1、感染性休克感染性休克血管活性药物进展血管活性药物进展邱海波东南大学医学院附属中大医院ICU东南大学急诊与危重病医学研究所血管活性药物的应用指征血管活性药物的应用指征 积极充分的液体复苏积极充分的液体复苏 PAWP I518mmHg MAP20ug/kg.min，应更换，应更换SVRI显著降低：显著降低：NESVRI增高：增高：Epi苯肾上腺素新福林苯肾上腺素新福林*药理作用：药理作用：强烈的强烈的 受体激动剂，受体激动剂，受体无兴奋作用受体无兴奋作用表现：表现：强大缩血管作用，无正性肌力和强大缩血管作用，无正性肌力和扩血管作用扩血管作用*常规剂量：常规剂量：2 210 10 ugug/kg.m
2、in/kg.min*应用指征：应用指征：常规剂量常规剂量dopadopa和和NENE引起心律失常引起心律失常去甲肾上腺素去甲肾上腺素(NE)药理作用药理作用:强兴奋强兴奋 受体，弱兴奋受体，弱兴奋 受体受体 临床效应：强烈的缩血管和正性肌力临床效应：强烈的缩血管和正性肌力 常规剂量：常规剂量：220ug/min(up to 200)应用指征：应用指征：SVRI明显降低的感染性休克明显降低的感染性休克肾上腺素肾上腺素(Epi)药理作用药理作用:强烈兴奋强烈兴奋 受体和受体和 受体受体 临床效应：正性肌力和缩血管临床效应：正性肌力和缩血管 常规剂量：常规剂量：0.052ug/kg.min 应用指征
3、应用指征NE无效无效低低CO低低SVRIdobu(110)+dopa/NE多巴酚丁胺多巴酚丁胺(Dobu)药理作用：药理作用：受体强烈激动剂，对受体强烈激动剂，对 受体受体无兴奋作用无兴奋作用 临床效应：正性肌力作用临床效应：正性肌力作用 常规剂量：常规剂量：220ug/kg.min 应用指征：感染性休克伴低心排应用指征：感染性休克伴低心排血管活性药物的进展血管活性药物的进展理想的血管活性药物理想的血管活性药物(1)迅速提高血压，改善心脏和脑灌注迅速提高血压，改善心脏和脑灌注(2)改善肾脏和肠道血流灌注改善肾脏和肠道血流灌注纠正组织缺氧纠正组织缺氧防止内脏器官衰竭防止内脏器官衰竭一、血管活性药
4、物与肾功能一、血管活性药物与肾功能传统观念传统观念Dopa30ml/min,UO0.5m1/kg.h分组：分组：5h更换更换Dopa 200ug/minDobu 175ug/minPlacebo 5GSMAPCIPAWP024681012MAPCIPAWPPlaceboDobuDopaCcrUrine volumeFna(%)020406080100120140160CcrUrine volumeFna(%)PlaceboDobuDopa Dobu不增加尿量，但明显增加不增加尿量，但明显增加Ccr Dopa增加尿量，并不增加增加尿量，并不增加CcrConclusion多巴酚丁胺能够改善肾脏灌注
5、多巴酚丁胺能够改善肾脏灌注多巴胺仅具有利尿作用多巴胺仅具有利尿作用2.Dopa与与Epi的比较的比较 实验对象：腹腔感染的绵羊实验对象：腹腔感染的绵羊 分组：分组：Dopa 2 ug/kg/minEpi 40ug/minDopa+Epi/4hFrom Bersten AD，et al，Crit Care Med,1995,23,537Effect of vaso on MAP025507510012515003060120180240EpiDopaEpi+Dopa Epi on RBF0255075060120180240Time/min Epi+Dopa0255075060 120 180
6、240Time/min Dopa on RVR-40-20020406080100120RVR/%Non-septicSepticEpi on RVR03060120 180 240Epi+dopa on RVR03060 120 180 240Time/minEffect of Epi and Epi+Dopa on CcrNsepticseptic010203040506070NsepticsepticBaseline15min180minNsepticSeptic010203040506070NsepticSepticEpi 40 ug/minEpi 40ug/min+Dopa 2ug/
7、kg.minComment 肾上腺素组肾上腺素组:肾血流明显增加肾血流明显增加Ccr先降低，之后增加先降低，之后增加 多巴胺组多巴胺组多巴胺肾上腺素组：多巴胺肾上腺素组：肾血流和肾血流和Ccr无明显增加无明显增加3.Dopa与与NE比较比较 试验设计：前瞻随机双盲对照试验试验设计：前瞻随机双盲对照试验 病例选择：低病例选择：低SVRI、高、高CI的感的感 染性休克患者染性休克患者 分组：分组：Dopa 2.525ug/kg.minNE 0.55ug/kg.minFrom Chest，1993，103：1826 预定的治疗目标预定的治疗目标MAP80mmHg,CI4 L/min.m2,尿量明显增
8、加尿量明显增加,持续持续6h 结果结果Dopa组组31,而而NE组组93达到治疗目标达到治疗目标NE能更快、更强的恢复血流动力学能更快、更强的恢复血流动力学4.NE vs NE+Dopa Patients with septic shock VasoNE:0.18 ug/kg.min Dopa:2.5 ug/kg.min GroupNE+DopaNE aloneFrom Intensive Care Med,1998,24:564NE vs NE+Dopa in septic pts NE+Dopa NE alone NE+DopaMAP89.581.293CI4.73.9*4.8PAWP12
