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. 2021 Feb 8;11:3279. doi: 10.1038/s41598-021-82291-4

Meta-analysis of the effect of the pringle maneuver on long-term oncological outcomes following liver resection

Elias Khajeh 1, Saeed Shafiei 1, Sadeq Ali-Hasan Al-Saegh 1, Ali Ramouz 1, Ahmed Hammad 1, Omid Ghamarnejad 1, Mohammed Al-Saeedi 1, Nuh Rahbari 3, Christoph Reissfelder 3, Arianeb Mehrabi 1,2,✉, Pascal Probst 1, Hani Oweira 3
PMCID: PMC7870962  PMID: 33558606

Abstract

Hepatic pedicle clamping reduces intraoperative blood loss and the need for transfusion, but its long-term effect on survival and recurrence remains controversial. The aim of this meta-analysis was to evaluate the effect of the Pringle maneuver (PM) on long-term oncological outcomes in patients with primary or metastatic liver malignancies who underwent liver resection. Literature was searched in the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (via PubMed), and Web of Science databases. Survival was measured as the survival rate or as a continuous endpoint. Pooled estimates were represented as odds ratios (ORs) using the Mantel–Haenszel test with a random-effects model. The literature search retrieved 435 studies. One RCT and 18 NRS, including 7480 patients who underwent liver resection with the PM (4309 cases) or without the PM (3171 cases) were included. The PM did not decrease the 1-year overall survival rate (OR 0.86; 95% CI 0.67–1.09; P = 0.22) or the 3- and 5-year overall survival rates. The PM did not decrease the 1-year recurrence-free survival rate (OR 1.06; 95% CI 0.75–1.50; P = 0.75) or the 3- and 5-year recurrence-free survival rates. There is no evidence that the Pringle maneuver has a negative effect on recurrence-free or overall survival rates.

Subject terms: Diseases, Medical research

Introduction

Liver resection remains the only curative treatment for hepatic malignancies, and can improve long-term survival1. Improvements in surgical techniques, better selection of patients, and improved perioperative care have increased the number of hepatectomies performed worldwide each year1,2. There is growing evidence that excessive blood loss during hepatectomy and the subsequent need for blood transfusions may contribute to a poor outcome for non-cirrhotic and cirrhotic liver resections1,2. Perioperative blood transfusion has been associated with recurrence and poorer long-term survival due to an immune response dysfunction3.

Vascular occlusion techniques have been used by some surgeons during hepatic resection to minimize intraoperative blood loss, especially in large tumors or tumors that are adjacent to major vessels4,5. Pringle described a technique whereby transient hepatic inflow was occluded by clamping the portal triad. Portal clamping in the Pringle maneuver (PM) has been modified several times in form of intermittent portal clamping6,7 and selective portal clamping8. These modifications can control intraoperative blood loss and decrease the need for transfusion. Some surgeons believe that this reduction in the rate of blood transfusions can improve long-term oncological outcomes. On the other hand, some argue that the PM may increase the risk of ischemia–reperfusion injury to the liver, which may impair hepatocyte function4,6,7.

The present systematic review and meta-analysis aimed to evaluate the effect of the PM on long-term oncological outcomes in patients with primary or metastatic liver malignancies who underwent liver resection.

Results

Literature search strategy and included studies

The literature search retrieved 435 studies excluding duplicates. Of these, 416 papers were excluded for various reasons, including redundant information and insufficient data on survival. In the end, 19 articles were included in the current meta-analysis (Fig. 1). During the primary evaluation, included articles were subdivided into three groups regarding their suggestions and conclusion on the effect of PM on oncological outcomes of the patients: in favor of the PM, neutral, and not in favor of the PM (Fig. 2).

Figure 1.

Figure 1

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PRISMA flow chart of study selection.

Figure 2.

Figure 2

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Distribution of studies according to oncological outcomes of Pringle maneuver.

Risk of bias assessment for included studies

Of the 19 articles included in this meta-analysis, only one was an RCT. This study included 80 patients (39 cases with PM and 41 cases without PM). The other 18 NRS included 7400 patients (4270 cases with PM and 3130 cases without PM). All studies were published between 2002 and 2020 (Table 1). As shown in Table 2, most studies had moderate bias.

