The impact of intraoperative vascular occlusion during liver surgery on postoperative peak ALT levels: A systematic review and meta-analysis

International Journal of Surgery 27 (2016) 99e104

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Review

The impact of intraoperative vascular occlusion during liver surgery on postoperative peak ALT levels: A systematic review and meta-analysis Tao Guo 1, Yusha Xiao 1, Zhisu Liu, Quanyan Liu* Department of General Surgery, Zhongnan Hospital, Wuhan University, Wuhan, 430071, PR China

h i g h l i g h t s
A comprehensive literature review and quantitative analysis were conducted.
The impact of intraoperative vascular occlusion during liver surgery on postoperative peak ALT levels was determined.
The Statistical methods were intensive.

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 November 2015 Received in revised form 14 January 2016 Accepted 21 January 2016 Available online 28 January 2016

Background and aims: Intraoperative vascular occlusion techniques during liver surgeries have been performed and refined for decades. However, the impact of these techniques on postoperative peak ALT levels remains uncertain. Thus, we performed a literature review and meta-analysis to determine the impact of intraoperative vascular occlusion during liver surgery on postoperative peak ALT levels. Methods: A systematic literature search of the PubMed database was conducted to discover relevant controlled clinical trials. Studies that reported postoperative peak ALT values for both an observation group and a control group were included. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Egger's test and Orwin's fail-safe N test. Results: Of the 281 retrieved articles, 10 articles fulfilled the inclusion criteria. These 10 articles involved 12 randomized controlled trials with a total of 1443 records. The pooled estimation results indicated that intraoperative vascular occlusion significantly elevated postoperative peak ALT levels (test for SMD: Z ¼ 4.09, P < 0.001; 95% CI: 0.59e1.68), with high heterogeneity (I2 ¼ 93.8%). Subgroup analysis revealed that intermittent inflow occlusion and Pringle's maneuver vascular occlusions may be the potential crucial factors. No obvious publication bias was detected by Egger's test (P ¼ 0.541) or Orwin's fail-safe N test (Nfs0.05 ¼ 2059.19). Conclusions: Intraoperative vascular occlusion, especially intermittent inflow occlusion and Pringle's maneuver vascular occlusions, may be a potential risk factor that could lead higher postoperative peak ALT values than non-occlusion procedures for liver surgeries. © 2016 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

Keywords: Vascular occlusion ALT Meta-analysis

1. Introduction Massive bleeding is a main cause of severe complications after hepatic surgery, although perioperative transfusion has also been demonstrated to be a factor in postoperative mortality [1e5]. To

* Corresponding author. Department of General Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, PR China. E-mail address: [email protected] (Q. Liu). 1 Both authors contributed equally to this work.

reduce the risk of bleeding, various vascular inflow occlusion techniques have been developed in recent decades [6]. Indeed, vascular occlusion significantly reduces blood loss during hepatic surgery; however, it can also cause ischemic damage and consequently result in postoperative liver dysfunction [7]. Furthermore, the liver is subjected to an aggravating insult when blood supply is restored, and ischemia-reperfusion liver injury, which is a multifactorial process involving interactions among metabolic, immunological and microvascular processes [8], could be exacerbated in patients with liver disease [9e12].

http://dx.doi.org/10.1016/j.ijsu.2016.01.088 1743-9191/© 2016 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

T. Guo et al. / International Journal of Surgery 27 (2016) 99e104

Alanine aminotransferase (ALT), which is mostly found in the cytosol of hepatocytes, is the most frequently used surrogate endpoint in hepatic surgery-related studies because ALT levels are a sensitive marker of hepatocyte injury and inflammation [13]. Accordingly, an elevated serum ALT level is a sign of ischemiareperfusion injury or other liver tissue damage because it indicates the occurrence of ALT leakage from liver tissue into the circulation. Thus, mostly postoperative ALT levels of liver surgeries were elevated. In contrast, intermittent inflow occlusion causes relatively little disturbance of hepatic microcirculation and preserves liver sinusoids relatively well after a hepatectomy. And the safety of continuous inflow occlusion for hepatic surgery has been evaluated [14e16]. Research has indicated that the liver has a higher tolerance for ischemia than for bleeding [17]. Vascular occlusion techniques have been devised and improved by surgeons over the course of the past several decades; to a certain extent, assessments of higher postoperative serum ALT levels may be an indication for evaluating more damages to the liver after vascular occlusion. However, the impact of vascular occlusion during hepatic surgery on postoperative peak ALT levels remains unclear and no specific comprehensive quantitative review with ample evidences published yet. Given all of the aforementioned facts, we decided to improve understanding with respect to quantitative identifying whether the vascular occlusion techniques could lead higher postoperative ALT levels than those cases without inflow occlusion. Therefore, we aimed to figure out the impact of vascular occlusion during liver surgery on postoperative peak ALT levels by conducting a systematic review and meta-analysis which approaches are currently regarded as the best tools for summarizing extant scientific evidence.

