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Intraoperative management of liver transplant patients
Available online at www.sciencedirect.com
Transplantation Reviews 25 (2011) 124 – 129 www.elsevier.com/locate/trre
Intraoperative management of liver transplant patients Linda L. Liua , Claus U. Niemanna,b,⁎ a b
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, USA Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Abstract Liver transplantation for end-stage liver disease results in excellent outcomes. Patient and graft outcome is closely monitored on a national level, and 1-year survival is between 80% and 95%. Liver transplantation relies on a multidisciplinary approach, with close involvement of anesthesiologists and intensivists. However, intraoperative care of these patients remains inconsistent and is highly institution dependent. This brief-review article will focus on controversial topics of intraoperative care. Existing evidence on intraoperative monitoring, intraoperative fluid and transfusion management, electrolyte and glucose management, postoperative patient disposition, and, lastly, anesthesia team management will be reviewed. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Organ transplantation has evolved over several decades into an extremely successful therapy for patients with endstage organ disease. This is in large part due to innovations in surgical techniques, perioperative care, and improvements in immunosuppressive regimens. The Scientific Registry of Transplant Recipients analyzes data for the Organ Procurement and Transplantation Network and monitors patient and graft survival. One-year survival for transplant recipients is between 80% and 95% (http://unos. org/data accessed 3/25/2010) (Table 1). Perhaps, more than with any other surgical program, graft and patient outcomes for organ transplantation reflect the combined efforts of several interrelated services. Despite the many advances in perioperative care, controversy exists related to the intraoperative care of liver transplant patients. Mandell [1] commented on the variability of perioperative practice patterns, which is due to the fact that most institutions use protocols that are based on institutional or individual practice for which little or no evidence exists. Indeed, there is no accepted standard for the intraoperative care for patients undergoing liver transplantation. Relevant aspects of care that anesthesiologists perform include invasive line placement, use of a range of drugs to ⁎ Corresponding author. Tel.: +1 415 502 2162; fax: +1 415 502 2224. E-mail address: [email protected] (C.U. Niemann). 0955-470X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2010.10.006
obtain hemodynamic stability, dictation of the transfusion patterns, monitoring of and correction of electrolytes and glucose homeostasis, and determining the disposition of patients (ie, extubation at the end of surgery). These interventions may directly influence both quality of care and outcomes, but relatively, little is known about their effects. The importance of the perioperative care is demonstrated by Hevesi et al [2] who reported significant improvements in liver transplant outcome by implementing the use of a dedicated, protocol-guided perioperative anesthesia care team. For this review, it is not possible to cover all aspects of the perioperative care of liver transplant patients. For example, the inclusion of the preoperative evaluation of comorbidities is beyond the scope of this review. However, it is generally appreciated that a detailed knowledge and understanding of all comorbidities such as coronary artery disease, portopulmonary hypertension, or hepatorenal syndrome have a profound impact on intraoperative decision making. Similarly, the planned surgical approach, such as total inferior vena cava occlusion, venous-venous bypass, or temporal portocaval shunt, will influence intraoperative patient care as well. Patient demographics and disease severity are also highly variable with liver transplantation occurring across a large age spectrum. In the United States, the age distribution has shifted significantly toward older patients with 42% of liver transplant recipients being 50 years or
L.L. Liu, C.U. Niemann / Transplantation Reviews 25 (2011) 124–129 Table 1 Survival and median waiting time by MELD score
MELD b10 MELD 11–18 MELD 19–24 MELD 25+
1-y survival rate
3-y survival rate
Median waiting time (d)
90.1% 89.9% 87.6% 84.6%
83.7% 83.3% 80.7% 76.6%
1776 641 106 20
Data were accessed from http://unos.org/ on March 25, 2010.
older in 1997 compared to 64% of recipients in 2006 [3]. It is increasingly not uncommon to transplant patients who are older than 60 years. Although some patients are critically ill before transplantation, others are admitted from home [3] and are often fairly well compensated with respect to their liver function. Patients with acute hepatic failure pose different challenges such as elevated intracerebral pressure and will frequently require continuous renal replacement therapy. The focus of this limited review will be on general concepts of intraoperative monitoring, transfusion and fluid management, electrolyte management, patient disposition, and anesthesia resource allocation. Each of the topics should be modified and adapted as dictated by patient characteristics, surgical approach, resource availability, institutional protocols, and individual experience. 2. Intraoperative monitoring Hemodynamic monitoring for liver transplantation usually includes at a minimum 1 arterial line and some form of central venous pressure (CVP) monitoring. Beyond CVP monitoring, use of a pulmonary artery catheter (PAC), transesophageal echocardiography (TEE), or continuous cardiac output (CCO) has been described. The type of monitoring differs among transplant centers and is mainly determined by individual or institutional practice. For example, Schumann [4] surveyed 62 transplant centers in the United States and found that PACs were used in 30% of the centers and that TEE was used in 11.3%. 2.1. Pulmonary artery catheter The PAC used to be a standard for liver transplantation monitoring at most centers. Evidence that PACs fail to improve outcomes in critical care [5,6] and its association with PAC-induced ventricular arrhythmias [7] have contributed to the trend toward less invasive monitoring for the orthotopic liver transplant (OLT) patient. Increasingly, transplant centers now rely on CVP monitoring alone or selective PAC usage, whereas others continue to routinely use PAC monitoring for all their patients. 2.2. Transesophageal echocardiography Transesophageal echocardiography usage has been gaining in popularity. It provides direct visualization of the heart,
