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.     

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.     

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.     

Pharmacology of inotropic agents in infants and children

Inotropic agents are drugs which increase the stroke work of the heart at a given pre-load and after-load. All of these agents work through a final common pathway involving the modulation of calcium interactions with various myocardial contractile proteins. The agents employed with pediatric patients include the cardial glycosides, catecholamine beta-agonists and the selective phosphodiesterase III inhibitors. Digoxin is the prototypic cardiac glycoside which has a long history of safe and effective use in infants and children. Its utility in improving right ventricular dysfunction in patients with cor pulmonale leading to biventricular dysfunction makes it ideally suited to the pediatric population. Monitoring digoxin pharmacokinetics in infants is confounded by the presence of an endogenous digoxin-like substance. Nevertheless, the drug is well suited for subacute and chronic myocardial support. In contrast, the catecholamines are the drugs of choice for acute intervention. Their pharmacokinetics permit rapid dosing titration. In infants and children the greatest experience has been accrued with dopamine, a mixed alpha- and beta-agonist but both epinephreine and norepinephrine are being used with increasing frequency as the need for drugs with increased potency and pressor activity becomes more common. The phosphodiesterase inhibitors amrinone and milrinone are the newest additions to our therapeutic armamentarium. In addition to their modest inotropic effects, amrinone and to a greater extent, milrinone offer significant pulmonary vasodilatation as part of their therapeutic package. These effects occur with little or any impact on myocardial oxygen consumpton while their lusitropic effects enhance relaxation in hypertrophied ventricular muscle. Of the two agents milrinone is probably preferred due to its greater therapeutic index and shorter elimination half-life. All of these agents remain important tools in the care of critically ill infants and children. The rational use of these drugs based upon their pharmacokinetic and pharmacodynamic properties is essential to achieve their optimal effects.     

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.     

磷酸二酯酶5抑制剂治疗先天性心脏病合并肺动脉高压

肺动脉高压在先天性心脏病中很常见,有效地降低患儿肺血管阻力,能够改善其远期生存率.对肺动脉高压病理生理的研究发现,使用磷酸二酯酶5抑制剂可使肺血管舒张,降低肺血管阻力.目前磷酸二酯酶5抑制剂西地那非在国外已用于治疗肺动脉高压.多个临床试验已经证明磷酸二酯酶5抑制剂能够显著降低肺血管阻力,改善患者远期生存率和生活质量,且能较好地被患者耐受.     

Rapid progression to pulmonary arterial hypertension crisis associated with mixed connective tissue disease in an 11-year-old girl

Mixed connective tissue disease (MCTD) is rare in pediatric rheumatic diseases. Pulmonary arterial hypertension (PAH) associated with MCTD usually progresses gradually and is difficult to note at the asymptomatic phase. We report a 11-year-old girl with MCTD complicated with rapidly progressive PAH. Although PAH was not detected by echocardiogram or chest CT scan at the initial examination, it became clear in 1 year and suddenly came to cardiac arrest during an invasive procedure. She was successfully treated with extracorporeal assist and both vasodilative and immunosuppressive medication. A combination of echocardiogram and plasma BNP levels could be a useful marker for the follow-up of such cases. PAH could develop early in the course of pediatric MCTD and needs attention to unexpected acute exacerbation, especially under emotional stress.     

Resolution of human immunodeficiency virus type 1 infection-related severe pulmonary hypertension in a very low-birth-weight infant

Pulmonary arterial hypertension (PAH) affects approximately 0.5% of human immunodeficiency virus (HIV)-infected adults with poor prognosis. The effectiveness of highly active antiretroviral therapy for treatment of HIV-related PAH (HIV-PAH) remains controversial. Little is known about the incidence, clinical course, and therapy options for PAH in HIV-1-infected pediatric patients. Here, we report the case of a preterm infant with HIV-related life-threatening PAH, which resolved after initiation of highly active antiretroviral therapy.     

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.     

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.     

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??Objective To evaluate the effect of plugging tests in the diagnosis and interventional treatment of pediatric patients with patent duct arteriosus complicated with severe pulmonary hypertension ??PAH??. Methods??All the clinical data of 5 patients of PDA with severe PAH were retrospectively reviewed??including the heart catheterization data??the relevant parameters before and after acute pulmonary vasodilator tests and the changes of Pp??Ps??PVRI??and aortic blood oxygen saturation before and after the plugging tests. Results??Only 1 patient was with dynamic PAH according to heart catheterization test??however??for the other 4 patients it was difficult to judge the property of PAH. Acute pulmonary vasodilator tests were performed in 5 patients and 4 were diagnosed with dynamic PAH. Plugging tests were conducted in 5 patients and all of them were diagnosed with dynamic PAH. All the patients underwent interventional therapy well and the follow-up results were good. Conclusion??For PDA patients with severe PAH??plugging test diagnosis can be made on the properties of the PAH and if the determination is dynamic??the intervention treatment can be completed at the same time. This method can effectively avoid the limitations of cardiac catheterization and acute pulmonary vasodilator testing evaluation of PAH properties.     

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.     

