波生坦治疗新生儿持续性肺动脉高压有效性及安全性的Meta分析北大核心CSCD

目的系统评估波生坦用于新生儿持续性肺动脉高压(persistent pulmonary hypertension of the newborn,PPHN)的有效性及安全性。方法计算机全面检索中国期刊全文数据库、维普中文科技期刊数据库、万方数据库、中国生物医学文献数据库、PubMed、Web of Science、Embase、Cochrane Library等数据库中关于波生坦治疗PPHN的文献,检索时间从建库至2021年8月31日。结果纳入8篇随机对照试验进行Meta分析。Meta分析结果示:波生坦组治疗失败率比对照组低[相对危险度(relative risk,RR)=0.23,P<0.001];肺动脉压力下降幅度大于对照组[均数差(mean difference,MD)=-11.79,P<0.001];氧分压(MD=10.21,P=0.006)及血氧饱和度(MD=8.30,P<0.001)上升幅度均高于对照组;住院时间短于对照组(MD=-1.35,P<0.001)。描述性分析提示波生坦组治疗后三尖瓣反流程度小于对照组;波生坦治疗的主要不良反应包括肝功能异常、贫血和水肿。对治疗方案、研究地域、药物剂量进行分层分析,结果显示与未分层前一致。结论波生坦治疗对PPHN是有效的,但使用波生坦治疗时要注意肝功能异常等不良反应。     

儿童重症相关肺动脉高压诊治研究进展

本文综述了2015年美国心脏病学会和2016年欧洲儿童肺血管疾病协作网制定的儿童肺动脉高压诊治指南,强调了对肺动脉高压危象的早期识别及规范治疗,同时介绍了常用肺动脉高压治疗药物的使用方法和注意事项,以指导儿童肺动脉高压的诊治.     

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。     

西地那非在小儿肺动脉高压中的应用

引起小儿肺动脉高压的原因很多,以先天性心脏病合并肺动脉高压多见,早期多为动力性肺动脉高压,术前应用药物降低肺动脉高压可改善患儿病情,术后及时有效处理肺动脉高压,能改善肺的氧合,预防右心功能不全,提高手术疗效.     

肺动脉高压的治疗现状与进展

肺动脉高压是一种威胁儿童生命的严重疾病.近10年来有关肺动脉高压的治疗取得了很大进展.目前有3类药物(前列环素类药物、内皮素受体拮抗剂及5型磷酸二酯酶抑制剂)在肺动脉高压患者治疗研究中取得很大进步,但多中心的随机对照研究尚待加强.房间隔切开术和心肺移植对于内科治疗无效的肺动脉高压患儿有一定疗效.     

一氧化氮吸入治疗在新生儿呼吸系统疾病中的应用

一氧化氮吸入治疗在新生儿呼吸系统疾病中的应用浙江医科大学附属儿童医院（３１０００３）杜立中新生儿低氧血症可由多种原因引起，而肺动脉高压在低氧血症中起重要作用。在临床上一直缺乏对体循环血压无影响而能特异性扩张肺血管、降低肺动脉压的药物。一氧化氮（ｎｉｔ...     

单中心儿童肺高血压病因组成和住院转归分析

目的　观察分析单中心儿童肺高血压（PH）病因组成和不同类型PH患儿住院转归及影响因素。方法　选取2016年1月至2018年12月在湖南省儿童医院确诊并接受治疗的PH患儿共1157例，根据患儿病历资料及出院诊断，对其PH病因按照2015年发布的《儿童肺动脉高压诊断与治疗专家共识》进行分类。收集并记录其住院期间相关临床资料。结果　本研究中肺动脉高压（PAH）患儿共1099例（94.9%），以先天性心脏病相关性PAH（APAH-CHD）、新生儿持续肺动脉高压（PPHN）为主，分别占84.7%、8.0%。特发性PAH死亡3例，放弃治疗6例，手术1例，余5例好转出院。APAH-CHD中以手术后出院676例（68.9%）。要求出院45例（4.6%），其中放弃治疗出院及死亡80例（8.2%）；服用波生坦共52例，有2例联用西地那非。PPHN患儿因其他器官手术后出院6例（6.5%），好转出院66例（70.9%），放弃出院及死亡14例（15.1%）。左心疾病所致PH好转18例，行左心疾病矫治手术11例（40.7%），放弃及死亡病例7例（25.9%）。呼吸系统疾病PH 27例，1例死亡，3例放弃治疗。未知因素所致PH 2例放弃出院，死亡1例，1例行姑息手术出院。结论　儿童PH分类以APAH-CHD及PPHN为主，特发性PAH、左心疾病相关PH的患儿预后差。     

儿童肺动脉高压靶向药物治疗

儿童肺动脉高压(PH)是以增高的肺动脉压力和肺血管阻力为特征的临床血流动力学综合征,预后不良,可导致心力衰竭和死亡。采用靶向药物可改善预后。根据美国食品药品管理局批准治疗PH的药物主要应用于以下3条分子通路之一:一氧化氮(NO)可溶性鸟苷酸(SGC)-环磷鸟苷(c GMP)通路,PGI2-环磷腺苷(c AMP)及内皮素-1(EF-1)通路。     

儿童动脉导管未闭治疗进展

动脉导管未闭是儿童常见先天性心脏病,及时有效治疗可防止肺炎、心力衰竭、感染性心内膜炎、肺动脉高压等并发症的发生.治疗方法包括药物治疗、经导管介入治疗和手术治疗.目前绝大部分动脉导管未闭通过介入封堵可获治愈.     