2. Methods 2.1. Literature search and study selection In accordance with PRISMA and MOOSE guidelines [18,19], we conducted an initial comprehensive literature search of the PubMed database using the following expressions in the “PubMed Advanced Search Builder”: [(((((((((vascular) OR inflow) OR vessel) OR vein) OR portal)) AND (((occlusion) OR clamping) OR exclusion))) AND ((((liver) OR hepatic)) AND (((surgery) OR hepatectomy) OR resection))) AND ((ALT) OR alanine aminotransferase)]. We did not apply any language, publication date or publication status restrictions. Using the selection criteria of this study, two reviewers (T. Guo and Y. Xiao) independently conducted systematic searches at different times. Subsequently, all of the included articles underwent evaluation by three investigators (T. Guo, Y. Xiao and Z. Liu), who engaged in in-house discussions regarding the preservation of these articles for meta-analysis. The inclusion and exclusion criteria for this study were based on the following characteristics. First, randomized controlled trials that provided raw data for postoperative ALT values in both a control group and an experimental group were considered. The examined intervention must have been limited to hepatic inflow occlusion. No restrictions were imposed regarding the details of the vascular occlusion techniques used in each examined study, although vascular occlusion was required to be the unique variable. The patients examined in each included article must have been clearly diagnosed and subjected to equal treatment during the perioperative period. We excluded commentaries, review papers, and articles with missing or unavailable data. In addition, studies limited to animals, cells, children, pregnant females or other unrelated subjects were directly excluded.

2.2. Data extraction and quality assessment Two authors (T. Guo and Y. Xiao) independently extracted quantitative raw data regarding postoperative peak ALT levels from the full text of each included article. Disagreements were resolved without assumptions or simplifications by reaching consensus with the third author (Z. Liu). Using the “Quality Index” system [20], all three investigators (T. Guo, Y. Xiao and Z. Liu) independently assessed the quality of the examined studies. The use of this scoring system, which includes the 5 items of “Reporting”, “External validity”, “Bias”, “Confounding” and “Power”, involved producing a checklist that provided a profile of each study; scores on each item alerted reviewers to each investigation's particular methodological strengths and weaknesses. Subsequently, detailed score lists indicating the quality assessment of each study were generated by the aforementioned three investigators and submitted to the senior investigator (Q. Liu). Using the “Quality Index” system, the senior investigator considered these score lists and provided final judgments regarding each study. In addition, we established the following standards for the quality grades of studies: low quality was defined as a score of less than 10 points; medium quality was defined as a score of 10e19 points; and high quality was defined as a score of more than 19 points. 2.3. Statistical analysis In this meta-analysis, the outcomes of postoperative peak ALT values, with comparisons, were pooled to produce estimates of overall effects. For pooling purposes, ALT data were expressed in terms of mean values and variances or standard deviations (SDs). In several included articles, data were presented in terms of medians and ranges; in these cases, the Hozo formula was used for data estimation and conversion [21]. Subsequently, continuous variable calculations were performed, including the determination of the summary statistic: standard mean difference (SMD) and its associated 95% confidence interval (CI). Heterogeneity was determined by the Q statistic and the I2 index statistic (with P < 0.05 and an I2>50% regarded as indicative of significant heterogeneity) [22]. Given the existence of significant heterogeneity across the included studies, forest plots were assessed using a random-effects model. We determined that the heterogeneity in this research originated from differences among data sources, which involved various interventions and diverse surgical techniques; these differences were explained as appropriate. Therefore, heterogeneity was quantitatively estimated for discussion using the restricted maximum likelihood (REML) approach. Moreover, subgroup analysis was applied when appropriate. Publication bias was evaluated using Egger's regression plot and was quantitatively analyzed by Egger's test [23]. In addition, to ensure the robustness of pooled estimates, Orwin's fail-safe N test (Nfs0.05) was utilized to assess publication bias. Given the insignificant results of Egger's test, Orwin's fail-safe N could statistically reflect the intensities of the pooled estimates [24]. All of the data manipulation and statistical analyses of this study were conducted by T. Guo and Q. Liu using the Stata software package (version 12.0). 3. Results After detailed evaluation, ten articles [25e34], including twelve studies that examined a total of 1443 patients, satisfied the study recruitment criteria (Fig. 1). All of these articles were published between 2004 and 2014, and no low-quality publications were included. In addition, Wen [16] and Takatsuki [17] each reported on two studies. The characteristics of the included studies are presented in Table 1.

