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1、概 要,人血白蛋白简介肝硬化概述人血白蛋白在肝硬化并发症治疗中应用,人血白蛋白制品,是从健康人血浆中提纯的一类特殊药品。目前国内外临床需求量最大、使用最多、最安全的一种血浆蛋白制品。与血浆相比，最大优势是经过病毒灭活处理，无传播病毒性传染病可能。,白蛋白分子特性,白蛋白含量最多，占52-58%。610个AA组成的多肽，不含糖，仅少量脂肪酸。分子量小，67KD。健康人血浆半衰期17-21天，危重患者则仅9天。水溶性好，粘度低，25%的白蛋白粘度与全血相当。,白蛋白的生理功能,维持和调节胶体渗透压 占血浆总胶体渗透压80%。运输 转运各种离子、激素、胆红素、药物等。解毒 如汞中毒。营养供给 合成组
2、织蛋白、氧化供能、氮源为组织提供营养。促进肝细胞修复和再生。,适应症,低蛋白血症（营养不良、合成障碍、丢失过多）大面积烧伤（补晶体液、补蛋白、维持血容量）血浆置换（丢失蛋白要及时补充，尤其有肝肾疾患者）扩容、维持胶体渗透压体外循环（用白蛋白和晶体液做底液，比血液安全，减少肾衰危险）新生儿溶血病（结合游离胆红素，避免胆红素脑病）脑水肿（提高胶渗压，减轻脑水肿）,不良反应与血浆相比要低得多,偶有寒战、发热、头痛症状，需对症处理。快速输注可引起循环超负荷导致肺水肿。极少发生低血压、呼吸困难、甚至休克等严重过敏性变态反应。输注被污染的白蛋白，会出现菌血症、休克甚至败血症。,禁忌症,对白蛋白有严重过敏者
3、病情难以承受血容量迅速增加，如心衰或心功能低下、高血压患者、肺功能不全严重贫血患者肾功能不全者脱水状态尚未补足液体,小 结,适应症广泛、副反应极少。提高胶体渗透压功能更强，时间更持久。制品纯度高，副作用小，无需考虑血型相合问题。浓缩制品体积小，最高浓度可达25%，质量稳定。使用和储存方便，便于运输。,概 要,人血白蛋白简介肝硬化概述人血白蛋白在肝硬化并发症治疗中应用,肝硬化概念,是一个病理解剖学概念多种原因引起的慢性、进行性、弥漫性肝病肝细胞弥漫性变性、坏死、凋亡残存肝细胞再生、结节结缔组织增生形成纤维隔正常小叶结构破坏代之硬化结节或假小叶,Normal liver histology,Cir
4、rhotic liver histology,病 因,病毒感染 乙、丙肝最常见、丁型、日本血吸虫病。药物与毒物 酒精、甲氨蝶呤、CCl4。代谢性 肝豆状核变性、血色病。心血管疾病 慢性右心衰竭、布-加综合征等等。其他可能原因 自身免疫性肝炎、空回肠短路术后 营养不良。,肝硬化病理生理与主要并发症,门静脉高压症侧支循环建立与扩大 腹水形成肝肾综合征自发性细菌性腹膜炎肝性脑病肝肺综合征原发性肝癌严重感染,Slight decrease in effective arterial blood volume,Increased blood/plasma volume,Portal hypertensi
5、on,CIRRHOSIS,Circulatory function in early cirrhosis,RAA,renin-angiotensin-aldosterone;ADH,antidiuretic hormone,Renal retention of sodium and water,Increased cardiac output,Release of vasodilators e.g.nitric oxide,PRIMARY PATHOPHYSIOLOGICAL EVENT,Decreased systemic vascular resistance;pooling of int
6、ravascular volume at splanchnic level,Transient activation of low and high pressure baroreceptors and RAAS,release of ADH and anti-natriuretic factors,Moderate splanchnic arterial vasodilatation,MAINTENANCE OF EFFECTIVE BLOOD VOLUME,RAA,renin-angiotensin-aldosterone;ADH,antidiuretic hormone,Marked d
7、ecrease in effective arterial blood volume血容量明显下降,Increased blood/plasma volume血容量增加,Portal hypertension门脉高压,CIRRHOSIS,Circulatory function in advanced cirrhosis,Avid renal retention of sodium and water钠水潴留,Increased cardiac output,Release of vasodilators e.g.nitric oxide,PRIMARY PATHOPHYSIOLOGICAL
8、EVENT,Decreased systemic vascular resistance;pooling of intravascular volume at splanchnic level,Pronounced splanchnic arterial vasodilatation,Chronic activation of baroreceptors and RAA system,release of ADH and anti-natriuretic factors,INADEQUATE MAINTENANCE OF EFFECTIVE BLOOD VOLUME有效循环血容量不能充分维护,
9、Prognostic scoring of cirrhosis肝硬化预后评分,PT,prothrombin time;MELD,Model for End-stage Liver Disease;INR,international normalised ratio1Pugh et al.Br J Surg 1973;60:646649;2Kamath et al.Hepatology 2001;33:464470,概 要,人血白蛋白简介肝硬化概述人血白蛋白在肝硬化并发症治疗中应用,白蛋白在肝硬化并发症的治疗,难治性腹水大容量穿刺后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤的预防肝肾综合征
10、治疗中血管收缩的辅助用药,Ascites,LVP,large-volume paracentesisGins 53:397417,腹水指过多的液体在腹腔内积聚是肝硬化最常见的并发症病史10年以上肝硬化患者腹水发生近50%传统治疗方案低钠饮食利尿剂应用LVP穿刺,James Heilman,MD/CC-BY-SA-3.0,RAA,renin-angiotensin aldosterone;ADH,antidiuretic hormone,Decrease in effective arterial blood volume,Increased blood/plasma volume,Portal
