Introduction
Liver resection is the most widely used curative treatment approach for hepatocellular carcinoma (HCC) as recommended by several guidelines [
1‐
3]. The control of bleeding during liver resection is an important aspect to ensure surgical safety and reduce complications [
4]. Current evidence shows that massive blood loss during liver resection and blood transfusion are the risk factors for poor overall survival (OS) and disease-free survival (DFS) of patients undergoing liver resection [
5,
6]. Intermittent Pringle maneuver (IPM) is the most common vascular occlusion method used worldwide to control bleeding [
7]. The clamping pattern of IPM included 15 min of ischemia followed by 5 min of reperfusion. However, blood flow occlusion inevitably causes ischemia–reperfusion injury in the liver, resulting in liver function damage [
8] and contributing to HCC recurrence [
9,
10]. Therefore, a part of hepatectomies was done without the Pringle maneuver.
The utility of IPM in reducing bleeding during liver resection was evaluated [
11]. The effect of IPM on the long-term survival of patients with liver malignancies was assessed [
12]. However, these studies did not focus on the effect of IPM on short- and long-term outcomes following hepatectomy specifically for HCC patients. It is known that patients with HCC usually have hepatitis or cirrhosis or other chronic liver diseases as coexisting illnesses. Consequently, the effects of IPM on these patients may differ from those on patients with normal liver [
13]. Hence, we conducted a meta-analysis to evaluate the effect of IPM on perioperative outcomes and long-term survival of patients with HCC who underwent liver resection.
Methods
This meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This systematic review is registered in the PROSPERO database (registration no. CRD42023411488).
Article search strategy
A systematic search was independently performed by two researchers to identify the relevant studies published on this topic in the PubMed, Embase, Web of Science, and Cochrane Library databases from conception to March 26, 2023. The following MeSH terms and keywords were used for search in PubMed: liver resection, hepatectomy, hepatic resection, hepatocellular carcinoma, Pringle maneuver, and blood occlusion. The details of search strategies are provided in Supplementary Material
1. Manual retrieval was performed to identify eligible studies from the included studies, meta-analyses, and reviews.
Selection criteria
The inclusion criteria were as follows: (1) studies involving patients with HCC; (2) studies on comparison between the use of IPM and no use of PM (non-Pringle maneuver [NPM]) during liver resection, both randomized controlled trials (RCTs) or retrospective studies published in English; and (3) studies reporting perioperative outcomes (including blood loss, blood transfusion, and complications) and/or long-term outcomes (including OS and DFS).
The exclusion criteria were as follows: (1) studies that included patients with liver cancers or benign tumors other than HCC; (2) studies that compared other blood occlusion methods, including continuous PM, selective hepatic flow occlusion, or hemihepatic blood flow occlusion; and (3) studies with duplicate data.
Quality assessment and data extraction
Quality assessment and data extraction were conducted by two independent researchers. The Cochrane risk assessment tool was used to assess the quality of RCTs. The Newcastle–Ottawa Scale with a score of up to 9 points was used to assess the quality of retrospective studies; the scores were assigned as follows: 5 or less, low quality; 6–7, moderate quality; and 8 or more, high quality.
Predesigned and standardized forms were used to extract relevant details from the included studies (first author, country, year of publication, patient information, and tumor characteristics). The survival outcomes, including OS, DFS, and recurrence rate, and perioperative outcomes, including operation time, blood loss, blood transfusion, and complications were extracted. Survival data were collected directly from the original reports or indirectly from estimation with the Kaplan–Meier curve using the Engauge Digitizer software (version 4.1). Any disagreements between the two independent researchers were resolved by a third researcher.
Statistical analysis
The inverse variance method was used to determine the hazard ratio (HR) and 95% confidence interval (CI) values. The Mantel–Haenszel method was used to determine the risk ratio (RR) and 95% CI values. The Hedges method was used to calculate the standardized mean difference (SMD) and 95% CI values. Heterogeneity was assessed using the
χ2 method (
I2 values of 25% and 50% indicated low heterogeneity and moderate heterogeneity, respectively) [
14]. The test model was selected based on the heterogeneity level, and the random-effects model was used for
I2 > 50%. Sensitivity analysis was performed to assess the robustness of the conclusion. The publication bias was determined using funnel plots. The trim and fill method was used if an apparent publication bias was noted. A
p value of < 0.05 indicated statistical significance. All statistical analyses were conducted in R program (version 4.2.3).
Discussion
Our present meta-analysis comprehensively analyzed the long-term survival and perioperative effects of IPM on HCC patients undergoing hepatectomy. The results demonstrated that perioperative outcomes, including operation time, blood transfusion, and postoperative complications, except for volume of blood loss, were comparable between the IPM and NPM groups. Additionally, IPM did not improve or worsen the long-term survival of HCC patients who underwent liver resection as compared to NPM.