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allowing for the quick assessment of changes in global and regional contractility and the rapid diagnosis of ventricular dilatation and failure [8]. During times of hemodynamic instability, a TEE can help with the immediate diagnosis of air or thromboembolus. The drawback to the use of TEE is that it requires experience with its use and equipment that may not be available at all centers at all times. Other problems specific to TEE are that movement of the operative field can make obtaining steady images difficult. One concern is the possible increased risk of variceal bleeding with TEE that can limit its use in all patients who present for OLT [9]. 2.3. Continuous cardiac output The lack of the perfect monitoring device has driven investigators to study other methods such as self-calibrating arterial pulse contour CO (cardiac output) monitoring system (FloTrac/Vigileo, Edwards, Lifesciences, Irvine, CA) or LiDCO (pulse contour waveform analysis [LiDCO Cardiac Sensor System] London, UK) (10,11). Unfortunately, these devices have not proven to be accurate during liver transplantation because of considerable variability during hemodynamic instability. Similarly, CCO (continuous cardiac output) by thermodilution did not satisfactorily perform because of the rapid changes in temperature, rapid infusion of fluids, and changes due to graft reperfusion [12]. The preferred choice of monitoring tool (CVP, PAC, or TEE) remains controversial because of the lack of evidence indicating a difference in patient outcomes. In summary, programs will place an arterial line (sometimes 2 arterial lines) and, then, choose between CVP, PAC, or TEE [13]. 2.4. Traditional coagulation monitoring/thromboelastography Even less consistency is found among centers regarding the monitoring of coagulation parameters. The inconsistency in monitoring was recently confirmed by Walia et al (Abstract O-59, 15th Annual International Liver Transplant Society, New York, USA, July 8th-11th, 2009) at the annual meeting of the International Liver Transplant Society in New York City, NY. In part, this is a result of a better understanding of the exceedingly complex coagulation cascade and evidence that a hypercoaguable state may exist in some patients undergoing liver transplantation. Indeed, in 1 recent study, coagulation parameters were not corrected preoperatively or intraoperatively unless there was uncontrollable bleeding. The authors found no link between coagulation defects and bleeding or red blood cell (RBC) or plasma transfusion. They concluded that, for liver transplant patients, it is neither useful nor necessary to correct perioperative coagulation defects with plasma transfusion [14]. Most programs measure prothrombin time, international normalized ratios, partial thromboplastin time, fibrinogen, and platelet (Plt) count intraoperatively. Thromboelastography
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(TEG) is used in approximately 33% of liver transplant centers, and the activated clotting time is used in approximately 18% [4]. Rotation thromboelastometry has been successfully used primarily in Europe. The reason for the disparity in monitoring of coagulation parameters is institutional availability and a lack of data demonstrating clear patient outcome benefits with either measurement. The literature does suggest, however, that the use of TEG and rotation thromboelastometry in more rationale transfusion algorithms can reduce the number of blood products transfused [15,16]. It certainly also can facilitate diagnosis of hypercoagulable states [16]. At this time, there is no consensus about the absolute need for TEG. There is the recommendation that institutions should establish strict transfusion protocols in a context-sensitive manner.
3. Intraoperative fluid and transfusion management 3.1. Central venous pressure management There is relatively solid evidence from elective hepatic resection surgeries that lower CVP during surgery can reduce blood loss [17]. Jones et al [18] showed that there is up to an 80% reduction in blood loss when the CVP was maintained at or below 5 cm H2O. The use of lower CVP in liver transplantation is still debated. Massicotte et al [19] in a retrospective study were able to reproduce the use of the lowCVP strategy during liver transplantation. Nevertheless, some centers still debate the risks (ie, renal injury and hemodynamic instability) and benefits of lowering CVP. A retrospective study found that there were higher rates of renal failure and mortality at centers using volume restriction [20], but this study had significant shortcomings such as lack of randomization, unaccounted variables, and center effect. Other centers use a regimen of fluid restriction, phlebotomy, vasopressors, and strict, protocol-guided product replacement. Massicotte et al propose that the physiologic benefit to the low-CVP algorithm is due to decreased portal venous pressure from phlebotomy, which was unaffected by the phenylephrine infusion that restored mean arterial pressure [21]. Further investigations are needed to determine which patients would benefit from restrictive volume management because adequately powered, randomized, prospective controlled trials are lacking. 3.2. Crystalloids/colloid No studies have been performed that examine the use of crystalloid vs colloid in OLT. If we extrapolate from the adult critical care literature, it appears that there is no advantage to using albumin over saline [22], but the fluid shifts during a liver transplant operation are not comparable to a septic patient in the intensive care unit (ICU). It does appear that, among colloids, albumin may be safer than hydroxyethyl starches because of the lower incidence of anaphylactic reactions, coagulation disorders, renal or liver failure, pruritus, and hemodynamic instability [23].
3.3. Restricted vs conventional transfusion triggers Liver transplantation was associated with massive blood transfusions in the past. The typical RBC requirement per adult liver transplant recipient was between 10 and 20 U of RBC in most centers. The variability between transplant centers in the amount and type of blood products used [24] may be due to differences in patient populations, surgical techniques, and transfusion practices at each institution [25]. Average blood requirements are now considerably lower with median transfusion rates between 1 and 3 U. Several patients have undergone successful transplantation without any transfusion [26]. In fact, some centers have developed programs specifically for patients who refuse all blood products [27]. Several multivariate analyses have been used to try to predict transfusion needs, and it appears that the transfusion of plasma increases the rate of RBC transfusions, whereas phlebotomy and a high starting hemoglobin level have a protective effect [28,29]. Model for End-stage Liver Disease (MELD) score was not predictive of blood loss and subsequent blood product requirement during liver transplantation [30]. There are no randomized controlled trials looking at the transfusion triggers used during OLT. In a different retrospective analysis, the number of RBC transfusions was predictive for 1-year survival. The effect on survival was found to be transfusion related with a hazard ratio of 1.057 per unit of RBC (P = .001) [26]. The difficulty in developing prediction models is that intraoperative blood loss can be affected by sudden intraoperative events or organ quality as well as unaccounted factors that cannot be included in the models [31]. Certainly, an important independent risk factor determining blood component transfusion is the local practice of the surgical and anesthesia teams [25]. In the most recent clinical practice guidelines published by a joint taskforce from the Eastern Association for Surgery of Trauma and the Society of Critical Care Medicine, there was level-1 evidence to recommend a restrictive strategy of RBC transfusion (hemoglobin level b7 g/dL) in critically ill patients with hemodynamically stable anemia [32]. The context is much different during liver transplantation, and results cannot necessarily be extrapolated to liver transplantation with possible acute blood loss and hemodynamic instability. Further trials testing rigorous transfusion protocols are necessary to allow the debate about transfusion practices to move forward, although in general, there has been a trend toward more restrictive transfusion practices. 3.4. Fresh frozen plasma/Plts Along with RBC, both Plts and fresh frozen plasma (FFP) have been associated with adverse outcomes. Pereboom et al [33] found that patient and graft survivals were significantly reduced in patients who received Plt transfusions when compared with those who did not. The lower rates of survival attributed to Plt transfusions were thought to be related to
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acute lung injury [26]. Similar effects on 1-year survival were also found with FFP [34].
