Non-congenital heart disease associated pediatric pulmonary arterial hypertension

Recognition of causes of pulmonary hypertension other than congenital heart disease is increasing in children. Diagnosis and treatment of any underlying cause of pulmonary hypertension is crucial for optimal management of pulmonary hypertension. This article discusses the available knowledge regarding several disorders associated with pulmonary hypertension in children: idiopathic pulmonary arterial hypertension (IPAH), pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hemoglobinopathies, hepatopulmonary syndrome, portopulmonary hypertension and HIV. Three classes of drugs have been extensively studied for the treatment of IPAH in adults: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase inhibitors (Sildenafil, tadalafil). These medications have been used in treatment of children with pulmonary arterial hypertension, although randomized clinical trial data is lacking. As pulmonary vasodilator therapy in certain diseases may be associated with adverse outcomes, further study of these medications is needed before widespread use is encouraged.     

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.     

Management of pulmonary arterial hypertension in children

In this review we discuss the new anti- Pulmonary Arterial Hypertension [PAH] drugs and the available data on their use in paediatric PAH. Treatment of patients with PAH, children and adults, is aimed at a reduction of symptoms, survival and improvement of haemodynamics as well as exercise capacity. PAH may reflect significant different disease conditions in infants and children when compared to PAH in adults. In contrast to adult PAH, characterized mainly by idiopathic PAH and PAH associated with connective tissue disease, more than half of the cases of PAH in children are associated with congenital heart disease. Therefore, efficacy of PAH drugs in these diseases can not be extrapolated from that in adults with PAH.     

Persistent pulmonary arterial hypertension of the new born

Persistent pulmonary hypertension of the newborn (PPHN) characterised by right to left shunting with intense cyanosis is difficult to manage, and in the best of centres carries a 40–60 percent mortality. We report our one year's experience of managing six neonates with PPHN. There were 5 males and 1 female with mean birth weight of 2.59±0.487 kg and gestation period 39±2.0 wks and 1 minute Apgar score 2.8±2.1. Four to six babies were born by cesarean section and 3–6 babies had aspiration pneumonia. All babies presented within 12 hours of age (mean 5.08±5 hrs) with intense cyanosis and respiratory distress. Diagnosis were confirmed in all by (a) hyperoxia test, (b) simultaneous determination of preductal and postductal paO₂ (c) contrast echocardiography and (d) hyperoxia-hyperventilation test. Babies were managed with hyperventilation using mean ventilatory rates of 100±45 per minute, an inspired oxygen concentration of 100%, peak inspiratory pressures 27±9 cm of H₂O, and expiratory pressures 5±1.6 cms of H₂O, and mean air way pressures of 10.4±2.7 cms H₂O. Alkali therapy was used in 3 of the six babies whereas low dose dopamine was infused in all six babies. Inspite of aggressive ventilatory therapy, only 3 out of 6 babies could be salvaged.     

肺动脉高压病因学最新研究进展

肺动脉高压(pulmonary arterial hypertension,PAH)是一组少见的、预后不良的疾病,以进行性增高的肺动脉压力和阻力为特征.其病理变化包括肺血管收缩与重构、肺血管平滑肌和内皮细胞的异常增殖、血栓形成等.PAH的发病机制复杂,最新研究表明肺动脉高压病因包括骨形成蛋白Ⅱ型受体(BMPR2)和活化素受体样激酶(ALK1)等遗传基因变异以及过氧化物酶增殖物激活受体(PPAR)、Rho激酶信号通路等的异常.这为肺动脉高压的治疗和预防提供了更多的理论依据.     

Treatment of pulmonary arterial hypertension in children]

Treatment strategies for pulmonary hypertension in children have dramatically evolved. Traditional therapy with calcium channel blockers and pulmonary transplantation is only indicated in selected patients and does not reduce mortality very significantly. New pulmonary vasodilators are emerging from recent trials in the adult population. Their indications are based on the patient's NYHA classification. The epoprostenol (prostacyclin, Flolan) has shown reduction in mortality and improvement in functional symptoms in pediatric patients. The frequent side effects and continuous intravenous infusion limit the indication of prostacyclin in NYHA class IV children. The endothelin receptor blocker bosentan (Tracleer) is an orally given agent. It improves functional symptoms in adults and hemodynamic measures in children. It can be started in children with moderate functional symptoms (NYHA class II and III). The type V phosphodiesterase inhibitor sildenafil (Viagra) is being evaluated and may represent a promising therapy in the future. Invasive strategies like catheter-based atrial septostomy may be useful in particular cases. Randomized-controlled studies are urgently needed to evaluate the safety and efficacy of these new therapies.     

肺动脉去神经治疗肺动脉高压研究进展

肺动脉去神经治疗(pulmonary artery denervation,PADN)可阻断局部肺动脉交感神经,降低肺动脉高压(pulmonary arterial hypertension,PAH)血流动力学参数,改善肺血管重塑及右心室心肌肥厚、纤维化,进而改善心室功能。前期基础实验已确定肺动脉交感神经在肺动脉内膜位置,并证实PADN对PAH动物模型安全有效,可能通过抑制交感神经系统和肾素-血管紧张素-醛固酮系统发挥作用。PADN已开展成人临床应用研究,取得良好临床效果。在此基础上正初步探索PADN在儿童PAH中应用的可能性。     