儿童肺血管炎

肺血管炎是一组以肺血管壁及周围组织炎症细胞浸润为特征,伴肺血管壁损伤的疾病的总称,多为系统性疾病在肺部的表现之一,也可以是孤立性肺血管炎。儿童肺血管炎属少见病,其病因繁杂。因受累血管不同,肺血管炎的呼吸系统临床表现多样,可并发肺动脉狭窄、肺动脉瘤、肺动脉血栓、肺梗死、肺泡出血、肺动脉高压等。治疗目标包括控制血管炎症、处理肺部并发症。糖皮质激素仍是多数原发性肺血管炎治疗的一线药物,而联合恰当的免疫抑制剂治疗是改善预后的关键。近年,生物制剂的应用也得到了较好疗效。     

Bosentan for Increased Pulmonary Vascular Resistance in a Patient with Single Ventricle Physiology and a Bidirectional Glenn Shunt

We present a case of the successful use of bosentan for increased pulmonary vascular resistance (PVR) in a 10-year-old male who underwent late single ventricle surgical palliation for double-inlet left ventricle with pulmonary artery banding and a bidirectional Glenn shunt. The patient was treated with bosentan for 16 weeks, with decreases in mean pulmonary artery pressure from 23 to 16 mmHg on the right and from 31 to 21 mmHg on the left, and a decrease of the transpulmonary gradient by 7–8 mmHg. Cardiopulmonary exercise testing demonstrated an increase in peak oxygen consumption (VO₂) by 8% and peak work rate by 10%. Bosentan is a relatively new oral therapy option for increased PVR in patients with single ventricle physiology and bidirectional Glenn shunts.     

Weaning of epoprostenol in a small infant receiving concomitant bosentan for severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia

Endothelin receptor antagonism is an important therapeutic tool of pulmonary arterial hypertension (PAH). Bosentan was the first orally active, dual antagonist of endothelin receptors in human adults, and has been recently considered for children as well. However, little is known about bosentan treatment in children weighing less than 10 kg. We describe the use of bosentan concomitantly to epoprostenol in an infant weighing 3.5 kg and affected with severe bronchopulmonary dysplasia (BPD) and PAH. At 5 months old, when she presented subsystemic PAH secondary to severe BPD, she was treated with oxygen, digoxin and diuretics. At 8 months old, due to severe PAH not responsive to 100% oxygen, high frequency oscillatory ventilation (HFOV) and nitric oxide (NO), we started epoprostenol and bosentan. Bosentan dose was doubled at 9 months old, when HFOV and NO were slowly discontinued due to improved oxygenation index. Regular echocardiographic measurements of systolic right ventricular pressure were recorded by the method of tricuspidal atrio-ventricular gradient. A four-month combined epoprostenol and bosentan treatment decreased systolic right ventricular pressure from 68% to 40% of the systemic level, till its normalization at 11 months old. Later, when bosentan and epoprostenol were discontinued and sildenafil was started, severe PAH was reported again. Our patient died due to septic shock and refractory hypoxia at 14 months old.     

Successful treatment of persistent pulmonary hypertension of the newborn with bosentan

The sophisticated and expensive treatment modalities of persistent pulmonary hypertension of the newborn (PPHN), such as nitric oxide, are limited in developing countries. Alternative (less expensive) treatments are being sought and bosentan, an oral dual endothelin-1 receptor antagonist, may be an option for the treatment of PPHN. We report our experience of using bosentan in a neonate with severe PPHN.
Conclusion:  Bosentan may be a useful adjuvant therapy in neonates with PPHN, providing significant improvement in oxygenation, and thus may be particularly useful in the treatment of PPHN in countries with limited resources.     

Persistent pulmonary hypertension of the newborn with transposition of the great arteries: successful treatment with bosentan

Persistent pulmonary hypertension of the newborn (PPHN) occurs in 1–4% of neonates with transposition of the great arteries with intact ventricular septum (TGA/IVS). This association is often lethal. To our knowledge, only eight survivors have been described in the literature, two of whom benefited from extracorporeal membrane oxygenation (ECMO). We report two cases of PPHN complicating a TGA/IVS that were refractory to multiple therapies and resolved 48 hours after initiation of bosentan therapy. Bosentan, an oral dual endothelin-1 receptor antagonist, is a new treatment for pulmonary arterial hypertension that was both effective and safe in these two cases of TGA/IVS with PPHN. To our knowledge, it is the first use of bosentan in newborns.     

