Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide [1]. Liver resection has been used as a curative treatment for patients with HCC, and recent developments in surgical techniques and perioperative care have dramatically improved postoperative outcomes. However, postoperative morbidity rate remains high, ranging from 38.4 to 45% [2,3,4,5].

Ascites is one of the most common postoperative complications among patients who have undergone liver resection. When large amounts of plasma are continuously lost in ascitic fluid, resulting in an imbalance of water and electrolytes, postoperative ascites may progress to cause liver failure [6]. Several reports have indicated that increased portal pressure after liver resection might also predispose to postoperative ascites, and refractory ascites might increase the risk of mortality [7, 8]. In addition, patients with refractory ascites after liver resection require longer hospital stays, resulting in higher treatment costs.

To date, few reports have focused on the short-term outcomes in patients with ascites after liver resection. Previous studies [9,10,11] have reported that postoperative ascites might be associated with decreased liver function. In this setting, it is likely that patients with decreased liver function might associate with postoperative complications other than ascites. However, no study has focused on the relationship between postoperative ascites and other complications. Therefore, this study aimed to identify the risk factors for ascites after liver resection and the relationship between postoperative ascites and other complications.

Materials and methods

Patients

A prospective database of patients treated at the Nara Medical University, Nara, Japan was retrospectively reviewed. We included patients who underwent hepatic resection for HCC between 2008 and 2015. We defined postoperative ascites as a daily ascitic fluid drainage exceeding 500 mL on postoperative day 3 or later. The patients were divided into a group with ascites (Group A, n = 17) and that without ascites (Group NA, n = 249).

Preoperative investigations included complete blood count, liver function tests (including measurement of the indocyanine green retention rate at 15 min), and routine cardiorespiratory evaluation. Patients were screened for hepatitis virus infection by measurement of hepatitis B virus surface antigen and anti-hepatitis C virus antibody. Computed tomography and magnetic resonance imaging were performed to assess the liver and tumor characteristics. Informed consent was obtained before surgery.

Operative procedures

All resections were performed with curative intent. Major liver resection was defined as resection of three or more Couinaud segments. Anatomic resection was classified as hemihepatectomy, extended hemihepatectomy, sectionectomy (resection of two Couinaud subsegments), or segmentectomy (resection of one Couinaud subsegment). The surgical approach was by laparotomy with a J-shaped right subcostal incision, and an ultrasound was always performed to confirm resectability. For all procedures, liver transection was performed with a crush-clamp under intermittent inflow occlusion by clamping of the hepatoduodenal ligament or hemihepatic inflow occlusion. Drains were inserted at the transected liver surface and were removed when the following criteria were met: (1) There was no visible bile staining in the effluent; (2) the fluid bilirubin level was <85.5 μmol/L; and (3) bacteriological culture was negative.

Postoperative care

We managed to prevent ascites after liver resection using an intravenous injection of potassium canrenoate and a transfusion of albumin to replace the plasma lost in the ascitic fluid. Potassium canrenoate is the first line drug used in the diuretic therapy of ascites after HCC resection because secondary hyperaldosteronism is the major factor that promotes renal sodium and water retention in patients with liver disease [12,13,14]. Furosemide was administered if water retention was observed or if potassium canrenoate alone was ineffective in controlling ascites.

Follow-up

Every 4 months we performed blood examination, including a serum alpha-fetoprotein (AFP) assay, and enhanced computed tomography. Postoperative antiviral treatment was usually administered.

Statistical analysis

Baseline patient characteristics, surgery-related factors, and short-term results are expressed as median (range) for continuous data or as numbers (percentages) for categorical data. The Mann–Whitney U test was used to compare continuous data, whereas the χ 2 test and t test were used for categorical data. A multivariate analysis was performed to identify risk factors for postoperative ascites. We included the following seven potentially important preoperative and intraoperative factors in the analysis. The results were expressed as adjusted odds ratios with 95% confidence intervals, and P values were calculated using the likelihood ratio test. All statistical analyses were performed using SPSS® for Windows® version 18.0 (IBM, Armonk, New York, USA), and statistical significance was accepted at the 0.05 level.

Results

Preoperative characteristics

Preoperative characteristics are detailed in Table 1. The median age was 71 years in entire cohort, and 79.7% were males. There were several noteworthy differences between the groups. More patients in Group A were positive for hepatitis C virus antibody than were those in Group NA (70.6 vs. 35.7%, P = 0.004). The preoperative platelet count and serum albumin level were also notably lower in Group A than in Group NA (P = 0.006 for both), but the indocyanine green retention rate at 15 min was higher in Group A than in Group NA (P < 0.001). Finally, those in Group A had more tumors than those in Group NA (P = 0.001).

Table 1 Patient background characteristics
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Surgery-related factors

The characteristics of surgery are detailed in Table 2. Though the types of resection were similar in the two groups, the average operation duration was longer in Group A than in Group NA (P = 0.002). In addition, blood loss was greater in Group A than in Group NA (P = 0.019).

