infants - Effects on Mortality and Development of Bronchopulmonary Dysplasia (BPD)

Background and aims: The effect of early surfactant treatment is uncertain. The aim of this study was to evaluate mortality and moderate/severe BPD in relation to timing of surfactant treatment.Methods: All 452 admitted infants with gestational age (GA) ≤ 30 weeks from a national cohort of infants with GA 220-276 weeks and/or birth weight (BW) 500-999 g were studied.Results. Only minor differences in mortality or BPD was found between infants given surfactant in delivery room (S-DR) only, NICU (S-NICU) only or both in DR and in NICU (S-DR/NICU) (Table 1).Table 1 Full size tableSurfactant missing for 23 infants in entire cohort, for 17 infants in BPD cohort*p < 0.05 versus S-DR and S-NICU, #p < 0.05 versus DR, §p < 0.05 versus S-NICUConclusions: Infants with a high rate of surfactant treatment still have a high incidence of BPD. Timing of surfactant treatment has only minor effects on mortality and morbidity in extremely premature infants.

Synchronized Nasal Intermittent Positive-Pressure Ventilation and Neonatal Outcomes

Synchronized nasal intermittent positive-pressure ventilation (SNIPPV) use reduces reintubation rates compared with nasal continuous positive airway pressure (NCPAP). Limited information is available on the outcomes of infants managed with SNIPPV. To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites. Clinical retrospective data was used to evaluate the use of SNIPPV in infants <or=1250 g birth weight (BW); and 3 BW subgroups (500-750, 751-1000, and 1001-1250 g, decided a priori). SNIPPV was not assigned randomly. Bronchopulmonary dysplasia (BPD) was defined as treatment with supplemental oxygen at 36 weeks' postmenstrual age. Overall, infants who were treated with SNIPPV had significantly lower mean BW (863 vs 964 g) and gestational age (26.4 vs 27.9 weeks), more frequently received surfactant (85% vs 68%), and had a higher incidence of BPD or death (39% vs 27%) (all P < .01) compared with infants treated with NCPAP. In the subgroup analysis, SNIPPV was associated with lower rates of BPD (43% vs 67%; P = .03) and BPD/death (51% vs 76%; P = .02) in the 500- to 750-g infants, with no significant differences in the other BW groups. Logistic regression analysis, adjusting for significant covariates, revealed infants with 500-700-g BW who received SNIPPV were significantly less likely to have the outcomes of BPD (OR: 0.29 [95% CI: 0.11-0.77]; P = .01), BPD/death (OR: 0.30 [95% CI: 0.11-0.79]; P = .01), neurodevelopmental impairment (NDI) (OR: 0.29 [95% CI: 0.09-0.94]; P = .04), and NDI/death (OR: 0.18 [95% CI: 0.05-0.62]; P = .006). SNIPPV use in infants at greatest risk of BPD or death (500-750 g) was associated with decreased BPD, BPD/death, NDI, and NDI/death when compared with infants managed with NCPAP.

Neurodevelopmental outcome of very-low-birth-weight infants with chorioamnionitis.

Chorioamnionitis (CAM) is one of the main causes of preterm labor and has been associated with an adverse perinatal outcome in preterm infants. The specific aim of our study was to evaluate whether there is significant difference in the Bayley developmental index scores at 6, 12, 18 and 24 months of corrected age for very-low-birthweight (birth body weight <1500 gm, VLBW) infants with or without placental CAM. Ninety-five cases (54 in CAM and 41 in non-CAM groups) available for the study were all VLBW infants with adequate histologic placental material for analysis. Neonatal characteristics and morbidities were recorded. The infants were followed up prospectively with Bayley Scales of Infant Development in the Neonatal Follow-up Clinic for 2 years. We found that 56.8% of placentas presented a picture of CAM. In comparison of the neonatal characteristics, VLBW infants with CAM had shorter gestational age (27.9 +/- 2.8 vs. 30.0 +/- 3.7 weeks, p = 0.003), lower Cesarean delivery rate (48.1% vs. 73.2%, p = 0.011), more maternal steroid use (44.4% vs. 12.2%, p = 0.004) and higher incidence of preterm premature rupture of membrane (PPROM, 37.0% vs. 12.2%, p = 0.009). In comparison of neonatal outcomes, the CAM group had higher incidence of bronchopulmonary dysplasia (BPD, 40.7% vs. 19.5%, p = 0.044), more mechanical ventilation (87.0% vs. 27/41, p = 0.023) and intubation (68.5% vs. 46.3%, p = 0.049), and more median days of ventilation (23.1 +/- 29.1 vs. 7.8. +/- 13.7 days, p = 0.001). As for the follow-up, at any test age, either the mean (Mental Development Index (MDI) / (Psychomotor Development Index (PDI) scores of Bayley test or the incidence of score below 85, there was no significant difference in both groups. The VLBW infants with histologic chorioamnionitis were not associated with an increased risk of lower MDI or PDI scores at the corrected ages of 6, 12, 18 and 24 months compared with the non-CAM control group.