present in the ICU, which is a more modest glucose control (with a target of b150 mg/dL).
4. Intraoperative electrolyte and glucose management
5. Patient disposition
4.1. Hyponatremia Severe electrolyte and glucose abnormalities may frequently develop during liver transplantation. Hyponatremia, often present preoperatively, is a serious concern in liver transplant patients because it has been associated with overall adverse outcomes [35] and can be the cause of central pontine myelinolysis [36] when sodium levels are rapidly corrected. Interestingly, the risk of delirium, acute rejection episodes, and increased ICU stay may persist regardless of whether hyponatremia is appropriately treated in the preoperative period [35]. Overall, the main goal for the intraoperative management is avoidance of rapid shifts in sodium levels [37]. 4.2. Hyperkalemia Hyperkalemia has been a long-standing intraoperative concern particularly during the reperfusion phase. Potassium levels have been found to be independent predictors of death after liver transplantation [38]. Not surprisingly, retrospective studies identified several variables that are associated with clinically significant hyperkalemia. Important variables included higher baseline potassium, RBC transfusion, organ recovery after cardiac death, longer warm ischemia time, and longer donor hospital stay [39]. The results may help to guide therapy and timely intervention such as the use of different types of insulin/glucose infusion protocols [40], bicarbonate or β-agonist administration, or even preemptive administration of renal replacement therapy. 4.3. Hyperglycemia Glucose homeostasis is frequently impaired in patients with severe liver disease. It ranges from hypoglycemia in patients with acute liver failure to hyperglycemia in patients with baseline diabetes. In this patient population, glucose metabolism may worsen during liver transplantation, and progressive hyperglycemia may ensue, especially in the reperfusion period. The proposed mechanisms for hyperglycemia include enhanced glycogenolysis by the donor liver, decreased glucose use, and insulin resistance [41]. Hyperglycemia is known to aggravate ischemia reperfusion injury in several organ systems, and because of its possible role in other critical care outcomes, intraoperative plasma glucose control becomes important. Three retrospective studies did show that severe hyperglycemia (glucose N200 mg/dL) was associated with an increased risk of liver allograft rejection [42], surgical site infection [43], and increased mortality [44]. Tight control of glucose (between 80–120 mg/dL) is not uniformly recommended [45,46]. Based on existing data, the most reasonable approach is to adopt the goals that are
Patient disposition is likely to be revisited in the near future because of changes in patient flow and resource allocation. Mandatory ICU admission will likely be replaced by a more selective approach based on the patient's profile and intraoperative course. For example, a patient with compensated liver disease undergoing uneventful liver transplantation for hepatocellular carcinoma may be admitted to the postanesthesia-care unit, with subsequent admission to the transplant floor. One important component of the disposition is whether the patient can be extubated in the operating room. Early extubation after liver transplant is often possible because of improvements in both surgical and anesthetic techniques. The concept of early postoperative tracheal extubation was started in cardiac surgery and is now possible with selected liver transplant patients [47]. Its proponents argue that early extubation reduces the risk of ventilatorassociated pneumonia and improves both splanchnic and liver blood flow. Early extubation has been shown to decrease ICU length of stay and diminish resource use. Mandell et al [48] reported that a 13% reduction in total liver transplantation costs had been achieved by using an early extubation protocol in their institution. In some centers, early extubation is performed in as many as 70% to 80% of cases [49]. Although these results are promising, extubation immediately after OLT is not a routine practice at all transplant centers. Successful attempts at early extubation depend on appropriate patient selection and adequate resource allocation such as telemetry capabilities on the transplant floor [50,51]. Biancofiore et al [52] attempted to find variables predictive of delayed tracheal extubation. By using logistic regression analysis of 168 patients, they identified primary graft dysfunction, renal and/or cardiovascular failure, serious neurologic impairment, transfusion of more than 12 U of intraoperative RBCs and pulmonary edema as variables predictive of delayed tracheal extubation. Of note, in their analysis, severity of liver disease, duration of surgery, nor duration of cold ischemia predicted prolonged time to extubation. Glanemann et al [53] reported that patients who were extubated early actually had a lower rate of reintubation when compared with patients who were extubated on average 5 hours postoperatively or those requiring prolonged mechanical ventilation of more than 24 hours. Mandell et al [54] conducted a multicenter trial to support the safety of early extubation. Despite the fact that investigators at all sites used a single uniform set of extubation criteria, extubation rates varied from 5% to 67%. The outcomes among the different centers revealed that there are a lot of inconsistencies that still exist despite efforts to provide uniformity. The authors concluded that there must
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have been institutional-specific practices that were not measured by the study. At this time, there is no consensus between transplant centers regarding early extubation after OLT, and whether it should be a therapeutic goal remains debatable [55,56].