Table 1.

Characteristics of included studies.

Author (year) Country Study type Age Sample size Type of hepatectomy Duration of Pringle (min) Type of Pringle Diagnosis
PM NPM PM NPM PM NPM
Al-Saeedi (2020)9 Germany Retrospective cohort 58.4 60.5 50 159 All patients underwent extended hepatectomy 19 Intermittent HCC and CRLM
Lee (2019)10 China Retrospective cohort 58 60.5 88 88

Minor: 51 (58.0%)

Major: 37 (42.0%)

Minor: 54 (61.4%)

Major: 34 (38.6%)

 Mean (range) 45 (15–87) Intermittent HCC
Famularo (2018)4 Italy Retrospective cohort 65.1 67.6 176 265

Minor: 153 (87.4%)

Major: 22 (12.6%)

Minor: 228 (86.4%)

Major: 36 (13.6%)

 Mean (range) 23 (14–30) Intermittent HCC
Jiang (2017)11 China Retrospective cohort NA NA 132 112 NA NA NA Intermittent HCC
Xu (2017)12 China Retrospective cohort 56.02 56.10 290 296

Minor: 38 (13.10%)

Major: 105 (36.20%)

Minor: 94 (31.75%)

Major: 126 (42.57%)

 163 cases < 15,127 cases 15–30 Continuous HCC
Hao (2017)6 China Retrospective cohort 52.65 55 303 52

Minor: 122 (40%)

Major: 181 (60%)

Minor: 25 (48%)

Major: 27 (52%)

 NA Intermittent HCC
Hao (2016)13 China Retrospective cohort 52.65 55 206 60

Minor: 79 (38.3%)

Major: 127 (61.6%)

Minor: 25 (41.6%)

Major: 35 (58.3%)

 29.6 Intermittent HCC
Tsang (2015)14 Canada Retrospective cohort 63.0 63.0 110 110

Minor: 41 (37.2%)

Major: 69 (63.3%)

Minor: 43 (39%)

Major: 67 (60.9%)

 Mean (range) 20 (15–30) Intermittent CRLM
Huang (2014)15 China Retrospective cohort 56.65 54.2 931 618

Minor: 592 (63.4%)

Major: 416 (44.6%)

Minor: 326 (52.7%)

Major: 289 (46.7%)

 Mean (range) 47.4 (3–208) Intermittent HCC
Weiss (2013)16 USA Retrospective cohort 62.7 64.3 874 54

Minor: 286 (32.7%)

Major: 548 (66.8%)

Minor: 15 (27.7%)

Major: 39 (72.2%)

 Mean (range) 35 (1–181) prolonged PM(> 60 min) and short (< 60 min) CRLM
Xia (2013)17 China Prospective cohort 48 57 224 162

Minor: 131 (58.4%)

Major: 93 (41.5%)

Minor: 85 (52.4%)

Major: 77 (47.5%)

 Mean (range) 50 (30–98) Intermittent HCC
De Carlis (2013)18 Italy Case-matched 61 61 60 60

Minor: 36 (60%)

Major: 24 (40%)

Minor: 34 (56.6%)

Major: 26 (43.3%)

 NA Intermittent CRLM
Ferrero (2010)19 Italy Randomized-controlled 61.3 64.8 39 41

Minor: 19 (48.7%)

Major: 20 (51.2%)

Minor: 22 (53.6%)

Major: 19 (46.3%)

 Mean (SD) 47.8 (17.2) Intermittent CRLM
Nijkamp (2010)20 Netherlands Retrospective cohort NA NA 50 72 All patients underwent partial hepatectomy 21 (2–69) and 40 (20–90) Intermittent, continuous CRLM
Giuliante (2010)21 Italy Retrospective cohort 62 ± 10 188 355