Comparison of the Effectiveness of Oral Sildenafil Versus Oxygen Administration as a Test for Feasibility of Operation for Patients with Secondary Pulmonary Arterial Hypertension

It is shown that phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil can modulate pulmonary arterial hypertension (PAH) via increasing the level of guanosine-3,5-cyclic monophosphate (cGMP) and decreases pulmonary artery pressure (PAP). In this study we determined the effectiveness of sildenafil and compared its efficacy with inhaled nasal oxygen (O₂) during cardiac catheterization in patients with congenital heart diseases (CHD) and PAH, as a test of feasibility for surgical repair of the patients. We studied 15 patients, 9 male and 6 female, with a mean age of 8.3 years. Hemodynamic measurements were made at baseline, after O₂ administration for 20 min (5 L/min by mask), and then 45 min after administration of a single dose of sildenafil (0.5 mg/kg orally or via nasogastric tube). Mean PAP at baseline was 72.2 ± 12.54 mm Hg and was reduced by sildenafil to 52.5 ± 9.6 and by O₂ to 61.3 ± 10.39. Both sildenafil and O₂ decreased PAP effectively (p = 0.08 and p = 0.04, respectively). Pulmonary vascular resistance (PVR) was calculated for 12 patients, with a baseline level of 9.08 ± 1.09 mm Hg · L⁻¹ · min, which was significantly decreased by O₂, to 3.74 ± 0.43, and by sildenafil, to 5.93 ± 0.75 (p = 0.005 and p = 0.05, respectively). Sildenafil, as a single oral dose, can effectively reduce PAP and PVR. This novel PDE5 inhibitor can be used for assessment of feasibility of operation for patients with CHD and PAH when inhaled NO is not available.     

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.     

Pulmonary arterial hypertension in a child with stage‐IV neuroblastoma after autologous hematopoietic stem cell transplantation and review of the literature

PH is a rare condition with high mortality rate after pediatric HSCT. As clinical presentation is non‐specific and may mimic other conditions, a high degree of suspicion is required for diagnosis. Here, we present a patient with stage‐IV neuroblastoma who developed PAH after autologous HSCT. After exclusion of other causes of PH, we regarded that this condition was secondary to HSCT.     

Reversal of tacrolimus-related hypertrophic cardiomyopathy after conversion to rapamycin in a pediatric liver transplant recipient

Tacrolimus (Tac)-related hypertrophic cardiomyopathy (HCM) has been reported to be an unusual but serious complication affecting pediatric patients after solid organ transplantation. Herein, we present a case of young liver transplant recipient with Tac-induced HCM, treated by discontinuation of Tac followed by conversion to rapamycin (Rap). Our case report points out the potential but rather low risk of HCM during Tac immunosuppression in pediatric liver transplants and demonstrates that replacement of calcineurin inhibitors with mammalian target of Rap (mTOR) inhibitors may be an efficacious therapeutic tool to effect regression of established cardiac hypertrophy.     

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.     

Recent advances in the treatment of pediatric pulmonary artery hypertension

As our understanding of the pathogenesis of PAH evolves, newer strategies for its treatment are being developed and implemented. Based on studies with adult PPH patients, anticoagulation is now regarded as a mainstay of therapy and is associated with prolonged survival. Before the era of vasodilator therapy, which began in the late 1970s, most children with PPH died within 1 year of diagnosis. Now with chronic calcium channel blockade, survival and QOL are improved in children who acutely respond to vasodilator drug testing. In the author's experience, the 5-year survival rate for patients treated with chronic oral calcium channel blockade who respond acutely to vasodilator testing is 97% versus 35% for those who do not respond acutely. Continuous i.v. prostacyclin has also been used successfully, with a 5-year survival rate of 92% in children in whom oral calcium channel blockade failed (although in some patients the prostacyclin therapy was used as a bridge to transplantation) versus 29% in children in whom oral calcium channel blockade also failed and for whom chronic prostacyclin was unavailable. Before the availability of long-term prostacyclin therapy, 30% to 40% of patients with PPH died while waiting for transplantation. Prostacyclin has virtually eliminated this situation. The results of lung transplantation for adult patients with PPH at 3 years are similar to the results of those on continuous i.v. prostacyclin. Ultimately, the best therapy for an individual child depends on the results of longer follow-up studies. Inhaled nitric oxide has also been used to treat PAH in newborns and other forms of acute and chronic PAH. Although less experience exists with long-term inhaled nitric oxide than with long-term prostacyclin, the preliminary results of long-term inhaled nitric oxide are promising and await further study. The "optimal" vasodilator for long-term therapy, (e.g., calcium channel blockade), prostacyclin, nitric oxide, or potential future therapies, such as prostacyclin analogs, endothelin receptor blockers and thromboxane synthase inhibitors or receptor blockers, must be based on a thorough evaluation with acute vasodilator testing and overall risk-benefit considerations for the various therapeutic regimens. Further clarification of the mechanisms of the development and perpetuation of the PAH process will undoubtedly lead to a refinement in treatment strategies for patients with PAH, which not too long ago was often considered untreatable and fatal. By increasing our understanding of the pathogenesis and pathophysiology of primary and secondary PAH disorders, one day we may be able to prevent or cure these diseases as opposed to providing only palliative therapy. Despite this, therapeutic advances have significantly improved the outcome for children with PAH.