11、 hypertension,CIRRHOSIS,Pathophysiology of ascites,Renal retention of sodium and water,Increased hydrostatic pressure in liver sinusoids,Increased hepatic lymph production and transudation in peritoneum,PRIMARY PATHOPHYSIOLOGICAL EVENT,Release of vasodilators e.g.nitric oxide,Decreased systemic vasc
12、ular resistance;pooling of intravascular volume at splanchnic level,Splanchnic arterial vasodilatation,Chronic activation of baroreceptors and RAA system,release of ADH and anti-natriuretic factors,ASCITES,Grading of ascites腹水分级,EASL clinical practice guidelines on the management of ascites,spontane
13、ous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417,轻、中度腹水治疗,轻度(grade 1)不需治疗，根据欧洲肝病研究学会指南，尚无轻度腹水进展到中、重度腹水的相关资料。中度腹水(grade 2):诱导负钠平衡，抵消肾钠潴留。限钠 4-6g/d，10%-20%患者有效。利尿首选醛固酮拮抗剂初始100mg/d，无效，增加100mg/7d直至400mg/d。最大剂量仍无效，加用呋塞米40mg/d，最大160mg/d。联合治疗是复发性腹水最合适的治疗方案。,补充白蛋白对利尿剂
14、效果的影响(RCT),Gentilini et al.J Hepatol 1999;30:639645,Results1:白蛋白增加了利尿剂的治疗效果！,p0.05,Group A,Group B,Gentilini et al.J Hepatol 1999;30:639645,Further evidence for the effects of albumin on survival in patients with ascites was provided by an open-label randomised comparative study of 100 patients.The
15、aim of this study was to determine the effects of albumin administration on the survival of patients,recurrence of ascites and incidence of further complications.Patients admitted to hospital with first-onset ascites were randomised to receive either diuretics plus albumin or diuretics alone.Albumin
16、 was administered at a dose of 25 g per week for the first year of the study,progressing to 25 g every 2 weeks for the remaining study period.,补充白蛋白对腹水患者生存率的影响,Results:长期的白蛋白补充显著提高腹水患者生存率！,Romanelli et al.World J Gastroenterol 2006;12:14031407,01224364860728496108120,p0.079,Albumin,No albumin,利尿剂+白蛋
17、白(25 g per week for the 1st year;25 g every 2 weeks thereafter),利尿剂,1.0,Survival probability生存率,Months,0.8,0.6,0.4,0.2,0,大量腹水的治疗,1EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417;,推荐LVP作为大量
18、腹水的一线选择。利尿剂+白蛋白联合使用下LVP更加安全有效。由于腹水形成的病因仍然存在，故LVP后仍需服用利尿剂以限制腹水迅速增加。,穿刺后循环功能障碍(PPCD)的发生机制,LVP对血液动力学的影响,LVP,large-volume paracentesis;PPCD,post-paracentesis circulatory dysfunction1Gins et al.Gastroenterology 1996;111:10021010;2Sal et al.J Hepatol 1997;27:645653,早期（within 12 hours)改善循环 血容量增加 血管收缩系统失活,后
19、期(after 24-48 hours)RAA系统激活 SNS激活 心输出量减少 中心静脉压降低,PPCD 不能自发逆转！PPCD是与内脏血管舒张有关，而不是血浆容量减少所致,穿刺后循环功能障碍(PPCD),意义：PPCD表明有效动脉血容量不足，肾功能受损，低钠血症，腹水的再生，影响生存。为了预防 PPCD的发生,同时必须输注血浆扩容剂。研究表明，LVP超过5L时，与其他扩容剂相比，白蛋白疗效更加明显。,1EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritoniti
20、s,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417;2Gins et al.Gastroenterology 1996;111:10021010;3Gins et al.Gastroenterology 1988;94:14931502,常用的血容量扩张剂,Intravenous fluids for plasma volume expansion include colloids(artificial and natural)and crystalloids 20%albumin 3.5%saline 6%dext
