Hangzhou, China

Clinical practice of early extubation after liver transplantation

Jian Wu, Vaibhav Rastogi and Shu-Sen Zheng

Hangzhou, China

BACKGROUND:Anesthetic practices such as early tracheal extubation facilitate postoperative recovery. Early extubation after liver transplantation has been adopted by some centers in the recent two decades. No universal clinical guidelines are used and questions remain. This review aimed to address the current status of early extubation after liver transplantation.

DATA SOURCES:A literature search of MEDLINE and ISI Web of Knowledge databases was performed using terms such as liver transplantation, early extubation, immediate tracheal extubation, fast tracking or fast track anesthesia and postoperative tracheal extubation. Additional papers were identified by a manual search of the references in the key articles.

RESULTS:Review of the available literature provided an insight into the definition, evolution, advantages and risks of early extubation, and anesthetic techniques that prompt early extubation in liver transplant patients. Early extubation has proved to be feasible and safe in these patients, but the outcomes are still uncertain.

CONCLUSIONS:Early extubation after liver transplantation is feasible, safe and cost-effective in the majority of patients and has been increasingly accepted as an option for conventional postoperative ventilation. Comprehensive and individualized evaluation of the patient's condition before extubation by an experienced anesthesiologist is the cornerstone of success. Understanding of its effect on the outcome remains incomplete. In the future, additional trials are required to establish universal early extubation guidelines and to determine its benefits for patients and practitioners.

(Hepatobiliary Pancreat Dis Int 2012;11:577-585)

liver transplantation; extubation; ventilation; anesthesia

Introduction

Prolonged postoperative mechanical ventilation has usually been used in patients who undergo large or complicated procedures because they experience many adverse events that increase the risk of perioperative morbidity and mortality. However, early extubation in these patients is not a new approach. In 1977, Prakash et al[1]and Klineberg et al[2]reported the results of early extubation within the first few hours after coronary artery bypass graft surgery. Both concluded that early extubation permits earlier recovery without increasing morbidity.[1,2]From that time onwards, early extubation after cardiac surgery was extensively studied and further increasingly accepted as a safe, cost-effective method that can improve resource utilization.[3,4]Early extubation in liver transplant recipients was reported in the 1990s.[5-10]At present, early extubation after liver transplantation has been successful in many patients and is gradually being adopted in more and more hospitals.[11]Its safety has also been validated by a recent multicenter study.[12]Nevertheless, limited data are available in the literature about early extubation in patients after liver transplantation, as compared with cardiac surgery. Early extubation after liver transplantation is not yet routine in all centers and debate regarding its implementation remains.[13,14]In this brief review, we address a variety of aspects concerning early extubation after liver transplantation including its definition, its evolution and current status, and anesthetic strategies.

Definition of early extubation after liver transplantation

Initially, early extubation after cardiac surgery wasdefined as removal of the endotracheal tube within several hours after operation.[1-3]Nowadays, it has been modified within the first postoperative hour.[15]Since the 1990s, early extubation has been applied to liver transplant recipients.[5-10,16,17]At that time, some investigators suggested that tracheal extubation with 3 hours after liver transplantation was feasible and safe[9,10,17]whereas others thought it suitable to extubate selected patients immediately after surgery in the operating room.[5,7,8]To date, no borderline exists in terms of time to extubation that clearly demarcates the early extubation time period but it can still be broadly defined as removal of the endotracheal tube within the first few postoperative hours or, in a narrow sense, it usually refers to immediate tracheal extubation (＜1 hour) in the operating room.[12]

Worldwide distribution of hospitals that use early extubation

Several reports on early tracheal extubation after liver transplantation have been published.[5-10,12,16-35]As reported, only a small number of hospitals in a few countries (USA,[6-8,12,19,21,22]Italy,[10,17,27,30,31]Turkey,[20,23,28,32]Germany,[5,18,29]UK,[16,26]Brazil,[9]Belgium,[24]Chile,[25]Poland,[33]Iran[34]and India[35]) have adopted this technique in such patients. However, early extubation may be used more extensively in liver transplant recipients in intensive care units than in those in other units.[36]Immediate tracheal extubation after liver transplantation has been performed in our center since March 2009.

Evolution of early extubation in liver transplant recipients

In 1990, Rossaint et al[5]found that endotracheal tubes can be removed immediately after operation in a small number of liver transplant recipients. They restricted fluid administration to hasten the recovery of the patients. However, it is quite difficult to use the fluid restriction strategy in such patients, particularly those with massive intraoperative blood loss. Although intraoperative fluid restriction may improve the outcome after major abdominal surgery, further investigation is needed. Moreover, rigorous fluid restriction may lead to an increased risk of adverse postoperative events in patients undergoing liver transplantation.[37]Therefore, the role of fluid restriction in these patients remains to be determined.

