血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響

1、毛恩強(qiáng)上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院外科ICU,,外源性血管活性物質(zhì)在Sepsis微循環(huán)障礙中的作用與地位,,微循環(huán)的構(gòu)成，見(jiàn)下圖,微循環(huán)的構(gòu)成，見(jiàn)下圖,膿毒血癥時(shí)微循環(huán)特點(diǎn)微小動(dòng)脈血管節(jié)律異常，成低反應(yīng)性壓力-血流自動(dòng)調(diào)節(jié)喪失兒茶酚胺和血管緊張素Ⅱ的縮血管作用降低(主導(dǎo))依賴內(nèi)皮的擴(kuò)血管作用喪失(大腦除外)>80μm 的微動(dòng)脈擴(kuò)張，< 80μm 的微動(dòng)脈收縮,【Proc Natl Acad Sci U S A

2、 2000;97:9753–9758】【Baker CH, Sutton ET. (1993). Arteriolar endothelium-dependent vasodilation occurs during endotoxin. shock. Am J Physiol 264:H1118–H1123.】,,,毛細(xì)血管灌注數(shù)量降低 微血栓形成紅細(xì)胞、白細(xì)胞變形降低、內(nèi)皮腫脹毛細(xì)血管表面積微靜脈內(nèi)皮屏障功能障礙毛細(xì)血管

3、滲漏(蛋白、液體)PMN組織內(nèi)浸潤(rùn),Aird WC.Blood 2003; 101:3765–77,不同時(shí)間點(diǎn)微循環(huán)狀態(tài) 不一相同時(shí)間點(diǎn)不同器官微循環(huán)狀態(tài)不一,微循環(huán)障礙表現(xiàn)形式：時(shí)間-空間上的異常,,調(diào)整血管節(jié)律的活性物質(zhì),α受體激動(dòng)劑去甲腎上腺素:收縮阻力血管隨著劑量增加，MAP升高，但FCD(vessels/mm2, )降低,【Arnaldo Dubin.Increasing arterial blood pressure

4、 with norepinephrine does not improve microcirculatory blood flow: a prospective study. Critical Care 2009, 13:R92 (doi:10.1186/cc7922)】,,收縮血管的活性物質(zhì),,,毛細(xì)血管流量指數(shù),,MAP逐漸由60、70、80升至90mmHg，去甲腎由0.18 μg/kg/min逐漸加至0.41 μg/kg/min

5、全身氧輸送、皮膚PtO2 、皮膚微血管紅細(xì)胞流量顯著升高M(jìn)AP升高并不增加FCD和舌下微循環(huán)血流指數(shù)大鼠小腸肌層FCD下降至25-60%，聯(lián)合多巴酚丁胺，F(xiàn)CD正常乳酸有升高趨勢(shì),【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy an

6、alysis. Anesthesia and analgesia 2010 110:2 (547-554) 】【The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Critical care medicine 

7、2009 37:6 (1961-1966) 】。,,去甲腎的應(yīng)用改善微循環(huán)灌注呈劑量依賴性; 建議65mmHg后，再增加MAP ，可導(dǎo)致微循環(huán)障礙,SB:125ml/h逐漸增加至500ml/h,,去氧腎上腺素大鼠小腸肌層FCD下降至25-60%腎、內(nèi)臟、皮膚及肢體血流減少腸系膜上靜脈內(nèi)的血乳酸顯著升高,【The effects of vasoactive drugs on intestinal functional c

8、apillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia 2010 110:2 (547-554) 】,,α和β受體興奮劑腎上腺素大樣本RCT，與去甲腎對(duì)MAP影響無(wú)差異，28-d和90-d死亡率無(wú)差異第一個(gè)24h，見(jiàn)心動(dòng)過(guò)速、乳酸酸中毒和增加胰島素用量 嚴(yán)重收縮小腸

9、肌層血管，加劇微循環(huán)障礙！不建議應(yīng)用,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia 2010 110:2 (547-554) 】【Myburg

10、h JA, Higgins A, Jovanovska A, et al., CAT Study investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:2226–2234.】,,多巴胺：中等以上劑量，α受體和β1 激動(dòng)劑多巴胺提高M(jìn)AP可保護(hù)腸道粘膜微循環(huán)

11、大鼠小腸肌層FCD無(wú)顯著改變顯著增加SMA血流；其乳酸濃度不高 增加心率以及心臟負(fù)性事件發(fā)生率高于去甲腎,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia 