21、ran 70右旋糖酐10%dextran 403.5%gelatin明胶6%羟乙基淀粉 200/0.66%羟乙基淀粉 200/0.56%羟乙基淀粉130/0.4,Natural colloid天然胶体,Crystalloid晶体,Artificial colloids人工胶体,大容量穿刺扩容剂的比较研究,Bernardi et al.Hepatology 2012;55:11721181,Results:白蛋白优于其他扩容剂！,Bernardi et al.Hepatology 2012;55:11721181,Subgroup analyses demonstrated that treat
22、ment with albumin significantly reduced incidence of PPCD compared with each alternative treatment,Incidence of hyponatraemia and mortality reduced by albumin,as compared with alternative treatments与替代疗法相比白蛋白减少低钠血症的发病率，降低了死亡率。,p=0.02,Evidence comparing albumin and saline infusion in LVP,Patients ran
23、domised to receive 3.5%saline(170 mL per L removed;n=35)or albumin(8 g per L removed;n=37)after total paracentesis,Sola-Vera et al.Hepatology 2003;37:11471153,6L的LVP，白蛋白组PPCD发生率显著低于高张盐水组！,Incidence of PPCD,Evidence comparing albumin and dextran 70 and gelatin in large-volume paracentesis,Gins et al.
24、Gastroenterology 1996;111:10021010,Patients randomised to receive either albumin（n=97）,dextran 70（n=93）or gelatin(n=polygeline)（99）8 g per L removed50%of dose within 2 hours of paracentesis 50%68 hours after,5 L LVP，白蛋白组PPCD发生率明显低于右旋糖苷组！,p=0.04,p=0.02,European guidelines for LVP,EASL clinical practi
25、ce guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.Hepatol 2010;53:397417,LVP is the first-line therapy for grade 3 ascites,LVP should be completed in a single session,Albumin(8 g/L ascitic fluid removed)should be administered to preven
26、t PPCDLVP 5 L:albumin must be used;other plasma expanders are less effective at preventing PPCDLVP 5 L:risk of PPCD is low but albumin is recommended推荐使用,Diuretics should be given after LVP to prevent re-accumulation of ascites,American guidelines for LVP,Runyon et al.Hepatology 2009;49:20872107,The
27、rapeutic abdominal paracentesis should be performed in patients with tense ascites,Albumin should be administered when 5 L ascitic fluid are removed albumin dose 8 g/L of fluid removed,The underlying cause of ascites should be addressedLVP should be followed by dietary restriction and diuretic thera
28、py to reverse sodium retention and prevent fluid re-accumulation,Home treatment of ascites with albumin,Treatment of ascites with albumin can be prolongedA Delphi study sought consensus on several issues surrounding the use of albumin,including its use at home following discharge from hospitalIt was
29、 agreed that benefits of domiciliary albumin could includereduced rate of ascites relapseimproved response to diureticsenhanced quality of lifedecreased need for hospitalisation,Gentilini et al.Dig Liver Dis 2004;36:539346,小 结,腹水的形成提示预后不良。LVP是3级腹水的一线治疗。LVP后同时应用血浆扩容剂对预防PPCD至关重要。,白蛋白在肝硬化并发症的治疗,难治性腹水大容
30、量穿刺后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤的预防肝肾综合征治疗中血管收缩的辅助用药,自发性细菌性腹膜炎(SBP),SBP 又称原发性或特发性腹膜炎，指在腹腔内或邻近组织内没有感染源（如腹腔脓肿、急性胰腺炎、胆囊炎、肠穿孔等）情况下发生的腹膜急性弥漫性细菌感染。肝硬化是发生SBP最常见的基础疾病。也可发生于急性肝衰竭及肾病综合征或晚期肿瘤伴大量腹水的患者。,自发性细菌性腹膜炎(SBP),SBP 是肝硬化腹水常见而严重的并发症，发生率高达10%-25%，国际腹水俱乐部的统计资料是10%-30%。重型肝炎SBP发生率17.7%-47%，预后较肝硬化SBP更差。临床表现可为典型的腹膜炎，
