Pulmonary arterial hypertension in children: A Medical Update

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980’s, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.     

Idiopathic pulmonary arterial hypertension in children

PURPOSE OF REVIEW: Until recently, the diagnosis of idiopathic pulmonary arterial hypertension was virtually a death sentence, particularly for children. Although there is no cure for idiopathic pulmonary arterial hypertension, recent medical advances have dramatically changed the course of this disease in children. A review of some of the latest medical advances will provide the reader with a better understanding of the most current treatment options for children with idiopathic pulmonary arterial hypertension. RECENT FINDINGS: The literature reviewed demonstrate sustained clinical and hemodynamic improvement in children with various types of pulmonary arterial hypertension as well as increased survival in patients with idiopathic pulmonary arterial hypertension using current treatment strategies. SUMMARY: This article will provide an overview of how the current diagnostic and treatment strategies of idiopathic pulmonary arterial hypertension in children have advanced over the last several years and how this impacts on clinical practice.     

Biological serum markers in the management of pediatric pulmonary arterial hypertension

Appropriate parameters are needed for the monitoring of children with pulmonary arterial hypertension (PAH). Various biologic markers seem to be of use in adults with PAH. No data are available on their value in children with PAH. In this study, the relation between serum markers, functional parameters, and hemodynamic variables in pediatric PAH and their ability to predict survival is determined. Serum N-terminal pro brain natriuretic peptide (NT-proBNP), uric acid, norepinephrine, and epinephrine were measured and correlated with invasive hemodynamics, functional parameters, and outcome in 29 pediatric patients with PAH who visited a tertiary reference center for pediatric PAH between 1997 and 2005. NT-proBNP correlated with functional class (R = 0.36; p = 0.03) and 6-min walking distance (6MWD) (R = -0.53; p < 0.001). Uric acid correlated with mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index (R = 0.63, p = 0.01; R = 0.71, p = 0.03, and R = -0.65, p = 0.007, respectively). After initiation of treatment, NT-proBNP decreased. This decrease correlated with an increased 6MWD. Finally, norepinephrine and NT-proBNP levels were highly predictive for mortality. In this series of children with PAH, biologic markers were correlated with hemodynamics and functional capacity, as parameters of disease severity. The data indicate that these markers can be used to monitor treatment effects and predict mortality in pediatric PAH.     

Pulmonale Hypertonie im Kindes- und Jugendalter

Background

Pediatric pulmonary hypertension (PH) is a significant cause of morbidity and mortality. Recommendations for the diagnosis and therapy of pediatric PH have been derived from guidelines for adults with PH. However, recent publications and international registry data demonstrate specific differences between PH in adulthood and in childhood.

Methods

Based on a selective literature research in PubMed with an emphasis on population-based studies, the most important aspects of pediatric PH are summarized. In addition, our own experiences from a national expert center for children with PH are considered.

Results

Idiopathic PAH (IPAH) and PAH associated with congenital heart disease (PAH-CHD) are the most frequent types of PAH in children. Follow-up studies have highlighted the importance of right ventricular function as a major determinant of the long-term prognosis of PAH-CHD patients and have led to the development of new combined interventional/surgical treatment strategies. The prognosis of children with PH has been improved by focusing on the right ventricular-pulmonary arterial unit and by recent developments of PAH-specific drugs. However, curative treatment of PAH is not within reach yet.

Conclusions

The specific pathophysiology of PAH-CHD, modified diagnostic algorithms, as well as new pathophysiologically orientated therapeutic strategies are different in pediatric PH compared with PH in adults. Nationwide registries and systematic treatment protocols are important in improving the care of these patients in the future.     

Evolving Management of Pediatric Pulmonary Arterial Hypertension: Impact of Phosphodiesterase Inhibitors

The treatment of pulmonary arterial hypertension (PAH) has undergone significant change in recent years, improving both quality of life and survival for patients. One of the principal new agents is sildenafil, a phosphodiesterase-V inhibitor with great PAH efficacy. Its success has led to consideration of other phosphodiesterase inhibitors not yet licensed for pediatric PAH including tadalafil and vardenafil, among others. This article summarizes the evidence base for phosphodiesterase inhibitors used to ameliorate pediatric PAH pathology and associated symptoms. It also analyzes their suitability for contemporary practice with the aim of clarifying and helping to direct regimens that produce improved patient outcomes.     

