Pulmonary hemodynamic responses to in utero ventilation in very immature fetal sheep

<p>Abstract</p> <p>Background</p> <p>The onset of ventilation at birth decreases pulmonary vascular resistance (PVR) resulting in a large increase in pulmonary blood flow (PBF). As the large cross sectional area of the pulmonary vascular bed develops late in gestation, we have investigated whether the ventilation-induced increase in PBF is reduced in immature lungs.</p> <p>Methods</p> <p>Surgery was performed in fetal sheep at 105 d GA (n = 7; term ~147 d) to insert an endotracheal tube, which was connected to a neonatal ventilation circuit, and a transonic flow probe was placed around the left pulmonary artery. At 110 d GA, fetuses (n = 7) were ventilated <it>in utero </it>(IUV) for 12 hrs while continuous measurements of PBF were made, fetuses were allowed to develop <it>in utero </it>for a further 7 days following ventilation.</p> <p>Results</p> <p>PBF changes were highly variable between animals, increasing from 12.2 ± 6.6 mL/min to a maximum of 78.1 ± 23.1 mL/min in four fetuses after 10 minutes of ventilation. In the remaining three fetuses, little change in PBF was measured in response to IUV. The increases in PBF measured in responding fetuses were not sustained throughout the ventilation period and by 2 hrs of IUV had returned to pre-IUV control values.</p> <p>Discussion and conclusion</p> <p>Ventilation of very immature fetal sheep <it>in utero </it>increased PBF in 57% of fetuses but this increase was not sustained for more than 2 hrs, despite continuing ventilation. Immature lungs can increase PBF during ventilation, however, the present studies show these changes are transient and highly variable.</p

Persistently Elevated Right Ventricular Index of Myocardial Performance in Preterm Infants with Incipient Bronchopulmonary Dysplasia

OBJECTIVES: Elevated pulmonary vascular resistance occurs during the first days after birth in all newborn infants and persists in infants at risk for bronchopulmonary dysplasia (BPD). It is difficult to measure in a non-invasive fashion. We assessed the usefulness of the right ventricular index of myocardial performance (RIMP) to estimate pulmonary vascular resistance in very low birth weight infants. STUDY DESIGN: Prospective echocardiography on day of life (DOL) 2, 7, 14, and 28 in 121 preterm infants (median [quartiles] gestational age 28 [26]-[29] weeks, birth weight 998 [743-1225] g) of whom 36 developed BPD (oxygen supplementation at 36 postmenstrual weeks). RESULTS: RIMP derived by conventional pulsed Doppler technique was unrelated to heart rate or mean blood pressure. RIMP on DOL 2 was similar in infants who subsequently did (0.39 [0.33-0.55]) and did not develop BPD (0.39 [0.28-0.51], p = 0.467). RIMP declined steadily in non-BPD infants but not in BPD infants (DOL 7: 0.31[0.22-0.39] vs. 0.35[0.29-0.48], p = 0.014; DOL 14: 0.23[0.17-0.30] vs. 0.35[0.25-0.43], p<0.001; DOL 28: 0.21[0.15-0.28] vs. 0.31 [0.21-0.35], p = 0.015). CONCLUSIONS: In preterm infants, a decline in RIMP after birth was not observed in those with incipient BPD. The pattern of RIMP measured in preterm infants is commensurate with that of pulmonary vascular resistance

Genome-wide association study of bronchopulmonary dysplasia : a potential role for variants near the CRP gene

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [ OR] 3.2, p = 3.4 x 10(-6)). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 x 10(-4)) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 x 10(-5)), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.Peer reviewe

An epidemiological study of respiratory syncytial virus associated hospitalizations in Denmark

Respiratory syncytial virus (RSV) is the most common viral pathogen that causes lower respiratory tract infections in infants. Studies have implicated severe RSV infections early in life as a risk factor for subsequent development of reactive airway disease. We are conducting a study to validate RSV-associated diagnoses in the Danish National Patient Registry, to assess whether the incidence of severe RSV infection is increasing in Denmark, to identify predisposing and protective factors for RSV-associated hospitalization in Denmark, and to examine the association of severe RSV infection with reactive airway disease. The influence of various biological, social and environmental factors on hospitalization for RSV infection will be studied through several population-based registers, including the Danish National Birth Cohort: 'Better health for mothers and children'. The RSV hospitalization cases will be compared with control individuals selected within the same population groups on a case–control or a cohort basis in order to produce estimates of age-adjusted and sex-adjusted relative risks (odds ratio and relative risk) for hospitalization associated with various risk factors. Using register linkage and unique registration of exposures collected through interviews and blood samples from the Danish National Birth Cohort, we will be able to resolve the issues referred to above in a very large sample of Danish children

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

<p>Abstract</p> <p>Background</p> <p>Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.</p> <p>Methods</p> <p>Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.</p> <p>Results</p> <p>Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).</p> <p>Conclusion</p> <p>Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.</p

Respiratory hospitalizations and respiratory syncytial virus prophylaxis in special populations

Palivizumab utilization, compliance, and outcomes were examined in infants with preexisting medical diseases within the Canadian Registry Database (CARESS) to aid in developing guidelines for potential “at-risk” infants in the future. Infants who received ≥1 dose of palivizumab during the 2006–2010 respiratory syncytial virus (RSV) seasons at 29 sites were recruited and utilization, compliance, and outcomes related to respiratory infection/illness (RI) events were collected monthly. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for premature infants ≤35 completed weeks gestational age (GA) who met standard approval criteria (group 1) compared to those with medical disorders (group 2) using Cox proportional hazards regression models with adjustment for potential confounding factors. Of 7,339 registry infants, 4,880 were in group 1 and 952 in group 2, which included those with Down syndrome (20.3%), upper airway anomalies (18.7%), pulmonary diseases (13.3%), and cystic fibrosis (12.3%). Group 2 were older at enrolment (10.2 ± 9.2 vs. 3.5 ± 3.1 months, p < 0.0005), had higher GA (35.9 ± 6.0 vs. 31.0 ± 5.4 weeks, p < 0.0005), and were less compliant with treatment intervals (69.4% vs. 72.6%, p = 0.048). A greater proportion of group 2 infants were hospitalized for RI (9.0% vs. 4.2%, p < 0.0005) and RSV (2.4% vs. 1.3%, p = 0.003) (unadjusted). Being in group 2 was associated with an increased risk of RI (HR = 2.0, 95%CI 1.5–2.5, p < 0.0005), but not RSV hospitalization (HR = 1.6, 95%CI 0.9–2.8, p = 0.106). In infants receiving palivizumab, those with underlying medical disorders, though not currently approved for prophylaxis, are at higher risk for RI events compared with preterm infants. However, risk of RSV hospitalizations is similar

Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies

Abstract Background Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Main body Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Conclusion Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem