本帖最后由 netfish7 于 2015-1-28 20:57 编辑
一．Hydroxyethyl Starch (HES) in the OR: Safetyand Applicability of Critical Care Trials 羟乙基淀粉（HES）：守得云开见月明？
There has been an array of prospective randomized trialsconducted recently in critical care settings comparing new generation HES tocrystalloids. Four major trials (CHEST, 6S, VISEP, CRYSTMAS) have concludedthat modern HES products increase the incidence in renal failure, transfusion,and, in some studies, mortality. (Table 1)
最近，在危重症医学方面有许多关于新一代胶体液（HES）和晶体液对照的前瞻性随机研究，四个主要的研究（CHEST,6S,VISEP,CRYSMAS)表明新一代的HES液会增加肾衰竭，输血的发生率，甚至增加死亡率（其中的某些研究）。（见表1）
表1
In glaring contrast to these fewrigorous trials with extended follow-up, there is a large body of literatureadvocatingthe safety and superiority of HES in various settings. Unfortunately,the majority of this work contains commonflaws.Not uncommonly, authors have an intimate connection to the industry. Manystudies have inherent design flaws: small sample size, shortfollow up, and insufficient power to detect adverse outcomes. Another worrisomesignquestioning the quality of this evidence is that an impressive number ofmeta-analyses and systematic reviewscurrentlyfar exceeds the quantity of actual trials on which they are based. 1 As aconsequence of a questionable safety profile and the abovefactors, both the FDA and regulatory agencies in Europe and Great Britainissued warnings regarding the use ofstarches. In addition to warnings against use of HES in the settings of ICU,cardiac surgery, pre-existing renaldysfunction, or coagulopathy, the FDA recommends continuousmonitoringof renal function for 90 days in anybody whoreceives HES. Such a recommendation makes its use in anyclinicalsetting extremely impractical andpotentially exposes prescribing physicians to liability. 和这几个设计严谨有着很长随访期的实验相对比，还有大量其它支持HES的文献。不过不幸的是，大部分这些文献都存在着共同的缺陷。其中一个普遍现象是有一些作者同厂家有着说不清道不明的关系。还有一些实验设计存在着内在缺陷：譬如样本量过小，随访期短，对不良后果的监测力度不够等。还有一个让人感到忧虑的现象是目前meta-分析和系统回顾的文献数量已经远远超过了它们所引用的实际文献的数量，这不得不让人对这些文献的质量产生质疑。基于此，FDA，欧洲和英国的监管机构对于羟乙基淀粉的使用发出了警告：禁止HES在ICU，心脏外科以及已经有肾功能不全，凝血功能障碍的患者中使用。FDA还推荐任何患者输注HES90天内应持续监测肾功能，这项规定极大的限制了HES的应用，并且会让处方医生需要承担潜在的风险。 The natural question that comes tomind is: do the results of HES trials examining ICU patients apply to theoperatingroom, wherein patients do not necessarily have a critical illness orpre-existenting renal injury? Indeed, wedonot have the data to support that HES would be injurious in surgicalpopulations without critical illness. In fact,high quality prospective data maynever be available owing to the lowerincidenceof renal injury, and other adverse outcomes, in this population. Inorder to achieve adequate statistical power, any study would need to enrollmany thousands of patients with long-termfollow up to perhaps even 90 days. Nevertheless, in light of current datademonstratingthe deleterious affects of HES in the ICU coupled with an absence ofwell-deigned clinical trials demonstrating its safety andimproved clinical outcomes in other surgical groups someexperts argue that risk to benefit ratio may favor avoidance ofHES in all surgical patients. 1,3 Additionally, we cannot predict when patientswhoreceived HES may develop a perioperative complicationunexpectedlyand move from a low-risk group to a high-risk “ICU” group. The latestCochrane Collaboration Review on resuscitation with colloids versuscrystalloids concluded that there is no evidenceto support use of colloids for resuscitation in the settings of trauma, burns,of following surgery, and that use ofHES may increase mortality.
