一．Hydroxyethyl Starch (HES) in the OR: Safetyand Applicability of Critical Care Trials
羥乙基澱粉（HES）：守得雲開見月明？
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，在危重症醫學方面有許多關於新一代膠體液（HES）和晶體液對照的前瞻性隨機研究，四個主要的研究（CHEST,6S,VISEP,CRYSMAS)表明新一代的HES液會增加腎衰竭，輸血的發生率，甚至增加死亡率（其中的某些研究）。（見表1）
表1
研究
（作者）
使用液體
對照液體
例數
研究對象
主要終點指標
結果
VISEP
（Brunkhorst等）
HES
200/0.5
林格液
537
重毒膿毒症
28天死亡率
HES組腎衰竭，血小板減少，輸血率增加
CRYSTMAS
(Guidet 等)
HES
130/0.4
0.9%氯化鈉液
196
重度膿毒症
復甦所需容量
腎衰竭及死亡率無差異
6S
（Perner 等）
HES
130/0.42
林格液
798
重度膿毒症
90天死亡率，腎臟替代治療需要率
HES組死亡率，腎臟替代治療需要率及輸血率增加
CHEST
（Myburgh等）
HES
130/0.4
0.9%氯化鈉液
6742
各種ICU
90天死亡率
ＨＥＳ組腎損傷，腎臟替代治療率，輸血率增高
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.
和這幾個設計嚴謹有著很長隨訪期的實驗相對比，還有大量其它支持HES的文獻。不過不幸的是，大部分這些文獻都存在著共同的缺陷。其中一個普遍現象是有一些作者同廠家有著說不清道不明的關係。還有一些實驗設計存在著內在缺陷：譬如樣本量過小，隨訪期短，對不良後果的監測力度不夠等。還有一個讓人感到憂慮的現象是目前meta-分析和系統回顧的文獻數量已經遠遠超過了它們所引用的實際文獻的數量，這不得不讓人對這些文獻的質量產生質疑。基於此，FDA，歐洲和英國的監管機構對於羥乙基澱粉的使用發出了警告：禁止HES在ICU，心臟外科以及已經有腎功能不全，凝血功能障礙的患者中使用。FDA還推薦任何患者輸注HES90天內應持續監測腎功能，這項規定極大的限制了HES的應用，並且會讓處方醫生需要承擔潛在的風險。
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.
二．Benefits ofColloids: Myth or Reality?
膠體的益處：海市蜃樓還是千真萬確？
膠體擴容作用的理論是基於作用於半透膜上的膠體滲透壓(starling方程式）的概念，已經有上百年的歷史。不過在現實情況中，影響血管內皮滲透的因素還有很多。最近，一種內皮多糖-蛋白質複合物引起了人們極大的興趣，它是附著在血管內皮的一層薄薄的蛋白-酶類物質，可以維持血管的完整性，同時調控微循環的滲透性。此外，它在凝血和炎症方面發揮著重要的作用。缺氧，局部低灌注，液體過量以及炎症可以造成這種複合物的破壞，導致血管內皮通透性增加，進一步造成大分子顆粒向組織間隙的滲漏。綜上所訴，由於血管內皮不同作用力的疊加，以及不同的疾病狀態，膠體可能表現出無法預知的作用方式。
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，如果要達到相同的血流動力學或復甦終點，膠體和晶體的比例應該為3:1，這是一種流傳已久的觀點。果真如此嗎？現實是：膠體的擴容效應並沒有想像的那麼明顯。在臨床實踐中，達到相同血流動力學參數所需的膠體液和晶體液的量似乎是一樣的。在VISEP，6S,CRYSTMAS以及CRISTAL這幾個研究中，針對ICU病人，為了達到相似的復甦終點，所使用的晶體液和HES液的比例大概分別是1.4:1；1.1:1；1.2:1以及1.5:1。此外，在SAFE和ALBIOS兩項研究中，達到復甦指標所需生理鹽水和白蛋白的比例分別為1.4:1和1:1。因此，當我們最後清點液體總量時，會發現膠體液只有那麼一丁點的優勢。
三．What is the latest on Albumin in the OR: Does anyonebenefit?
白蛋白手術室的應用：誰用誰知道？
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,theseimprovements in physiologicparameters are partially attributed to albumin’s scavenging of nitric oxide,which isone 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.
