Peter M. Mourani

Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease.

OBJECTIVE To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy. STUDY DESIGN We conducted a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms. RESULTS Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis. CONCLUSION These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.

Clinical Utility of Echocardiography for the Diagnosis and Management of Pulmonary Vascular Disease in Young Children With Chronic Lung Disease

OBJECTIVE. The goal was to determine the clinical utility of Doppler echocardiography in predicting the presence and severity of pulmonary hypertension in patients with chronic lung disease who subsequently underwent cardiac catheterization. METHODS. A retrospective review of data for all patients <2 years of age with a diagnosis of bronchopulmonary dysplasia, congenital diaphragmatic hernia, or lung hypoplasia who underwent echocardiography and subsequently underwent cardiac catheterization for evaluation of pulmonary hypertension was performed. The accuracy of echocardiography in diagnosing pulmonary hypertension, on the basis of estimated systolic pulmonary artery pressure, was compared with the detection of pulmonary hypertension with the standard method of cardiac catheterization. RESULTS. Thirty-one linked measurements for 25 children were analyzed. Systolic pulmonary artery pressure could be estimated in 61% of studies, but there was poor correlation between echocardiography and cardiac catheterization measures of systolic pulmonary artery pressure in these infants. Compared with cardiac catheterization measurements, echocardiographic estimates of systolic pulmonary artery pressure diagnosed correctly the presence or absence of pulmonary hypertension in 79% of the studies in which systolic pulmonary artery pressure was estimated but determined the severity of pulmonary hypertension (severe pulmonary hypertension was defined as pulmonary/systemic pressure ratio of ≥0.67) correctly in only 47% of those studies. Seven (58%) of 12 children without estimated systolic pulmonary artery pressure demonstrated pulmonary hypertension during subsequent cardiac catheterization. In the absence of estimated systolic pulmonary artery pressure, qualitative echocardiographic findings, either alone or in combination, had worse predictive value for the diagnosis of pulmonary hypertension. CONCLUSION. As used in clinical practice, echocardiography often identifies pulmonary hypertension in young children with chronic lung disease; however, estimates of systolic pulmonary artery pressure were not obtained consistently and were not reliable for determining the severity of pulmonary hypertension.

Early Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia

RATIONALE Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. OBJECTIVES To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). METHODS Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. MEASUREMENTS AND MAIN RESULTS A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). CONCLUSIONS Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.

Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is associated with impaired vascular and alveolar growth. Antenatal factors contribute to the risk for developing BPD by unclear mechanisms. Endothelial progenitor cells, such as angiogenic circulating progenitor cells (CPCs) and late-outgrowth endothelial colony-forming cells (ECFCs), may contribute to angiogenesis in the developing lung. We hypothesise that cord blood angiogenic CPCs and ECFCs are decreased in preterm infants with moderate and severe BPD. We quantified ECFCs and the CPC/nonangiogenic-CPC ratio (CPC/non-CPC) in cord blood samples from 62 preterm infants and assessed their relationships to maternal and perinatal risk factors as well as BPD severity. The CPC/non-CPC ratio and ECFC number were compared between preterm infants with mild or no BPD and those with moderate or severe BPD. ECFC number (p<0.001) and CPC/non-CPC ratio (p<0.05) were significantly decreased in cord blood samples of preterm infants who subsequently developed moderate or severe BPD. Gestational age and birth weight were not associated with either angiogenic marker. Circulating vascular progenitor cells are decreased in the cord blood of preterm infants who develop moderate and severe BPD. These findings suggest that prenatal factors contribute to late respiratory outcomes in preterm infants.

Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond.

Purpose of review Pulmonary hypertension contributes significantly to morbidity and mortality of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD). Advances in pulmonary vascular biology over the past few decades have led to new insights into the pathogenesis of BPD; however, many unique issues persist regarding our understanding of pulmonary vascular development and disease in preterm infants at risk for chronic lung disease. Recent findings Recent studies have highlighted the important contribution of the developing pulmonary circulation to lung growth in the setting of preterm birth. These studies suggest that there is a spectrum of pulmonary vascular disease (PVD) in BPD rather than a simple question of whether or not pulmonary hypertension is present. Epidemiological studies underscore gaps in our understanding of PVD in the context of BPD, including universally accepted definitions, approaches to diagnosis and treatment, and patient outcomes. Unfortunately, therapeutic strategies for pulmonary hypertension in BPD are based on small observational studies with poorly defined endpoints and rely on results from older children and adult studies. Yet, unique characteristics of this population create other potential risks for the adoption of these strategies. Summary Despite many recent advances, PVD remains an important contributor to poor outcomes in preterm infants with BPD. Substantial challenges persist, especially with regard to understanding mechanisms and the clinical approach to PVD. Future studies are needed to develop evidence-based definitions and clinical endpoints through which the pathophysiology can be investigated and potential therapeutic interventions evaluated.