不过人们自然而然会产生一个疑问：上面的试验都是针对ICU的患者而言，对于那些普通的没有重大相关疾病及术前没有肾功能损伤的手术室患者是否同样适用？的确，目前我们还没有相关数据认为HES对此类（非重症）患者有害。事实上，对于此类相对健康的患者，输注HES之后肾损伤及其它副作用发生几率很低，因此，高质量的前瞻性研究几乎不可能完成。为了达到统计效力，需要纳入数千名受试者，并且需要长达90天的随访，难度可想而知。不过，鉴于HES在ICU患者中应用的有害性，以及目前缺乏设计良好的临床试验来证实其在其它病人身上应用的安全性，一些专家出于收益风险比的考虑，建议在所有的手术病人中停止使用HES。此外，我们也无法预估在使用HES期间病人会不会出现意料之外的并发症从而从“低危”组转变为“高危”组。最近的一项Cochrane 系统评价对比了使用胶体液及晶体液进行复苏，结论是对创伤及烧伤的病人不宜使用胶体液进行复苏，使用HES会增加这类患者的死亡率。 二．Benefits ofColloids: Myth or Reality? 胶体的益处：海市蜃楼还是千真万确？ 胶体扩容作用的理论是基于作用于半透膜上的胶体渗透压(starling方程式）的概念，已经有上百年的历史。不过在现实情况中，影响血管内皮渗透的因素还有很多。最近，一种内皮多糖-蛋白质复合物引起了人们极大的兴趣，它是附着在血管内皮的一层薄薄的蛋白-酶类物质，可以维持血管的完整性，同时调控微循环的渗透性。此外，它在凝血和炎症方面发挥着重要的作用。缺氧，局部低灌注，液体过量以及炎症可以造成这种复合物的破坏，导致血管内皮通透性增加，进一步造成大分子颗粒向组织间隙的渗漏。综上所诉，由于血管内皮不同作用力的叠加，以及不同的疾病状态，胶体可能表现出无法预知的作用方式。 Furthermore, there is along-standing belief that the colloid to crystalloid ratio required for thereplacement of an intravascular fluid deficit is 1:3to accomplish similar hemodynamic and resuscitation endpoints. In reality,colloids have a marginal and short-actingfluid sparing effect. In clinical practice, the ratio of crystalloid to colloidneeded to achieve similar hemodynamicparameters appears to be smaller. In the VISEP, 6S, CRYSTMAS, and CRISTALtrials,patients received respectively an approximate 1.4:1, 1.1:1, 1.2:1, and 1.5:1ratio of crystalloid to HES to obtain similar resuscitativeendpoints in ICU patients. In the Saline Versus Albumin Fluid Evaluation (SAFE)and Albumin Italian Outcome Sepsis(ALBIOS) trials, the ratios of crystalloid to albumin required forresuscitation were1.4:1 and 1:1. Accordingly, colloids appear to confer, atbest, a small benefit when examining total fluidadministration.4 此外，如果要达到相同的血流动力学或复苏终点，胶体和晶体的比例应该为3:1，这是一种流传已久的观点。果真如此吗？现实是：胶体的扩容效应并没有想象的那么明显。在临床实践中，达到相同血流动力学参数所需的胶体液和晶体液的量似乎是一样的。在VISEP，6S,CRYSTMAS以及CRISTAL这几个研究中，针对ICU病人，为了达到相似的复苏终点，所使用的晶体液和HES液的比例大概分别是1.4:1；1.1:1；1.2:1以及1.5:1。此外，在SAFE和ALBIOS两项研究中，达到复苏指标所需生理盐水和白蛋白的比例分别为1.4:1和1:1。因此，当我们最后清点液体总量时，会发现胶体液只有那么一丁点的优势。 三．What is the latest on Albumin in the OR: Does anyonebenefit? 白蛋白手术室的应用：谁用谁知道？ Albumin has a long andwell-established safety track record in the operating room and intensive careunit settings. One explanation for itspopularity is the belief that, following administration, it will remainpredominantly intravascular. Anotheris a frequently observed short-lived improvement in hemodynamic profile,especially in septic patients. Indeed,with regard to sepsis, and especially septic shock, albumin may have sometemporary benefits in the acutephase of resuscitation. The SAFE trial demonstrated improved outcomes inpatients with septic shock. In the mostrecent multicenter prospective randomized double-blinded clinical trial(ALBIOS), the addition of 20% albumin toconventional crystalloid resuscitation in severe sepsis and septic shock didnot improveoutcomes.However, patients