Pulmonary arterial hypertension in children: Diagnostic work-up and challenges

The diagnostic evaluation of a pediatric patient with suspected pulmonary arterial hypertension (PAH) is extensive but essential, given the rapid progression of the disease if left undiagnosed and untreated. The major goals of performing a complete diagnostic work-up are to confirm the diagnosis of PAH, assess disease severity, rule out associated diseases, and begin to formulate an individualized treatment plan for the pediatric patient with pulmonary hypertension. This article will provide a comprehensive review of the diagnostic work-up of the child with suspected PAH as well as a review of some of the challenges faced when assessing a child for PAH.     

Clinical Manifestations and Long-Term Follow-Up in Pediatric Patients Living at Altitude With Isolated Pulmonary Artery of Ductal Origin

This study's aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery (PA) of ductal origin (IPADO). This was a retrospective cohort study of 17 consecutive cases of IPADO at a single center. All patients lived at modest altitude (median 2050 m [range 1700 m to 3050 m]). Fifteen children (88%) were symptomatic at presentation. High-altitude pulmonary edema was present in 2 patients (12%) at diagnosis, and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up, and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with IPADO at modest altitude can potentially rehabilitate the isolated PA and reverse PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown.     

儿童肺动脉高压的药物治疗进展

本文综述了儿童肺动脉高压（PAH）的药物治疗现状,并简要介绍了新的治疗靶点。前列环素类似物、内皮素受体拮抗剂及磷酸二酯酶 5抑制剂等3类药物能显著改善PAH患儿的血流动力学、运动耐量并延长生存。随着这些药物在儿科的逐步应用,儿童PAH的治疗取得了明显进步,但仍需开展进一步的大样本随机对照试验,同时还必须努力研发新型药物。     

Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program

The oral dual endothelin receptor antagonist bosentan has been shown to improve the short- and medium-term course of adult pulmonary arterial hypertension (PAH); however, data from clinical studies in children are limited. This analysis investigated the safety profile of bosentan in pediatric patients in a European, prospective, noninterventional, Internet-based postmarketing surveillance database (Tracleer PMS). Pediatric patients (aged 2-11 y) were compared with patients aged > or =12 y. Over a 30-mo period, 4994 patients, including 146 bosentan-na?ve pediatric patients (51.4% males), were captured in the database. Predominant etiologies in children were idiopathic PAH (40.4%) and PAH related to congenital heart disease (45.2%). The majority of children were in New York Heart Association functional class II (28.1%) or III (50.7%), and median exposure to bosentan was 29.1 wk. Elevated aminotransferases were reported in 2.7% of children versus 7.8% of patients > or =12 y. The discontinuation rate was 14.4% in children versus 28.1% in patients > or =12 y. The Tracleer PMS results provide unique information on pediatric PAH in Europe. They also suggest that Tracleer may be better tolerated in children than in adults. This observation confirms the value of monthly monitoring of liver function for the duration of bosentan treatment.     

儿童先天性心脏病血清Apelin水平与肺动脉压关系的初步探讨

目的 初步探讨先天性心脏病患儿血清Apelin 水平与肺动脉压的关系.方法 手术治疗的先心病患儿126 例,检测患儿术前及术后第7 天的血清Apelin 水平.建立体外循环前检测并计算肺动脉收缩压/体循环收缩压(Pp/Ps)的比值,依据Pp/Ps 分组:无肺动脉高组压(PAH)组、轻度PAH 组、中度PAH 组和重度PAH 组;术后第7 天超声心动图估测肺动脉平均压(PAMP).结果 无PAH,以及轻、中、重度PAH 各组术前及术后的血清Apelin 水平依次降低,差异有统计学意义(PPr=-0.51,-0.54,P结论 先心病患儿并发肺动脉高压及其发展与血清Apelin 水平降低有关系,血清Apelin 对诊断先心病患儿是否并发肺动脉高压及其程度的意义值得深入研究.     

Advances in diagnosis and treatment of pulmonary arterial hypertension in neonates and children with congenital heart disease

Background  

This article aims to review recent advances in the diagnosis and treatment of pulmonary arterial hypertension in neonates and children with congenital heart disease.     