T. Guo et al. / International Journal of Surgery 27 (2016) 99e104

certain factors. More specific, we divided the included studies into 2 subgroups, based on 7 different categories, respectively, ignoring the specific surgical methodology used in each study (Table 3). The results of subgroup analysis again indicated that vascular occlusion clearly elevated postoperative peak ALT levels in both subgroups of each subcategory except for the subgroup of continuous occlusion, subgroup of without preoperative chemotherapy or cirrhosis and subgroup of selective vascular occlusions (P ¼ 0.061, P ¼ 0.077 and P ¼ 0.315, respectively). So we found that intermittent inflow occlusion had more effective impact on postoperative peak ALT levels compared with continuous inflow occlusion. And patients with preoperative chemotherapy or cirrhosis were also more sensitive to this impact. Moreover, Pringle's maneuver vascular occlusions was also a factor elevating the ALT levels versus selective vascular occlusions. (Table 3). 3.3. Publication bias We measured publication bias using Egger's test, which demonstrated that no significant publication bias existed (t ¼ 0.63, P ¼ 0.541) (Fig. 3). Moreover, the statistical outcome of Orwin's fail-safe N test indicated that publication bias was highly improbable (Nfs0.05 ¼ 2059.19). Based on these comprehensive quantitative evaluations, we concluded that no obvious publication bias existed in the assessed research.

Fig. 1. Flow diagram of the study selection procedures.

3.1. Vascular occlusion clearly impacted postoperative peak ALT values

4. Discussion

Quantitative data synthesis from statistical pooling using random-effects modeling revealed significant differences in patients' results (test for SMD: Z ¼ 4.09, P < 0.001; 95% CI: 0.59e1.68) (Fig. 2). This statistical result exhibited that intraoperative vascular occlusion led higher postoperative ALT levels. Given these statistical findings, we have proven that vascular occlusion clearly impacted postoperative peak ALT values; in particular, vascular occlusion elevated postoperative peak ALT levels.

3.2. Heterogeneity and subgroup analysis As evident from the forest plot, overall assessments of the pooling estimates revealed high heterogeneity (I2 ¼ 93.8%, P < 0.001) (Fig. 2). To detect the sources of this heterogeneity, we performed quantitative estimation using the REML method. In the evaluation of several related contingency factors, “Surgical procedure” exhibited significant heterogeneity (P ¼ 0.042) (Table 2). Subsequently, we performed a subgroup analysis based on

It has been decades since the impact of vascular occlusion during hepatic surgery on postoperative ALT levels was first identified in animal models [35]. Subsequently, in combination with the gradual maturation of surgical approaches, various vascular occlusion techniques for liver surgery have been applied and refined. After summarizing clinical research addressing the benefits of vascular occlusion for the postoperative outcomes of hepatic surgeries in different nations, we found that the impact of vascular occlusion during hepatic surgery on postoperative peak ALT levels remained controversial. Two prior systematic reviews partially supported the notion that liver enzymes were elevated after vascular occlusion during liver resection [36,37]. However, both of these studies declared that their conclusions lacked sufficient evidentiary support. Based on these facts, we performed a systematic review and metaanalysis that provided the first comprehensive examination of the impact of vascular occlusion during hepatic surgery on postoperative peak ALT levels. By focusing on postoperative peak ALT levels, we assessed the potential risk factors of damaging to the liver based on vascular occlusion during operations.

