D. Dunbar Ivy

Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension

Bosentan, a dual endothelin‐receptor antagonist, is registered for the treatment of pulmonary arterial hypertension. Little is known about the effects of bosentan in children. This study was conducted to investigate the pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.

Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide

We studied the efficacy of low-dose nitric oxide inhalation in nine consecutive patients with severe persistent pulmonary hypertension of the newborn (PPHN) who were candidates for extracorporeal membrane oxygenation (ECMO). All patients had marked hypoxemia despite aggressive ventilator management and echocardiographic evidence of pulmonary hypertension. Associated diagnoses included meconium aspiration syndrome (3 patients), sepsis (3 patients), and congenital diaphragmatic hernia (2 patients). Infants were initially treated with inhaled nitric oxide at 20 ppm for 4 hours and then at 6 ppm for 20 hours. In all infants, oxygenation promptly improved (arterial/alveolar oxygen ratio, 0.077 +/- 0.016 at baseline vs 0.193 +/- 0.030 at 4 hours; p < 0.001) without a decrease in systemic blood pressure. Sustained improvement in oxygenation was achieved in eight patients treated with inhaled nitric oxide for 24 hours at 6 ppm (arterial/alveolar oxygen ratio, 0.270 +/- 0.053 at 24 hours; p < 0.001 vs baseline). One patient with overwhelming sepsis had an initial improvement of oxygenation with nitric oxide but required ECMO for multiorgan and cardiac dysfunction. We conclude that low doses of nitric oxide cause sustained clinical improvement in severe PPHN and may reduce the need for ECMO. However, immediate availability of ECMO is important in selected cases of PPHN complicated by severe systemic hemodynamic collapse.

Hypoplastic Left Heart Syndrome : Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients.

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial Hypertension

Background— Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results— Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1–17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV[Combining Dot Above]O2) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV[Combining Dot Above]O2 for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, −0.2% to 15.6%; P=0.056). PV[Combining Dot Above]O2, functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions— Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV[Combining Dot Above]O2 for the 3 sildenafil doses combined was only marginally significant; however, PV[Combining Dot Above]O2, functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00159913.

Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

Survival in Childhood Pulmonary Arterial Hypertension Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management

Background— Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. Methods and Results— We analyzed data from 216 patients ⩽18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m2, respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts (P=0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P=0.087) and lower brain natriuretic peptide (P=0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Conclusion— Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00370214.Background— Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. Methods and Results— We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m2, respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts ( P =0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P =0.087) and lower brain natriuretic peptide ( P =0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Conclusion— Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. Clinical Trial Registration— URL: [www.clinicaltrials.gov][1]. Unique identifier: [NCT00370214][2]. # Clinical Perspective {#article-title-31} [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00370214&atom=%2Fcirculationaha%2F125%2F1%2F113.atom

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.

Short- and Long-Term Effects of Inhaled Iloprost Therapy in Children With Pulmonary Arterial Hypertension

OBJECTIVES This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost. BACKGROUND Inhaled iloprost has been approved for the treatment of adults with PAH, but little is known about the effects in children with PAH. METHODS We evaluated the acute effects of inhaled iloprost on hemodynamic status and lung function and the response to long-term therapy in 22 children (range 4.5 to 17.7 years) with PAH (idiopathic, n = 12; congenital heart disease, n = 10). Cardiac catheterization, standard lung function testing before and after iloprost inhalation, 6-min walk test, World Health Organization functional class, and hemodynamic parameters were monitored. RESULTS Acute administration of inhaled iloprost lowered mean pulmonary artery pressure equivalent to the response to inhaled nitric oxide with oxygen. Acute iloprost inhalation reduced forced expiratory volume in 1 s and mid-volume forced expiratory flow by 5% and 10%, respectively, consistent with acute bronchoconstriction. At 6 months, functional class improved in 35%, decreased in 15%, and remained unchanged in 50% of children. Sixty-four percent of patients continued receiving long-term iloprost therapy, 36% stopped iloprost, due to lower airway reactivity, clinical deterioration, or death. In 9 patients on chronic intravenous prostanoids, 8 transitioned from intravenous prostanoids to inhaled iloprost, which continued during follow-up. CONCLUSIONS Inhaled iloprost caused sustained functional improvement in some children with PAH, although inhaled iloprost occasionally induced bronchoconstriction. Most patients tolerated the transition from intravenous to inhaled prostanoid therapy. Clinical deterioration, side effects, and poor compliance, owing to the frequency of treatments, could limit chronic treatment in children.

Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization.

BACKGROUND:Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is considered to be associated with an increased risk of perioperative cardiovascular complications. METHODS:We reviewed the medical records of children with PAH who underwent anesthesia or sedation for noncardiac surgical procedures or cardiac catheterizations from 1999 to 2004. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined. RESULTS:Two hundred fifty-six procedures were performed in 156 patients (median age 4.0 yr). PAH etiology was 56% idiopathic (primary), 21% congenital heart disease, 14% chronic lung disease, 4% chronic airway obstruction, and 4% chronic liver disease. Baseline pulmonary artery pressure was subsystemic in 68% patients, systemic in 19%, and suprasystemic in 13%. The anesthetic techniques were 22% sedation, 58% general inhaled, 20% general IV. Minor complications occurred in eight patients (5.1% of patients, 3.1% of procedures). Major complications, including cardiac arrest and pulmonary hypertensive crisis, occurred in seven patients during cardiac catheterization procedures (4.5% of patients, 5.0% of cardiac catheterization procedures, 2.7% of all procedures). There were two deaths associated with pulmonary hypertensive crisis (1.3% of patients, 0.8% of procedures). Baseline suprasystemic PAH was a significant predictor of major complications by multivariate logistic regression analysis (OR = 8.1, P = 0.02). Complications were not significantly associated with age, etiology of PAH, type of anesthetic, or airway management. CONCLUSION:Children with suprasystemic PAH have a significant risk of major perioperative complications, including cardiac arrest and pulmonary hypertensive crisis.