儿童肺动脉高压的诊治傅立军课件

儿童肺动脉高压的诊治儿童肺动脉高压的诊治 傅立军傅立军 上海交通大学医学院附属上海儿童医学中心上海交通大学医学院附属上海儿童医学中心 1 PAH PAH 定义定义 儿童肺动脉高压的定义和成人患者相似(右心导管检查) ： 安静状态下平均肺动脉压(mPAP) 25 mmHg PCWP/LAP/LVEDP 15 mm Hg 肺血管阻力指数(PVRI) 3 Wood unitsm 2 流行病学流行病学 儿童肺高压的发病率没有精确的资料。 WHO临床分类中的所有类型的肺高压均可在儿童期见到。 先天性心脏病合并的肺动脉高压以及IPAH是儿童时期最常 见的两种肺动脉高压。 结缔组织病、HIV感染、药物和毒物相关的肺动脉高压在儿 童期较少见。 早产儿的慢性肺疾病(chronic lung disease，CLD)合并的肺 高压也引起了重视。 3 特发性特发性PAH: PAH: 生存率生存率 未经治疗未经治疗 儿童患者生存率较低儿童患者生存率较低 Adult median survival: 2.8 years (n=194)Adult median survival: 2.8 years (n=194) Pediatric median survival: 0.8 yearsPediatric median survival: 0.8 years (n=16)(n=16) 0 0 2020 4040 6060 8080 100100 0 0 0.50.5 1 1 1.51.5 2 2 2.52.5 3 3 3.53.5 4 4 4.54.5 5 5 Years of Follow-upYears of Follow-up % Survival% Survival DAlonzoDAlonzo, et al. , et al. Ann Internal MedAnn Internal Med 1991 1991 (n=194)(n=194) 68%68% 48%48% 34%34% 4 病理及病理生理 儿童肺高压的病理、病理生理及发病机制与成人患者类似。 儿童时期肺和肺血管仍处于发育阶段，其病理改变与成人患 者也不尽相同，成人IPAH患者常出现严重的阻塞性病变，相反 ，儿童IPAH患者更多地表现为肺小动脉中膜的肥厚，内膜的纤 维化较少见，丛样病变更少见。尸检表明，在15岁以下的儿童 患者中，严重的中膜的肥厚是最常见的病理学改变，而在婴儿 患者中，中膜的肥厚通常为唯一的病理改变。 对于引起肺血管收缩和舒张的因素，年幼儿的肺血管床的反 应性更强，在某些引起肺血管收缩的刺激的触发下，年幼儿更 容易出现肺高压危向。 5 PAH: PAH: 诊断性评估诊断性评估 病史病史* * 体格检查体格检查 血液检查血液检查 心电图心电图 心超心超 生理功能检查生理功能检查* * - - 肺功能检查肺功能检查 - - 运动试验运动试验 影像学检查影像学检查 睡眠试验睡眠试验 右心导管检查右心导管检查 * * 儿童患者较为困难儿童患者较为困难 6 临床表现 儿童肺高压患者的很多症状是非特异性，容易造成误诊和 漏诊。 IPAH的婴儿患者，通常出现低心排的表现，如纳差、生长 发育迟缓，倦怠，多汗，气急，心动过速、易激惹。部分患 者出现阵发性哭吵，可能与胸痛有关。此外，婴儿患者在用 力后可出现紫绀，与通过卵圆孔的右向左分流有关。 婴幼儿期后，儿童肺高压的症状与成人患者相似，年长儿 最常见的症状是活动后气急 ，有时也可出现胸痛等表现。 在右心功能不全时可出现肢体水肿，但儿童患者出现明显 的右心衰竭相对较晚，有些儿童患者在出现右心衰竭之前就 可能出现猝死。 儿童患者出现晕厥表现较成人更常见。 先心病合并的肺动脉高压的临床表现出现较晚，与IPAH完 全不同。 7 PPHN PPHN是一组以肺血管阻力持续升高、右向左分 流以及严重低氧血症为特点的临床综合征。 _肺血管适应不良 _肺血管发育不全 _肺血管发育不良 PPHN 也划分在肺动脉高压范畴，但是它的自然 病史、临床表现、治疗方法和疗效与其他类型的肺 动脉高压差异很大。 8 先心病相关的PAH 未经外科手术治疗的先心病患者大约三分一死于严重的肺 动脉高压。 对于同样病变的先心病患者，有的患者很早就出现严重的 肺动脉高压而丧失手术就会，而有的肺动脉高压出现很晚， 程度很轻，其机制目前尚不清楚。 在先心病合并重度肺动脉高压时，需要精确评估肺动脉高 压的程度和性质，以决定外科手术和介入治疗的指征。 先天性心脏病也是儿童肺静脉高压的最常见的原因 (TAPVC合并梗阻, 左心梗阻性病变等). 9 急性肺血管扩张试验 IPAH 阳性标准 mPAP下降到40 mm Hg之下； mPAP下降幅度 超过10 mm Hg；心输出量增加或至少不变。 必须同时满足此三项标准 PAH with CHD 阳性标准(有争议) 传统标准: PVRI 6 wood Um2 or Rp/Rs 0.3 ，反应性肺动脉高 压，可以进行双室修补。 Rp/Rs 25 mmHg at rest PCWP/LAP/LVEDP 15 mm Hg Pulmonary vascular resistance index (PVRI) 3 Wood unitsm 29 EpidemiologyEpidemiology The exact incidence of PH in children is not clear. All forms of PH included in the clinical classification have been described in children. PAH related to congenital heart disease (CHD) and IPAH are two major forms of PAH in children. The prevalence of PAH associated with CTD, portal hypertension, HIV infection, and drugs and toxins is lower. Patients with chronic lung disease of prematurity are a growing population. 30 Idiopathic PAH: SurvivalIdiopathic PAH: Survival Untreated - survival worse in childrenUntreated - survival worse in children Adult median survival: 2.8 years (n=194)Adult median survival: 2.8 years (n=194) Pediatric median survival: 0.8 yearsPediatric median survival: 0.8 years (n=16)(n=16) 0 0 2020 4040 6060 8080 100100 0 0 0.50.5 1 1 1.51.5 2 2 2.52.5 3 3 3.53.5 4 4 4.54.5 5 5 Years of Follow-upYears of Follow-up % Survival% Survival DAlonzoDAlonzo, et al. , et al. Ann Internal MedAnn Internal Med 1991 1991 (n=194)(n=194) 68%68% 48%48% 34%34% 31 Pathology and Pathophysiology Pediatric PH is similar to adult disease in pathobiology, pathophysiology and mechannisms even if the lungs are still developing. Adults with IPAH often have “fixed” obstructive vascular changes. In contrast, children with IPAH have more pulmonary vascular medial hypertrophy and less intimal fibrosis and fewer plexiform lesions. Postmortem studies suggest medial hypertrophy was severe in patients younger than 15 years of age, and it was usually the only abnormality seen in infants. Younger children appear to have a more reactive pulmonary vascular bed relative to both vasodilatation and vasoconstriction. Severe acute pulmonary hypertensive crises occur in response to pulmonary vasoconstrictor triggers more often than in older children or adults. 