Table 1 Characteristics of the included trials. Author

Country

Year

Surgical procedure

Intervention

Data type

Remarks

Boleslawski Capussotti Chouker Dua Miller Park Patriti Shin Wen Study 1 Study 2 Takatsuki Study 1 Study 2

France Italy Germany USA USA S. Korea Italy S. Korea

2014 2006 2014 2014 2004 2012 2012 2012

Diverse elective hepatectomy Major hepatic resection Diverse hepatectomy Laparoscopic liver resection Livingdonor hepatectomy Living donor liver transplantation Laparoscopic minor resection Right hepatectomy

Diverse inflow occlusion Intermittent inflow occlusion Continuous inflow occlusion Intermittent inflow occlusion Intermittent inflow occlusion Intermittent inflow occlusion Intermittent inflow occlusion Intermittent inflow occlusion

Median (range) Median (range) Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD

e e e e e e e e

China China

2007 2007

Irregular hepatectomy Irregular hepatectomy

Continuous inflow occlusion Continuous inflow occlusion

Mean ± SD Mean ± SD

Occlusion time: 60e90 min Occlusion time: >90 min

Japan Japan

2014 2014

Liver transplantation Liver transplantation

Intermittent inflow occlusion Intermittent inflow occlusion

Median (range) Median (range)

Comparison between donors Comparison between recipients

T. Guo et al. / International Journal of Surgery 27 (2016) 99e104

Fig. 2. Pooled estimation of the impact of vascular occlusion during liver surgery on postoperative peak ALT values.

Table 2 Heterogeneity analysis of different sources. Item

Coef.

Std. Err.

t

P>jtj

95% Conf. Interval

Publication Year Region Surgical procedure Data type Intervention

0.1430814 0.6116557 0.4001933 0.0324836 0.17487

0.0858696 0.332645 0.1721442 0.7298734 0.6157811

1.67 1.84 2.32 0.04 0.28

0.127 0.096 0.042 0.965 0.782

0.048248 1.352835 0.7837544 1.593776 1.546916

Twelve studies, including 1443 patients from ten articles, were included in this research. After qualitative appraisals and the statistical aggregation of the published data by meta-analysis, we used random-effects modeling and determined that vascular occlusion had an obvious impact on postoperative peak ALT levels (test for SMD: Z ¼ 4.09, P < 0.001). This surgical technique bring higher postoperative ALT levels. Based on this result, we concluded that vascular occlusion during hepatic surgery was a critical factor that might increasing risk for liver damage, to some extent. This finding can be regarded as a supplemental result that contributes to evidence from prior studies. With respect to statistical analysis, high heterogeneity (I2 ¼ 93.8%) appeared in the pooled estimation, although the inclusion criteria for the literature search were strictly satisfied. Therefore, we quantitatively analyzed possible sources of heterogeneity, considering the aforementioned factors, and found that “Surgical procedure” provided a particularly notable contribution to the observed heterogeneity (P ¼ 0.042), although there may also be other sources of potential confounders (Table 2). Subsequently, subgroup analysis according to certain factors was conducted. The results of this subgroup analysis indicated that the continuous occlusion subgroup, selective vascular occlusions subgroup and non-preoperative chemotherapy or cirrhosis subgroup revealed insignificant results (P ¼ 0.061, 0.315 and 0.077, respectively). But for other categories, the statistical analysis did not reveal any differences between each subgroup. These results

0.3344108 0.1295234 0.0166321 1.658743 1.197176

supported that preoperative chemotherapy or cirrhosis, intermittent occlusion and Pringle's maneuver vascular occlusions may be the potential key factors influencing the ALT levels. Moreover, high heterogeneity was also detected in each subgroup. Based on these findings, we may conclude that vascular occlusion, especially intermittent occlusion, could have a widespread impact on postoperative ALT levels across various types of liver operations. And for those patients who underwent preoperative chemotherapy or cirrhosis, the impact would be also obvious. However, due to the high heterogeneity in each subgroup, we assumed that differences in the details of the surgical methods used in included studies contributed significantly to overall heterogeneity. To evaluate publication bias, quantitative analysis was conducted using Egger's regression plot, and a simple statistical analysis of publication bias was performed using Orwin's fail-safe N test; both of these analyses produced insignificant results (P ¼ 0.541 and Nfs0.05 ¼ 2059.19). To a certain extent, these results suggested to us that no obvious publication bias existed in the included research. All of the included studies, which were conducted in seven different nations, were published during the prior decade. In addition, raw data from four of the included studies, which presented findings in terms of medians and ranges, were converted to means and SDs using the Hozo formula. Therefore, we must acknowledge that differences in data types might inevitably have influenced the final results of our analysis, although the quality