6. Liver transplant anesthesia teams Recently, the concept of a dedicated anesthesia team for liver transplantation has gained momentum. The American Society of Anesthesiologists passed a proposal that requires credentialing for the director of a liver transplant anesthesia service. Suggested criteria can be reviewed at the following link: http://www.asahq.org/publicationsAndServices/stan dards/53.pdf. As previously mentioned, some preliminary data from an observation study support the clinical observation that dedicated anesthesia teams can significantly contribute to excellent graft and patient outcome [2].
7. Conclusion The intraoperative management of liver transplant patients is not uniform between institutions and is often dictated by local practice patterns. This variety reflects, in part, the lack of good outcome studies. Recent studies about coagulation monitoring, transfusion triggers, and fluid management have challenged our ingrained practice patterns and may allow transplant centers to draft best practices. Unfortunately, large areas in the management of liver transplantation exist where no evidence is available to guide practitioners. The authors report no conflict of interest. References [1] Mandell MS. Anesthesia for liver transplantation: is this generalist or specialist care? Liver Transpl Surg 1999;5:345-6. [2] Hevesi ZG, Lopukhin SY, Mezrich JD, et al. Designated liver transplant anesthesia team reduces blood transfusion, need for mechanical ventilation, and duration of intensive care. Liver Transpl 2009;15:460-5. [3] 2007 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1997-2006. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, HSB, Department of Transportation; 2007. [4] Schumann R. Intraoperative resource utilization in anesthesia for liver transplantation in the United States: a survey. Anesth Analg 2003;97:21-8. [5] Connors Jr AF, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. Jama 1996;276:889-97. [6] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213-24.
[7] Gwak MS, Kim JA, Kim GS, et al. Incidence of severe ventricular arrhythmias during pulmonary artery catheterization in liver allograft recipients. Liver Transpl 2007;13:1451-4. [8] Burtenshaw AJ, Isaac JL. The role of trans-oesophageal echocardiography for perioperative cardiovascular monitoring during orthotopic liver transplantation. Liver Transpl 2006;12:1577-83. [9] Spier BJ, Larue SJ, Teelin TC, et al. Review of complications in a series of patients with known gastro-esophageal varices undergoing transesophageal echocardiography. J Am Soc Echocardiogr 2009; 22:401-3. [10] Biancofiore G, Critchley LA, Lee A, et al. Evaluation of an uncalibrated arterial pulse contour cardiac output monitoring system in cirrhotic patients undergoing liver surgery. Br J Anaesth 2009;102:47-54. [11] Biais M, Nouette-Gaulain K, Cottenceau V, et al. Cardiac output measurement in patients undergoing liver transplantation: pulmonary artery catheter versus uncalibrated arterial pressure waveform analysis. Anesth Analg 2008;106:1480-6. [12] Bao FP, Wu J. Continuous versus bolus cardiac output monitoring during orthotopic liver transplantation. Hepatobiliary Pancreat Dis Int 2008;7:138-44. [13] Manley JL, Plotkin JS, Yosaitis J, et al. Controversies in anesthetic management of liver transplantation. HPB (Oxford) 2005;7:183-5. [14] Massicotte L, Beaulieu D, Thibeault L, et al. Coagulation defects do not predict blood product requirements during liver transplantation. Transplantation 2008;85:956-62. [15] Roullet S, Pillot J, Freyburger G, et al. Rotation thromboelastometry detects thrombocytopenia and hypofibrinogenaemia during orthotopic liver transplantation. Br J Anaesth 2010;104:422-8. [16] Coakley M, Reddy K, Mackie I, et al. Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests. J Cardiothorac Vasc Anesth 2006;20:548-53. [17] Moug SJ, Smith D, Leen E, et al. Selective continuous vascular occlusion and perioperative fluid restriction in partial hepatectomy. Outcomes in 101 consecutive patients. Eur J Surg Oncol 2007;33: 1036-41. [18] Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg 1998;85:1058. [19] Massicotte L, Sassine MP, Lenis S, et al. Transfusion predictors in liver transplant. Anesth Analg 2004;98:1245-51. [20] Schroeder RA, Collins BH, Tuttle-Newhall E, et al. Intraoperative fluid management during orthotopic liver transplantation. J Cardiothorac Vasc Anesth 2004;18:438-41. [21] Massicotte L, Perrault MA, Denault AY, et al. Effects of phlebotomy and phenylephrine infusion on portal venous pressure and systemic hemodynamics during liver transplantation. Transplantation 2010; 89:920-7. [22] Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. [23] Barron ME, Wilkes MM, Navickis RJ. A systematic review of the comparative safety of colloids. Arch Surg 2004;139:552-63. [24] de Boer MT, Molenaar IQ, Hendriks HG, et al. Minimizing blood loss in liver transplantation: progress through research and evolution of techniques. Dig Surg 2005;22:265-75. [25] Ozier Y, Pessione F, Samain E, et al. Institutional variability in transfusion practice for liver transplantation. Anesth Analg 2003; 97:671-9. [26] de Boer MT, Christensen MC, Asmussen M, et al. The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation. Anesth Analg 2008;106:32-44. [27] Detry O, Roover AD, Delwaide J, et al. Liver transplantation in Jehovah's witnesses. Transpl Int 2005;18:929-36. [28] Massicotte L, Capitanio U, Beaulieu D, et al. Independent validation of a model predicting the need for packed red blood cell transfusion at liver transplantation. Transplantation 2009;88:386-91.