31、也可完全无症状。易漏诊，预后差，病死率高。,自发性细菌性腹膜炎(SBP),诊断主要依靠诊断性腹腔穿刺后腹水多形核细胞计数和腹水培养。腹水培养阳性率低，国外报道40%，国内更低腹水PMN计数最敏感的临界值(0.25x109/L)最特异的临界值0.5x109/L推荐对肝硬化腹水患者进行诊断性腹腔穿刺进行筛查。,SBP肾损害,1/3的SBP患者发生肾功能损害。肾功能的恶化与RAAS激活，肾脏血管收缩，有效灌注不足有关。因此扩容治疗可能获益。,1Follo et al.Hepatology 1994;20:14951501;2Navasa et al.Hepatology 1998;27:122712
32、32;3Sort et al.N Engl J Med 1999;341:403409,Effects of albumin infusion on renal impairment in SBP,Sort et al.N Engl J Med 1999;341:403409,Results:白蛋白联合抗生素（头孢噻肟）有效预防了SBP肾损害！降低了在院以及3个月死亡率！,Sort et al.N Engl J Med 1999;341:403409,Patients(%),p=0.002,p=0.01,p=0.03,21/63,6/63,18/63,6/63,14/63,26/63,Albu
33、min infusion in SBP,SBP,spontaneous bacterial peritonitis;RCTs,randomised controlled trialsSalerno et al.Clin Gastroenterol Hepatol 2013;11:123130,Results:Albumin infusion in SBP,SBP,spontaneous bacterial peritonitis;RCT,randomised controlled trials;AASLD,American Association for the Study of Liver
34、Diseases Salerno et al.Clin Gastroenterol Hepatol 2013;11:123130,This meta-analysis provides the basis for a Level A recommendation that patients with SBP should be treated with albumin,Albumin infusion decreased the incidence of renal impairment and mortality in patients with SBP,European guideline
35、s recommend all patients with SBP should receive albumin infusion until further evidence is available2,小 结,肝硬化腹水住院患者中，SBP发生率10%。肾损害是SBP的常见并发症。白蛋白输注预防SBP患者肾衰竭的发生。推荐白蛋白作为SBP治疗中广谱抗生素的辅助用药。,白蛋白在肝硬化并发症的治疗,难治性腹水大容量穿刺后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤的预防肝肾综合征治疗中血管收缩的辅助用药,肝肾综合征,Hepatorenal syndrome,是严重肝脏病变时发生的无肾脏器质性
36、病变的一种功能性肾衰竭。是终末期肝病的严重并发症。腹水患者中，1 year:18%;at 5 years:39%2病情顽固、预后凶险。平均中位生存期3月功能性肾衰持续可导致急性肾衰。,肝肾综合征的病理生理机制,门脉高压时内脏血管扩张导致有效循环血量减少、平均动脉压的下降。为了恢复有效循环血量和动脉压，血管收缩机制启动。RAAS激活以及其他血管收缩介质释放SNA激活 结果肾血管收缩，肾灌注不足，肾功能损害。,RAA,renin-angiotensin-aldosterone Gins et al.Lancet 2003;362:18191827;EASL clinical practice gu
37、idelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417,Marked decrease in effective arterial blood volume,Increased blood/plasma volume,Portal hypertension,CIRRHOSIS,Circulatory and renal function in advanced cirrhosis,A
38、vid renal retention of sodium and water,Increased cardiac output,RAA,renin-aldosterone-angiotensin;ADH,antidiuretic hormone,Release of vasodilators e.g.nitric oxide,PRIMARY PATHOPHYSIOLOGICAL EVENT,Decreased systemic vascular resistance;pooling of intravascular volume at splanchnic level,Pronounced
39、splanchnic arterial vasodilatation,MAINTENANCE OF RENAL PERFUSION,Activation of low and high pressure baroreceptors and RAA system,release of ADH and anti-natriuretic factors,Pathogenesis of hepatorenal syndrome,Marked decrease in effective arterial blood volume,Increased blood/plasma volume,Portal
40、hypertension,CIRRHOSIS,RAA,renin aldosterone angiotensin;ADH,antidiuretic hormone,Renal retention of sodium and water,Insufficient increase in cardiac output,Release of vasodilators e.g.nitric oxide,PRIMARY PATHOPHYSIOLOGICAL EVENT,Decreased systemic vascular resistance;pooling of intravascular volu