T. Guo et al. / International Journal of Surgery 27 (2016) 99e104 Table 3 Subgroup analysis according to certain factors. Subcategory

No. of studies

Surgical procedure Total 12 Liver transplantation 4 Liver resection 8 Occlusion methods Total 11 Intermittent occlusion 8 Continuous occlusion 3 With preoperative chemotherapy or cirrhosis Total 12 With 5 Without 7 Total occlusion time Total 9 <45 min 3 45 min 6 Resection size of hepatectomy Total 6 Major hepatic resection 4 Minor or segment resection 2 Anatomical resection Total 10 Anatomical 6 Non-anatomical 4 Type of vascular occlusions Total 12 Selective 2 Pringle's maneuver 10

Pooled estimation

Test of heterogeneity

P Value

95% Conf. Interval

P Value

Chi-squared

I-squared

<0.001 <0.001 <0.001

0.59 0.58 0.93

1.68 1.11 2.12

<0.001 0.002 <0.001

178.02 14.75 118.47

93.8% 79.7% 94.1%

0.002 0.011 0.061

0.395 0.255 0.064

1.802 1.997 2.837

<0.001 <0.001 <0.001

173.96 134.97 17.55

94.3% 94.8% 88.6%

<0.001 <0.001 0.077

0.59 0.991 0.088

1.68 2.232 1.718

<0.001 <0.001 <0.001

178.02 28.09 126.96

93.8% 85.8% 95.3%

<0.001 <0.001 0.007

0.814 1.121 0.248

1.958 3.545 1.559

<0.001 <0.001 <0.001

134.51 49.97 52.16

94.1% 96.0% 90.4%

0.003 0.025 0.028

0.469 0.127 0.235

2.318 1.859 4.207

<0.001 <0.001 <0.001

110.27 45.54 17.03

95.5% 93.4% 94.1%

0.002 0.022 0.047

0.427 0.179 0.016

1.936 2.337 2.096

<0.001 <0.001 <0.001

162.67 119.53 32.56

94.5% 95.8% 90.8%

<0.001 0.315 <0.001

0.59 0.317 0.708

1.68 0.983 1.884

<0.001 0.094 <0.001

178.02 2.81 144.35

93.8% 64.4% 93.8%

Fig. 3. The use of Egger's regression plot for assessing publication bias.

assessment of the included studies and the heterogeneity evaluation of study data produced no significant results. Furthermore, the high heterogeneity detected in this meta-analysis, which could constitute a potential limitation of the applicability of the analysis to clinical practice, was partially explained. However, the influences of pooled estimation, in combination with the impacts of measured and unmeasured confounders, have not yet been specifically addressed. Finally, due to limitations of the literature retrieval strategies and inclusion criteria of this investigation, we could have overlooked certain relevant studies. To various degrees, all of these aforementioned drawbacks might have contributed to our final results. This review provided the first comprehensive statistical aggregation of all published data on postoperative peak ALT values after intraoperative vascular occlusion during liver surgery. We demonstrated that intraoperative vascular occlusion significantly

elevated postoperative peak ALT levels. This finding might be regarded as proof that intraoperative vascular occlusion is a potential risk factor that likely associates intraoperative liver injury. Based on this reasoning, we suggest that vascular occlusion during liver surgery may provide fewer benefits than we had previously believed; instead, this procedure could cause additional damage to patients. On the other hand, based on the results of subgroup analysis, intermittent inflow occlusion have significant impact on the postoperative peak ALT values compared with continuous inflow occlusion. It may indicated that frequent vascular occlusion and reperfusion may bring more damages to liver tissue. At meantime, compared with Pringle's maneuver vascular occlusions, selective vascular occlusions did not elevate the ALT levels. At last, patients with preoperative chemotherapy or cirrhosis may be more vulnerable during vascular occlusion. Notably, although we considered the impact of intraoperative vascular occlusion on death ratios, a question relevant to long-term prognoses, we were unable to perform a meta-analysis to address this question due to a lack of relevant data. Therefore, by focusing on postoperative peak ALT levels, this research only provided a perspective regarding patients' perioperative tolerance. Additional data are necessary to assess long-term prognoses; thus, in the future, we may perform more comprehensive analyses that relate to the current study. In addition, although we suggested that vascular occlusion during liver surgery may provide fewer benefits than expected and actually could cause additional damage to liver, but using vascular occlusion during hepatic resection limits excessive blood loss. So we raised the question which causes less harm, excessive bleeding or vascular occlusion. And we expect more future clinical trails. Despite the existence of several limitations, our final conclusion from this investigation is that intraoperative vascular occlusion, especially intermittent inflow occlusion and Pringle's maneuver vascular occlusions, significantly impacted postoperative peak ALT levels. It may lead higher postoperative ALT levels than nonocclusion procedures. And the patients with preoperative