12、;2010 110:2 (547-554) 】,,V1、V2受體激動(dòng)劑垂體后葉素收縮全身和局部微循環(huán)消除低血壓、降低液體積聚和逆轉(zhuǎn)毛細(xì)血管滲漏冠脈血管收縮致心排量降低等內(nèi)臟血管過(guò)度收縮引起缺血壞死,【Torgersen C, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a rando

13、mized, controlled, open-label trial. Intensive Care Med. 2010;36:57–65.】,,膿毒血癥時(shí)狀態(tài)機(jī)體缺乏AVP感染性休克需0.067 U/min(4IU/h)方恢復(fù)至近正常水平特點(diǎn)激動(dòng)兩個(gè)受體的作用相似，選擇性差半衰期是6min、作用維持30-60min,【Torgersen C, et al. Comparing two different arginine

14、vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36:57–65.】,,特利加壓素(Terlipressin)V1a收縮血管為主要作用降低毛細(xì)血管滲漏、逆轉(zhuǎn)低血壓半衰期6小時(shí)，療效2-10小時(shí)持續(xù)緩慢靜推(1.3μg/kg/h)，最大劑量是2

15、μg/kg/h 負(fù)性心血管作用，需多巴酚丁胺抵消,【Ertmer C. Current place of vasopressin analogues in the treatment of septic shock. Curr Infect Dis Rep 2008;10:362–367.】【Ryckwaert F.Terlipressin, a provasopressin drug exhibits direct vasocon

16、strictor properties: consequences on heart perfusion and performance. Crit Care Med 2009;37:876–881. 】,,血管加壓素的應(yīng)用建議在兒茶酚胺抵抗時(shí)再給予應(yīng)用劑量：恢復(fù)生理水平精氨酸加壓素的劑量 0.03~ 0.067 U/min(4IU/h)特利加壓素， 1.3μg/kg/h，最大劑量是2μg/kg/h,,縮血管物質(zhì)的作用提高M(jìn)A

17、P，儲(chǔ)備毛細(xì)血管前灌注壓力降低體液積聚和逆轉(zhuǎn)毛細(xì)血管滲漏恢復(fù)毛細(xì)血管灌注負(fù)性作用皮膚、內(nèi)臟阻力血管和微循環(huán)過(guò)度收縮心臟負(fù)性作用,,擴(kuò)張血管的活性物質(zhì),NO供體硝酸甘油(NTG)：改善微循環(huán)灌注，但褒貶不一主要擴(kuò)張靜脈和微小動(dòng)脈降低肺動(dòng)脈壓、恢復(fù)組織灌注和提高生存率擴(kuò)容穩(wěn)定后，硝酸甘油并不能改善微循環(huán)，甚至對(duì)存活率有負(fù)性作用,【Lamontagne F, Meade M, Ondiveeran HK, et al. Ni

18、tric oxide donors in sepsis: a systematic review of clinical and in vivo preclinical data. Shock 2008;30:653–659.】,【Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic

19、 shock after a strict resuscitation protocol: A double-blind randomized placebo controlled trial. Crit Care Med 2010; 38:93–100.】,60天存活率也顯著降低,NTG ,2mg 持續(xù)靜推30分鐘，然后23.5h持續(xù)2mg/h。維持MAP>60mmHg,,死亡率升高的原因NTG不是NO前體長(zhǎng)期應(yīng)用，血管收縮

20、占主導(dǎo)(兒茶酚胺、加壓素、醛固酮和腎素水平升高)NTG打開(kāi)線粒體的滲透轉(zhuǎn)運(yùn)孔致其產(chǎn)生的氧自由基漏出線粒體的衰竭與NTG的高死亡率相關(guān),【Parker JD, Farrell B, Fenton T, et al: Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation 1991; 84:23

21、36–2345.】【Gori T, Daiber A, Di Stolfo G, et al: Nitroglycerin causes mitochondrial reactive oxygen species production: In vitro mechanistic insights. Can J Cardiol 2007; 23:990–992】,,L-精氨酸大循環(huán)穩(wěn)定后應(yīng)用改善微循環(huán)血流單用即可改善微循環(huán)紊亂聯(lián)合

22、血管加壓素對(duì)改善微循環(huán)有疊加效應(yīng),Nakajima Y, Baudry N, Duranteau J, et al. Effects of vasopressin, norepinephrine and L-arginine on intestinal microcirculation in endotoxemia. Crit Care Med 2006; 34:1752–1757】【De Backer D. L-arginine a