Acute pulmonary hypertension complicating the arterial switch procedure

Two neonates undergoing arterial switch procedure developed life-threatening pulmonary hypertension intraoperatively. In one patient, bradycardia, hypotension, and electrocardiographic (ECG) evidence of myocardial ischemia suddenly occurred 20 minutes after uneventful weaning from cardiopulmonary bypass. Lifting a palpably hypertensive main pulmonary artery (MPA) resulted in reproducible hemodynamic improvement. Because the patient was already on full ventilatory support and a nitroglycerin infusion, the MPA was suspended onto the anterior chest wall. In the other patient, after removal of intraoperative drapes, severe generalized swelling and cyanosis were noted. The central venous pressure had risen to 25 mmHg, and the PO₂ had dropped to 52 mmHg on 100% FIO₂. The systolic arterial pressure and ECG remained normal. Immediate reexploration revealed a palpably hypertensive MPA. The coronary arteries implanted more laterally on the neoaorta were uncompromised. Amrinone loading and infusion produced immediate improvement. We believe that surgeons should be aware that pulmonary hypertension can cause coronary artery compression and right heart failure in neonates undergoing the arterial switch procedure. Lateral placement of the coronary artery and aggressive use of pulmonary vasodilators can minimize the problem.     

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.     

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。     

Pulmonary arterial hypertension from a pediatric perspective.

This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.     

Cardiac catheterization in children with pulmonary arterial hypertension

Cardiac catheterization of childhood pulmonary arterial hypertension (PAH) is used to assess the severity of the disease as well as prognosis, selection of the most adequate pulmonary vasodilators, and evaluation of effectiveness. Sudden deterioration of cardiovascular hemodynamics, however, can be easily induced by pain, patient agitation, catheter manipulation, and by vasodilator provocation tests; these could trigger a pulmonary hypertension crisis, vagotony, respiratory distress, and hemoptysis resulting in critical complications, including death. Those patients with New York Heart Association functional class IV are at an especially high risk. It is noteworthy that pulmonary arteriography is a contraindication in patients with PAH. In a review of 7218 adult patients, 76 (1.1%) serious complications, including four deaths, were reported; with regard to the pediatric patients, 29 (10.7%) out of 270 patients with complications, including one with cardiogenic shock requiring cardiopulmonary resuscitation in addition to minor complications, were reported. To prevent serious complications, basic and routine precautions, such as oxygen and concomitant transcutaneous oxygen saturation and electrocardiogram monitoring during transportation to and from the catheter laboratory, are mandatory. Furthermore, the cooperation of experienced physicians and well informed medical staff in addition to meticulous preparation, for example, calculation of prior doses of catecholamine and confirmation of the presence of emergency equipment, is required.     

Immunosuppressant-induced endothelial damage and pulmonary arterial hypertension

Cyclosporine A, used to prevent graft-versus-host-disease, is known to induce endothelial injury. Endothelial dysfunction is an important feature of pulmonary arterial hypertension (PAH). In this article, we describe 2 children who developed cyclosporine-induced acute respiratory distress syndrome. Lung biopsy showed patchy loss of endothelial caveolin-1 and von Willebrand factor to occur early. Significant loss of endothelial caveolin-1 was associated with robust expression of caveolin-1 in smooth muscle cells with subsequent neointima formation leading to fatal PAH. Thus, patients who develop acute respiratory distress syndrome after immunosuppressive therapy are at risk of developing PAH.     

Pharmacokinetics of sildenafil in children with pulmonary arterial hypertension

Background

Recently, sildenafil was introduced to treat pulmonary arterial hypertension (PAH); however, there are currently few studies on the pharmacokinetics of sildenalfil in children. Therefore, we aimed to carry out a pharmacokinetic study of sildenafil in children with PAH using a single dose.

Methods

Twelve children diagnosed with PAH, consisting of with ten males and two females, were recruited for the study after obtaining written consent from their parents or guardians. Blood samples were obtained predose and at 0.25, 0.5, 1, 2, 4, 8 and 12 hours after the oral administration of 1 mg/kg of sildenafil using an extemporal pediatric formulation developed in our laboratory. The samples were analyzed using a previously validated high performance liquid chromatography method.

Results

A pharmacokinetic analysis using the WinNonlin 3.1 program that considered the Akaike information criterion (AIC) for selecting a more adjustable model was performed. The following pharmacokinetic parameters were obtained: maximal concentration (C_max): 366±179 ng/mL, time to maximal concentration: 0.92±0.30 hours, elimination half-life (t_1/2): 2.41±1.18 hours, total clearance (CL_tot/F): 5.85±2.81 L/hour, volume of distribution (Vd/F): 20.13±14.5 L, absorption rate constants (Ka): 0.343 hour^–1, elimination rate (Ke): 0.35 hour^–1, area under curve from zero to infinity: 2061±618 ng/mL/hour. The data of all patients adjusted to the model of one compartment were corroborated using AIC.

Conclusions

The parameters Ka, Ke and t_1/2 were found to be similar to those reported in adults; however, the values of C_max and Vd/F were significantly higher. Based on these findings, we propose that treatment regimen of sildenafil be adjusted in children with PAH.

     

西地那非在儿童肺动脉高压的应用现状

西地那非(sildenafil)用于治疗男性勃起功能障碍的一线药,具有里程碑意义.近些年相关研究已证实西地那非通过选择性抑制5型磷酸二酯酶(PDE5),该酶是肺动脉血管中主要的磷酸二酯酶,抑制该酶可使环磷酸鸟苷(cGMP)维持在较高水平,后者促进内源性一氧化氮(NO)的血管扩张作用,具有治疗肺动脉高压(PAH)的功效.