228 cases (42%) underwent major hepatectomy

315 cases ( 58%) underwent minor hepatectomy

 NA Intermittent, continuous CRLM
Wang (2009)22 Taiwan Retrospective cohort NA NA 114 359 NA NA NA Intermittent HCC
Wong (2008)23 UK Retrospective cohort NA NA 289 274

Minor: 19 (48.7%)

Major: 150 (51.9%)

Minor: 22 (53.6%)

Major: 143 (52.18%)

 Mean (range) 22 (2–104) Intermittent CRLM
Tanaka (2008)24 Japan Retrospective cohort NA NA 100 19 NA NA NA Intermittent HCC
Buell (2002)25 USA Retrospective cohort 58 62.3 85 15 NA NA NA Intermittent CRLM
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Table 2.

Assessment of study quality.

ROBINS-I tool
Author (year) Confounding Participant selection Classification of intervention Deviation from intended intervention Missing data Outcome measurement Selection of reported results Overall bias
Al-Saeedi (2020)9 Low Low Low No information Low Low No information Moderate
Lee (2019)10 Low Low Low Low Low Low No information Low
Famularo (2018)4 Low No information Low No information Low Low No information Moderate
Jiang (2017)11 Low Low Low No information Low Low No information Moderate
Xu (2017)12 Low No information Low No information Low Low No information No information
Hao (2017)6 Low Low Low No information Low Low No information Moderate
Hao (2016)13 Low Low Low No information Low Low No information Moderate
Tsang (2015)14 Low Low Low Low Low Low No information Low
Huang (2014)15 Low Low Low No information Low Low No information Moderate
Weiss (2013)16 Low Low Low No information Low Low No information Moderate
Xia (2013)17 Low Low Low No information Low Low No information Moderate
De Carlis (2013)18 Low Low Low No information Low Low No information Moderate
Nijkamp (2010)20 No information Low Low No information Moderate Low No information Moderate
Giuliante (2010)21 low Low Low No information Moderate Low No information Moderate
Wang (2009)22 Low No information Low No information Low Low No information No information
Wong (2008)23 Low No information Low No information Low Low No information No information
Tanaka (2008)24 Low No information Low Low Low Low No information Moderate
Buell (2002)25 Moderate No information Low No information Low Low No information Moderate
Cochrane risk of bias tool for randomized controlled trials
First author Ferrero (2010)22
Bias arising from the randomization process Some concerns
Bias arising from the timing of identification and recruitment of individual participants in relation to timing of randomization Some concerns
Bias due to deviations from intended interventions Some concerns
Bias due to missing outcome data Low risk
Bias in measurement of the outcome Some concerns
Bias in selection of the reported result Some concerns
Overall bias Some concerns
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Recurrence-free survival rate

One-year recurrence-free survival rate

One-year RFS rates were reported for 6758 patients from 17 studies (4223 patients were in the PM group and 2744 patients in the non-PM group). The recurrence of malignant hepatic lesions was reported in 1023 cases (24.2%) in the PM group and in 742 cases (27%) in the non-PM group. Meta-analysis indicated that the PM did not decrease 1-year RFS rate (OR 1.06; 95% CI 0.75–1.50; P = 0.75; Fig. 3A) using a random-effects model. There was considerable heterogeneity among the studies (I2 = 84%; P < 0.00001).

Figure 3.

Figure 3

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(A) Forest plot showing 1-year recurrence of hepatic malignant lesions. (B) Forest plot showing 3-year recurrence of hepatic malignant lesions after hepatectomy. (C) Forest plot showing 5-year recurrence of hepatic malignant lesions after hepatectomy.

Three-year recurrence-free survival rate

Recurrence of malignant lesions during the first 3 years after hepatectomy was reported in 6138 cases from 15 studies. Of these, recurrence was reported in 2037 patients (54.6%) in the PM group and in 1233 patients (51.1%) in the non-PM group. Meta-analysis revealed no significant difference in 3-year RFS rate between the groups (OR 0.99; 95% CI 0.74–1.34; P = 0.97) using the random-effects model (Fig. 3B). The studies that reported 3-year RFS rates were not homogeneous (I2 = 81%; P < 0.00001).

