肺动脉高压的治疗进展

肺动脉高压的治疗进展,赵成,VC,RA,RV,PA,PV,PC,LA,LV,Ao,Post-Capillary PH PCWP15 mmHg,Systemic HTNAoV Disease,Myocardial DiseaseDilated CMPHypertrophic CMPRestrictive CMP,Atrial Myxoma,PVOD,PAHRespiratoryDiseasesPE,Pulmonary Hypertension,MV Disease,LVEDP,Mixed PH,Pre-capillary PHPCWP500m 正常330m 预后不佳,常规治疗,Supplemental O2Diuretics (excessive preload)DigoxinIV inotropes (low dosedopamine 1-2 ug/kg/min),抗凝治疗,原发性PAH患者尸检可见多发性微血栓抗凝治疗可以改善生存率（弱证据）推荐口服华发令（INR1.5-2.5）风湿病继发PAH抗凝是否有益？增加消化道出血等风险,急性血管扩张试验,使用右心导管 (iNO, epoprostenol, adenosine),无反应者,有反应者（10-25%）考虑 CCB (no RHF),BosentanSildenafilInhaled IloprostTreprostinilEpoprostenol,CCB治疗需监测血流动力学指标,mPA 10 mmHg mPA 40 mmHg,钙离子拮抗剂,通过急性血管扩张实验确认氨氯地平、硝苯地平、地尔硫卓（无负性肌力作用）通常需要使用高剂量,NEJM. 1992 Jul 9; 327(2): 76-81,CCB剂量,在IPAH和PAH合并其他疾病时，内皮素水平是增加的,先心病,Non-PH,PH,0,1,2,3,4,5,P0.001,Delta ET-LI (PV-RV) (pg/ml),IPAH,IrET-1 (pg/ml),Non-PPH,PPH,0,2,4,6,8,10,硬皮病,Concentration of ET-1(pg/ml),4,6,8,10,LcSSc PAH,LcSSc Non-PAH,P0.05,P0.001,Stewart et al.Ann Inter Med,1991,Vancheeswaran et al. J. Rheum, 1994,Yoshibayashi et al., Circulation, 1991,ET在PAH发病机制中起重要作用,内科药物治疗-内皮素拮抗剂,ET- 1 是一种强力内源性血管收缩剂。ET- 1有2 个受体: 内皮素A 受体和内皮素B 受体。,Haemodynamic effects of placebo and bosentan at week 12（351研究）,6分钟步行距离改善,351研究,BREATHE-1研究,BREATHE-1:到达临床恶化的时间,临床恶化定义为死亡、肺移植、因肺动脉压升高住院或终止研究、需要epoprostenol治疗,Bosentan作为一线药物治疗IPAH患者的存活率（1）,-实际观察到的存活率预期存活率,Eur Respir J. 2005 Feb;25(2):244-9,Bosentan作为一线药物治疗IPAH患者的存活率（2）,Bosentan:副作用,肝脏毒性 推荐：每月复查肝功能致畸性 育龄女性应避孕，推荐每月复查HCG,磷酸二酯酶抑制剂,减少了NO途径中CGMP的降解CGMP作为第二信使介导血管平滑肌的扩张和抗增殖作用,Sildenafil Citrate Therapy for PulmonaryArterial Hypertension,Random，double-blind, placebo-controlled study278名患者（IPAH，CTD相关PAH）分组：安慰剂/20mg/40mg/80mg主要指标：6MWT，血流动力学参数，WHO功能分级，临床恶化事件,12W时6MWT变化,Mean Change in Hemodynamic Variables from Baseline to Week 12,Incidence of Clinical Worsening,Sildenafil versus Bosentanfor Pulmonary Hypertension (SERAPH) Study,6MWT,平均75m(0m for one patient died),平均59m,P=0.058,Sildenafil versus Bosentanfor Pulmonary Hypertension (SERAPH) Study,Acute and chronic effects of sildenafil in patientswith pulmonary arterial hypertension,Sildenafil副反应,前列环素类似物,花生四烯酸的代谢产物，血管内皮细胞产生半衰期短，血浆清除率高刺激cAMP的生成引起肺血管平滑肌舒张并抑制平滑肌的生长强大的抗血小板聚集作用,依前列醇epoprostenol（Flolan）,FDA批准的第一种治疗PAH的前列环素药物，半衰期约35 min,需要静脉持续给药。,A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension,6MWT在12w时改善约60m（修正后）症状改善,NEJM，1996;334:296-302.,A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension,MPAP、CI、PVR等血流动力学参数均有明显改善,NEJM，1996;334:296-302.,改善严重PAP患者存活率,Flolan副作用,药物相关面部潮红下颌痛头痛胃肠道疼痛皮疹血小板减少,给药系统相关气胸蜂窝织炎败血症,曲前列素 Treprostin