Rethinking the classical hepatic inflow occlusion time in hepatectomy for hepatocellular carcinoma under new circumstances
Substantial intraoperative blood loss or massive transfusion during hepatectomy is an established independent risk factor for tumor recurrence and mortality in hepatocellular carcinoma (HCC) patients. Among various hepatic inflow occlusion techniques, the intermittent Pringle maneuver (IPM) remains the most convenient and widely accepted method for reducing intraoperative hemorrhage during liver resection. The classical IPM protocol of 15-minute clamping followed by 5-minute reperfusion cycles, first proposed over three decades ago (1), continues to be widely adopted. Recently, increased use of systemic therapies for HCC has led to a higher proportion of radical resections following conversion therapy for advanced HCC cases (including huge tumors and multinodular presentations), consequently increasing demand for major hepatectomies. Moreover, the advancement of minimally invasive liver surgery has heightened requirements for bleeding control during laparoscopic liver resection, as intraoperative hemorrhage not only directly impairs parenchymal transection efficiency and surgical field visibility but is also the primary reason for conversion to open surgery. These evolving paradigms in HCC management compel surgeons to explore prolonged clamping durations to reduce intraoperative bleeding and improve parenchymal transection efficiency, while raising concerns about the potential exacerbation of ischemia-reperfusion injury in the remnant liver. Achieving the optimal balance between these competing priorities to maximize the benefits of IPM is an issue worth exploring. This article presents viewpoints and preliminary data based on our team’s prior clinical research in this area.
Reasonably prolonging hepatic inflow occlusion time is safe and efficient in hepatectomy for HCC patients
Three randomized controlled trials (RCTs) have compared the effects of 15 vs. 30-min IPM on perioperative outcomes following hepatectomy (2-4). In the two studies by van den Broek et al. (2) and Esaki et al. (3), in 2011 and 2006, respectively, reported that similar hepatocellular injury was observed between the 30 and 15-min IPM group, but neither study included the HCC patients. Although the study by Kim et al. (4) included HCC patients, the combined utilization of gabexate mesylate, a protease inhibitor with protective effects against ischemic injury, may confound the results. On the other hand, most enrolled patients with metastatic liver cancer or benign tumors in those RCTs had a relatively healthy liver background with abundant functional hepatocytes. Theoretically, those patients can better tolerate longer periods of hepatic ischemia/reperfusion (I/R) injury. In contrast, for HCC patients, especially in China, over 80% have underlying liver diseases such as hepatitis B virus-related fibrosis or cirrhosis, which result in a reduced absolute number of normal hepatocytes and compromised liver function. Theoretically, those HCC patients should tolerate I/R for a shorter duration than 30 minutes. Thus, the feasibility and safety of a longer ischemic interval during IPM in HCC patients remain unclear. Our clinical experience suggests that in specific scenarios (e.g., intraoperative tumor rupture, severe cirrhosis), 25-min IPM did not exacerbate postoperative hepatic injury, provided they have Child-Pugh class A liver function preoperatively. To obtain high-level evidence, we chose the 25-min IPM as the experimental group in our following RCTs (5,6). The detailed data of the above RCTs are summarized in Table 1.