In 1997, Plevak and Torsher[6]demonstrated that use of a fast-track pathway reduced the postoperative ventilation time from 37.7 to 15.3 hours and shortened the intensive care unit stay from 63.5 to 32.3 hours. Also in 1997, Mandell et al[7]and Neelakanta et al[8]published studies of immediate tracheal extubation after liver transplantation. However, this had not been accepted as "early extubation" at that time. In 1999, tracheal extubation within 3 hours of surgery was used by some authors as early extubation.[9,10,17]Biancofiore et al[17]found that immediate tracheal extubation can only be performed in highly-selected patients, while more patients benefit from extubation within 3 hours after liver transplantation (in the intensive care unit). Since 2001 the number of reports on early extubation after liver transplantation has markedly increased and immediate postoperative extubation has been mentioned frequently.[12,18,20,21,23-30,32,33,35]Later, the previous point of view on early extubation of some anesthesiologists changed. Biancofiore et al[27]probed into the reasons for prolongation of postoperative ventilation after liver transplantation, which had been performed before beginning immediate extubation in their center, and concluded that this was probably mainly due to subjective factors (convenience and excessive caution of the operating theater staff) rather than clinical needs. Immediate extubation was also used in pediatric liver transplant recipients to facilitate early postoperative recovery[23,26,32]and has even been carried out routinely in most of the patients in some centers.[26,32]

Significant differences in the immediate postoperative extubation rate were reported among various centers and during different study periods (Table 1). In the mid 1990s, immediate postoperative extubation rates were estimated to be about 20% in selected adult liver transplant patients in some centers[7,18]whereas a much higher rate (51.4%) was found in a small sample study.[8]Later, it rose to above 50% in adult recipients[20,27-29]and even close to 80% in selected pediatric recipients.[26,32]Owing to advances in surgical technology and anesthetic management, the immediate extubation rate by year increased in some centers. Biancofiore et al[27]found that the annual percentage of recipients who received immediate extubation increased considerably during the study period (19.0% in the first year and 82.5% in the last year). Similarly, Alper and Ulukaya[32]found that this rate by year increased substantially from 0% in 1997 to 95.6% in 2008. These increases indicate that, at present, immediate extubation after liver transplantation has been almost fully accepted in centers that adopted an early extubation protocol, but they also mirror the importance of the "learning curve" or "experience curve" effect, because early extubationafter liver transplantation or other complex procedures requires experience and a context-sensitive attitude of all the actors involved in the process of care.

Table 1.Immediate extubation rate after liver transplantation in some centers

Advantages and potential risks of early extubation in liver transplant recipients

Advantages

Early extubation following liver transplantation may have several potential advantages. A study[3]from cardiac surgery showed that early extubation decreases the incidence of pulmonary morbidity and reduces sedative and narcotic requirements, indicating that liver transplant patients may also benefit. Theoretically, however, early extubation can improve splanchnic and liver blood flow, which might result in better liver graft recovery. But clinically there is debate on this practice. The influence of prolongation of postoperative ventilation on graft liver function still needs determination.[38]

Early extubation after liver transplantation reduces the use of the intensive care unit,[7,20,21,23,28]decreases the total cost,[7,21,25]and thus improves resource utilization.[7,21,22]Cost-effectiveness seems to be the most interesting and important advantage of early extubation. In 1997 Mandell et al[7]found a significant reduction in the length of stay for patients immediately extubated as compared with controls (20.4±7.4 versus 35.0±8.0 hours,P＜0.05), and accordingly an average cost saving of $2709 was found to be associated with reduced intensive care unit services in these patients. This finding was supported by some studies,[20,21,23,28]but others did not hold the same point of view.[8,19,26,27]The different views may be due to the different postoperative care protocols adopted for liver transplant patients in hospitals.[14,39]A reduction in intensive care unit stay is associated with better management of available resources; this is especially important in developing countries with limited resources, and there is always a shortage of high-acuity care. Recently early extubation after liver transplantation has been recommended with respect to costs and benefits in a systematic review.[40]Considering that liver transplant candidates generally have multiple organ disease before operation or experience a complicated procedure, some investigators recommend the use of an intermediate care unit to avoid unnecessary delay in extubation.[14,19,33]In a study,[30]376 of 575 (65.4%) immediately-extubated patients were transferred directly to an intermediate care unit after surgery and only 18 (4.7%) of them were subsequently admitted to the intensive care unit. Thus what matters is that physicians should extubate these patients as early as possible.