9、.813.213.7Uvol(ml/2h)391234*380Unaex28.5 15.2*32.4(mmol/2h)FEna(%)5.23.8*3.9Ccr(ml/min)42.239.456CommentNE+小剂量小剂量Dopa动脉压、心输出量明显增加动脉压、心输出量明显增加 尿量尿量,尿钠排泄明显增加尿钠排泄明显增加肌酐清除率无明显影响肌酐清除率无明显影响NE vs NE+Dopa in volunters From Critical Care Med,1998,26:260Normotensive healthy volunteersVasoNE:40,80,150 ug/min D
10、opa:4 ug/kg.minGroupNE+DopaNE aloneBaselineEffect of NE and NE+Dopa on SBP050100150200SBP/mmHgBaselineNE40NE80NE150NE aloneNE+DopaConclusionNE:明显降低肾脏血浆流量明显降低肾脏血浆流量 不降低肾小球滤过率不降低肾小球滤过率加小剂量加小剂量Dopa(4ug/kg.min):肾血浆流量肾血浆流量肾排泄分数均明显增加肾排泄分数均明显增加肾小球滤过率无明显增加肾小球滤过率无明显增加血管活性药物对肾脏功能的影响血管活性药物对肾脏功能的影响 Dopa Dobu Ep
11、i NE NE+Dopa肾血流量肾血流量-尿量尿量-Unaex -FEna -Ccr-去甲肾上腺素去甲肾上腺素 多巴酚丁胺多巴酚丁胺Notice(1)Renal dose dopamineProtective effect on kidney By reducing oxygen demand By maintaining tubular flow Notice(2)21 century strategies of ARF by NIH Renal dose dopamine is not recommended二、血管活性药物与肠系膜血管活性药物与肠系膜血流供应血流供应1.Dopa与与NE比
12、较比较 试验设计：随机对照试验试验设计：随机对照试验 病例选择：感染性休克病例选择：感染性休克20例例高高CI低低SVRI、MAP75mmHgDopaNEFrom：JAMA,1994,272:1354Effect of NE vs Dopa on MAPNEDopaBaseline 3hBaseline 3hMAP 5587*6387*CI4.24.74.25.3*PAWP15161516SVRI1110 1405*10351221Effect of NE vs Dopa on DO2 and VO2NEbaseNE3hDopabaseDopa3h0100200300400500600700N
13、EbaseNE3hDopabaseDopa3hDO2VO2Effect of NE vs Dopa on pHiNEDopa7.107.157.207.257.30NEDopaBaseline3hComment1.NE:DO2、VO2、pHi均增加均增加2.Dopa DO2增加增加,但但pHi降低降低肠道氧债增加肠道氧债增加?Effect of dopa vs NE on DO2 of gut 65%16%33%28%0%20%40%60%80%DopaNEdeltaDO2gutdeltaVO2gutCritical Care Med,1993,21:1296 Dopa in animal e
14、xp.Net increased gut blood flow But redistribution away from gut mucosa Dopa in hemorrhagic shock dogDopa decreased the ability of gut to extract oxygen Effect of dopa vs NE on gutComment-DopamineIncrease CI,DO2,VO2Increase DO2 of gut Increase gut mucosal oxygen need?Redistribution blood away from g
15、ut mocosalVO2 of gut decreased Splanchnic oxygen debt 2.Epi与与NE 比较比较(1)Prospective,controlled,randomized crossover study 12 patients with septic shock Patient groupsEpi Aim:MAP 7080mmHgNEFrom Crit Care Med,1999,27:893Effect of Epi vs NE on CI and DO2NEEpiMAP7474PAWP1514CI4.45.2*DO2563671*VO2150158O2
16、 ext0.280.24Effect of Epi vs NE on pHi and GMPNEEpipHi7.247.25deltaPCO21313GMP256350*GMP/DO20.520.46Comment Gastric mucosal perfusion:Epi NE Gut ischemia:improved by Epi?Epi与与NE 比较比较(2)Porcine endotoxin shock Epi Aim:MAP 70mmHgNEDopexFrom Annals of Surgery,1998,228:239Effect of NE and Epi on mucosa%
17、damageileum%damagecolon%damagesigmoid020406080100%damageileum%damagecolon%damagesigmoidControlDopexEpiNECommentEpinephrine induce gut damage In animal expriment Epi与与NE 比较比较(3)Clinial trial 30 patients with septic shock Patient groupsEpi Aim:MAP 80mmHgNE+DobuFrom Intensive Care Med,1997,23:282Effect
