Janette T. Reyes

Beneficial Effect of Oral Sildenafil Therapy on Childhood Pulmonary Arterial Hypertension Twelve-Month Clinical Trial of a Single-Drug, Open-Label, Pilot Study

Background—Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH. Methods and Results—After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278±114 to 443±107 m over 6 months (P=0.02), and at 12 months, the distance walked was 432±156 m (P=0.005). A plateau was reached between 6 and 12 months (P=0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg (P=0.014). Median pulmonary vascular resistance decreased from 15 Wood units m2 (range, 9 to 42) to 12 Wood Units m2 (range, 5 to 29) (P=0.024). Conclusions—Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.

Usefulness of the right ventricular systolic to diastolic duration ratio to predict functional capacity and survival in children with pulmonary arterial hypertension.

The objective of this study was to investigate the systolic to diastolic duration ratio (S:D ratio) in children with pulmonary arterial hypertension (PAH) and its association with right ventricular (RV) performance, hemodynamics, 6-minute walk test, clinical outcomes, and survival. We reviewed 503 serial echocardiograms in 47 children with PAH (mean pulmonary artery pressure >or=25 mm Hg) and compared the S:D ratio, assessed from Doppler flow of tricuspid valve regurgitation, to that in 47 age-matched controls. We reviewed echocardiograms, catheterization data, 6-minute walk tests, clinical data, lung transplantation, and death and used univariate linear regression models with a maximum likelihood algorithm for parameter estimation to investigate associations between S:D ratio and RV function, hemodynamics, functional capacity, and clinical outcomes. The S:D ratio was significantly higher in patients than in controls (1.38 +/- 0.61 vs 0.72 +/- 0.16, p <0.001). A higher S:D ratio was associated with worse echocardiographic RV fractional area of change, worse catheterization hemodynamics, shorter 6-minute walk distance, and worse clinical outcomes independent of pulmonary resistance or pressures. An increase of 0.1 in the S:D ratio was associated with a 13% increase in yearly risk for lung transplantation or death (hazard ratio 1.13, p <0.001). An S:D ratio 1.00 to 1.40 was associated with a moderate risk and an S:D ratio >1.40 was associated with a high risk of a negative outcome. In conclusion, in children with PAH, an increased S:D ratio is temporally associated with worse RV function, hemodynamics, exercise capability, clinical status, and survival.

Safety of Maximal Cardiopulmonary Exercise Testing in Pediatric Patients With Pulmonary Hypertension

BACKGROUND Maximal cardiopulmonary exercise testing (CPX) is valuable to quantifying functional capacity in patients with pulmonary hypertension (PH), but information on CPX in children is limited possibly because of safety concerns. The purpose of this study was to examine the safety of CPX in pediatric patients with PH. METHODS Data were obtained retrospectively from patients referred for CPX at our institution between January 2001 and September 2007. Patients with a 6-min walk distance < 275 m were excluded. Exercise test complications were grouped according to ischemic ECG changes, presence of arrhythmia, and oxygen desaturation at peak exercise and were graded as mild, moderate, or severe. RESULTS Twenty-seven patients (4 with idiopathic PH, 23 with secondary PH), 12.5 years of age (range, 6.9 to 18 years), participated in 64 CPX sessions. The mean (+/- SD) peak oxygen uptake was 23.3 +/- 5.4 mL/kg/min, with a mean decrease in arterial oxygen saturation to 85% +/- 15.7% at peak exercise. Mild arrhythmia was detected in 30% of the patients. ST-segment depression was graded as mild (19%) or moderate (1.5%). There were no significant adverse events, such as syncope, chest pain, or dizziness. CPX was stopped for fatigue in 53% of patients, leg fatigue in 23%, dyspnea in 21%, and miscellaneous reasons in 3%. CONCLUSIONS This study suggests that CPX can be performed safely in pediatric patients with PH, with the exception of patients with severe limitation who were excluded from exercise testing. Although the number of patients in the sample is small, the data imply that the absence of significant patient symptoms and low incidence of arrhythmia or significant ST-segment depression make CPX a safe choice for measuring functional capacity in this patient population.