in septic shock had significant improvements in MAP, lowerheart rate, reduced vasopressor requirements, a smallerpositive fluid balance, and lower mortality that did not achieve statisticalsignificance.The MAP increase amongst the albumin group was most substantial in the first 6hrs. of resuscitation, a time period when many septicpatients are subject to “source control” in the operating room. Of interest,these improvements in physiologicparameters are partially attributed to albumin’s scavenging of nitric oxide,which is one of the mediators ofsepsis-induced vasoplegia. 5 According to the 2013 Surviving Sepsis CampaignGuidelines, albumin has been recommended as analternative to crystalloid resuscitation, especially when large volumes offluid are required for resuscitation. 在手术室和ICU，白蛋白有着很长安全应用的历史。白蛋白之所以流行的一个重要的因素是输注后它大部分都会保留在血管内。另一个原因是它可以在短期内改善患者的血流动力学参数，特别是对于感染的患者。事实是，对于脓毒症，尤其感染性休克的患者，白蛋白在复苏的急性期可以发挥短暂的作用。SAFE研究证实白蛋白可以提高感染性休克患者的预后。不过最新的一项多中心前瞻性随机对照双盲临床研究（ALBIOS）却表明，对于严重感染性休克患者，在传统晶体复苏的基础上额外使用20%白蛋白不能改善预后。然而，却可以明显提高患者MAP，降低心率，减少血管活性药物的使用，减轻液体过负荷，以及降低死亡率（没有统计学意义）。白蛋白组MAP升高在复苏最初的6个小时内最为明显，这个时间段正是大部分感染患者在手术室进行感染源去除的阶段。有意思的是，白蛋白导致的血流动力学参数的改善有一部分要归因于其对一氧化氮的清除作用（一氧化氮为脓毒症中的一种中间介质，导致血管麻痹）。2013年出版的《拯救脓毒血症运动指南》中已经推荐使用白蛋白可以作为晶体液复苏的替代物，尤其是在患者需要大容量复苏的时候。 While albumin may be beneficial in the setting of sepsis,it should not be used in thesetting of traumatic brain injury. SAFE-TBI (a predefined sub-group analysis ofSAFE trial) compared albumin to NS and demonstrated an almost doubled 28-daymortality in patients with moderate and severe TBI. One explanation for thesefindings is a disruption of the blood-brain barrier leading to “leakage” ofalbumin and impairing brain perfusion.6 Patients undergoing spinal surgery inthe prone position also may benefit from albumin administration in order to decreasethe likelihood of a rare but devastating complication: Perioperative VisualLoss (POVL). Updated in 2012, the ASA Practice Advisory on POVL recommended acombination of colloids and crystalloids for fluid replacement in patients atrisk for POVL. In clinical practice, the most frequently administered colloidin this setting is albumin solution of various concentrations. Althoughevidence on this subject is scant, one proposed mechanism of benefit relies onpremise of minimizing orbital and facial edema, which may occur followingcrystalloid resuscitation. Lastly, albumin has been shown to decrease theincidence of renal failure and mortality in the settings of liver cirrhosiswith superimposed spontaneous bacterial peritonitis. 7 尽管白蛋白对感染的患者可能有益，不过却不应该在创伤性脑外伤的患者中使用。SAFE_TBI（SAFE研究的一项亚组分析）对比了白蛋白和生理盐水分别用于中重度创伤性脑外伤患者，发现白蛋白组的28天死亡率为生理盐水组的2倍。对于这种现象一种可能的解释是：创伤性脑外伤患者的血脑屏障被破坏，造成白蛋白外漏，导致脑灌注的下降。对于那些在俯卧位下行脊柱手术的患者，白蛋白也可能有益，它可能会降低围术期视力丧失（POVL）的风险。2012年ASA最后更新的《预防POVL实践指南》推荐对于存在POVL风险的患者，应该联合使用胶体液和晶体液进行液体治疗。