Five-year recurrence-free survival rate

A total of 14 studies with 3781 patients in the PM group and 2591 patients in the non-PM group reported 5-year recurrence. As is seen in Fig. 3C, recurrence was reported in 2521 patients (66.67%) in the PM group and in 1862 patients (71.86%) in the non-PM group. The meta-analysis showed that 5-year RFS rate is not significantly different between the two groups (OR 0.82; 95% CI 0.65–1.04; P = 0.1) using the random-effects model (Fig. 3C). The studies that reported 5-year RFS rates were not homogeneous (I2 = 67%; P = 0.0002).

Overall survival rates

One-year overall survival rate

Fifteen studies including 5569 patients reported the 1-year OS rate. Of these, 2776 patients (87.15%) were in the PM group and 2092 patients (87.7%) were in the non-PM group. According to our analysis using the random-effects model, the 1-year OS rate was not significantly different between the PM and non-PM group (OR 0.86; 95% CI 0.67–1.09; P = 0.22) (Fig. 4A). The I2 was 31% with a P value of 0.12.

Figure 4.

Figure 4

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(A) Forest plot showing 1-year survival of patients with hepatic malignant lesions. (B) Forest plot showing 3-year survival of patients with hepatic malignant lesions. (C) Forest plot showing 5-year survival of patients with hepatic malignant lesions.

Three- and five-year overall survival rates

The 3-year OS rate was 64% in the PM group and 63.6% in the non-PM group. The 5-year OS rate was 46.11% in the PM group and 42.9% in the non-PM group (Fig. 4B,C). Meta-analysis indicated that the 3- and 5-year OS rates were not significantly different between the PM and non-PM groups.

Subgroup analysis

The type of malignant tumor (i.e., primary or metastatic) had no significant effect on the 1-year RFS rate in the PM and non-PM groups (primary tumors: OR 1.16; 95% CI 0.86–1.56; P = 0.34; metastatic tumors: OR 0.82; 95% CI 0.43–1.56; P = 0.56), nor did it have an effect on the 3-year RFS rate (primary tumors: OR 0.96; 95% CI 0.68–1.37; P = 0.84; metastatic tumors: OR 1.10; 95% CI 0.60–2.02; P = 0.77) or the 5-year RFS rate (primary tumors: OR 0.84; 95% CI 0.63–1.12; P = 0.24; metastatic tumors: OR 0.77; 95% CI 0.47–1.24; P = 0.28).

The type of malignant tumor had no significant effect on the 1-year OS rate in the PM and non-PM groups (primary tumors: OR 0.87; 95% CI 0.67–1.14; P = 0.31; metastatic tumors: OR 0.74; 95% CI 0.49–1.12; P = 0.15), nor did it have an effect on the 3-year OS rate (primary tumors: OR 1.04; 95% CI 0.85–1.29; P = 0.69; metastatic tumors: OR 1.12; 95% CI 0.72–1.76; P = 0.61) or 5-year OS rate (primary tumors: OR 1.10; 95% CI 0.88–1.38; P = 0.39; metastatic tumors: OR 0.89; 95% CI 0.62–1.28; P = 0.53) (Supplemental Figs. 1 and 2).

Discussion

Intraoperative bleeding is one of the most common and life-threatening complications during liver surgery, and has been associated with increased long-term morbidity and mortality26. In addition, intraoperative hemorrhage increases the rate of blood transfusions, which have a negative impact on long-term postoperative outcomes by reducing the patient’s immune defense26,27. Excessive bleeding and blood transfusion also reduce patient survival26,27. Excessive intraoperative bleeding and vascular occlusion are both associated with an increased risk of postoperative surgical complications and unfavorable clinical outcomes. Therefore, the optimal approach to liver resection is to perform surgery without hepatic vascular occlusion while minimizing blood loss and the need for blood transfusion.