Table 1
| Author [year] | Patient number | Patient age, years | Inclusion/exclusion criteria | IPM durations, min | Estimated blood loss, mL | AST changes | ALT changes | Postoperative liver failure, (%) |
|---|---|---|---|---|---|---|---|---|
| van den Broek, et al. [2011] (2) | 30 (10/group) | 62 in 30-min IPM; 64 in 15-min IPM; 60 in no IPM; P=0.63 | Exclusion criteria: presence of liver cirrhosis confirmed by biopsy; concomitant extra-hepatic procedures or bilioenteric anastomosis; steroid hormone medication; renal dysfunction; laparoscopic liver resection | 30 vs. 15 vs. 0 | 450 in 30-min IPM; 575 in 15-min IPM; 500 in no IPM; P=0.92 | Mean AUC (U/L × d): 3,800±799 in 30-min IPM; 3,147±713 in 15-min IPM; 2,129±276 in no IPM; P=0.55 | Mean AUC (U/L × d): 3,609±812 in 30-min IPM; 3,196±797 in 15-min IPM; 2,075±332 in no IPM; P=0.72 | 10 in 30-min IPM; 20 in 15-min IPM; 10 in no IPM; P>0.99 |
| Esaki, et al. [2006] (3) | 92 (48 vs. 44) | 63 in 30-min IPM; 61 in 15-min IPM; P=0.06 | Inclusion criteria: elective hepatectomy; age less than 75 years; adequate cardiopulmonary and renal function. Exclusion criteria: HCC patients | 30 vs. 15 | 352 in 30-min IPM; 391 in 15-min IPM; P=0.06 | Peak value (U/L): 235 in 30-min IPM; 274 in 15-min IPM; P=0.56 | Peak value (U/L): 255 in 30-min IPM; 224 in 15-min IPM; P=0.67 | – |
| Kim, et al. [2007] (4) | 120 (60/group) | 59 in 30-min IPM; 55 in 15-min IPM | Inclusion criteria: non-complicated resection; no evidence of significant visceral congestion caused by IPM; no extrahepatic disease at the time of laparotomy | 30 vs. 15 | 430 in 30-min IPM; 663 in 15-min IPM; P=0.02 | Peak value (U/L): 382 in 30-min IPM; 344 in 15-min IPM; P>0.05 | Peak value (U/L): 279 in 30-min IPM; 226 in 15-min IPM; P>0.05 | 1.7 in 30-min IPM; 1.7 in 15-min IPM; P>0.99 |
| Huang, et al. [2022] (5) | 344 (172/group) | 54 in 25-min IPM; 54.8 in 15-min IPM; P=0.49 | Exclusion criteria: presence of portal vein thrombosis or tumor thrombus; presence of hepatic artery thrombosis; previous portal vein embolization or transarterial chemoembolization; concomitant local ablation, extrahepatic procedures or bilioenteric anastomosis | 25 vs. 15 | 230 in 25-min IPM; 270 in 15-min IPM; P=0.009 | Median AUC (U/L × d): 654 in 25-min IPM; 645 in 15-min IPM; P=0.26 | Median AUC (U/L × d): 943 in 25-min IPM; 914 in 15-min IPM; P=0.10 | 1.2 in 25-min IPM; 0.6 in 15-min IPM; P>0.99 |
| Huang, et al. [2023] (6) | 270 (135/group) | 54 in dexamethasone group; 56 in control group; P=0.78 | Exclusion criteria: aged <18 or >80 years; diseases receiving preceding systemic therapy with glucocorticoids; anesthesiologist judge that the subjects cannot use the dexamethasone; intraoperative findings of extrahepatic disease; intraoperative findings of additional intrahepatic lesions, need to combine with other procedures, such as ablation or bilioenteric anastomosis | 25 | 249 in dexamethasone group; 215 in control group; P=0.29 | Median AUC (U/L × d): 710 in dexamethasone group; 804 in control group; P=0.009 | Median AUC (U/L × d): 1,104 in dexamethasone group; 1,128 in control group; P=0.04 | 1.5 in dexamethasone group; 4.4 in control group; P=0.28 |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; HCC, hepatocellular carcinoma; IPM, intermittent Pringle maneuver; RCT, randomized controlled trial.