L.L. Liu, C.U. Niemann / Transplantation Reviews 25 (2011) 124–129 [29] McCluskey SA, Karkouti K, Wijeysundera DN, et al. Derivation of a risk index for the prediction of massive blood transfusion in liver transplantation. Liver Transpl 2006;12:1584-93. [30] Massicotte L, Beaulieu D, Roy JD, et al. MELD score and blood product requirements during liver transplantation: no link. Transplantation 2009;87:1689-94. [31] Ozier Y, Tsou MY. Changing trends in transfusion practice in liver transplantation. Curr Opin Organ Transpl 2008;13:304-9. [32] Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med 2009;37:3124-57. [33] Pereboom IT, de Boer MT, Haagsma EB, et al. Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury. Anesth Analg 2009;108:1083-91. [34] Massicotte L, Sassine MP, Lenis S, et al. Survival rate changes with transfusion of blood products during liver transplantation. Can J Anaesth 2005;52:148-55. [35] Hackworth WA, Heuman DM, Sanyal AJ, et al. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int 2009;29:1071-7. [36] Yun BC, Kim WR, Benson JT, et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 2009;49:1610-5. [37] Lee EM, Kang JK, Yun SC, et al. Risk factors for central pontine and extrapontine myelinolysis following orthotopic liver transplantation. Eur Neurol 2009;62:362-8. [38] Dawwas MF, Lewsey JD, Watson CJ, et al. The impact of serum potassium concentration on mortality after liver transplantation: a cohort multicenter study. Transplantation 2009;88:402-10. [39] Xia VW, Ghobrial RM, Du B, et al. Predictors of hyperkalemia in the prereperfusion, early postreperfusion, and late postreperfusion periods during adult liver transplantation. Anesth Analg 2007;105: 780-5. [40] Xia VW, Obaidi R, Park C, et al. Insulin therapy in divided doses coupled with blood transfusion versus large bolus doses in patients at high risk for hyperkalemia during liver transplantation. J Cardiothorac Vasc Anesth 2010;24:80-3. [41] Merritt WT. Metabolism and liver transplantation: review of perioperative issues. Liver Transpl 2000:S76-S84.
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[42] Wallia A, Parikh ND, Molitch ME, et al. Posttransplant hyperglycemia is associated with increased risk of liver allograft rejection. Transplantation 2010;89:222-6. [43] Park C, Hsu C, Neelakanta G, et al. Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation. Transplantation 2009;87:1031-6. [44] Ammori JB, Sigakis M, Englesbe MJ, et al. Effect of intraoperative hyperglycemia during liver transplantation. J Surg Res 2007;140: 227-33. [45] Marik PE, Preiser JC. Towards understanding tight glycemic control in the ICU: a systematic review and meta-analysis. Chest 2009;137:544-51. [46] Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-97. [47] Mandell MS, Lockrem J, Kelley SD. Immediate tracheal extubation after liver transplantation: experience of two transplant centers. Anesth Analg 1997;84:249-53. [48] Mandell MS, Lezotte D, Kam I, et al. Reduced use of intensive care after liver transplantation: influence of early extubation. Liver Transpl 2002;8:676-81. [49] Salizzoni M, Cerutti E, Romagnoli R, et al. The first one thousand liver transplants in Turin: a single-center experience in Italy. Transpl Int 2005;18:1328-35. [50] Biancofiore G, Bindi ML, Romanelli AM, et al. Fast track in liver transplantation: 5 years' experience. Eur J Anaesthesiol 2005;22:584-90. [51] Glanemann M, Hoffmeister R, Neumann U, et al. Fast tracking in liver transplantation: which patient benefits from this approach? Transplant Proc 2007;39:535-6. [52] Biancofiore G, Romanelli AM, Bindi ML, et al. Very early tracheal extubation without predetermined criteria in a liver transplant recipient population. Liver Transpl 2001;7:777-82. [53] Glanemann M, Busch T, Neuhaus P, et al. Fast tracking in liver transplantation. Immediate postoperative tracheal extubation: feasibility and clinical impact. Swiss Med Wkly 2007;137:187-91. [54] Mandell MS, Stoner TJ, Barnett R, et al. A multicenter evaluation of safety of early extubation in liver transplant recipients. Liver Transpl 2007;13:1557-63. [55] Mandell MS, Hang Y. Pro: early extubation after liver transplantation. J Cardiothorac Vasc Anesth 2007;21:752-5. [56] Steadman RH. Con: immediate extubation for liver transplantation. J Cardiothorac Vasc Anesth 2007;21:756-7.