Leukemoid Reaction and Bronchopulmonary Dysplasia: A Primary Inflammatory Mechanism?

To the Editor .— We read with great interest “Outcome of Extremely Low Birth Weight Infants With Leukemoid Reaction” by Hsiao and Omar.1 Their objective was to examine the effect of leukemoid reaction (LR) in morbidity, mortality, and long-term developmental outcome in extremely low birth weight (ELBW) infants. The study showed that LR in ELBW infants is associated with a higher incidence of bronchopulmonary dysplasia (BPD), compared with no-LR infants. Although hypothesized in their discussion, the study by Hsiao and Omar did not investigate if …

Outcome of Extremely Low Birth Weight Infants With Leukemoid Reaction

Leukemoid reaction (LR) is defined as an absolute neutrophil count (ANC) of >30 x 10(3)/mm(3). No previous study has systemically examined the clinical and prognostic significance of this phenomenon in extremely low birth weight (ELBW) infants. The purpose of this study was to examine the effect of LR in morbidity, mortality, and long-term developmental outcome in ELBW infants. Infants with gestational age of <or=30 weeks and birth weight <or=1000 g were included in the study (n = 152). The medical records were reviewed for the clinical characteristics and long-term developmental outcome of these infants. Serial complete blood cell count and ANC were calculated on day 1 and weekly thereafter until discharge. LR was defined as an ANC of >30 x 10(3)/mm(3). LR was detected in 17% of the study infants (26 of 152). ANC increased postnatally in LR (n = 26) and no-LR (n = 126) infants during hospitalization, peaked in the second week of life (43 +/- 3 vs 14 +/- 1 x 10(3)/mm(3)), and remained significantly higher in LR infants during the first 5 weeks of life. LR occurred more frequently during the first 2 weeks of life and lasted for 3 +/- 1 days. There was no significant difference between the LR and no-LR infants in gestational age, birth weight, delivery mode, gender, Apgar scores, or incidence of respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity. LR infants required a significantly longer duration of ventilatory support (36 +/- 4 vs 21 +/- 2 days), longer duration of oxygen requirement (58 +/- 6 vs 40 +/- 3 days), and had a higher incidence of bronchopulmonary dysplasia (BPD) (54% vs 25%) compared with no-LR infants. Furthermore, the length of hospitalization was significantly longer in LR infants (69 +/- 6 vs 54 +/- 3 days). There was no significant difference between the groups in developmental outcome at 2 years of age including receptive/expressive language, fine/gross motor skills, and hearing. Incidence of abnormal neurodevelopment outcome was also similar between LR and no-LR infants. LR in ELBW infants is associated with a prolonged need for ventilatory and oxygen support, a higher incidence of BPD, and a tendency for lower mortality. The findings from our study suggest that LR is associated with conditions known to have an excess of proinflammatory cytokines. Additional prospective study is needed to understand the relationship between LR, proinflammatory cytokines, and development of BPD.

Changing trends in the management of respiratory distress syndrome (RDS).

The management of respiratory distress syndrome (RDS) has advanced because of improvements in mechanical ventilators, promotion of antenatal steroids, availability of surfactant and overall advancements in neonatal intensive care. Intermittent mandatory ventilation still forms the mainstay of assisted ventilation. Newer modes of ventilation have not delivered the results as promised. Because of the continued high incidence of bronchopulmonary dysplasia, there is a renewed interest in non-invasive modes of ventilation like CPAP and nasal IPPV. The present trend is to follow gentle ventilatory strategies accepting higher arterial carbon dioxide and lower oxygen. The role of antenatal steroids has been established beyond doubt but still they fall short of universal acceptance. Surfactant replacement therapy is the standard of care for RDS but beyond the reach of majority in India. Postnatal steroids are out of vogue because of probable links with cerebral palsy and abnormal neurological outcomes.

Long-term pulmonary sequelae in children with congenital diaphragmatic hernia.

Neonates with congenital diaphragmatic hernia (CDH) often suffer from respiratory insufficiency due to lung hypoplasia and pulmonary hypertension. Artificial ventilation is frequently required, and this leads to a high incidence of bronchopulmonary dysplasia. Long-term follow-up studies have shown persisting airway obstruction. To evaluate the long-term pulmonary sequelae in CDH, we studied 40 CDH patients of age 7 to 18 yr (median 11.7 yr) and 65 age-matched controls without CDH and lung hypoplasia who underwent similar neonatal treatment. Mild airway obstruction was found in both groups with more peripheral airway obstruction in CDH patients than in control subjects. Both groups had normal TLC and single-breath carbon monoxide diffusion capacity (DLCO). CDH patients had increased residual volume (RV) and RV/TLC compared with controls. Increased airway responsiveness to methacholine (MCH) was common but bronchoconstriction to inhaled metabisulfite (MBS) was rare both in CDH and control subjects. We conclude that this group of CDH patients has minor residual lung function impairment. Mild airway obstruction and increased airway responsiveness to inhaled MCH but not to MBS suggest that structural changes in distal airways are involved and not autonomic nerve dysfunction. Both artificial ventilation in the neonatal period and residual lung hypoplasia seem important determinants of persistent lung function abnormalities in CDH patients.