In 2022, our team published the first RCT (5) comparing the short-term outcomes between HCC patients undergoing 25- and 15-min IPM during hepatectomy (ChiCTR1900027417). This study demonstrated that 25-min IPM was safe, significantly improved the hepatic transection efficiency, and reduced intraoperative blood loss. Preoperative glucocorticoid administration prior to the Pringle maneuver is a well-established strategy to mitigate postoperative inflammatory responses. Multiple studies have confirmed its efficacy in promoting postoperative liver function recovery; however, these findings are primarily based on the conventional 15-min IPM. Whether glucocorticoids confer comparable protective effects during HCC resection with prolonged IPM durations remains unclear. To address this clinical question, we designed and published another RCT (6) in 2023, confirming that low-dose corticosteroids could enhance postoperative liver function recovery in HCC patients undergoing 25-min IPM (ChiCTR220006638). None of the adverse effects associated with corticosteroid use, such as stress ulcers, intra-abdominal or wound infections, or delayed wound healing, were observed in our study. Our 25-min IPM protocol is now adopted in several medical centers across China. While surgeons traditionally believe HCC patients with underlying liver disease (e.g., fibrosis, particularly cirrhosis) cannot tolerate prolonged hepatic inflow occlusion, our first RCT’s stratified analysis revealed that even in cirrhotic HCC patients diagnosed by histological Ishak’s classification, as long as they meet Child-Pugh class A liver function and adequate future liver remnant volume (for HCC patients without cirrhosis, we considered 40% remnant liver volume after liver resection to be adequate; however, for cases with intermediate or advanced cirrhosis, the remnant volume should be more than 50%), the 25-min IPM appears safe and efficient in selected patients based on our findings (5). We speculate that the opening of collateral circulation secondary to portal hypertension in cirrhosis may partly alleviate the effects of IPM on liver function and intestinal congestion (Figure 1A). Histopathological analysis from the remnant liver showed that HCC patients with cirrhosis had lower hepatocyte apoptosis rates after 25-min IPM compared to benign tumor patients with a normal liver background (Figure 1B-1F). In other words, the HCC patients with cirrhosis appear to better tolerate the sudden hepatic inflow occlusion caused by IPM. However, this is still a hypothesis at present; it is also necessary to verify the guiding role of its mechanism in clinical practice through clinical multi-center or even international research designs. In addition, our two RCTs only provide valuable preliminary data; broader validation across independent institutions is lacking. In the future, we need to design prospective multi-center trials to further verify their clinical application value.
Effect of prolonged hepatic inflow occlusion on postoperative HCC recurrence
Animal studies indicated that the IPM may promote HCC recurrence after liver resection, potentially via IPM-induced intestinal congestion driving bacterial translocation through the gut-liver axis, enhancing toll-like receptor 4 signaling in the liver and facilitating HCC recurrence (7). Clinically, however, avoiding IPM during major hepatectomy (open or laparoscopic) is often impractical, especially in patients with underlying liver disease (e.g., cirrhosis, fatty liver) or previous conversion therapy for intermediate/advanced HCC. Moreover, animal models cannot fully replicate the complex pathophysiological alterations observed in humans. As shown in Figure 1G,1H, intraoperative photographs from one HCC patient who underwent liver transplantation revealed no significant change in gastrointestinal surface congestion during the anhepatic phase and after portal vein reperfusion, indicating that clinically relevant bacterial translocation from intestinal congestion may be minimal and unlikely to promote recurrence via the gut-liver axis as in animal models. However, this hypothesis is derived solely from observational intraoperative photographs of a single patient. Currently, it is not possible to draw broad conclusions based on these findings; validation through further research is required.
In our initial RCT cohort (5), 134 patients (in 15-min IPM group) and 128 patients (in 25-min IPM group) with solitary HCC were included in long-term follow-up analysis (Figure S1). As shown in Table 2, no significant differences were observed between the two groups regarding patients’ demographics, intraoperative and pathological data, or postoperative follow-up data. During a median follow-up period of 45.6 months (range 6.2–61 months), the 1-, 3- and 5-year overall survival (OS) rates were comparable between two groups (89.6%, 72.4%, 58.0% in the 15-min IPM group vs. 92.2%, 68.8%, 56.3% in the 25-min IPM group, respectively, P=0.85, Figure 1I). Similarly, no significant difference was found in the 1-, 3- and 5-year recurrence-free survival (RFS) rates (76.9%, 51.5%, 41.8% in the 15-min IPM group vs. 72.7%, 49.2%, 44.5% in the 25-min IPM group, respectively, P=0.86, Figure 1J). Currently, no high-level evidence directly links IPM use in HCC hepatectomy to increased tumor recurrence risk. In view of this, well-designed RCTs are needed to further clarify the oncological safety of IPM, particularly for prolonged IPM in liver resection for HCC. To address this, we designed a single-center, parallel, double-blind RCT (ChiCTR2400083647) to compare the effects of the 25-min IPM vs. 15-min IPM on tumor recurrence in HCC patients undergoing liver resection and recently published its study protocol.