Initial Experience With Tadalafil in Pediatric Pulmonary Arterial Hypertension

This study aimed to investigate the safety, tolerability, and effects of tadalafil on children with pulmonary arterial hypertension (PAH) after transition from sildenafil or after tadalafil received as initial therapy. A total of 33 pediatric patients with PAH were retrospectively evaluated. Of the 33 patients, 29 were switched from sildenafil to tadalafil. The main reason for the change from sildenafil was once-daily dosing. The average dose of sildenafil was 3.4 ± 1.1 mg/kg/day, and that of tadalafil was 1.0 ± 0.4 mg/kg/day. For 14 of the 29 patients undergoing repeat catheterization, statistically significant improvements were observed after transition from sildenafil to tadalafil in terms of mean pulmonary arterial pressure (53.2 ± 18.3 vs. 47.4 ± 13.7 mmHg; p < 0.05) and pulmonary vascular resistance index (12.2 ± 7.0 vs 10.6 ± 7.2 Units/m(2); p < 0.05). Clinical improvement was noted for four patients treated with tadalafil as initial therapy. The side effect profiles were similar for the patients who had transitioned from sildenafil to tadalafil including headache, nausea, myalgia, nasal congestion, flushing, and allergic reaction. Two patients discontinued tadalafil due to migraine or allergic reaction. One patient receiving sildenafil had no breakthrough syncope after transition to tadalafil. Tadalafil can be safely used for pediatric patients with PAH and may prevent disease progression.     

Connective Tissue Disease Presenting With Signs and Symptoms of Pulmonary Hypertension in Children

Our case series describes three children who were initially diagnosed as having severe pulmonary arterial hypertension (PAH) and subsequently found to be positive for specific autoantibodies suggestive of an underlying autoimmune process. The signs and symptoms of PAH are subtle and may be part of the initial presentation of childhood connective tissue disease (CTD). Evaluation for connective tissue disease in the newly diagnosed pulmonary hypertension (PH) patient is important because early diagnosis of PH as well as CTD is crucial in the successful management of these complex patients. Ongoing monitoring for CTD in patients with severe PAH is warranted.     

Critical care in cardiovascular medicine

The field of cardiac intensive care is rapidly evolving with nearly simultaneous advances in surgical techniques and adjunctive therapies, respiratory care, intensive care technology and monitoring, pharmacologic research and development, and computing and electronics. The focus of care has now shifted toward reducing morbidity and improving "quality of life" while the survival of infants and children with congenital heart defects, including those with univentricular hearts has dramatically improved during the last three decades. Despite these advances, there remains a predictable fall in cardiac output after cardiopulmonary bypass. This article focuses on early identification and aggressive treatment of the low cardiac output syndrome peculiar to these patients. The authors also briefly review the recent advances in the treatment of pulmonary hypertension, mechanical support, and neurologic surveillance after cardiac surgery.     

西地那非治疗小儿高原性心脏病合并重度肺动脉高压疗效和安全性的初步评估

目的 观察西地那非治疗对小儿高原性心脏病合并重度肺动脉高压（PAH）患儿的临床疗效和安全性。方法 选择2011 年1 月至2013 年10 月连续转入重症监护病房的小儿高原性心脏病合并重度PAH 患儿50 例（年龄2 个月至2 岁）,随机分为观察组和对照组。对照组给予常规方法治疗,观察组在此基础上给予口服西地那非治疗（剂量为每日1 mg/kg,分3 次口服,连服7~10 d）。记录治疗前后血流动力学改变、血气、血常规和血生化等的变化。结果 治疗后观察组患儿平均肺动脉压的下降程度、动脉血氧分压、心输出量、心脏指数及氧合指数的上升程度均明显优于对照组（PP>0.05）,未发现明显不良反应。结论 西地那非治疗小儿高原性心脏病合并重度PAH,可有效降低肺动脉压力,改善患儿的心功能,且无不良反应,初步安全性评估良好。     

Sildenafil for the Treatment of Pulmonary Hypertension in Pediatric Patients

Sildenafil is a phosphodiesterase 5 inhibitor widely used for the treatment of pulmonary hypertension in children. Despite limited available safety and efficacy evidence, use of sildenafil continues to increase. To date, sildenafil use for pediatric pulmonary hypertension has been characterized for 193 children through 16 studies and 28 case series and reports. The primary efficacy data suggest that sildenafil is beneficial for facilitating the weaning of inhaled nitric oxide in children after cardiac surgery. Compiled safety data suggest that sildenafil is well tolerated among children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. This review summarizes the available data describing the use, safety, and efficacy of sildenafil for children with pulmonary hypertension.     