Sildenafil therapy for neonatal and childhood pulmonary hypertensive vascular disease

OBJECTIVES We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal. PATIENTS AND METHODS We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal. RESULTS We recruited 25 patients (median age 180 days, 10-1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5-1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1-13.6) Wood units metre square and decreased to 5.8 (2.7-15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9-499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384-1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8-1.4) during nitric oxide withdrawal to 0.4 (0.3-0.8) p = 0.006 after pre-treatment with sildenafil. CONCLUSION In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.

Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: Relation to pulmonary vascular resistance, exercise capacity, and survival

BACKGROUND Pediatric pulmonary arterial hypertension (PAH), whether idiopathic PAH (iPAH) or PAH associated with congenital heart disease (aPAH), carries high morbidity and mortality. Low pulmonary arterial capacitance (PAC), defined as right ventricular stroke volume/pulmonary artery pulse pressure, is a risk factor for mortality in adults with PAH. However, the relation of PAC to pulmonary vascular resistance (PVR), exercise endurance, and survival is poorly defined in children. METHODS Catheterization and clinical data of children with PAH (mean pulmonary artery pressure >25 mm Hg) were reviewed. Children with pulmonary shunts, stents, collaterals, or pulmonary venous hypertension were excluded. Primary outcomes were 6-minute walk distance and freedom from death/lung transplant. RESULTS Forty-seven patients were studied. Nineteen (43%) had iPAH, and 28 (57%) had aPAH (7.1 ± 6.2 vs 8.4 ± 5.5 years, P = .45). Patients with iPAH had higher PVR indexed for body surface area (PVRi), lower indexed PAC (PACi), lower exercise tolerance, and lower freedom from death/lung transplant than patients with aPAH. Both higher PVRi (P < .0001) and lower PACi (P = .02) were associated with shorter 6-minute walk distance. A PACi <0.70 mL/mm Hg per square meter or >1.25 mL/mm Hg per square meter and a PVRi >13 Wood units × m(2) were associated with decreased freedom from death or lung transplant. The relationships between PVRi and PACi and survival were independent of each other and not confounded by etiologic group. CONCLUSIONS Low PACi and high PVRi are independently associated with low 6-minute walk distance and survival in children with PAH. Therefore, both should be assessed for better prognostication and management in this high-risk population.

Pharmacokinetic and hemodynamic responses to oral sildenafil during invasive testing in children with pulmonary hypertension.

OBJECTIVES The purpose of our study was to characterize the hemodynamic and corresponding pharmacokinetic responses to a single dose of oral sildenafil by children with pulmonary arterial hypertension (PAH) undergoing invasive testing. BACKGROUND Although used frequently for the treatment of children with PAH, data regarding the acute responses to sildenafil are limited. METHODS Thirty-six patients (mean age 7.5+/-5.9 years; 24 females) were studied during cardiac catheterization with general anesthesia. Eight of 36 (22%) had idiopathic PAH; the remainder had associated congenital heart disease. Hemodynamics and serum cyclic-guanosine monophosphate levels (cGMP) were evaluated at baseline and after inhaled nitric oxide (NO) (40 ppm). In addition, cGMP and sildenafil levels were measured 30 min after administration of sildenafil (0.5 mg/kg, suspended in 5 ml sterile water) through a nasogastric tube. RESULTS For the 36 patients, the pulmonary vasodilating capability of oral sildenafil was lower than that of inhaled NO (2.8% vs. 11.6% reduction in pulmonary vascular resistance indexed to body surface area [PVRI], respectively; p=0.01). However, only 21 of 36 (58%) patients had a detectable sildenafil level. In those with detectable sildenafil levels, the fall in PVRI was greater (-11.6% vs. -19.1%, p=NS). Mean cGMP levels at baseline and after NO were 41.8+/-20.0 pmol/ml and 83.8+/-35.5 pmol/ml, respectively (p<0.0001). Surprisingly, there was no significant increase in cGMP in patients with either undetectable (37.5+/-29.8 pmol/ml) or detectable (44.4+/-31.7 pmol/ml) sildenafil levels (p=NS compared with baseline) with sildenafil. CONCLUSIONS Our study demonstrates suboptimal absorption of sildenafil in almost half the children undergoing acute hemodynamic testing. When detectable, there was no statistically significant difference between the fall in PVRI associated with sildenafil and NO despite lower circulating cGMP levels in the sildenafil group. These data should be taken into account when designing acute testing protocols, and assessing the acute response to sildenafil in patients with PAH.