Despite several strategies to reduce intraoperative bleeding, the PM remains the most commonly used technique because it was shown to reduce blood loss with high efficacy in initial randomized trials10,26. However, some studies have not confirmed these initial findings and have even suggested a higher risk of ischemia–reperfusion injury for healthy liver tissue28,29. Furthermore, an increased rate of postoperative complications has been shown in patients who undergo PM during hepatectomies in some studies30. To prevent liver injuries, portal pedicle clamping was modified in the PM to an intermittent approach31. Despite this modification, the overall efficacy of the PM remains controversial32,33. Whether the PM promotes liver injury remains a topic of debate. Furthermore, how the PM affects recurrence and survival in patients with malignant lesions who underwent hepatectomy is not well understood. Although some studies have suggested that prolonged PM increases recurrence1,20, others have demonstrated no effect15,19,34. For instance, Al-Saeedi et al. revealed that a PM of less than 20 min did not increase the recurrence rate after 3 years9. Recent studies showed that the PM has no significant positive impacts on clinical outcomes after minor liver surgeries13,32. However, major liver resections, which have more intraoperative blood loss, probably benefit more from the PM. To address this controversy, we performed a meta-analysis to compare the long-term oncological outcomes of hepatectomy with and without a PM.

The PM, regardless of whether it is complete or intermittent, was shown to be an independent risk factor for cancer recurrence in one study13. However, other studies have reported no negative impact of the PM on patient survival and disease recurrence17,18. In a recent randomized-controlled trial, the intermittent PM did not affect disease-free survival after hepatectomy, but did improve the OS rate10. The positive effect of the intermittent PM was particularly promising in patients with hepatic disorders such as cirrhosis10. In the present analysis, we observed no significant differences in 1-, 3-, and 5-year overall and recurrence-free survival between the PM and non-PM groups. Furthermore, subgroup analysis revealed no significant effects of tumor type (i.e., primary or metastatic) on 1-, 3-, and 5-year survival between the PM and non-PM groups. This is in accordance with previous findings from large patient cohorts and clinical trials.

The PM was shown to be a risk factor for disease recurrence in several studies. It has been hypothesized that ischemia during portal pedicle clamping causes microvascular damage by breaking adhesions between tumor cells and endothelial cells35. The hepatic ischemia-perfusion cycle might increase the expression of E-selectin, which plays a crucial role in cancer cell metastasis36,37. However, we found no significant increase in disease recurrence following hepaectomy with the PM, indicating that the PM is not associated with disease recurrence after hepatectomy.

During reperfusion, liver parenchymal cells are thought to be injured by cytokines and radical oxygen species, which are produced by active Kupffer cells38. However, a meta-analysis reported no significant patient benefits of hemihepatic vascular occlusion over complete hepatic vascular occlusion, despite a lower rate of liver injury39. This suggests that significant hepatic injury is not caused by the PM, and that the potential benefits outweigh the potential disadvantages. In addition, of enrolled studies in this meta-analysis, four studies (2335 cases) reported the number of patients with steatosis, and no significant difference was observed in means of fatty liver distribution among patients with and without PM a. However, included studies failed to provide more detailed data on clinical or oncological impacts of liver texture characteristics (e.g. macrovesicular or microvesicular liver steatosis, or liver fibrosis) on outcomes of the pringle maneuver, which prohibited us from carrying out subgroup analyses.

A study by Fagenson et al. reported that patients undergoing minor liver resection and cases with metastatic disease had a worse outcome when PM was performed40. This finding is in similar line with our previously published report. Our results showed that PM is useful in patients who underwent extended liver resection, but this surgical maneuver may not be beneficial in minor hepatectomies9. It can be derived that PM is associated with encouraging early perioperative outcomes without worsening the long-term survival among well-selected patients. On this basis, it cannot be denied that the selection of patients undergoing PM plays a principal role in increasing of safety and efficacy of PM.

There are some limitations to the present study. The main weakness is the variability in PM techniques, underlying liver disease, tumor stage status, and preoperative liver function between the included studies. Due to lack of subgroup results regarding the underlying liver disease, especially liver cirrhosis, it was not possible to assess the impact of PM in cirrhotic patients. In addition, although several studies have compared the PM with non-PM techniques, the number of RCTs is low, and most studies have a retrospective design, which can have a selection bias because PM enable surgeons to perform more aggressive hepatectomy in patients with more advance tumors with worse prognosis. We have added to study from the same center in our meta-analysis6,13; the first study was performed between January 2007 and December 201013 and the second study was performed between January 2010 and December 20126. These two studies may include overlapping patients in 2010 which can create some bias in present meta-analysis.