18、 of Epi vs NE+Dobu MAP/mmHg406080100Base1h6h12h24hEpiNE+DobuCI/L/min.m223456Base1h6h12h24hEpiNE+DobuEffect of Epi vs NE+Dobu Lactate/mmol/L23456Base1h6h12h24hEpiNE+DobuL/P ratio10141822Base1h6h12h24hEpiNE+DobuEffect of Epi vs NE+Dobu pHi7.17.27.37.4Base1h6h12h24hEpiNE+DobuPCO2 GAP0246810121416Base1h
19、6h12h24hEpiNE+DobuComment -EpinephrineIncrease CI,DO2,VO2Increase DO2 of gut (GMP)Increase gut mucosal and whole body oxygen needIncrease lactate Decrease pHi&induce gut damage3.NE+Dobu on Gut(1)Prospective,controlled,randomized crossover study 12 patients with septic shock Patient groupsEpi Aim:MAP
20、 7080mmHgNENE+Dobu 5 ug/kg.minFrom Crit Care Med,1999,27:893Effect of NE+Dobu vs NENENE+Dobu EpiMAP747474PAWP151414CI4.44.75.2*DO2563621671*VO2150152158O2 ext0.280.250.24Effect of Epi vs NE on GMPNE NE+Dobu EpiGMP256419*350*GMP/DO20.520.61*0.46CommentNE+Dobu1.明显提高肠系膜血流量明显提高肠系膜血流量肠系膜血流量肠系膜血流量/心输出量的比值
21、心输出量的比值2.改善肠道缺血改善肠道缺血？3.NE+Dobu on Gut(2)21 patients with septic syndrome Dobutamine:0,5,10 ug/kg.min From Crit Care Med,1994,150:324 pHi7.17.27.37.40510High lactateNormal lactatepHi7.17.27.37.4510600670DO2CommentDobu1.改善肠道缺血改善肠道缺血2.剂量依赖关系剂量依赖关系机制机制增加增加DO2，同比例增加肠道，同比例增加肠道DO2gut血流重分布血流重分布:血流从肠壁向粘膜分布血
22、流从肠壁向粘膜分布Effect of Epi vs NE+Dobu Lactate/mmol/L23456Base1h6h12h24hEpiNE+DobuL/P ratio10141822Base1h6h12h24hEpiNE+DobuEffect of Epi vs NE+Dobu pHi7.17.27.37.4Base1h6h12h24hEpiNE+DobuPCO2 GAP0246810121416Base1h6h12h24hEpiNE+DobuComment-NE+DobuIncrease CI,DO2,VO2Increase DO2 of gut (GMP)Decrease lacta
23、te Increase pHi4.NE+Dopa11 pats with septic shockNE+Dopa 3 ug/kg.min Effect of Dopa on gut 肠系膜血流占肠系膜血流占CO30%:无明显影响无明显影响 30%:增加胃肠道血流灌注增加胃肠道血流灌注 pHi均无明显改善均无明显改善From Intensive Care Med,1997,23:31Comment-NE+DopaIncrease CI,DO2,VO2Increase DO2 of gut?(Only sp30%)不能改善肠道缺氧不能改善肠道缺氧5.Comment-NorepinephrineIn
24、crease CI,DO2,VO2Increase DO2 of gut Increase gut pHi去甲肾上腺素对感染性休克的治疗去甲肾上腺素对感染性休克的治疗改善异常的血管扩张改善异常的血管扩张改善心肌抑制改善心肌抑制增加或不影响心输出量增加或不影响心输出量增加冠脉血流增加冠脉血流提高肾脏灌注压，改善肾脏灌注提高肾脏灌注压，改善肾脏灌注改善肠系膜血管低灌注状态改善肠系膜血管低灌注状态 Dopa Epi NE NE+Dobu NE+DopaMAP CI SVRI -DO2 VO2 Lactate -Gut血流量血流量 DO2gut VO2gut -pHi 新型血管活性药物新型血管活性药物多培沙明多培沙明(Dopexamine,Dopex)药理药理 2受体受体:强激动剂强激动剂DA-1/2受体受体:弱激动剂弱激动剂 1受体受体:弱激动剂弱激动剂 受体受体:no effect强心强心,扩血管扩血管,舒张内脏血管的作用舒张内脏血管的作用Comment-DopexamineIncrease CI,DO2,VO2Decrease SVRIIncrease VO2 of heartIncrease pHi and mucosal PtissO2Prevent liver injuryTarget Is right?