32 PAH: Diagnostic EvaluationPAH: Diagnostic Evaluation History*History* Physical Physical Blood Blood EKG EKG ECHO ECHO Physiologic*Physiologic* - Lung function- Lung function - Exercise testing- Exercise testing Imaging Imaging Sleep study Sleep study Right Heart Catheterization Right Heart Catheterization * * Difficult in young childrenDifficult in young children 33 Clinical Features Many of the symptoms of pediatric PH are nonspecific. Infants with IPAH often present with signs of low cardiac outpu. Some infants have crying spells, presumably as a result of chest pain. In addition, infants may develop cyanosis with exertion, due to right-to-left shunting through a patent foramen ovale. After early childhood, children present with similar symptoms as adults. In older children, the most common symptoms are exertional dyspnea and, occasionally, chest pain. Peripheral edema is generally a reflection of right ventricular failure, but overt RV failure is a late event and the child may die suddenly before the appearance of RV failure. Syncope occur more frequently in children than in adults. The child with congenital heart disease is completely different. 34 PPHN PPHN is a syndrome characterized by increased pulmonary vascular resistance, right-to-left shunting (at the atrial and/or ductal level), and severe hypoxemia. _Maladaption _Underdevelopment _Maldevelopment PPHN is also classified under PAH. Its natural history, treatment, and outcome are sufficiently different from those in other forms of PAH. 35 PAH Realted CHD Approximately one-third of patients with uncorrected congenital heart disease will die from pulmonary vascular disease. It is not known why some children with the same underlying congenital heart defect develop irreversible pulmonary vascular obstructive disease in the first year of life and others maintain operability into the second decade and beyond. The assessment of surgical operability requires an accurate determination of the degree of pulmonary vasoreactivity or reversibility. Congenital heart disease is also the most common cause of pulmonary venous hypertension in children (total anomalous pulmonary venous return with obstruction, left heart obstruction, or severe left ventricular failure). 36 Acute Vasodilator Testing IPAH Responsiveness Decrease of mPAP at least 10mmHg AND mPAP decreasing to 40mmHg or less AND normal or high CO ALL THREE CRITERIA NEED TO BE SATISFIED PAH with CHD Responsiveness (debatable) Conventional criteria: PVRI 6 wood Um2 or Rp/Rs 0.3 is indicative of reversibility of the pulmonary vascular disease and thus eligible to the biventricular repair. Rp/Rs of less than 0.33 and a 20% decrease in Rp/Rs from baseline as the two criteria for operability (The Inhaled Nitric Oxide as a Preoperative (INOP) Test Study group） Some medical institutes have even surpassed above criteria to offer corrective surgery to patients with more advanced pulmonary vasculopathy. 37 Only 7.4% of those with IPAH and 6% of those with APAH responded positively to vasodilator testing.（the UK Pulmonary Hypertension Service for Children 20012006 ） Haworth SG, et al. Heart 2009;95;312-317; A significantly greater percentage （31/74 ，40%) of children are acute responders Barst RJ, et al. Circulation 1999;99;1197-1208 IPIPAH: Acute vasodilator responseAH: Acute vasodilator response 38 PAH-Treatment (1) In children who are responsive to a specific treatment strategy, the response is often far better than that seen in adult patients. Conversely, if they fail to respond to these therapeutic modalities, their survival is often even shorter than that of adult patients with severe disease. Due to limited data in children with PAH, management decisions are often extrapolated from adult studies. 39 Since the children with PAH often have a more reactive pulmonary vascular bed than the adults, any respiratory tract infection that results in ventilation/perfusion mismatching from alveolar hypoxia can result in a catastrophic event if not aggressively treated The use of anticoagulation is controversial as no studies are availaible in children. The riskbenefit profile is a problem in small children. The use of aspirin instead of coumadin is also controversial. The consensus is to anticoagulate patients with overt right heart failure. PAH-Treatment (2) 40 Years after DiagnosisYears after Diagnosis Event Free ProportionEvent Free Proportion Idiopathic PAH in Children: Survival and Treatment Success with Chronic Oral CCB in Acute Responders Yung, et al. Yung, et al. CirculationCirculation 