小儿结缔组织病并发的肺动脉高压临床分析

目的 研究小儿结缔组织病(CTD)并发的肺动脉高压(PAH)的发病情况、临床特点和预后.方法 回顾性分析我院儿科2000年1月-2007年1月CTD并发PAH住院患儿的临床资料.结果(1)299例有完整心脏彩超资料的CTD患儿共发生PAH 31例(10.4%),女28例,男3例,年龄7～18岁,平均12.5岁.不同CTD中PAH的发病率分别为:重叠综合征(OCTD):62.5%(5/8),抗磷脂综合征(APS)50.0%(2/4),系统性血管炎(SV):28.6%(4/14),皮肌炎(DM):10.7%(3/28),系统性红斑狼疮(SLE)7.6%(17/223).PAH在CTD患儿出现的时间为CTD起病后3周～5年,平均为1.5年.(2)小儿CTD相关PAH起病多隐匿,重者可出现呼吸困难(18/31,58.1%)、心功能衰竭(9/31,29.0%).有雷诺现象和抗磷脂抗体或狼疮抗凝物阳性的PAH患儿易表现为中重度PAH.(3)超声心动图和肺功能尤其肺CO弥散量(DL>CO)检查对早期发现PAH更有意义.(4)治疗后轻中度PAH转归较好,重度PAH可降至轻中度.CTD并发PAH死亡组患儿较存活组患儿动脉氧分压(PaO2)明显降低(P＜0.01),肺动脉收缩压(PASP)明显升高(P＜0.05).结论 CTD患儿并发PAH不少见,一般在CTD发病后平均1.5年,早期症状较隐匿,重者表现为呼吸困难和心功能衰竭.雷诺现象和抗磷脂抗体或狼疮抗凝物阳性者多为中重度PAH.早期定期监测超声心动图和肺功能对早期发现PAH非常必要.严重PAH将影响CTD患儿的预后,PASP分度和PaO2水平,是决定预后的重要因素.     

Safety and Tolerability of Targeted Therapies for Pulmonary Hypertension in Children

The objective of this study is to evaluate the safety and tolerability of the pharmacological treatment of pulmonary hypertension in pediatric patients. It is a retrospective, longitudinal, observational study on pediatric patients undergoing treatment with pulmonary targeted therapies. 63 patients were included (51 % male), with a median age of 3.4 years (IQR, 3.6 months–10 years) and a median weight 13 kg (IQR, 6–30 kg). Congenital heart disease was the etiology of pulmonary hypertension in the majority of cases (n = 33) and 28 patients were in NYHA functional class III–IV. The most commonly used drug was sildenafil (n = 79, 56 %), followed by bosentan (n = 27, 23 %), and a combination of both (n = 14, 41 %). 34 patients had adverse reactions (54 %) with an incidence rate of 1.02 per patient per year. The most commonly reported reactions were gastrointestinal symptoms (22 %) and spontaneous erections (22 %) in males. Nine severe adverse reactions (10 %) occurred, requiring eight treatment withdrawal and one hospital admission. Treatment with targeted therapies for pulmonary hypertension is safe in the pediatric population. Severe ADRs were uncommon both in monotherapy and in combination therapy. Combination therapy was associated with a higher rate of ADRs. We observed similar survival rates in children receiving sildenafil doses according to the European Medicines Agency (EMA) recommendations or higher.     

Current management of Wilms' tumor in children

PurposeWilms’ tumor is the most common renal tumor in children. Outcomes have improved dramatically over the past few decades, but important treatment questions remain. These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current treatment of Wilm's tumor.Materials and methodsThe medical literature and results of all cooperative group studies reporting treatment of children with Wilms’ tumor were reviewed.ResultsOverall survival exceeds 90% for most patients with nephroblastoma. However, outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral tumors it continues to be defined.ConclusionsCurrent protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and mortality rates.     

Long-term therapy for pulmonary hypertension in children.

This review recounts recent advances in the understanding and treatment of the processes that cause pulmonary hypertension in infancy and childhood. New discoveries have begun to unveil connections between the basic physiological mechanisms responsible for the regulation of pulmonary vascular tone and the abnormal responses of the pulmonary vasculature in a variety of disease conditions. These discoveries raise hope for new therapeutic interventions that may improve the high mortality and morbidity of both children and adults with pulmonary vascular disease. In the meantime, treatment efforts continue to be focused on the relief of pulmonary vasoconstriction with inhaled nitric oxide and intravenous prostacyclin in the short term and oral calcium channel blockers as the mainstay of long-term therapy. Lung transplantation often remains as the only viable option for continued survival when the pulmonary vascular disease is progressive.