Table 2
| Items | 15-min IPM group (n=134) | 25-min IPM group (n=128) | P |
|---|---|---|---|
| Age, years | 55.1±11.1 [30–80] | 53.4±11.4 [25–79] | 0.23 |
| Male | 116 [86.6] | 110 [85.9] | 0.88 |
| HBsAg positivity | 114 [85.1] | 101 [78.9] | 0.19 |
| AFP ≥400 ng/mL | 31 [23.1] | 37 [28.9] | 0.29 |
| Largest tumor size, cm | 3.5 [2.5–6.3] | 4.1 [2.6–6.2] | 0.34 |
| Resected margin positivity | 0 [0] | 1 [0.8] | 0.98 |
| No. of the cycle of IPM | 3 [2–6] | 2 [1–6] | <0.001 |
| Blood loss during transection, mL | 153 [10–1,050] | 101 [50–803] | <0.001 |
| Number of blood transfusion | 6 [4.5] | 5 [3.9] | 0.82 |
| Open/laparoscopic hepatectomy, n/n | 93/41 | 82/46 | 0.36 |
| Microvascular invasion | 58 [43.3] | 59 [46.1] | 0.65 |
| Tumor grade | 0.81 | ||
| G1 | 3 [2.2] | 3 [2.3] | |
| G2 | 95 [70.9] | 86 [67.2] | |
| G3–G4 | 36 [26.9] | 39 [30.5] | |
| 90-day mortality | 0 [0] | 0 [0] | >0.99 |
Data are presented as mean ± SD [range], or n [%], or median [range] unless otherwise indicated. AFP, alpha-fetoprotein; G, grade; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; IPM, intermittent Pringle maneuver; SD, standard deviation.
Acknowledgments
The authors would like to thank Dr. Min Jiang for her contribution to statistical analysis.
Footnote
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References
- Huguet C, Gavelli A, Chieco PA, et al. Liver ischemia for hepatic resection: where is the limit? Surgery 1992;111:251-9.
- van den Broek MA, Bloemen JG, Dello SA, et al. Randomized controlled trial analyzing the effect of 15 or 30 min intermittent Pringle maneuver on hepatocellular damage during liver surgery. J Hepatol 2011;55:337-45. [Crossref] [PubMed]
- Esaki M, Sano T, Shimada K, et al. Randomized clinical trial of hepatectomy using intermittent pedicle occlusion with ischaemic intervals of 15 versus 30 minutes. Br J Surg 2006;93:944-51. [Crossref] [PubMed]
- Kim YI, Fujita S, Hwang YJ, et al. Successful intermittent application of the Pringle maneuver for 30 minutes during human hepatectomy: a clinical randomized study with use of a protease inhibitor. Hepatogastroenterology 2007;54:2055-60.
- Huang Y, Liao A, Pu X, et al. A randomized controlled trial of effect of 15- or 25-minute intermittent Pringle maneuver on hepatectomy for hepatocellular carcinoma. Surgery 2022;171:1596-1604.
- Huang Y, Xu L, Wang N, et al. Preoperative dexamethasone administration in hepatectomy of 25-min intermittent Pringle’s maneuver for hepatocellular carcinoma: a randomized controlled trial. Int J Surg 2023;109:3354-64. [Crossref] [PubMed]
- Orci LA, Lacotte S, Delaune V, et al. Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver. J Hepatol 2018;68:978-85. [Crossref] [PubMed]