Inhibition of in vivo constriction of fetal ductus arteriosus by endothelin receptor blockade in rats

The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied the preventive effect of a dual ET receptor antagonist (bosentan) and a selective ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near-term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal ductus was constricted by four medications: orogastric administration of indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1, 10, or 100 mg/kg) was injected intraperitoneally either simultaneously with indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally simultaneously with indomethacin. After maternal atlas dislocation, cesarean section, fetal whole-body freezing, and cutting on the freezing microtome, measurements were made of the inner diameters of the ductus, main pulmonary artery, and ascending aorta. Bosentan blocked fetal ductal constriction by indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal constriction was nearly completely blocked by simultaneously administered 100 mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan) and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus arteriosus induced by ductus-constricting agents in rats, indicating that ET and ET-A receptors are essential in fetal ductal constriction.     

Role of endothelins and nitric oxide in the pulmonary circulation of perinatal lambs during hyperoxia and hypoxia

Endothelins (ET) have opposite vascular effects mediated through different receptors: ET(A) receptors mediating vasoconstriction and ET(B) receptors mediating vasoconstriction as well as vasodilation. The role of ET in acute hypoxic pulmonary vasoconstriction (HPV) was studied after dual ET receptor blockade with bosentan and nitric oxide (NO) synthase inhibition with nitro-L-arginine (L-NA). We started from the hypothesis that ET antagonism may inhibit HPV but, if not, would do so after NO synthase inhibition. HPV was evaluated in anesthetized lambs, with an intact pulmonary circulation, by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at different levels of pulmonary flow (multipoint pressure/flow relationships). ET receptor antagonism decreased pulmonary and systemic vascular tone both in hyperoxia and hypoxia. ET antagonism had no effect on HPV. NO synthase inhibition increased pulmonary vascular tone more in hypoxia than in hyperoxia so that HPV was enhanced. After L-NA, bosentan still decreased pulmonary vascular tone in hypoxia but did not affect the magnitude of HPV. The present results suggest that ET and NO are involved in the regulation of basal pulmonary vascular tone. Furthermore, the vasodilator effect of bosentan persisted in the presence of NO synthase inhibition, suggesting a non NO-dependent vasodilator mechanism. The results from these experiments are in agreement with the idea that ET do not play a major role in HPV in the perinatal lamb, even when it is enhanced by NO synthase inhibition.     

Combination therapy for life-threatening pulmonary hypertension in a premature infant: first report on bosentan use

Premature infants with preterm premature rupture of membranes (PPROM) are at high risk of severe respiratory failure because of lung hypodysplasia associated with persistent pulmonary hypertension of the newborn (PPHN). We describe the clinical course of a 28-week gestation infant with PPROM from the 20th week and prolonged oligohydramnios before delivery, who developed refractory hypoxia treated with oral bosentan as adjunct therapy to inhaled nitric oxide (iNO) and oral sildenafil. Conclusion Our experience suggests that bosentan can be used in the premature infant with PPHN after PPROM. To the best of our knowledge, this is the first report of bosentan treatment in a premature infant.     

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.     

Late-Onset Pulmonary Arterial Hypertension After a Successful Atrial or Arterial Switch Procedure for Transposition of the Great Arteries

Common complications after surgery for transposition of the great arteries (TGA) include systemic ventricular dysfunction and arrhythmia after atrial baffle repair (AB) and outflow tract stenosis or regurgitation after the arterial switch (AS). Severe pulmonary hypertension (PHT) is a rarely reported problem after AB and AS. In this study we sought to evaluate the frequency of late onset severe PHT following surgical repair for TGA. We report 3 cases, 2 after AB and 1 after AS, describe the frequency of this complication and treatment response, by comparing the response to pulmonary vasodilators in this group of patients to that of idiopathic or connective tissue disease (CTD) related PHT. We currently follow 85 patients ≥17 years of age with repaired TGA; 77 after AB and 8 after AS. 3.5% of our adult congenital heart disease patients with TGA have developed late severe PHT. None of these patients demonstrated clinical improvement with Bosentan at 6 months, however 2 of 3 were stabilised with the addition of Sildenafil to initial therapy. The third patient died 4 months after the diagnosis of severe PHT, whilst waiting for heart-lung transplantation, despite Bosentan, Sildenafil and inotropic support. By contrast, of 37 patients with idiopathic or CTD related PHT commenced on Bosentan as initial therapy, 32 (86.5%) demonstrated a clinical response at 6 months; the other patients had Sildenafil as added therapy after 6 months. Our data suggest that patients with TGA and late onset PHT are less likely to achieve a clinical response on pulmonary vasodilator monotherapy (P = 0.006). Whilst more investigation is needed, our experience suggests an aggressive clinical course, often requiring combination PHT treatment.