在临床实践中，在这种情况下最常用的胶体液为不同浓度的白蛋白。尽管证据不足，不过其理论依据在于最大程度的减少眼窝和面部水肿，而这些（水肿）有可能在使用晶体液复苏后发生。最近，白蛋白还被证实可以降低肝硬化合并自发性细菌性腹膜炎患者肾衰竭的发生率及死亡率。 四．Choice ofcrystalloid: Does it matter? 晶体液的选择：众里寻它千百度 Normal saline is the most frequently used crystalloidworldwide. Its use can lead to the development of hyperchloremic metabolic acidosis,impairment of renal perfusion, decrease in systemic vascular resistance, and coagulationabnormalities. Additionally, a few trials have demonstrated worse clinicaloutcomes. One large database analysis comparing perioperative NS to physiologicbalanced salt solution administration in the setting of abdominal surgerydemonstrated increased mortality, renal failure, electrolyte abnormalities, andacidosis in the NS group. 8 Another prospective study comparing the use ofchloride-restricted and chloride-liberal fluid therapy in the ICU demonstrated an increased incidence of renal failurein patients receiving solutions with high chloride concentration. 9 Whileadditional investigations are pending, it is prudent to avoid NS in theperioperative period as a primary resuscitative solution. 在世界范围内，生理盐水是使用最广泛的晶体液。它的使用可能会造成高氯性代谢性酸中毒，肾脏灌注受损，全身血管阻力下降以及凝血功能异常。此外，一些研究还证实了更为严重的后果。一项基于大的数据库的研究对比了在腹部手术围术期分别使用生理盐水和生理平衡盐溶液，发现生理盐水组在死亡率、肾衰竭，电解质异常及酸中毒的发生率都增加。另一项前瞻性研究对比了限氯液体和不限氯液体在ICU患者的使用，提示高氯液体组肾衰的发生率更高。由于缺乏进一步的相关研究，在围术期应当尽量避免使用生理盐水作为液体复苏的主要液体。 五．Potassium-containingsolutions: Are they really contraindicated in the setting of renal failure? 含钾溶液：肾衰患者当真不能用？ In the setting of renal failure, many practitionersswitch from balanced-salt solutions to normal saline with the goal to avoid orminimize additional potassium load. Surprisingly, this approach may in factlead to increased serum potassium concentrations. An elegant prospectivedouble-blinded study examining the effects of perioperative administration ofNS versus LR in patients with renal failure undergoing renal transplantationhad to be stopped due to safety concerns when an interim analysis demonstrateda significantly increased incidence of hyperkalemia in the NS group. 10 Hyperchloremic metabolic acidosis leading totrans-cellular potassium shifts is most likely responsible for this phenomenon. 对于有肾衰的患者，许多医生习惯用生理盐水代替平衡盐液以避免或减少钾超载。不过让人意想不到的是，这样做反而会造成血清钾离子浓度增加。一项设计精良的前瞻性双盲实验研究生理盐水和林格氏液在因肾衰而行肾移植的患者中的使用，因为中期分析发现生理盐水组高钾血症的发生率明显增加，处于安全方面的考虑，结果这项实验不得不提前终止。造成这种现象的原因极有可能是高氯性酸中毒造成钾离子跨细胞的转运。 六．Blood transfusion:Do I really have to use normal saline? 输血与生理盐水齐飞？ It is common practice to switch from balanced saltsolutions to NS in the settings of perioperative blood transfusion. Somehospitals have policies prohibiting co-administration of balanced salt solutionsand packed red cells in the same intravenous line. The most commonly citedrationale is the possibility of clotting following admixture owing to calciumions contained it those solutions. The American Association of Blood Banksidentifies NS as the only solution that can be co-administered with PRBCs. Inreality, this increased risk of clotting is present only with slow rate ofblood transfusion, usually over 2 hours or more, which happens on hospitalwards. There are a handful of studies demonstrating the safety of co-administering packed red cells with lactated ringerand other calciumcontaining solutions when transfusion of the units occurswithin less than 30 min. 11,12 In the demanding settings of resuscitation,unnecessarily switching fluids to comply with outdated guidelines may increasetask load, cost, and the potential for adverse events 在围术期输血过程中，我们通常会将平衡液换成生理盐水。有一些医院还明确规定不允许经由同一静脉通道同时输入平衡盐液和袋装红细胞。对此他们的解释是平衡盐液中含有钙离子，和血液混合后可能会产生凝结。美国血库协会规定生理盐水是唯一可以和浓缩红细胞同时输注的液体。不过实际情况却是：凝结只是在慢速输注（输血时间大于2小时）的情况下才有可能发生，通常在病房中常见。一些研究表明如果在30分钟内完成袋装红细胞的输注，那么同时输入林格氏液以及其他含钙溶液是安全的。在实施液体复苏的过程中，如果我们还遵循过时的指南将液体替换成生理盐水，就有可能造成工作量和相关费用的增加，同时还可能导致潜在的副作用。 七．Liberal vs.Restrictive intraoperative fluid strategy – No more third space? 开放性vs限制性输液策略：莫须有的第三间隙？ Over the last decade, a restrictive perioperative fluidstrategy has emerged as an alternative to conventional liberal perioperativefluid administration. The old approach of accounting for pre-operative fluiddeficit due to fasting, maintenance IV fluids to meet basic metabolicrequirements, and estimation of insensible loses has been replaced in manycenters world-wide by minimal fluid administration, usually as intermittentboluses to maintain an acceptable hemodynamic profile. Numerous studies, mainlyin the settings of abdominal surgery, have demonstrated shorter hospital stays, faster return of bowel function, andimproved intestinal motility. It is important to distinguish this “blind”restrictive approach from goal directed therapy (GDT), which guided by some formof cardiac output monitoring, such as pulse pressure or stroke volumevariation. It is, however, important to examine the exact definition of“restricted volume” as outlined in the current literature. Surprisingly, arecently published systematic review on this topic emphasized greatheterogeneity of the trials, with restricted volume ranging from 994ml to 2740ml.13 Certainly for many perioperative physicians, a fluid volume of nearly threeliters is not considered to be “restricted.” Despite heterogeneity andlimitations of study designs, a restrictive fluid strategy was beneficial andled to either shorter hospital stays, decreased incidence of ileus, or at leastwas not harmful in comparison to a traditional approach. 在过去的10年当中，限制性输液策略逐渐取代了传统的开放性输液策略。传统的输液策略需要补充术前禁食导致的生理需要量，满足基础代谢所需的维持量以及麻醉导致的血管扩张造成的相对损失量，不过目前世界范围内的许多医学中心 都采用最低限度的输液策略，只需间断输注液体以保证血流动力学参数在可接受的范围内即可。许多研究证实在腹部手术中采用限制性输液策略可以缩短患者住院时间，促进肠功能恢复以及提升肠动力。值得注意的是我们需要将这种“盲的”限制性输液策略同目标导向性液体治疗（GDT）策略区分开来，后者是在心输出量监测（脉压，每搏量变异等）的指导下进行的。另一个需要明确的关键点是到底输多少才算是限制性输液？