波生坦治疗先天性心脏病术后肺动脉高压的前瞻性随机对照研究

Treatment of patients with bosentan in post-operation of congenital heart disease with pulmonary arterial hypertension： a double-blind, randomized controlled trial

目的 评价应用波生坦治疗婴幼儿先天性心脏病术后肺动脉高压的疗效.方法 30例术前合并肺动脉高压且手术治疗后仍有肺动脉高压的先大性心脏病病儿入选.所有病儿均在低温体外循环辅助下完成心内畸形根治术,术后1周行超声心动图检查,估测肺动脉收缩压＞30mm Hg者随机分配到波生坦治疗组（15例）及对照组（15例）中.研究周期12周,波生坦组：传统治疗＋波生坦,波生坦给药方案：10～20 kg病儿,31.25 mg,每日1次（qd）4周,31.25 mg,每日2次（bid）8周;5～10 kg病儿,15.6 mg,qd（4周）,15.6 mg,bid（8周）;对照组：传统治疗（地高辛、双氢克脲塞）.两组病例于术后13周接受门诊随访、调查问卷、超声检查和血液检查.比较两组心功能及临床症状,超声心动图评价血流动力学和肺动脉高压变化,以及血浆内皮素（Endothelin-1,ET-1）变化.结果 两组病例年龄、平均体重、病种分布、基线肺动脉收缩压力、基线血浆ET-1浓度均无统计学差异.心功能改善方而,依据NYHA心功能分级（级数增高定义为心功能恶化,降低则为心功能改善）.波生坦治疗组93%的病儿心功能较基线水平改善Ⅰ级,无心功能恶化;对照组只有73%病儿心功能较基线水平改善Ⅰ级,13%病儿心功能较基线水平恶化Ⅰ级.将术后因心肺功能不全再入院及死亡定义为临床恶化,波生坦治疗组无再入院及死亡发生;而对照组13%的病儿发生了临床恶化（1例病儿术后11大死亡,1例病儿术后60天再入院）.波生坦治疗组：基线（术后1周）肺动脉收缩压（48.5±9）mm Hg,治疗12周后（29.0±8.0）mm Hg,治疗前后差异有统计学意义（P＜0.01,95%CI：12～27）;对照组：基线（术后1周）肺动脉收缩压（45.4±16）mm Hg,12周后（35.1±15.0）mm Hg手术前后差异无统计学意义（P＞0.1）.两组之间比较,波生坦治疗组较对照组能更好的降低肺动脉压力（P＜0.05,95%CI：0.1～1 8.3）.应用波生坦治疗后血浆ET下降（2.01±0.03）fmol/ml（1 fmol/ml=10-15mol/ml,P=0.03）,对照组血浆ET升高（0.15±0.10）fmol/ml（P=0.77）.波生坦组有2例肝脏转氨酶升高,停药后自然恢复正常,后未继续服药;无其他明显副作用.结论 波生坦治疗左向右分流的先天性心脏病术后残留肺动脉高压疗效明显,有助于病儿术后心功能及临床症状的恢复.

Objective Endothelin is a key role in the pathogenic of pulmonary arterial hypertension. High concentrations of endothelin-1 have been recorded in plasma and lungs of patients with pulmonary artery hypertension associated with congenital heart disease, and the concentrations of endothelin-1 was correlated with severity degree of pulmonary arterial disease.Endothelin exerting vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth muscle cells： endothelin A and B receptors. Bosentan is an orally active dual （ A and B） endothelin receptor antagonist that has been shown to improve exercise capacity, haemodynamics, and clinical worsening in many clinical trials, but have no experience in post-operation of congenital heart disease with PAH. In our country, there are lots of elder patients of congenital heart disease accompany with pulmonary arterial hypertension. And they have poor prognosis after operation because pulmonary arterial hypertension leads to right ventricular failure and sudden death. So we hope bosentan can improve clinical outcome of these patients. This time we present the results of the bosentan trial in post-operative patients still with pulmonary arterial hypertension, a randomized controlled trial designed to assess the efficacy and safety of the dual endothelin receptor antagonist bosentan in post-operative pulmonary arterial hypertension, and present the first experience of bosentan for these patients.Methods This study was a prospective clinical trial. The objects were 30 patients （ age：4 months - 6.8years,weight：5 - 15 kg） who still had pulmonary artery hypertension at one week after cardiac defects repaired. They were randomized to controlled （ n = 15 ） or to bosentan （ n = 15 ）. Dosage regimen： 10 - 20 kg patients, 31. 25 mg qd （ 4 weeks ） ,31.25 mg bid （ 8 weeks）;5 - 10 kg patients, 15.6 mg qd （ 4 weeks）, 15.6 mg bid （ 8 weeks）. Evaluate the efficacy and safety of Bosentan through the amelioration of pulmonary arterial systolic pressure, WHO functional class, and clinical worsening. Results We monitored pulmonary arterial systolic pressure after operation by echocardiogram 2 times, baseline （ 1 week after operation） and at 12 weeks later. The pulmonary arterial systolic pressure decreased 19.5 mm Hg in Bosentan group（ P =0. 000）, and decreased 10.3 mm Hg in control group（P =0. 164）, with the mean treatment effect of 9.2 mm Hg （P=0.049,95%CI：0. 1 -18.3）. The effct of bosentan on haemodynamics is also reflected in the reduction plasma ET-1 concentration in bosentan group. Plasma ET-1 in control group increased （0. 15 ±0.1 ）fmol/ml（P =0.77）, however, decreased （2.01 ±0.3）fmol/ml （P=0. 03） in bosentan group; Bosentan prevented post-operation PAH. Bosentan treatment was associated with lower incidence of worsening NYHA functional class compared with controlled（0 in the bosentan group vs 13% in the placebo group） There was a delay in time to clinical worsening with bosentan compared wih controlled group. Abnormal liver function occurred in 2 cases in bosentan group but resolved after discontinuation of bosentan treatment, no other side effects. Bosentan produced hemodynamic improvement and was well tolerated in infant. Conclusion Bosentan administration in patients with postoperative PAH is safe and efficient. Bosentan is a new effective approach to therapy for postoperative pulmonary arterial hypertension in children.