In conclusion, the present study shows that the PM is a suitable surgical technique for managing intraoperative bleeding during liver resection, and does not increase tumor recurrence and long-term mortality. We believe that the PM is a useful and acceptable aopproach to major or extended liver resection. However, further studies in large patient cohorts and randomized trials are needed to comprehensively evaluate the advantages and disadvantages of this procedure.

Methods

This systematic review and meta-analysis was reported according the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines41.

Eligibility criteria

The research question was formulated according to the PICOS strategy.

  • Population: all adult patients who underwent liver resection

  • Intervention: PM during liver resection

  • Comparators: no PM

  • Outcome: overall or recurrence-free survival rates

  • Study design: all study types methodological designs, including human subjects, except case series with less than ten patients, narrative or systematic reviews, letters, conference abstracts, and study protocols.

Duplicate publications or overlapping cohorts were excluded.

Search strategy

According to Goossen et al.42 the following databases were searched.

  1. Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Medline (via PubMed)

  3. Web of Science

Databases were last searched for relevant publications in May 2020. The references of each included study were also searched for additional relevant articles. The combination of search terms is presented in Supplemental Text 1.

Study selection

Two investigators (SS and AH) independently screened all papers identified by the search strategy and selected eligible studies based on the PICOS criteria. Two authors (SAHS and AR) then reviewed and evaluated the full-text of eligible articles and extracted the data. Discrepancies were settled by a discussion with a third author (EK).

Outcomes and data items

Recurrence-free survival rate

The recurrence-free survival (RFS) rate was defined as the number of the patients who survived without signs of recurrence after primary liver resection. We measured the RFS after 1, 3, and 5 years.

Overall survival rate

The overall survival (OS) rate was defined as the number of patients who survived after liver resection, regardless of disease recurrence. We measured the OS at 1, 3, and 5 years.

Quality assessment

The Cochrane risk-of-bias tool was used to assess the quality of randomized-controlled trials (RCT) and the ROBINS-I tool was used to assess the quality of non-randomized studies (NRS)43,44. The Cochrane risk-of-bias tool evaluated several items, including bias arising from the randomization process, bias arising from the timing of identification and recruitment of individual participants in relation to the timing of randomization, bias due to deviations from intended interventions, bias due to missing outcome data, and bias in the selection of the reported result. The overall risk of bias was low if the study was judged to be at low risk of bias for all domains. There were some concerns of bias if some concern of bias was detected in at least one domain. The risk of bias was high if the study was judged to be at high risk of bias in at least one domain or if some concerns of bias were detected in multiple domains.

Statistical analysis

Statistical analyses were performed by RevMan version 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Pooled results were analyzed using the Mantel–Haenszel method. Results were presented as odds ratios (OR) or as survival rates with 95% confidence intervals (CI). Because of clinical heterogeneity between studies, a random‐effects model was used. A P value < 0.05 for the Q-test or a I2 index more than 75% indicated statistical heterogeneity among studies. An I2 index between 50 and 75% indicated moderate statistical heterogeneity.

Supplementary Information

Supplementary Information 1. (15KB, docx)
Supplementary Information 2. (1.2MB, tiff)
Supplementary Information 3. (1.2MB, tiff)
Supplementary Information 4. (728.4KB, tiff)
Supplementary Information 5. (1.7MB, tiff)
Supplementary Information 6. (1.2MB, tiff)
Supplementary Information 7. (1.1MB, tiff)

Author contributions

E.K., S.S., S.A.H.A.S., A.R., A.H., O.G. designed the study, collected and analyzed data, and wrote the manuscript. M.A., N.R., and C.R. contributed knowledge and revised the manuscript. H.O., P.P. and A.M. co-designed the study and revised the manuscript. All authors read and approved the final version of the manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-021-82291-4.

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