41、me at splanchnic level,Pronounced splanchnic arterial vasodilatation,Activation of low and high pressure baroreceptors and RAA system,release of ADH and anti-natriuretic factors,Cardiac dysfunction,Impaired activity of renal vasodilator systems,HEPATORENAL SYNDROME,HRS,hepatorenal syndromeGins et al
42、.Lancet 2003;362:18191827;Lameire et al.Lancet 2005;385:417430,Diagnosis of hepatorenal syndrome,RENAL FAILURE(Serum creatinine 1.5 mg/dL),Nephrotoxic drugs,Volume depletion,Shock,Biochemicalparameters,Abnormalrenal ultrasonography,Signs of infection,Proteinuriaand/or haematuria,Clinical signs,Renal
43、ultrasonography,HRS,PRERENAL FAILURE,ACUTE TUBULARNECROSIS,INFECTION-INDUCEDRENAL FAILURE,NEPHROTOXICITY,PARENCHYMALNEPHROPATHY,Classification of hepatorenal syndrome:Type 1,SBP,spontaneous bacterial peritonitisSalerno et al.Gut 2007;56:13101318;EASL clinical practice guidelines on the management of
44、 ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417,Rapidly progressive acute renal failure急进性肾衰竭Defined by doubling of initial serum creatinine to 226 mol/L(2.5 mg/dL)within 2 weeksOften develops following a precipitating event(e.g.SBP)but may o
45、ccur spontaneouslyAssociated withacute deterioration of circulatory function(arterial hypotension and activation of the endogenous vasoconstrictor systems)rapid impairment in liver function and encephalopathyVery poor prognosismean survival approximately 1 month if untreated,Classification of hepato
46、renal syndrome:Type 2,HRS,hepatorenal syndrome;SBP,spontaneous bacterial peritonitisSalerno et al.Gut 2007;56:13101318;EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417,Slowly progressive mo
47、derate renal failure缓慢进展中度Defined by serum creatinine 1.5 mg/dL or 133 mol/LOften develops spontaneously Usually associated with refractory ascites May progress to Type 1 HRSeither spontaneously or precipitated by an event(e.g.SBP)Decreased survival compared with ascitic patients without renal failu
48、re(median survival approximately 6 months),肝肾综合征对肝移植结局的影响,HRS,hepatorenal syndromeGonwa et al.Transplantation 1995;59:361365,HRS患者肝移植后结局更差!,肝肾综合征治疗史对移植后结局的影响,前瞻性研究比较有HRS治疗的患者与无HRS患者肝移植后结局,移植前经历HRS治疗的患者与无HRS患者，在肝移植后结局无明显差异！,Initial management of hepatorenal syndrome:a checklist,Admission to hospital(
49、general ward/intensive care unit*)Central line placement is helpful but not mandatoryComplete blood testsAbdominal ultrasound to examine the liver and kidneys24-hour urine collectionurine Na+/K+urine volume urine sediment/proteinDiagnostic paracentesis to exclude ongoing infectionalbumin,cell count,
50、fluid culture in blood culture bottlesPlasma expansion with albumin to rule out prerenal failureNutritionist consultation to manage malnutritionEvaluation for orthotopic liver transplantation,Adapted from Cardenas et al.Clin Liver Dis 2006:10:371385,Treatment of HRS with albumin and terlipressin,Mar
