肺动脉高压的药物治疗现状与进展

肺动脉高压(pulmonary hypertension,PH)是以肺动脉压和肺血管阻力升高为特征的临床血流动力学症候群,可导致右心衰竭和死亡.近年来研究认为,肺血管收缩、重构和原位血栓形成是PH发生发展的重要病理生理基础,内皮功能障碍在其中起着关键性作用,血管活性因子一氧化氮(NO)和前列环素的生成障碍伴血管收缩因子如内皮素-1长时间的过度表达,不仅可引起肺血管的收缩,还可促进和导致肺血管的重构.针对这些环节的药物治疗明显提高了患者的生存率,改善生存质量[1-2].     

小儿先天性心脏病重度肺高压手术后远期疗效

目的　评估小儿先天性心脏病 (先心病 )重度肺高压手术治疗的远期疗效 ,分析影响其远期疗效的因素。方法　系统观察 1 981～ 2 0 0 1年 ,1 1 2例 (其中男 68例 ,女 44例 ,年龄 2个月～ 1 6岁 )左向右分流先心病伴重度肺高压手术治疗后的转归。病种包括房间隔缺损 (ASD) 3例 ,室间隔缺损 (VSD) 81例 ,室间隔缺损伴动脉导管未闭 (PDA) 1 2例 ,室间隔缺损伴房间隔缺损 1例 ,室间隔缺损伴房间隔缺损伴动脉导管未闭 1例 ,动脉导管未闭 1 3例 ,主肺动脉隔缺损 1例。肺动脉收缩压与体动脉收缩压之比 (Pp/Ps)≥0 .75者列为观察对象。年龄 2个月～ 1 6岁。结果　住院死亡 3例 ,术后半年、2年、3年各死亡 1例 ,手术生存率 97.32 % ,1年生存率 96 .43 % ,5年生存率 94.64 %。生存者纽约心脏病学会 (NYHA)心功能分级 :Ⅰ、Ⅱ级 (优良组 ) 99例 (93 .4 % ) ,Ⅲ级 (差组 ) 7例 (6 .60 % )。死亡病例均为术后持续肺高压。生存病例 ,优良组与差组术时年龄比较 ,(3 .39± 2 .94)岁对 (6 .57±3 .51 )岁 (P <0 .0 5)。肺血管阻力比较 ,(6 .78± 4 .0 4 )U/M2 对 (1 2 .2 6± 4 .1 7)U/M2 (P <0 .0 1 )。结论　小儿左向右分流先心病伴重度肺高压术后远期疗效与术时年龄 ,肺血管阻力有关 ,婴幼儿期手术预后较理想。     

Long-term liposteroid therapy for idiopathic pulmonary hemosiderosis

Control of refractory bleeding in idiopathic pulmonary hemosiderosis (IPH) is challenging. Based on the effect of liposteroid (dexamethasone palmitate) for acute bleeding in two reported cases, the long-term utility was assessed in all nine IPH children (including the first two cases) treated in a tertiary center for 20 years. The median at disease onset was 2.3 years (range, 1.2 to 8.6). All had life-threatening and/or repetitive bleeding on prednisolone (PSL) therapy. Liposteroid was intravenously infused at 0.8 mg/kg/day for three consecutive days at the time of acute bleeding. Single infusion was followed by a longer interval from weekly to monthly accompanied by low-dose PSL (less than 0.3 mg/kg/day). Monthly infusion as maintenance therapy was continued for prophylaxis of bleeding. Treatment outcomes were retrospectively analyzed. During the observation period of a median of 11.0 years (range 2.4–16.9 years), no one died. Five patients were weaned and the other one was being weaned from liposteroid for the cure or long remission (median, 5.5 years). Three others were on liposteroid therapy because of active disease. Neither patient had respiratory symptoms, although three showed subnormal %vital capacity. Serum levels of KL-6 and ferritin were normal in all and all but one patient(s), respectively. Four patients (three on liposteroid therapy) showed low bone mineral density. There were no obese patients. Height SD score did not significantly decrease except for one patient. Conclusion: The liposteroid therapy might improve the survival of IPH patients with reducing the adverse effects of steroids, although prospective control studies are needed.     

Propranolol therapy for portal hypertension in children

Administration of propranolol to 13 children with portal hypertension reduced splenic pulp pressure by greater than 50 mm H2O (P less than 0.01) in approximately 2 weeks, when the pulse rate became three fourths the initial rate. The influence was found to be greater in compensated than in decompensated portal hypertension. This observation might be interpreted to mean that the effect of propranolol in the reduction of portal venous pressure results not only from decreased intestinal blood flow secondary to decreased cardiac output but also to the stimulation of sympathetic nervous system alpha-adrenoreceptors of the portal tract. Although arterial blood pressure changes were not significant, peripheral venous pressure was reduced significantly (P less than 0.01). We conclude that propranolol has considerable usefulness in treating portal hypertension in children.     

Minoxidil therapy in children with severe hypertension.