Transplantation Reviews 25 (2011) 124 – 129 www.elsevier.com/locate/trre
Intraoperative management of liver transplant patients Linda L. Liua , Claus U. Niemanna,b,⁎ a b
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, USA Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Abstract Liver transplantation for end-stage liver disease results in excellent outcomes. Patient and graft outcome is closely monitored on a national level, and 1-year survival is between 80% and 95%. Liver transplantation relies on a multidisciplinary approach, with close involvement of anesthesiologists and intensivists. However, intraoperative care of these patients remains inconsistent and is highly institution dependent. This brief-review article will focus on controversial topics of intraoperative care. Existing evidence on intraoperative monitoring, intraoperative fluid and transfusion management, electrolyte and glucose management, postoperative patient disposition, and, lastly, anesthesia team management will be reviewed. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Organ transplantation has evolved over several decades into an extremely successful therapy for patients with endstage organ disease. This is in large part due to innovations in surgical techniques, perioperative care, and improvements in immunosuppressive regimens. The Scientific Registry of Transplant Recipients analyzes data for the Organ Procurement and Transplantation Network and monitors patient and graft survival. One-year survival for transplant recipients is between 80% and 95% (http://unos. org/data accessed 3/25/2010) (Table 1). Perhaps, more than with any other surgical program, graft and patient outcomes for organ transplantation reflect the combined efforts of several interrelated services. Despite the many advances in perioperative care, controversy exists related to the intraoperative care of liver transplant patients. Mandell [1] commented on the variability of perioperative practice patterns, which is due to the fact that most institutions use protocols that are based on institutional or individual practice for which little or no evidence exists. Indeed, there is no accepted standard for the intraoperative care for patients undergoing liver transplantation. Relevant aspects of care that anesthesiologists perform include invasive line placement, use of a range of drugs to ⁎ Corresponding author. Tel.: +1 415 502 2162; fax: +1 415 502 2224. E-mail address: [email protected] (C.U. Niemann). 0955-470X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2010.10.006
obtain hemodynamic stability, dictation of the transfusion patterns, monitoring of and correction of electrolytes and glucose homeostasis, and determining the disposition of patients (ie, extubation at the end of surgery). These interventions may directly influence both quality of care and outcomes, but relatively, little is known about their effects. The importance of the perioperative care is demonstrated by Hevesi et al [2] who reported significant improvements in liver transplant outcome by implementing the use of a dedicated, protocol-guided perioperative anesthesia care team. For this review, it is not possible to cover all aspects of the perioperative care of liver transplant patients. For example, the inclusion of the preoperative evaluation of comorbidities is beyond the scope of this review. However, it is generally appreciated that a detailed knowledge and understanding of all comorbidities such as coronary artery disease, portopulmonary hypertension, or hepatorenal syndrome have a profound impact on intraoperative decision making. Similarly, the planned surgical approach, such as total inferior vena cava occlusion, venous-venous bypass, or temporal portocaval shunt, will influence intraoperative patient care as well. Patient demographics and disease severity are also highly variable with liver transplantation occurring across a large age spectrum. In the United States, the age distribution has shifted significantly toward older patients with 42% of liver transplant recipients being 50 years or
L.L. Liu, C.U. Niemann / Transplantation Reviews 25 (2011) 124–129 Table 1 Survival and median waiting time by MELD score
MELD b10 MELD 11–18 MELD 19–24 MELD 25+
1-y survival rate
3-y survival rate
Median waiting time (d)
90.1% 89.9% 87.6% 84.6%
83.7% 83.3% 80.7% 76.6%
1776 641 106 20
Data were accessed from http://unos.org/ on March 25, 2010.
older in 1997 compared to 64% of recipients in 2006 [3]. It is increasingly not uncommon to transplant patients who are older than 60 years. Although some patients are critically ill before transplantation, others are admitted from home [3] and are often fairly well compensated with respect to their liver function. Patients with acute hepatic failure pose different challenges such as elevated intracerebral pressure and will frequently require continuous renal replacement therapy. The focus of this limited review will be on general concepts of intraoperative monitoring, transfusion and fluid management, electrolyte management, patient disposition, and anesthesia resource allocation. Each of the topics should be modified and adapted as dictated by patient characteristics, surgical approach, resource availability, institutional protocols, and individual experience. 2. Intraoperative monitoring Hemodynamic monitoring for liver transplantation usually includes at a minimum 1 arterial line and some form of central venous pressure (CVP) monitoring. Beyond CVP monitoring, use of a pulmonary artery catheter (PAC), transesophageal echocardiography (TEE), or continuous cardiac output (CCO) has been described. The type of monitoring differs among transplant centers and is mainly determined by individual or institutional practice. For example, Schumann [4] surveyed 62 transplant centers in the United States and found that PACs were used in 30% of the centers and that TEE was used in 11.3%. 2.1. Pulmonary artery catheter The PAC used to be a standard for liver transplantation monitoring at most centers. Evidence that PACs fail to improve outcomes in critical care [5,6] and its association with PAC-induced ventricular arrhythmias [7] have contributed to the trend toward less invasive monitoring for the orthotopic liver transplant (OLT) patient. Increasingly, transplant centers now rely on CVP monitoring alone or selective PAC usage, whereas others continue to routinely use PAC monitoring for all their patients. 2.2. Transesophageal echocardiography Transesophageal echocardiography usage has been gaining in popularity. It provides direct visualization of the heart,
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allowing for the quick assessment of changes in global and regional contractility and the rapid diagnosis of ventricular dilatation and failure [8]. During times of hemodynamic instability, a TEE can help with the immediate diagnosis of air or thromboembolus. The drawback to the use of TEE is that it requires experience with its use and equipment that may not be available at all centers at all times. Other problems specific to TEE are that movement of the operative field can make obtaining steady images difficult. One concern is the possible increased risk of variceal bleeding with TEE that can limit its use in all patients who present for OLT [9]. 2.3. Continuous cardiac output The lack of the perfect monitoring device has driven investigators to study other methods such as self-calibrating arterial pulse contour CO (cardiac output) monitoring system (FloTrac/Vigileo, Edwards, Lifesciences, Irvine, CA) or LiDCO (pulse contour waveform analysis [LiDCO Cardiac Sensor System] London, UK) (10,11). Unfortunately, these devices have not proven to be accurate during liver transplantation because of considerable variability during hemodynamic instability. Similarly, CCO (continuous cardiac output) by thermodilution did not satisfactorily perform because of the rapid changes in temperature, rapid infusion of fluids, and changes due to graft reperfusion [12]. The preferred choice of monitoring tool (CVP, PAC, or TEE) remains controversial because of the lack of evidence indicating a difference in patient outcomes. In summary, programs will place an arterial line (sometimes 2 arterial lines) and, then, choose between CVP, PAC, or TEE [13]. 2.4. Traditional coagulation monitoring/thromboelastography Even less consistency is found among centers regarding the monitoring of coagulation parameters. The inconsistency in monitoring was recently confirmed by Walia et al (Abstract O-59, 15th Annual International Liver Transplant Society, New York, USA, July 8th-11th, 2009) at the annual meeting of the International Liver Transplant Society in New York City, NY. In part, this is a result of a better understanding of the exceedingly complex coagulation cascade and evidence that a hypercoaguable state may exist in some patients undergoing liver transplantation. Indeed, in 1 recent study, coagulation parameters were not corrected preoperatively or intraoperatively unless there was uncontrollable bleeding. The authors found no link between coagulation defects and bleeding or red blood cell (RBC) or plasma transfusion. They concluded that, for liver transplant patients, it is neither useful nor necessary to correct perioperative coagulation defects with plasma transfusion [14]. Most programs measure prothrombin time, international normalized ratios, partial thromboplastin time, fibrinogen, and platelet (Plt) count intraoperatively. Thromboelastography
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(TEG) is used in approximately 33% of liver transplant centers, and the activated clotting time is used in approximately 18% [4]. Rotation thromboelastometry has been successfully used primarily in Europe. The reason for the disparity in monitoring of coagulation parameters is institutional availability and a lack of data demonstrating clear patient outcome benefits with either measurement. The literature does suggest, however, that the use of TEG and rotation thromboelastometry in more rationale transfusion algorithms can reduce the number of blood products transfused [15,16]. It certainly also can facilitate diagnosis of hypercoagulable states [16]. At this time, there is no consensus about the absolute need for TEG. There is the recommendation that institutions should establish strict transfusion protocols in a context-sensitive manner.