Potential risks

Early extubation also carries risks, including postoperative respiratory insufficiency and urgent re-intubation. Patients suffering from mild respiratory insufficiency after early extubation can be treated successfully by physiotherapy or non-invasive ventil ation,[12,23,26,27]whereas those with severe respiratory insufficiency probably need urgent re-intubation. In addition, if patients suffer from surgical problems that require re-operation, re-intubation is necessary. Glanemann et al[41]investigated the incidence and indications for re-intubation in patients who underwent liver transplantation in their center between January 1992 and September 1996 and found that the main indications were pulmonary (44.6%), cerebral (19.1%), and surgical complications (14.5%). According to the current literature, the re-intubation rate in patients who are extubated immediately in the operating room is similar to that in those extubated early in the intensive care unit (＜24 hours), whereas it is relatively higher in patients requiring prolonged mechanical ventilation(＞24 hours) (Table 2). One possible reason is that the patients extubated early are always better than those on prolonged ventilation. However, predictors of reintubation in early extubation patients after liver transplantation are difficult to investigate because most patients require urgent surgery (Table 2). Therefore, to identify the predictors of safe early extubation in these patients is important to avoid re-intubation owing to premature extubation.

Table 2.Re-intubation rate and its causes following liver transplantation in some centers

Table 3.Predictors of delayed tracheal extubation

The predictors for early extubation after liver transplantation have been investigated[17,18,22,27-30]and the results vary greatly. Table 3 summarizes the predictors of delayed extubation in liver transplant recipients according to the literature. Hence, clinicians involved in early extubation must pay high attention to risk factors such as poor preoperative medical status (e.g. renal and/ or cardiovascular failure, mechanical ventilation prior to transplantation, poorly controlled encephalopathy, and morbid obesity), extremely unstable hemodynamics at the end of surgery, pulmonary edema, and primary graft dysfunction, because these risk factors predict that early extubation is almost impossible.

Queries about early extubation after liver transplantation

Is early extubation feasible and safe?

It has been well demonstrated in a large number of retrospective reviews and case series that early extubation after liver transplantation is feasible.[7-10,17,18,20,21,23-32]However, it should be kept in mind that feasibility is not equal to safety. It has been argued that validation of the safety of early extubation requires randomized controlled trials with adequate sample sizes.[13,14]Recently, the results of a multicenter trial reported by Mandell et al[12]provide accurate information about the incidence of adverse events in the first 3 days following transplantation, and found that the incidence was only 7.7%. Most adverse events were either pulmonary or surgically-related and were mild. Aside from 6 patients who required re-laparotomy, the rate of re-intubation within 3 days remained at the low level of 0.26%.[12]Therefore, a reasonable conclusion can be drawn from the current literature that early extubation after liver transplantation is feasible and safe.

Are outcomes improved by early extubation?

Investigators reported that early extubation improves the outcome.[13,18]However, patients who require prolonged ventilatory support after transplantation are usually severely ill, or experience a more complicated procedure, or even receive a worse graft than those who are extubated early.[18,27]Specifically, the most important difference between liver transplantation and other complex surgeries is that good function of the grafted liver is the foundation of recovery. That is, the outcome depends first and foremost on graft function. However, reliable laboratory indicators reflecting graft dysfunction at the end of surgery are needed. Although some researchers use blood lactate levels as a surrogate marker of graft function,[30]its role needs to be confirmed. Hence whether or not early extubation can improve the outcome is uncertain and needs further investigation. In addition, to date there is no evidence demonstrating that early extubation has adverse effects on patient outcome.

Is early extubation necessary?

Liver transplant recipients experience a complicated procedure. Potential intraoperative problems, such as prolonged surgery, metabolic and hemodynamic disturbances, and major blood loss, may increase the risk of respiratory compromise. Therefore, these patients are usually ventilated postoperatively for a long time. Some physicians believed that postoperative ventilation may decrease surgical stress and facilitate early recovery.[42]However, postoperative mechanical ventilation may not be beneficial in all liver transplant patients. In addition, advances in surgical techniques and anesthetic management, along with newer and short-acting anesthetics, contribute to rapid postoperative recovery. Moreover, the decision to extubate a patient in a specific hospital is probably highly influenced by factors[13,22,43]such as physician decision-making on extubation, the opinion of the transplant team as a whole, and the resources available. Therefore, since most liver transplant patients can now be extubated early, anesthetists should consider following this practice.

Since early extubation is feasible and safe and has potential advantages, then why is it not routinely accepted by all centers and why have universal early extubation clinical guidelines not been established? Clearly, early extubation is not possible in all liver transplant patients because a minority have severe coexisting disorders requiring prolonged postoperative ventilatory support; but prolonged ventilation is also not necessary for all patients.[21]In addition, as mentioned above, early extubation requires experience and confidence.[27,32]Thus, the key to success in early extubation is that experienced clinicians should evaluate the patients carefully before extubation and then treat them accordingly.