Six children, from 1.3 to 18 years of age, with severe hypertension associated with the hemolytic uremic syndrome, periarteritis, and renal transplant rejection received minoxidil, an antihypertensive agent, for three to 36 weeks. All had severe hypertension resistant to oral antihypertensive medications; five required frequent intravenous diazoxide therapy prior to minoxidil therapy. The mean pretreatment systolic and diastolic blood pressures were 176 and 117 mm Hg, respectively. Following treatment, the mean systolic and diastolic blood pressures were 133 and 82 mm Hg, respectively. Concomitant antihypertensive medications were decreased in all six patients once optimal blood pressure control was obtained. The initial dosage of minoxidil was 0.1 to 0.2 mg/kg/day; maximal dosage for blood pressure was 0.3 to 1.4 mg/kh/day. Major complications of therapy were fluid retention and hirsutism. Transient asymptomatic pericardial effusions occurred in two patients. Three patients on prolonged minoxidil therapy had persistent increases in right ventricular end diastolic diameters. Minoxidil is an effective oral antihypertensive agent for treatment of severe hypertension in pediatric patients. Avoidance of fluid retention is mandatory to prevent congestive heart failure.     

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.     

儿童特发性肺动脉高压的急性肺血管扩张试验

目的 探讨儿童特发性肺动脉高压(IPAH)患者急性肺血管扩张试验的指征、方法学.方法 2009年10月到2011年6月收治的WHO心功能Ⅱ～Ⅲ级的IPAH患儿参与了该项研究.在右心导管检查获取了基线血流动力学资料后,从中心静脉泵入腺苷,起始剂量为50 μg/(kg·min),每2分钟递增25 μg/(kg·min),直至达到最大剂量250μg/(kg·min)或达到阳性反应.结果 15例IPAH患儿纳入了该项研究,平均年龄为6.3岁,平均肺动脉压(mPAP)为(67.1±15.9)mm Hg (1 mm Hg =0.133 kPa),肺毛细血管楔压(PCWP)为(9.7±2.9) mm Hg,肺血管阻力指数(PVRI)为(17.9±7.5) Wood U·m2.在急性肺血管扩张试验中,3例mPAP下降幅度超过10 mm Hg,并且绝对值≤40 mm Hg,为阳性反应;另外12例为阴性反应.15例中有5例在试验中出现不良反应,包括胸闷不适(n=1)、体循环低血压(n=3)、心动过缓(n=1).停用腺苷后30～60 s,上述不良反应均迅速消失.结论 静脉用腺苷是一种安全、有效的肺血管扩张剂,可作为儿童IPAH患者急性肺血管扩张试验的试验药物.     

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.     

先天性心脏病并肺动脉高压的治疗进展

肺动脉高压 (PH)治疗的目的是改善患者生活质量 ,提高生存率。为达到此目标 ,主要是进行病因治疗。左向右分流致PH的病因从根本上讲 ,是由于先天存在心内缺陷 ,所以治疗原发病、尽早手术修补缺损是彻底矫治PH的重要手段。但PH可发生于左向右分流型先天性心脏病 (CHD)演变过程的各阶段 ,即使早期手术 ,患儿在手术期间或术后也可能会并发严重PH。因此 ,积极寻求有效途径 ,减缓或改善血流增加所致PH的形成 ,对于左向右分流型CHD患者的手术成功及预后改善甚为重要 ,目前 ,左向右分流型CHD并PH的治疗包括以下。一、原发病治疗　根除原…     

Clinical practice: pulmonary hypertension in children

Introduction  

Pulmonary arterial hypertension is a rare disorder in childhood, the two most common types being idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with congenital left-to-right shunt lesions, together accounting for almost 90% of cases.     

The management of pulmonary hypertension in children

Pulmonary hypertension is relatively common in children and has many causes. The management of the condition has changed dramatically in the past 5 years with the introduction of new medicines. However, diagnosis, investigation and choice of therapy remain a challenge. In 2002 the United Kingdom Pulmonary Hypertension Service for Children was established and this has become the mainstay of management in this country. This service, based at Great Ormond Street Hospital for Children, provides advice, expertise and infrastructure support for the most severely affected patients, particularly those with idiopathic pulmonary arterial hypertension for whom chronic intravenous prostacyclin remains the most effective medication. New medicines are being developed which, rather than focussing on dilating a diseased pulmonary vascular bed, aim to structurally remodel the pulmonary vasculature towards normal.     

Long-term pulmonary function in children with Hodgkin's disease

We studied the long-term pulmonary function of 25 patients who were at least 5 years post-treatment for Hodgkin's disease. The mean age of the patients was 17 years (range 9.5–25 years) at the time of study. Twenty-one of the patients were male. All patients received six courses of COPP chemotherapy and, in addition, 8 of the 25 patients received radiotherapy to the mediastinum in low or moderate doses (20–30 Gy). One patient had symptoms of bronchiectasia. The chest radiographs of nine patients (36%) showed minimal abnormalities. We divided patients into two groups while evaluating their pulmonary function tests according to whether they received mantle irradiation or not. In patients who received mantle irradiation, pulmonary function tests showed a minimal decrease in FEV₁. The decrease in FEV₁ indicated an obstructive ventilatory defect. We concluded that our treatment protocols for paediatric Hodgkin's disease were curative, well tolerable and might minimize pulmonary functional changes.     

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.     

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.     

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.