在手術室和ICU，白蛋白有著很長安全應用的歷史。白蛋白之所以流行的一個重要的因素是輸注後它大部分都會保留在血管內。另一個原因是它可以在短期內改善患者的血流動力學參數，特別是對於感染的患者。事實是，對於膿毒症，尤其感染性休克的患者，白蛋白在復甦的急性期可以發揮短暫的作用。SAFE研究證實白蛋白可以提高感染性休克患者的預後。不過最新的一項多中心前瞻性隨機對照雙盲臨床研究（ALBIOS）卻表明，對於嚴重感染性休克患者，在傳統晶體復甦的基礎上額外使用20%白蛋白不能改善預後。然而，卻可以明顯提高患者MAP，降低心率，減少血管活性藥物的使用，減輕液體過負荷，以及降低死亡率（沒有統計學意義）。白蛋白組MAP升高在復甦最初的6個小時內最為明顯，這個時間段正是大部分感染患者在手術室進行感染源去除的階段。有意思的是，白蛋白導致的血流動力學參數的改善有一部分要歸因於其對一氧化氮的清除作用（一氧化氮為膿毒症中的一種中間介質，導致血管麻痺）。2013年出版的《拯救膿毒血症運動指南》中已經推薦使用白蛋白可以作為晶體液復甦的替代物，尤其是在患者需要大容量復甦的時候。
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
儘管白蛋白對感染的患者可能有益，不過卻不應該在創傷性腦外傷的患者中使用。SAFE_TBI（SAFE研究的一項亞組分析）對比了白蛋白和生理鹽水分別用於中重度創傷性腦外傷患者，發現白蛋白組的28天死亡率為生理鹽水組的2倍。對於這種現象一種可能的解釋是：創傷性腦外傷患者的血腦屏障被破壞，造成白蛋白外漏，導致腦灌注的下降。對於那些在俯臥位下行脊柱手術的患者，白蛋白也可能有益，它可能會降低圍術期視力喪失（POVL）的風險。2012年ASA最後更新的《預防POVL實踐指南》推薦對於存在POVL風險的患者，應該聯合使用膠體液和晶體液進行液體治療。在臨床實踐中，在這種情況下最常用的膠體液為不同濃度的白蛋白。儘管證據不足，不過其理論依據在於最大程度的減少眼窩和面部水腫，而這些（水腫）有可能在使用晶體液復甦後發生。最近，白蛋白還被證實可以降低肝硬化合併自發性細菌性腹膜炎患者腎衰竭的發生率及死亡率。
四．Choice ofcrystalloid: Does it matter?
晶體液的選擇：眾裡尋它千百度
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.
在世界範圍內，生理鹽水是使用最廣泛的晶體液。它的使用可能會造成高氯性代謝性酸中毒，腎臟灌注受損，全身血管阻力下降以及凝血功能異常。此外，一些研究還證實了更為嚴重的後果。一項基於大的資料庫的研究對比了在腹部手術圍術期分別使用生理鹽水和生理平衡鹽溶液，發現生理鹽水組在死亡率、腎衰竭，電解質異常及酸中毒的發生率都增加。另一項前瞻性研究對比了限氯液體和不限氯液體在ICU患者的使用，提示高氯液體組腎衰的發生率更高。由於缺乏進一步的相關研究，在圍術期應當儘量避免使用生理鹽水作為液體復甦的主要液體。
五．Potassium-containingsolutions: Are they really contraindicated in the setting of renal failure?
含鉀溶液：腎衰患者當真不能用？
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.
對於有腎衰的患者，許多醫生習慣用生理鹽水代替平衡鹽液以避免或減少鉀超載。不過讓人意想不到的是，這樣做反而會造成血清鉀離子濃度增加。一項設計精良的前瞻性雙盲實驗研究生理鹽水和林格氏液在因腎衰而行腎移植的患者中的使用，因為中期分析發現生理鹽水組高鉀血症的發生率明顯增加，處於安全方面的考慮，結果這項實驗不得不提前終止。造成這種現象的原因極有可能是高氯性酸中毒造成鉀離子跨細胞的轉運。
六．Blood transfusion:Do I really have to use normal saline?