3. Intraoperative fluid and transfusion management 3.1. Central venous pressure management There is relatively solid evidence from elective hepatic resection surgeries that lower CVP during surgery can reduce blood loss [17]. Jones et al [18] showed that there is up to an 80% reduction in blood loss when the CVP was maintained at or below 5 cm H2O. The use of lower CVP in liver transplantation is still debated. Massicotte et al [19] in a retrospective study were able to reproduce the use of the lowCVP strategy during liver transplantation. Nevertheless, some centers still debate the risks (ie, renal injury and hemodynamic instability) and benefits of lowering CVP. A retrospective study found that there were higher rates of renal failure and mortality at centers using volume restriction [20], but this study had significant shortcomings such as lack of randomization, unaccounted variables, and center effect. Other centers use a regimen of fluid restriction, phlebotomy, vasopressors, and strict, protocol-guided product replacement. Massicotte et al propose that the physiologic benefit to the low-CVP algorithm is due to decreased portal venous pressure from phlebotomy, which was unaffected by the phenylephrine infusion that restored mean arterial pressure [21]. Further investigations are needed to determine which patients would benefit from restrictive volume management because adequately powered, randomized, prospective controlled trials are lacking. 3.2. Crystalloids/colloid No studies have been performed that examine the use of crystalloid vs colloid in OLT. If we extrapolate from the adult critical care literature, it appears that there is no advantage to using albumin over saline [22], but the fluid shifts during a liver transplant operation are not comparable to a septic patient in the intensive care unit (ICU). It does appear that, among colloids, albumin may be safer than hydroxyethyl starches because of the lower incidence of anaphylactic reactions, coagulation disorders, renal or liver failure, pruritus, and hemodynamic instability [23].
3.3. Restricted vs conventional transfusion triggers Liver transplantation was associated with massive blood transfusions in the past. The typical RBC requirement per adult liver transplant recipient was between 10 and 20 U of RBC in most centers. The variability between transplant centers in the amount and type of blood products used [24] may be due to differences in patient populations, surgical techniques, and transfusion practices at each institution [25]. Average blood requirements are now considerably lower with median transfusion rates between 1 and 3 U. Several patients have undergone successful transplantation without any transfusion [26]. In fact, some centers have developed programs specifically for patients who refuse all blood products [27]. Several multivariate analyses have been used to try to predict transfusion needs, and it appears that the transfusion of plasma increases the rate of RBC transfusions, whereas phlebotomy and a high starting hemoglobin level have a protective effect [28,29]. Model for End-stage Liver Disease (MELD) score was not predictive of blood loss and subsequent blood product requirement during liver transplantation [30]. There are no randomized controlled trials looking at the transfusion triggers used during OLT. In a different retrospective analysis, the number of RBC transfusions was predictive for 1-year survival. The effect on survival was found to be transfusion related with a hazard ratio of 1.057 per unit of RBC (P = .001) [26]. The difficulty in developing prediction models is that intraoperative blood loss can be affected by sudden intraoperative events or organ quality as well as unaccounted factors that cannot be included in the models [31]. Certainly, an important independent risk factor determining blood component transfusion is the local practice of the surgical and anesthesia teams [25]. In the most recent clinical practice guidelines published by a joint taskforce from the Eastern Association for Surgery of Trauma and the Society of Critical Care Medicine, there was level-1 evidence to recommend a restrictive strategy of RBC transfusion (hemoglobin level b7 g/dL) in critically ill patients with hemodynamically stable anemia [32]. The context is much different during liver transplantation, and results cannot necessarily be extrapolated to liver transplantation with possible acute blood loss and hemodynamic instability. Further trials testing rigorous transfusion protocols are necessary to allow the debate about transfusion practices to move forward, although in general, there has been a trend toward more restrictive transfusion practices. 3.4. Fresh frozen plasma/Plts Along with RBC, both Plts and fresh frozen plasma (FFP) have been associated with adverse outcomes. Pereboom et al [33] found that patient and graft survivals were significantly reduced in patients who received Plt transfusions when compared with those who did not. The lower rates of survival attributed to Plt transfusions were thought to be related to
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acute lung injury [26]. Similar effects on 1-year survival were also found with FFP [34].
present in the ICU, which is a more modest glucose control (with a target of b150 mg/dL).