T. Guo et al. / International Journal of Surgery 27 (2016) 99e104

chemotherapy or cirrhosis revealed more obvious. Thus, vascular occlusion during liver surgery could be a potential risk factor which may bring damages to liver tissue. Based on these findings, we expect more researches to clarify the accurate clinical efficacy.

[13]

Ethical approval

[14]

This is a systematic review and meta-analysis. We don't think we need Ethical Approval.

[15]

Sources of funding

[16]

None. Author contribution Guo T and Xiao YS contributed equally to this work. Guo T and Liu QY designed the research; Guo T, Xiao YS and Liu ZS performed the research; Guo T and Xiao YS contributed new reagents/analytic tools; Liu QY and Guo T wrote the paper. Conflicts of interest We declare that we have no financial and personal relationship with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service an/or company that could be construed as influencing the position presented in, or the review of. Guarantor Liu QY and Guo T. References [1] D.A. Kooby, J. Stockman, L. Ben-Porat, M. Gonen, W.R. Jarnagin, R.P. Dematteo, S. Tuorto, et al., Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases, Ann. Surg. 237 (2003) 860e869, 869e870. [2] H. Shiba, Y. Ishida, S. Wakiyama, T. Iida, M. Matsumoto, T. Sakamoto, R. Ito, et al., Negative impact of blood transfusion on recurrence and prognosis of hepatocellular carcinoma after hepatic resection, J. Gastrointest. Surg. 13 (2009) 1636e1642. [3] K.R. Stephenson, S.M. Steinberg, K.S. Hughes, J.T. Vetto, P.H. Sugarbaker, A.E. Chang, Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastases, Ann. Surg. 208 (1988) 679e687. [4] W.R. Jarnagin, M. Gonen, Y. Fong, R.P. DeMatteo, L. Ben-Porat, S. Little, C. Corvera, et al., Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade, Ann. Surg. 236 (2002) 397e406, 406e407. [5] R.T. Poon, S.T. Fan, C.M. Lo, C.L. Liu, C.M. Lam, W.K. Yuen, C. Yeung, et al., Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database, Ann. Surg. 240 (2004) 698e708, 708e710. [6] W.Y. Lau, E.C. Lai, S.H. Lau, Methods of vascular control technique during liver resection: a comprehensive review, Hepatobiliary Pancreat. Dis. Int. 9 (2010) 473e481. [7] S.Q. Li, L.J. Liang, J.F. Huang, Z. Li, Ischemic preconditioning protects liver from hepatectomy under hepatic inflow occlusion for hepatocellular carcinoma patients with cirrhosis, World J. Gastroenterol. 10 (2004) 2580e2584. [8] O. Heizmann, F. Loehe, A. Volk, R.J. Schauer, Ischemic preconditioning improves postoperative outcome after liver resections: a randomized controlled study, Eur. J. Med. Res. 13 (2008) 79e86. [9] J. Melendez, E. Ferri, M. Zwillman, M. Fischer, R. DeMatteo, D. Leung, W. Jarnagin, et al., Extended hepatic resection: a 6-year retrospective study of risk factors for perioperative mortality, J. Am. Coll. Surg. 192 (2001) 47e53. [10] J. Belghiti, K. Hiramatsu, S. Benoist, P. Massault, A. Sauvanet, O. Farges, Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection, J. Am. Coll. Surg. 191 (2000) 38e46. [11] M. Makuuchi, T. Mori, P. Gunven, S. Yamazaki, H. Hasegawa, Safety of

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