Table 4.Anesthetic techniques and early extubation in liver transplant patients

Anesthetic approaches facilitate early extubation in liver transplant recipients

Over the years, the use of high-dose narcotic-based anesthesia has led to prolonged postoperative ventilation in cardiac surgical patients. Then, a change in technique to a balanced one could facilitate early extubation after cardiac surgery.[44]Some investigators suggested that the key to success in early extubation after cardiac surgery is the use of inhalation-based anesthetic techniques.[45]Similarly, it has been noted that a balanced anesthetic regimen using inhalational agents combined with narcotics was predominantly adopted to prompt early extubation after liver transplantation. Although the selection of inhalational anesthetics and muscle relaxants varies among centers, there is a trend toward increased use of remifentanil in the more recently published case series (Table 4). Changes in anesthetic practice accompanied by reduction in fentanyl dosing and increased use of remifentanil assists rapid recovery and early extubation after liver transplantation.[19,32]

The use of propofol in liver transplant patients has been limited and to date there are only a few reports with small sample sizes on early extubation in adult[24]or pediatric[26]recipients with propofol-remifentanil total intravenous anesthesia. The primary reason is probably that the propofol concentration during the anhepatic phase increases significantly[46,47]and even more, it is highly influenced by factors such as blood loss[48-50]and graft function,[46]which all lead to unpredictable variations in propofol concentration. Therefore, whenever propofol is used for anesthesia maintenance during liver transplantation, it is generally administered as a supplement to inhalation-based anesthesia,[46,47]but if it is used as the primary or sole hypnotic, monitoring it using a monitor such as the bispectral index is useful in order to facilitate early extubation.[24]In addition, the advantages of propofol total intravenous anesthesia over inhalation-based anesthetic techniques in liver transplant patients are unknown and need further study.

At present, the bispectral index is used as a convenient tool to titrate hypnotic agents and to reduce drug consumption that allows faster recovery.[51,52]Its use in liver transplant patients has gradually increased.[24,53-55]Studies[53-55]showed that bispectral index monitoring is easy for the individual administration of inhalational anesthetics in patients undergoing liver transplantation. Similarly, a study[24]found that bispectral index monitoring in propofol-remifentanil total intravenous anesthesia facilitates early extubation in this population and may be an alternative to inhalation-based anesthesia. In a preliminary study, we also found that 85% of conscious patients who are not ventilated preoperatively can be extubated in the operating room after liver transplantation (mean time to extubation about 30 minutes) with bispectral index-guided propofolremifentanil anesthesia (unpublished data). However, the utilization of bispectral index monitoring in livertransplant patients has recently been questioned.[55]Furthermore, no large studies on awareness after bispectral index monitoring have been conducted in this population. Therefore, its clinical benefits remain uncertain and need further study.

Epidural analgesia has also been used in highly selected liver transplant recipients as a supplementary component of general anesthesia. Trzebicki et al[33]reported 67 patients, who received thoracic epidural analgesia, meeting the inclusion criteria: international normalized ratio ＜1.5, activated partial thromboplastin time ＜45 seconds, and platelets ＞70 g/L. Fifty-six (83.6%) of the patients were extubated in the operating room and no complications induced by analgesia were observed. This finding, however, is not convincing. First, the immediate extubation rate was not higher than that in patients without epidural analgesia. Furthermore, the patients with end-stage liver disease undergoing transplantation had lower postoperative analgesic requirements than patients having other major abdominal surgery.[56,57]Moreover, even in healthy patients undergoing living liver donor surgery, coagulopathies are common in the postoperative period.[58,59]Liver transplant patients experience exceedingly complex changes in coagulation, and the risk of epidural hematoma after the placement of an epidural catheter for postoperative analgesia is unknown. Therefore, epidural analgesia in this patient population is rarely recommended.

Conclusions

The currently available evidence supports the safety and cost-effectiveness of early extubation in the majority of liver transplant patients because of advances in surgical technique and perioperative management. Early extubation in these patients is increasingly accepted as an option for conventional postoperative ventilation. Comprehensive and individualized evaluation of the patient's condition before extubation by an experienced anesthesiologist is the cornerstone of success. The effect of early extubation on patient outcome remains to be seen. In the future, additional trials are required to establish universal early extubation guidelines and to determine its benefits for patients and practitioners.

Contributors:WJ wrote the first draft of this paper. All authors contributed to the intellectual context and approved the final version. ZSS is the guarantor.

Funding:This study was supported by a grant from the National S&T Major Project of China (2012ZX10002-017).

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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October 29, 2011

Accepted after revision April 10, 2012

Author Affiliations: Department of Anesthesiology (Wu J), Medical Student (Rastogi V), and Division of Hepatobiliary and Pancreatic Surgery (Zheng SS), First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Shu-Sen Zheng, MD, PhD, FACS, Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel/Fax: 86-571-87236601; Email: shusenzheng@zju.edu.cn)

? 2012, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(12)60228-8