儿童与成人肺动脉高压特点比较A Comparison Between Children And Adults吴炳祥哈尔滨医科大学附属第一医院PAH的定义PAH流行病学及自然病程PAH的病理改变PAH的临床表现PAH的诊断流程PAH的治疗及预后主要内容肺动脉高压的定义Rich S,etal.Primary pulmonary hypertension.A national prospective study.Ann Intern Med 1987;107:216-223.成人:在海平面状态下,静息时,右心导管检查肺 动脉平均压(mPAP) 25mmHg,肺毛细血管楔压(PCWP)15mmHg,且肺血管阻力(PVR) 3WU.Barst RJ,etal.Pulmonary Arterial Hypertension:a comparison between between children and adults.Eur Respir.2011,37:665-677.婴儿:平均肺动脉压/平均体循环动脉压,或肺动脉收缩压/体循环动脉收缩压0.4儿童患者:APAH-CHD,IPAH/HPAH高发成人患者:APAH-CTD则相对较常见.CHD-PAHThere is a heterogeneity in the nature of CHD-PAH,with some patients developing irreversible disease in the first year of life and others remaining free of symptoms untill their second or third decade, or even later.IPAH/HPAHThe natural history of untreated IPAH/HPAH is most often rapidly progressive and fatal.Sheila G etal,Assessment of endpoint in pediatric population:congenital heart disease and idiopathic pulmonary arterial hypertension.Curr Opin Pulm Med 16(Suppl1):S35-S41.流行病学及自然病程流行病学及自然病程病理学成人:内膜增生,纤维化,丛样病变,扩张样病变;外膜增厚,中膜肥厚,炎细胞浸润,局部血栓形成等.儿童:中膜肥厚,内膜纤维化,非肌型小动脉肌化,丛样病变,扩张样病变等.The presenting symptoms are usually more severe in children , with syncopal episodes occuring more frequently than in adults,and a rate of disease progression that is typically faster. 临床表现劳力性呼吸困难,乏力,晕厥晕厥,胸痛,右心功能不全伴外周水肿.治疗原发病与肺高压严重程度不匹配病史/症状/体征怀疑肺高压ECG,胸片,超声心动图,肺功能,HRCT确诊为第二或第三大类肺通气灌注扫描与肺高压严重程度匹配节段性灌注缺损PAH可能,建议RHC检查CTEPHPVOD/PCHmPAP25mmHg,PCWP15mmHg其它原因是是是否否否是诊断流程是儿童患者对症状表述不准确,多需要家长的观察 儿童患者运动量大,且患上呼吸道感染的机会高,故儿童在疾病的早期即可出现相应的症状,有利于早期诊断.儿童IPAH/HPAH,APAH-CHD患者在诊断时,其心功能分级和血流动力学指标好于成人.儿童患者的特殊性严重程度评估严重程度评估1. 临床特点 WHO心功能分级的评估对成人及大龄儿童适用,但不适宜应用于新生儿或低龄儿童. uTime to clinical worsening is a reliable and appropriate means of assessing disease progression. (though not adopted in children)uUsing clinical worsening as an endpoint in children could be particularly helpful because of the faster rate of disease progression in many children with IPAH.Sheila G etal,Assessment of endpoint in pediatric population:congenital heart disease and idiopathic pulmonary arterial hypertension.Curr Opin Pulm Med 16(Suppl1):S35-S41.2. 运动耐量六分钟步行试验(6MWT):试验过程不适合评估儿童患者,试验所得数据不可靠.心-肺吸氧运动试验(CPET):适用于成人和7-8岁以上的儿童.有助于发现在休息时肺动脉压力正常,而运动后则出现异常的患者.CPET,in contrast to the 6-minute walk test,may be particularly relevant to identify those children who have an exaggerated response of the pulmonary vascular bed to exercise and appear to have good exercise capacity with normal activities of daily living,but have a history of syncopal episodes with over-exertion or in response to mild hypoventilation with sleepRosenzweig EB,etal.Pulmonary arterial hypertension in children.Pediatr Pulmonol 2004;38:2-22.3.