Effectiveness of influenza vaccine against life-threatening RT-PCR-confirmed influenza illness in US children, 2010-2012

BACKGROUND No studies have examined the effectiveness of influenza vaccine against intensive care unit (ICU) admission associated with influenza virus infection among children. METHODS In 2010-2011 and 2011-2012, children aged 6 months to 17 years admitted to 21 US pediatric intensive care units (PICUs) with acute severe respiratory illness and testing positive for influenza were enrolled as cases; children who tested negative were PICU controls. Community controls were children without an influenza-related hospitalization, matched to cases by comorbidities and geographic region. Vaccine effectiveness was estimated with logistic regression models. RESULTS We analyzed data from 44 cases, 172 PICU controls, and 93 community controls. Eighteen percent of cases, 31% of PICU controls, and 51% of community controls were fully vaccinated. Compared to unvaccinated children, children who were fully vaccinated were 74% (95% CI, 19% to 91%) or 82% (95% CI, 23% to 96%) less likely to be admitted to a PICU for influenza compared to PICU controls or community controls, respectively. Receipt of 1 dose of vaccine among children for whom 2 doses were recommended was not protective. CONCLUSIONS During the 2010-2011 and 2011-2012 US influenza seasons, influenza vaccination was associated with a three-quarters reduction in the risk of life-threatening influenza illness in children.

Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation

Background Studies evaluating risk factors for in-hospital venous thromboembolism in children are limited by quality assurance of case definition and/or lack of controlled comparison. The objective of this study is to determine risk factors for the development of in-hospital venous thromboembolism in children. Design and Methods In a case-control study at The Children’s Hospital, Colorado, from 1st January 2003 to 31st December 2009 we employed diagnostic validation methods to determine pediatric in-hospital venous thromboembolism risk factors. Clinical data on putative risk factors were retrospectively collected from medical records of children with International Classification of Diseases, 9th edition codes of venous thromboembolism at discharge, in whom radiological reports confirmed venous thromboembolism and no signs/symptoms of venous thromboembolism were noted on admission. Results We verified 78 cases of in-hospital venous thromboembolism, yielding an average incidence of 5 per 10,000 hospitalized children per year. Logistical regression analyses revealed that mechanical ventilation, systemic infection, and hospitalization duration of five days or over were statistically significant, independent risk factors for in-hospital venous thromboembolism (OR=3.29, 95%CI=1.53–7.06, P=0.002; OR=3.05, 95%CI=1.57–5.94, P=0.001; and OR=1.03, 95%CI=1.01–1.04, P=0.001, respectively). Using these factors in a risk model, post-test probability of venous thromboembolism was 3.6%. Conclusions These data indicate that risk of in-hospital venous thromboembolism in children with this risk factor combination may exceed that of hospitalized adults in whom prophylactic anticoagulation is indicated. Substantiation of these findings via multicenter studies could provide the basis for future risk-stratified randomized control trials of pediatric venous thromboembolism prevention.

Scope and Impact of Early and Late Preterm Infants Admitted to the PICU with Respiratory Illness

OBJECTIVE To determine the clinical course and outcomes of children born early preterm (EPT, <32 weeks), late preterm (LPT, 32 to 35 weeks), and full term (FT, >or=36 weeks) who were subsequently admitted to the pediatric intensive care unit (PICU) with respiratory illness. STUDY DESIGN Retrospective chart review of patients <2 years old admitted to a tertiary PICU with respiratory illness. RESULTS Two hundred seventy-one patients met inclusion criteria: 17.3% were EPT, 12.2% were LPT, and 70.5% were FT. Lower respiratory tract infection was the most common diagnosis (55%) for all groups. Median PICU length of stay was longer for EPT (6.3 days) and LPT infants (7.1 days) compared with FT infants (3.7 days; P < .03 for both comparisons). EPT and LPT infants had longer hospital stays (median, 11.7 and 13.8 days, respectively) compared with FT infants (median, 7.1 days; P < .03 and P = .004, respectively). Median hospital charges were also greater for EPT (

Left ventricular diastolic dysfunction in bronchopulmonary dysplasia.

85 151) and LPT (

Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia

83 576) groups compared with FT group (