4. Intraoperative electrolyte and glucose management
5. Patient disposition
4.1. Hyponatremia Severe electrolyte and glucose abnormalities may frequently develop during liver transplantation. Hyponatremia, often present preoperatively, is a serious concern in liver transplant patients because it has been associated with overall adverse outcomes [35] and can be the cause of central pontine myelinolysis [36] when sodium levels are rapidly corrected. Interestingly, the risk of delirium, acute rejection episodes, and increased ICU stay may persist regardless of whether hyponatremia is appropriately treated in the preoperative period [35]. Overall, the main goal for the intraoperative management is avoidance of rapid shifts in sodium levels [37]. 4.2. Hyperkalemia Hyperkalemia has been a long-standing intraoperative concern particularly during the reperfusion phase. Potassium levels have been found to be independent predictors of death after liver transplantation [38]. Not surprisingly, retrospective studies identified several variables that are associated with clinically significant hyperkalemia. Important variables included higher baseline potassium, RBC transfusion, organ recovery after cardiac death, longer warm ischemia time, and longer donor hospital stay [39]. The results may help to guide therapy and timely intervention such as the use of different types of insulin/glucose infusion protocols [40], bicarbonate or β-agonist administration, or even preemptive administration of renal replacement therapy. 4.3. Hyperglycemia Glucose homeostasis is frequently impaired in patients with severe liver disease. It ranges from hypoglycemia in patients with acute liver failure to hyperglycemia in patients with baseline diabetes. In this patient population, glucose metabolism may worsen during liver transplantation, and progressive hyperglycemia may ensue, especially in the reperfusion period. The proposed mechanisms for hyperglycemia include enhanced glycogenolysis by the donor liver, decreased glucose use, and insulin resistance [41]. Hyperglycemia is known to aggravate ischemia reperfusion injury in several organ systems, and because of its possible role in other critical care outcomes, intraoperative plasma glucose control becomes important. Three retrospective studies did show that severe hyperglycemia (glucose N200 mg/dL) was associated with an increased risk of liver allograft rejection [42], surgical site infection [43], and increased mortality [44]. Tight control of glucose (between 80–120 mg/dL) is not uniformly recommended [45,46]. Based on existing data, the most reasonable approach is to adopt the goals that are
Patient disposition is likely to be revisited in the near future because of changes in patient flow and resource allocation. Mandatory ICU admission will likely be replaced by a more selective approach based on the patient's profile and intraoperative course. For example, a patient with compensated liver disease undergoing uneventful liver transplantation for hepatocellular carcinoma may be admitted to the postanesthesia-care unit, with subsequent admission to the transplant floor. One important component of the disposition is whether the patient can be extubated in the operating room. Early extubation after liver transplant is often possible because of improvements in both surgical and anesthetic techniques. The concept of early postoperative tracheal extubation was started in cardiac surgery and is now possible with selected liver transplant patients [47]. Its proponents argue that early extubation reduces the risk of ventilatorassociated pneumonia and improves both splanchnic and liver blood flow. Early extubation has been shown to decrease ICU length of stay and diminish resource use. Mandell et al [48] reported that a 13% reduction in total liver transplantation costs had been achieved by using an early extubation protocol in their institution. In some centers, early extubation is performed in as many as 70% to 80% of cases [49]. Although these results are promising, extubation immediately after OLT is not a routine practice at all transplant centers. Successful attempts at early extubation depend on appropriate patient selection and adequate resource allocation such as telemetry capabilities on the transplant floor [50,51]. Biancofiore et al [52] attempted to find variables predictive of delayed tracheal extubation. By using logistic regression analysis of 168 patients, they identified primary graft dysfunction, renal and/or cardiovascular failure, serious neurologic impairment, transfusion of more than 12 U of intraoperative RBCs and pulmonary edema as variables predictive of delayed tracheal extubation. Of note, in their analysis, severity of liver disease, duration of surgery, nor duration of cold ischemia predicted prolonged time to extubation. Glanemann et al [53] reported that patients who were extubated early actually had a lower rate of reintubation when compared with patients who were extubated on average 5 hours postoperatively or those requiring prolonged mechanical ventilation of more than 24 hours. Mandell et al [54] conducted a multicenter trial to support the safety of early extubation. Despite the fact that investigators at all sites used a single uniform set of extubation criteria, extubation rates varied from 5% to 67%. The outcomes among the different centers revealed that there are a lot of inconsistencies that still exist despite efforts to provide uniformity. The authors concluded that there must
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have been institutional-specific practices that were not measured by the study. At this time, there is no consensus between transplant centers regarding early extubation after OLT, and whether it should be a therapeutic goal remains debatable [55,56].
6. Liver transplant anesthesia teams Recently, the concept of a dedicated anesthesia team for liver transplantation has gained momentum. The American Society of Anesthesiologists passed a proposal that requires credentialing for the director of a liver transplant anesthesia service. Suggested criteria can be reviewed at the following link: http://www.asahq.org/publicationsAndServices/stan dards/53.pdf. As previously mentioned, some preliminary data from an observation study support the clinical observation that dedicated anesthesia teams can significantly contribute to excellent graft and patient outcome [2].
7. Conclusion The intraoperative management of liver transplant patients is not uniform between institutions and is often dictated by local practice patterns. This variety reflects, in part, the lack of good outcome studies. Recent studies about coagulation monitoring, transfusion triggers, and fluid management have challenged our ingrained practice patterns and may allow transplant centers to draft best practices. Unfortunately, large areas in the management of liver transplantation exist where no evidence is available to guide practitioners. The authors report no conflict of interest. References [1] Mandell MS. Anesthesia for liver transplantation: is this generalist or specialist care? Liver Transpl Surg 1999;5:345-6. [2] Hevesi ZG, Lopukhin SY, Mezrich JD, et al. Designated liver transplant anesthesia team reduces blood transfusion, need for mechanical ventilation, and duration of intensive care. Liver Transpl 2009;15:460-5. [3] 2007 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1997-2006. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, HSB, Department of Transportation; 2007. [4] Schumann R. Intraoperative resource utilization in anesthesia for liver transplantation in the United States: a survey. Anesth Analg 2003;97:21-8. [5] Connors Jr AF, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. Jama 1996;276:889-97. [6] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213-24.
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