生化标记物NT-proBNP , BNP , 血尿酸,C反应蛋白等指标也可应用于儿童病情严重程度及预后的评估.Lower NT-proBNP and BNP concentrations have been reported in children compared with adults,consistent with right heart failure being less frequent in children as compared with adult patients.Lammer AE,etal.Prognostic value of B-type natriuretic peptide in children with pulmonary arterial hypertension.Int J Cardiol 2009;135:21-26由于非侵入性评估指标在儿童患者中难以执行,所得结果可信度差,因此,血流动力学指标仍然作为儿童患者评估疾病严重程度及疗效的金标准.Barst RJ,etal.Pulmonary Arterial Hypertension:a comparison between between children and adults.Eur Respir.2011,37:665-677.治治 疗疗p一般治疗p支持治疗p靶向药物治疗p其它一般治疗支持治疗儿童患者抗凝风险评估有争议,可在特殊情况时考虑抗凝,如右心功能不全,高凝状态,中心静脉置管等.靶向药物治疗1.钙拮抗剂只有肺血管扩张试验阳性者才能从CCBs治疗中获益.It is important to remember that vasoreactive patients require constant re-evaluation, as reactivity can be lost at any time.Sheila G etal,Assessment of endpoint in pediatric population:congenital heart disease and idiopathic pulmonary arterial hypertension.Curr Opin Pulm Med 16(Suppl1):S35-S41.阳性标准:mPAP下降幅度超过10mmHg并且绝对 值40mmHg,CO增加或至少不变.(儿童是否适用有争议)In children with IPAH,the probality of having a positive response to the pulmonary vasoractivity test appears to be age dependent,with the youngest having the greatest likelihood of pulmonary vasodilation;the percentage of responders in children is 30-40% compared with 10-15% in adults.Barst RJ,etal.Vasodilator therapy for primary pulmonary hypertension in children.Circulation 1999;99:1197-1208.血管舒张试验阳性率Yung D,etal.Outcomes in Children With Idiopathic Pulmonary Arterial Hypertension.Circulation 2004:110:660-665.儿童儿童Long-term CCB responders represented 54% of acute responders and 6.8% (95% CI, 4.7% to 8.9%) of the patient sample.Sitbon O,etal.Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension . Circulation. 2005;111:3105-3111.成人成人2.前列环素类依前列醇(Epoprostenol)伊洛前列素(Iloprost)曲前列环素(Treprostinil)贝前列环素(Beraprost)伊洛前列素,曲前列环素,贝前列环素在儿童患者应用相关报道较少.u依前列醇(Epoprostenol)在儿童及成人患者中均有较好疗效,但在儿童患者中其最佳剂量常较高.由于其用药途径特殊,故在儿童患者中应用不便.Epoprostenol has also been used in children of all ages with similar safety and efficacy as shown in adult ptients. However,optimal dosing in children is frequently higher in a nanograms per kilogram per minute basis.Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension?Int J Clin.PractSuppl.2010,64(168):23-32.成人成人儿童儿童一年生存率80-91%94%三年生存率49-65%88%五年生存率47-55%81%Yung D,etal.Outcomes in children with idiopathic pulmonary arterial hypertension.Circulation 2004;110:660-665.依前列醇依前列醇3.内皮素受体拮抗剂波生坦(bosentan)塞他生坦(sitaxsentan)安贝生坦(Ambrisentan)塞他生坦,安贝生坦在儿童患者应用相关报道较少.u波生坦在儿童及成人中均有较好疗效,可改善WHO心功能分级和血流动力学等指标.Bosentan significantly reduced pulmonary vascular resistance and significantly increased 6-minute walk distance without compromising peripheral oxygen saturation, in patients with Eisenmenger syndrome.Gatzoulis MA,etal. Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease.Eur Respir Rev.2009,18(113):154-61.Ivy DD, etal.Long-Term Outcomes in Children With Pulmonary Arterial Hypertension Treated With Bosentan in Real-World Clinical Settings.Am J Cardiol. 2010 Nov 1;106(9):1332-8. 