The Use of Dexamethasone in Premature Infants at Risk for Bronchopulmonary Dysplasia or Who Already Have Developed Chronic Lung Disease: A Cautionary Note

To the Editor.— The distressingly high incidence of bronchopulmonary dysplasia (BPD) in today's very low birth weight premature infant population and the prolonged morbidity and tumultuous clinical problems associated with BPD in these tiny infants have led to a trial usage of dexamethasone treatment to try to assuage these problems in this patient population. The report of Kazzi et al1 is noteworthy because the authors not only indicate in clear fashion the failure of relatively prolonged dexamethasone treatment to ameliorate the hospital course of infants with BPD (in a randomized prospective double-blind study), but they also clearly identify potential risk factors associated with dexamethasone treatment that are of concern to them as clinical investigators, risk factors based both on clinical and experimental animal studies.

High-Frequency Oscillatory Ventilation

The improved survival rate of premature infants with respiratory failure is attributable to advances in mechanical ventilation, although an adverse consequence has been an increased incidence of bronchopulmonary dysplasia (BPD) (1;32). Positive pressure ventilation with its attendant “barotrauma” is suspected in the causation of BPD. While many attempts to alter respirator variables, such as pressure and time components, have produced optimal patterns for gas exchange, evidence is lacking to support any one pattern that minimizes the incidence of chronic lung injury. The high incidence of BPD has promoted a search for alternative methods of ventilation that might reduce lung injury through a reduction in peak pressure applied to the lung. Additional motivation has come from the need for oxygenation when mechanical ventilation has failed or pulmonary interstitial emphysema has developed. Less compelling reasons have come from the desire to avoid high swings in thoracic pressure that might adversely affect cardiac output, venous return, and cerebral blood flow.

Mitigation of Pulmonary Oxygen Toxicity in Premature Lambs with Intravenous Antioxidants

Deficiencies of antioxidants and increased free radical generation may explain the high incidence of bronchopulmonary dysplasia in premature infants. Long-acting antioxidants such as polyethylene glycol (PEG) conjugated superoxide dismutase (SOD), and catalase might modify this process. We delivered 32 premature lambs, 16 pairs of twins, by cesarean section at 125-141 days of gestation (term 146 days) and stabilized them on ventilators in normocapnic hyperoxia for a period of 8 h. One lamb of each twin pair received an intravenous dose of 7,500-50,000 IU/kg of PEG-SOD and of 37,500-1,000,000 IU/kg of PEG-catalase at birth. Their siblings acted as controls. Mean airway pressure, arterial pressure, and heart rate were recorded continuously. Arterial blood gases and pH were obtained every 30 min. After sacrifice, standardized lung biopsies were prepared for quantitative morphometrics and electron microscopy. Administration of PEG antioxidants at birth reduced the influx of neutrophils and macrophages into the lung and damage to arterioles, bronchiolar mucosa, and type II pneumocytes without major changes in alveolar surface area or pulmonary function. These effects were dose-related and detectable even at the lowest doses of PEG antioxidants administered.

Patent ductus arteriosus in neonates with severe respiratory disease

Daily aortic contrast echo studies were carried out in 200 neonates with severe respiratory disease to determine the natural history of the ductus arteriosus during the first days of life and the effect of patency on subsequent morbidity and mortality. Decisions related to surgical or pharmacologic closure of a PDA were not based on the results of the contrast echo studies. The risk that intervention would be required was greater in infants weighing less than 1500 gm (P less than 0.005) and in patients in whom the ductus had not closed spontaneously by day 3 (P less than 0.001) regardless of birth weight. The clinical course in infants with a PDA on the third day of life revealed a lower survival rate (P less than 0.005), a greater requirement for prolonged respiratory support (P less than 0.005), and a higher incidence of bronchopulmonary dysplasia (P less than 0.005) in all birth weight categories. Ductal patency often was not associated with early clinical manifestations. No infant who had a negative echo study on the third day of life subsequently developed signs or symptoms of patent ductus arteriosus. We conclude that patency of the ductus arteriosus is a negative prognostic factor in the severely ill neonate with respiratory distress.

Patent Ductus Arteriosus Ligation and Respiratory Distress Syndrome in Premature Infants

Ligation of a patent ductus arteriosus was carried out in 22 premature infants, 20 with concomitant respiratory distress. The duration of high-volume shunting is critical in determining the prognosis for these infants. Because of the low surgical mortality and morbidity and the high incidence of bronchopulmonary dysplasia in babies managed conservatively, infants with respiratory distress syndrome (RDS) who are respirator dependent should undergo ligation as soon as the presence of large left-to-right shunting is determined. Premature infants without RDS or those with mild RDS who are not respirator dependent can be managed medically or with elective ligation. Surgical intervention is strongly indicated in patients with persistent congestive heart failure and respiratory failure. Echocardiography offers an accurate and risk-free approach to the early diagnosis of a large left-to-right shunt through the ductus.