23、nd vasopressor agents: when antagonists have unexpected synergistic effects. Crit Care Med 2006; 34:1847–1849.】,受體興奮劑多培沙明 有很強(qiáng)β2-受體興奮作用， β1和DA1、DA2較弱顯著擴(kuò)張動(dòng)脈血管，能增加心肌、腎臟、肝臟、骨骼肌的血流量，降低心臟后負(fù)荷心肌收縮力加強(qiáng)，心率加快，并有輕微排鈉利尿作用；0.5ug/kg

24、/min開(kāi)始應(yīng)用,Effects of Dopamine, Dobutamine, and Dopexamine on Microcirculatory Blood Flow in the Gastrointestinal Tract during Sepsis and Anesthesia. Anesthesiology 2004; 100:1188–97,,受體阻斷藥物α受體阻斷藥，酚妥拉明和酚芐明解除去甲腎導(dǎo)致的微血管過(guò)度收縮

25、M受體阻斷藥:山莨菪堿、東崀菪堿、鹽酸戊乙喹醚(阻斷M1、M3)解除毛細(xì)血管前括約肌痙攣抑制PAF-1和TF的激活,【Effects of penehyclidine hydrochloride on the splanchnic perfusion of patients with septic shock. Chinese Critical Care Medicine 2008 20:3 (183-186)

26、 】【Anisodamine counteracts lipopolysaccharide-induced tissue factor and plasminogen activator inhibitor-1 expression in human endothelial cells: Contribution of the NF-κB pathway. J Vas Res 2001 38:1 (13-19),,

27、抗氧化劑：Vit C恢復(fù)依賴內(nèi)皮的血管節(jié)律(舒張和收縮)血管舒張作用(NO)抑制iNOS活性增加eNOS的活性抑制內(nèi)皮細(xì)胞內(nèi)的NADPH酶活性阻止NO氧化,【Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and

28、is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 2008; 36:2355–2362】【 Delayed ascorbate bolus protects against maldistribution of microvascular blood flow

29、in septic rat skeletal muscle. Crit Care Med 2005; 33:1823–1828.】,,同時(shí)收縮與擴(kuò)張血管的活性物質(zhì),,收縮血管作用提高兒茶酚胺的敏感性去甲腎上腺素和血管緊張素Ⅱ,【Lehr1 HA. Eur J Med Res 2006;11: 516-526】【Nualart FJ. J Biol Chem 2003; 278:10128–101331】,增加氧攝取的活性物質(zhì),,

30、降低PMN與內(nèi)皮的粘附多巴酚丁胺主要興奮β1、對(duì)β2及α受體作用相對(duì)弱增加心臟指數(shù)和全身血流抑制PMN粘附到血管內(nèi)皮或促進(jìn)內(nèi)皮完整性增加微循環(huán)血流,【Secchi A, Ortanderl JM, Schmidt W, et al. Effects of dobutamine and dopexamine on hepatic micro- and macrocirculation during experimental end

31、otoxemia: an intravital microscopic study in the rat. Crit Care Med 2001; 29:597–600.】 【Birnbaum J, Klotz E, Spies CD, et al. Effects of dopexamine on the intestinal microvascular blood flow and leukocyte activation in

32、a sepsis model in rats. Crit Care 2006; 10:R117.】,,Vit C封閉內(nèi)皮細(xì)胞、降低PMN粘附、降低微血栓形成降低毛細(xì)血管滲漏減少液體復(fù)蘇的液體量改善組織水腫縮短毛管和細(xì)胞的距離,Crit Care Med. 2005;33(8):1823-8.,,抗凝 降低微血栓形成增加FCD人重組活化蛋白C不能降低28天死亡率顯著增加出血率APC用于膿毒血癥的療效仍不確定AT Ⅲ，

33、顯著出血,Human recombinant activated protein C for severe sepsis.Cochrane database of systematic reviews (Online) 2011; 4 (CD004388),,肝素降低微血栓抑制PMN激活和粘附早期治療劑量應(yīng)用可顯著提高生存率5-15IU/kg/h，INR控制1.5,,Early intravenous un

34、fractionated heparin and mortality in septic shock. Crit Care Med 2008;36(11):2973-2979,如何應(yīng)用外源性血管活性物質(zhì),感染性休克早期部分微循環(huán)關(guān)閉是機(jī)體自我保護(hù)(代償機(jī)制)液體復(fù)蘇為主要措施避免應(yīng)用擴(kuò)張微循環(huán)物質(zhì),,微循環(huán)關(guān)閉失代償，阻力血管擴(kuò)張和微循環(huán)持續(xù)關(guān)閉可轉(zhuǎn)為微循環(huán)障礙—感染性休克應(yīng)用縮血管藥物保證大循環(huán)穩(wěn)定，即達(dá)到微循環(huán)前灌注壓同時(shí)