波生坦(儿童) 波生坦(成人) Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension Eur Heart J. 2006 Mar;27(5):589-95. 4. PDE5抑制剂西地那非(sildenafil)sildenafil) 伐地那非(vardenafil)(vardenafil) 他达那非(tadalafil)(tadalafil) 伐地那非,他达那非在儿童患者应用相关报道较少.西地那非在儿童及成人中均有较好疗效,可改善血流动力学,提高运动耐量.Xu XQ,etal.The efficacy and safety of sildenafil in Chinese patients with pulmonary arterial hypertension. Hypertension Reseach(2009)32,911-915.西地那非(成人)Oliveira EC,etal.Sildenafil in the management of idiopathic pulmonary arterial hypertension in children and adolescents.J Pediatr,2005;81(5):390-4.西地那非(儿童)靶向药物治疗后的生存率Haworth SG,etal.Treatment and survival in children with pulmonary arterial hypertension:the UK Pulmonary Hypertension Service for children 2001-2006.Heart 2009;95:312-317.药物药物剂量剂量给药途径给药途径适应症适应症副作用副作用氧气保持SaO2为94%吸入低氧血症儿童用量过多安全性差NO2-20ppm吸入NICU,PICU低血压CCB(硝苯地平)0.2mg/kg ,每8小时口服IPAH低血压5-磷酸二酯酶抑制剂(西地那非)0.25mg/kg,每6小时口服新生儿慢性肺疾病,艾森曼格综合症低血压,视觉障碍内皮素受体拮抗剂(波生坦)15-125mg(按体重),每12小时口服IPAH,艾森曼格综合症低血压,肝功损害前列环素(依前列醇)2-60ng/kg/min静脉注射艾森曼格综合症低血压,出血前列环素(伊洛前列环素)5ug,每2-3小时,逐渐增至最大耐受量吸入慢性肺部疾病,艾森曼格综合症低血压儿童患者肺动脉高压治疗药物儿童患者肺动脉高压治疗药物Robert T.Etiology,Diagnosis,and Pharmacologic Treatment of Pediatric Pulmonary Hypertension.Pediatr Drugs,2009,11(2):115-128肺动脉高压支持疗法:抗凝,吸氧,改善生活习惯血管舒张试验阳性阴性CCB稳定性WHO/不稳定性WHO/波生坦,前列环素类依前列醇持续监测症状性WHO,进行性呼吸困难,难治性心衰,晕厥(CCB阳性患者:治疗数月后对CCB反应性下降)联合药物治疗移植房间隔造瘘术治疗流程National Pulmonary Hypertension Centres of the UK and Ireland.Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland.Heart 2008;94(Supp1):i1-i41.未经治疗的儿童IPAH患者预后比成人差.在靶向治疗药物应用之前儿童PAH患者中位生存时间只有10个月,而成人为2.8年. (DAlonzo GE,etal.Survival in patients with primary hypertension.Ann Intern Med 1991;115:343-349)靶向药物应用后生存率显著提高.预 后美国国立卫生研究院(NIH)对194例特发性PAH 患者的统计，平均生存期仅为2.8年, 1年、3年和5年的生存率分别为68、48和34.IPAHAPAH一年生存率85.6%92.3%三年生存率79.9%83.8%五年生存率71.9%56.9%Haworth SG,etal.Treatment and survival in children with pulmonary arterial hypertension:the UK Pulmonary Hypertension Service for children 2001-2006.Heart 2009;95:312-317.儿童靶向药物治疗后IPAH,APAH一年,三年,五年总体生存率分别为90.5%,82.8%,和64.2%. IPAH和APAH生存率无明显差别.成人IPAH患者靶向药物治疗后一年，三年生存率分别为92.1% 和75.1%,(Zhang R,etal.Survival of Chinese Patients with Pulmonary Arterial Hypertension in the Modern Management Era. . Chest. 2011 Feb 17. )靶向药物治疗预后It is possible that children,who may have greater vasodilator responsiveness and more reversible lesions,respond better to treatment than adults.Barst RJ,etal.Pulmonary Arterial Hypertension:a comparison between between children and adults.Eur Respir.2011,37:665-677.项目项目儿童儿童成人成人定义婴儿:Infant:平均肺动脉压/平均体循环动脉 压,或 肺动脉收缩压/体循环动脉收缩压0.4右心导管检查肺动脉平均压(mPAP) 25mmHg,肺毛细血管楔压15mmHg,且伴有PVR增加流行病学APAH-CHD(50%),IPAH高发APAH-CTD高发病理中膜肥厚更多见内膜增生纤维化,丛样病变多临床表现劳力性呼吸困难,乏力,晕厥劳力性呼吸困难,乏力,右心衰伴周围性水肿病情进展疾病进展快,可早期诊断进展较缓,诊断时心功能分级和血流动力学较差严重程度评估WHO心功能分级,6-MWT实用性差,NT-ProBNP/BNP水平较成人低WHO心功能分级,6MWT评估价值高治疗抗凝治疗争议大,在特殊情况时考虑使用;依前列醇剂量差异大.联合治疗获益,强调持续监测.一般靶向药物治疗均有效,急性肺血管舒张试验阳性率较儿童低.对治疗的反应不如儿童.小小 结结