Congenital diaphragmatic hernia: Observed/expected lung-to-head ratio as a predictor of long-term morbidity.

AIM The aim of this study was to investigate the association of observed/expected (O/E) lung-to-head ratio (LHR) with long-term morbidity for isolated fetal congenital diaphragmatic hernia (CDH) patients in a single institution. METHODS We performed a retrospective study of prenatally diagnosed CDH from 18 to 38weeks of gestation (01/2002-04/2010). Two cohorts of O/E LHR were defined (22.6-45%, 45.1-78.3%) based upon previous studies. Survivors with at least 1-year follow-up of prospectively collected long-term morbidity assessments were included. RESULTS O/E LHR was available in 43 survivors (median 40%, range 22.8-78.3%). Follow-up data were available in 41 survivors (M:F=24:17, left CDH=39/41). Median follow-up was 6.5years (1-11years). Height/weight trajectories were similar between the two cohorts, with the majority below the 50th centile. There were no differences between the two cohorts by age 3years for Bayley scales (developmental domains) and/or REEL-3 (language development). In addition, V/Q scans in the two cohorts demonstrated similar degrees of mismatch (mean delta V/Q=35.4 versus 31.3). CONCLUSIONS In fetuses with isolated CDH, a reduction in O/E LHR does not predict a worse outcome in long-term follow-up. There is no association between a lower O/E LHR and a reduction in REEL-3 or Bayley score nor V/Q mismatch.

Pulmonary hypertension in congenital diaphragmatic hernia patients: Prognostic markers and long-term outcomes

Prenatal observed/expected lung-to-head ratio (O/E LHR) by ultrasound correlates with postnatal mortality for congenital diaphragmatic hernia (CDH) patients. The aim of this study is to determine if O/E LHR correlates with pulmonary hypertension (PH) outcomes for CDH patients. METHODS A single center retrospective chart review was performed for CDH neonates from January 1, 2006, to December 31, 2015, (REB #1000053124) to include prenatal O/E LHR, liver position, first arterial blood gas, repair type, echocardiogram (ECHO), and lung perfusion scan (LPS) results up to 5years of age. RESULTS Of 153 newborns, 123 survived (80.4%), 58 (37.9%) had prenatal O/E LHR, and 42 (27.5%) had postnatal ECHO results. High mortality risk neonates (O/E LHR ≤45%) correlated with higher right ventricular systolic pressure (RVsp) at birth. Generally PH resolved by age 5years. LPS results did not change over time (p>0.05) regardless of initial PH severity, suggesting that PH resolution did not correlate with increased ipsilateral lung perfusion to offload the right ventricle. CONCLUSION Prenatal prognostic markers correlated with initial PH severity for CDH newborns, but PH resolved over time despite fixed perfusion bias to the lungs. These results suggest favorable PH outcomes for CDH patients who survive beyond infancy. TYPE OF STUDY Retrospective Cohort Study. LEVEL OF EVIDENCE 3b.

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children

Acquired von Willebrand syndrome (AVWS) is reported in high‐flow high‐shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross‐sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in‐depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3–5). All 8 patients showed very prolonged platelet function analyser (PFA)‐100 closure times. Six children demonstrated either mild thrombocytopenia or low‐normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61–91); VWF activity: 57 (34–70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53–123 iu/dl), with low‐normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post‐surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.

Resolution of Periodic Breathing in a Child with Idiopathic Pulmonary Arterial Hypertension

Central sleep apnea (CSA) and periodic breathing are unusual findings described in pediatric patients with congestive heart failure. However, CSA has not been reported in children with pulmonary hypertension. We hereby report on a 10-year-old girl with idiopathic pulmonary arterial hypertension who had frequent central events in a periodic breathing fashion seen in her polysomnography, which was normalized following medical treatment leading to improvement of the pulmonary pressures.