我们查阅了一篇与此相关的系统评价，让我们感到惊讶的是，文中指出不同文献中采用限制性输液策略时使用液体量的差异相当大，跨度从994ml到2740ml不等。很显然，对于大多医生而言，接近3L的输液量已经不能算作是“限制性输液”了。虽然一些实验的设计存在一定的缺陷，不过采用限制性输液策略是有益的，它可以缩短住院时间，降低肠梗阻的发生率，或者即使退一万步来讲，同传统的补液方法相比，它至少不会有害。 At this time, GDT using dynamic markers of resuscitationseems to be the most promising approach that is both individualized and has asound physiological underpinning. There is a lack of studies showing long-termoutcome benefits of GDT beyond the typically short post-operative period. Inorder to achieve conclusive answers, future investigators will need to extendtheir interventions beyond the operating room, where we exercise great control,to post-operative care units and hospital wards to avoid “empiric” fluidadministration and unnecessary fluid loading. 就目前来看，采用动态指标指导复苏的目标导向液体治疗（GDT）似乎是最好的方法，它具有生理学的理论支撑，同时兼顾了个体化原则。不过目前还缺乏其对患者远期结局影响的研究。我们进一步要做的是延长我们的随访期，并且走出手术室，深入到术后恢复室、病房等地方，用我们的理论去指导那些“经验主义者”医生更好的补液。避免不必要的液体过负荷。 八．Use ofcrystalloids for GDT? 晶体液用于GDT：那人却在，灯火阑珊处？ Since the early days of GDT, various colloids have been afluid of choice for obvious reasons outlined previously. The whole premise ofGDT relies on the idea of optimization of cardiac output and oxygen deliveryand avoidance of excessive fluid administration. As colloids are currentlyfalling out of favor due to safety concerns, it is important to confirm ifpositive clinical outcomes related to use of GDT would remain when crystalloidsare used. A recent double blinded prospective trial compared the use of newgeneration hetastarch 130/0.4 to balanced salt solution in the setting ofcolorectal surgery and found no benefits despite slightly lower 24 hour fluidbalance in HES group. 14 Another recent study compared effects of crystalloid(LR) versus colloid (HES) co-loading during administration of spinal anesthesiain the setting of elective cesarean section and showed no difference in cardiacoutput, hemodynamic stability, or vasopressor requirements. 15 Innear future, we will likely see a shift from HES to balanced salt solutions asthe fluid of choice for GDT. 在GDT的早期，基于前述的各种原因，各种各样的胶体被大量应用。GDT指导补液的理论基础在于优化心输出量和氧供，避免液体过负荷。考虑到近来胶体由于安全方面的因素已经“失宠”，一个重要的问题摆在了我们面前， 那就是能否使用晶体液代替胶体进行GDT？用晶体液是否也能达到GDT的各种好处？最近一项前瞻双盲对照实验对比了新一代羟乙基淀粉130/0.4和平衡盐液在结直肠外科中的运用，发现HES组除了24小时液体平衡轻度减少之外，并无其它优势。另一项实验对比了晶体液（LR）和胶体液（HES）联合输注用于择期剖宫产腰麻的患者，发现在心输出量、血流动力学稳定性及血管收缩药物的需要量方面并无差异。相信在不远的将来，我们会看到GDT中会使用平衡盐液替代胶体液。 九．Futuredirections 我们的征途是星辰大海 过去10年，我们关于围术期液体治疗的理念在不断进化。液体治疗可以影响预后，这已经是一个公认了的理念，不过我们仍然缺乏能被广泛接受的1级证据来指导我们的补液实践。为了评价补液对远期预后的影响，我们需要设计一项长时间随访的实验。RELIEF（限制性VS开放性输液策略在大的腹部手术中应用的研究）实验正是为此而设计。它是一项前瞻、随机、多中心、双盲对照实验，在GDT指导下对比采用晶体及胶体进行限制性输液和开放性输液，随访1年后患者的机能状态及健康生存状态，这是很好的两项指标。该实验正在进行中，预计2016年完成。希望这项实验完成之后，能让我们更好的解释这些让我们每晚为之辗转反侧的问题：我们该输什么液体？？什么时候输？？输多少？？ | 
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发表于 2015-1-25 14:23:09
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