2004 2004 41 Prostanoids Barst and colleagues found a 90% survival rate at four years for children with severe IPAH treated with prostacyclin, and studies have suggested that prostacyclins improve hemodynamic function and quality of life. Long-term intravenous epoprostenol has also been used successfully in children with PAH associated with CHD, improving hemodynamics and quality of life parameters. Indications for epoprostenol are similar to those in adults. The usual starting dose is 2 ng/kg/min with a rapid increase. Subcutaneous trepostinil may be an option, but local pain is a serious problem in children. While the short duration of action of iloprost and delivery system is a drawback for children in the outpatient setting, the role of inhaled iloprost in the critical care setting appears to be receiving greater recent attention. 42 Endothelin Receptor AntagonistsBosentan Tracleer (bosentan) receives EU approval for pediatric formulation from two years of age. the first and only licensed pulmonary arterial hypertension therapy for children. -06 July 2009 The new quadrisect, dispersible 32mg tablet formulation of bosentan, which was specifically developed for children, allows a convenient, accurate and more flexible dosing regimen according to low body weight. 43 BREATHE-3 BREATHE-3 (Bosentan Randomized trial of Endothelin Antagonist THErapy for pulmonary hypertension) an open- label study, provided safety and efficacy data in children with PAH,. It also provided important information on the dose required in the pediatric formulation. In the BREATHE-3 study, WHO functional class improved in five of the 19 patients over the 12-week treatment period. Improvements were observed in each weight group, and only one patient deteriorated; 13/19 remained stable. These clinical results were consistent with those obtained in earlier studies conducted in adult patients and support that pediatric patients with PAH may derive significant clinical benefit from therapy with bosentan. 44 FUTURE-1 patients initially received 2 mg/kg bid for 4 weeks followed by 4 mg/kg bid until Week 12. The trial enrolled 36 patients aged from 2 years up to 12 years with idiopathic PAH or familial PAH. The safety and tolerability profile of bosentan was consistent with that observed in previous placebo-controlled clinical trials in the adult population. An open-label safety extension, FUTURE-2, is ongoing to assess long-term safety and outcome data. 45 Phosphodiesterase Type-5 Inhibitors Sildenafil was the first drug of this class and is still the most commonly used, particularly in young children with APAH, but data are limited to small case series. An initial small-scale pilot study suggested that sildenafil improves hemodynamics and exercise capacity in children with IPAH and PAH secondary to congenital heart disease. Research has suggested that there is a direct dose- response relationship between sildenafil and exercise capacity, measured by 6-MWD. Vardenafil, More recently, research has suggested that another PDE type 5 inhibitor, vardenafil, may be more effective than sildenafil in vitro. 46 Combination Therapy Based on distinct mechanisms, a role for combination therapy may further improve overall efficacy in treating a childs pulmonary arterial hypertension. An increasing number of paediatric patients are on combination therapy even though evidence is still lacking. 47 Serial Reevaluations Response to treatment is less predictable in children, and therefore, close monitoring and rapid alteration of treatment as necessary is required in pediatric patients. The response to therapy is difficult to predict, with some patients having a dramatic response and some requiring rapid escalation of therapy. Therapy should include close follow-up. Serial reevaluations, including repeat acute vasodilator testing, to maintain an optimal chronic therapeutic regimen is essential to the care of children with IPAH. 48 Hawkins A, Tulloh. Vasc Health Risk Manag. 2009;5(2):509- 24. 49 Atrial Septostomy & lung transplantation Patients with PAH with recurrent syncope or right heart failure significantly improve clinically, as well as hemodynamically, following atrial septostomy. Successful palliation of symptoms with atrial septostomy was reported in child