輸血與生理鹽水齊飛？
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
在圍術期輸血過程中，我們通常會將平衡液換成生理鹽水。有一些醫院還明確規定不允許經由同一靜脈通道同時輸入平衡鹽液和袋裝紅細胞。對此他們的解釋是平衡鹽液中含有鈣離子，和血液混合後可能會產生凝結。美國血庫協會規定生理鹽水是唯一可以和濃縮紅細胞同時輸注的液體。不過實際情況卻是：凝結只是在慢速輸注（輸血時間大於2小時）的情況下才有可能發生，通常在病房中常見。一些研究表明如果在30分鐘內完成袋裝紅細胞的輸注，那麼同時輸入林格氏液以及其他含鈣溶液是安全的。在實施液體復甦的過程中，如果我們還遵循過時的指南將液體替換成生理鹽水，就有可能造成工作量和相關費用的增加，同時還可能導致潛在的副作用。
七．Liberal vs.Restrictive intraoperative fluid strategy – No more third space?
開放性vs限制性輸液策略：莫須有的第三間隙？
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.
在過去的10年當中，限制性輸液策略逐漸取代了傳統的開放性輸液策略。傳統的輸液策略需要補充術前禁食導致的生理需要量，滿足基礎代謝所需的維持量以及麻醉導致的血管擴張造成的相對損失量，不過目前世界範圍內的許多醫學中心
都採用最低限度的輸液策略，只需間斷輸注液體以保證血流動力學參數在可接受的範圍內即可。許多研究證實在腹部手術中採用限制性輸液策略可以縮短患者住院時間，促進腸功能恢復以及提升腸動力。值得注意的是我們需要將這種「盲的」限制性輸液策略同目標導向性液體治療（GDT）策略區分開來，後者是在心輸出量監測（脈壓，每搏量變異等）的指導下進行的。另一個需要明確的關鍵點是到底輸多少才算是限制性輸液？我們查閱了一篇與此相關的系統評價，讓我們感到驚訝的是，文中指出不同文獻中採用限制性輸液策略時使用液體量的差異相當大，跨度從994ml到2740ml不等。很顯然，對於大多醫生而言，接近3L的輸液量已經不能算作是「限制性輸液」了。雖然一些實驗的設計存在一定的缺陷，不過採用限制性輸液策略是有益的，它可以縮短住院時間，降低腸梗阻的發生率，或者即使退一萬步來講，同傳統的補液方法相比，它至少不會有害。
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.
就目前來看，採用動態指標指導復甦的目標導向液體治療（GDT）似乎是最好的方法，它具有生理學的理論支撐，同時兼顧了個體化原則。不過目前還缺乏其對患者遠期結局影響的研究。我們進一步要做的是延長我們的隨訪期，並且走出手術室，深入到術後恢復室、病房等地方，用我們的理論去指導那些「經驗主義者」醫生更好的補液。避免不必要的液體過負荷。
八．Use ofcrystalloids for GDT?
晶體液用於GDT：那人卻在，燈火闌珊處？
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，基於前述的各種原因，各種各樣的膠體被大量應用。GDT指導補液的理論基礎在於優化心輸出量和氧供，避免液體過負荷。考慮到近來膠體由於安全方面的因素已經「失寵」，一個重要的問題擺在了我們面前， 那就是能否使用晶體液代替膠體進行GDT？用晶體液是否也能達到GDT的各種好處？最近一項前瞻雙盲對照實驗對比了新一代羥乙基澱粉130/0.4和平衡鹽液在結直腸外科中的運用，發現HES組除了24小時液體平衡輕度減少之外，並無其它優勢。另一項實驗對比了晶體液（LR）和膠體液（HES）聯合輸注用於擇期剖宮產腰麻的患者，發現在心輸出量、血流動力學穩定性及血管收縮藥物的需要量方面並無差異。相信在不遠的將來，我們會看到GDT中會使用平衡鹽液替代膠體液。
九．Futuredirections
我們的徵途是星辰大海
過去10年，我們關於圍術期液體治療的理念在不斷進化。液體治療可以影響預後，這已經是一個公認了的理念，不過我們仍然缺乏能被廣泛接受的1級證據來指導我們的補液實踐。為了評價補液對遠期預後的影響，我們需要設計一項長時間隨訪的實驗。RELIEF（限制性VS開放性輸液策略在大的腹部手術中應用的研究）實驗正是為此而設計。它是一項前瞻、隨機、多中心、雙盲對照實驗，在GDT指導下對比採用晶體及膠體進行限制性輸液和開放性輸液，隨訪1年後患者的機能狀態及健康生存狀態，這是很好的兩項指標。該實驗正在進行中，預計2016年完成。希望這項實驗完成之後，能讓我們更好的解釋這些讓我們每晚為之輾轉反側的問題：我們該輸什麼液體？？什麼時候輸？？輸多少？？
（netfish7站友原創 新青年麻醉論壇專用)