Regarding perioperative outcomes, we found no significant differences in the volume of blood loss, blood transfusion, operation time, and postoperative complications between both groups; this finding indicated that both IPM and NPM were safe for liver resection. However, the heterogeneity among the included studies was relatively high. Subgroup analysis showed that the proportion of patients with liver cirrhosis, the proportion of patients with Child A, the proportion of patients receiving major liver resections, and the proportion of patients with multiple tumor resections are the source of heterogeneity. These results suggest that the implementation of IPM should take into account the patient’s liver background, the number of tumors, and the volume of the liver removed. For blood loss, we found that the study by Fumularo et al. [
18] was one source of heterogeneity. The obvious differences between this study and others were that the relatively short time of PM, the lowest proportion of patients with multiple tumors and patients who received major live resection, and the highest proportion of patients with liver cirrhosis in the study by Fumularo et al. After omitting this study, we found that IPM significantly reduced blood loss compared with NPM. These results may indicate that for these hepatectomies that do require a longer hilar occlusion time, IPM can significantly reduce the volume of blood loss. These results for blood transfusion and postoperative complications in our study were similar to another meta-analysis assessing the value of IPM in reducing bleeding during hepatectomy for both HCC and colorectal liver metastasis [
11]. Although several RCTs have studied the effect of IPM on blood loss [
24‐
27], RCTs specifically focused on the effect of IPM on HCC patients are required because these patients often have cirrhosis as a coexisting condition.
IPM could affect the long-term survival of HCC patients in two ways: (1) reduction in intraoperative blood loss and (2) induction of ischemia–reperfusion injury. Increased intraoperative blood loss during HCC resection is an independent prognostic factor for tumor recurrence and death [
6]. The subsequent blood transfusion can promote HCC recurrence and reduce long-term patient survival [
5]. However, our study found that IPM reduces blood loss for these hepatectomies that do require a longer hilar occlusion time, but did not the need for blood transfusion in HCC patients who underwent liver resection. The amount of blood lost between the two groups did not affect survival, possibly due to the large differences in blood loss values among the included studies. Earlier studies have found that blood loss greater than 1000 ml compared to less than 1000 ml may affect long-term survival in patients with HCC after surgery [
6,
28]. However, the average blood loss in most included studies was less than 1000 ml. When blood loss is less than 1000 ml, whether blood loss affects long-term survival is controversial [
17,
18]. The choice of cutoff value is important when assessing whether the amount of blood loss affects prognosis. And this value may be different in different studies, so the conclusions will be controversial. On the other hand, different measurements for the amount of blood loss may influence the conclusion. When bleeding occurs and blood transfusion is unavoidable, an allogeneic blood transfusion may also lead to a worse prognosis [
29]. Studies on liver transplantation have provided conclusive evidence that ischemia–reperfusion injury affects the long-term survival of patients with liver cancer [
30,
31]. Alleviating inflammation caused by ischemia–reperfusion injury can reduce HCC recurrence [
9]. However, the time of ischemia occurrence and its characteristics are not completely similar between patients with liver resection and those who have undergone liver transplantation. IPM, continuous PM, selective hepatic flow occlusion, and hemihepatic blood flow occlusion are selected based on tumor characteristics and the preferences of surgeons. The duration of blood flow disruption also varies, which can lead to different survival outcomes for HCC patients [
32,
33]. Hence, we compared IPM with NPM in our present study; however, we did not find a significant difference in long-term survival between both groups.
Lin et al. conducted a meta-analysis and concluded that IPM increased the risk of early HCC recurrence but did not affect long-term survival [
11]. However, this study had some limitations. Most 1-, 3-, and 5-year OS or DFS rates were extracted from the Kaplan–Meier curve because these data were not reported in the original article; this may have affected the calculated results. Additionally, an inappropriate study was included because the comparison was conducted between NPM and hepatic inflow occlusion (including IPM and selective hemihepatic occlusion) [
22]. Wassmer et al. also conducted a meta-analysis on this topic and concluded that PM negatively affected OS and DFS [
34]. However, they combined the cases of IPM and continuous PM rather than comparing IPM alone with NPM, which could lead to heterogeneity. Compared with these previous meta-analyses, ours is more homogeneous in terms of inclusion criteria.
The present study has several limitations that should be acknowledged. First, only one RCT was included in our study. Second, relatively high heterogeneity was observed among the studies used for the comparison of perioperative outcomes. Third, regarding long-term survival, publication bias was detected despite low heterogeneity among the studies used for comparison. However, sensitivity analysis showed that the results of OS and DFS were stable; moreover, the trim and fill method revealed that the unpublished studies did not affect the results. Fourth, the number of studies included in the meta-analysis was small.
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