Table 2 Surgery-related factors
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Multivariate analysis of factors associated with postoperative ascites

Multivariable analysis revealed that serum albumin <4.0 g/dL [odds ratio (OR), 9.879; 95% confidence interval (CI), 1.847–52.838; P = 0.007], platelet count <100 × 103/μL (OR 4.706; 95% CI 1.141–19.412; P = 0.032), and operation duration >250 min (OR 13.023; 95% CI 1.407–120.577; P = 0.024) were independent risk factors for postoperative ascites (Table 3).

Table 3 Multivariate analysis of factors associated with postoperative ascites
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Comparison of postoperative outcomes in patients with and without ascites

The relationship between postoperative ascites and other complications is detailed in Table 4. Sixteen (94.1%) of the 17 patients with postoperative ascites experienced other associated complications. Group A had more pleural effusion (70.6 vs. 17.7%, P < 0.001) than group NA. Postoperative morbidity, except for pleural effusion, was similar in the two groups. The postoperative hospital stay duration was significantly longer in group A than in group NA (P = 0.003).

Table 4 Postoperative clinical course in patients with and without postoperative ascites
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Discussion

Ascites is one of the most common postoperative complications in patients who undergo liver resection. In this study, postoperative ascites developed in 17 of 266 patients (6.4%) after liver resection, and multivariate analysis indicated that serum albumin, platelet count, and the operation duration were independent risk factors for this outcome. Moreover, the presence of ascites was significantly associated with postoperative pleural effusion.

When large amounts of plasma are continuously lost, postoperative ascites can lead to liver failure. However, the mechanism underlying the development of ascites after liver resection remains unclear. Previous studies have indicated that in patients with cirrhosis, portal hypertension can trigger massive ascites by stimulating neurohormonal systems to promote renal water and sodium resorption [12, 13]. Similarly, the high portal pressure that may result after liver resection can cause insufficient urinary output in the early postoperative period, and a subsequent increase in the volume of ascites. Several authors [9,10,11] have also indicated that risk factors for ascites after liver resection include cirrhosis, low serum albumin level, low platelet count, high indocyanine green level, blood loss, and the need for a transfusion of red blood cells. Consistent with the reports, our results showed that factors associated with liver functional reserve, such as the serum albumin level and platelet count, were independent preoperative risk factors for postoperative ascites. However, we additionally showed that operation duration was an independent surgical risk factor (Table 3).

Liver resection for patients with liver dysfunction before surgery might further damage liver function and lead to the development of ascites postoperatively. However, liver resection is a potentially curative treatment even for patients with liver dysfunction. In this study, no postoperative mortality was observed among patients with postoperative ascites. Therefore, we believe that HCC patients with risk factors for postoperative ascites are candidates for surgical treatments but require more strict postoperative management. A therapeutic option that may facilitate this is laparoscopic liver resection, which is a minimally invasive surgical procedure that can reduce the risk of complications and promote smooth recovery, but without a high risk of liver failure. This technique can significantly affect patients with severe chronic liver disease [15], with previous studies showing a significantly reduced incidence of ascites after laparoscopic liver resection in patients undergoing this type of surgery [16,17,18]. In this study, our results demonstrated that the proportion of laparoscopic surgery was not significantly different between the two groups. However, we believe that if the number of patients undergoing laparoscopic liver resection increases in the future, laparoscopic liver resection may significantly reduce the risk of postoperative ascites.

Sparing residual liver function was, unsurprisingly, a key prognostic factor for good overall survival in patients with postoperative ascites. Li et al. [19] also reported that there was a significantly greater improvement in the residual liver volume per unit surface area at 6 months among patients receiving antiviral therapy after liver resection. In a meta-analysis by Wong et al. [20], antiviral therapy was also shown to improve the liver failure-related mortality and the overall mortality significantly. These reports indicate that antiviral therapy may be used to improve liver function after liver resection.

Some authors have reported the clinical efficacy of supplementation with branched-chain amino acids (BCAAs) in patients with liver cirrhosis who underwent liver resection for HCC. Okabayashi et al. [21] examined the overall incidence of postoperative complications, including ascites, and reported lower rates among patients who received perioperative supplementation with BCAAs than in a control group who did not. Muto et al. [22] also reported that oral supplementation with a BCAA for a long period could improve the rates of event-free survival without liver failure among patients with decompensated cirrhosis.

To date, no study has focused on the relationship between postoperative ascites and pleural effusion. Pleural effusion generally results from diaphragmatic injury, obstruction of thoracic venous or lymphatic systems, or surgical manipulation of the hepatic coronary ligament [23]. On the other hand, Tamano et al. [24] demonstrated the presence of peritoneal-pleural communications in liver cirrhosis patients using real-time contrast-enhanced ultrasonography with Sonazoid. Moreover, the velocity of ascitic fluid movement into the pleural cavity is reportedly proportional to the pressure difference between the pleural and peritoneal cavities [25]. In this setting, our results have indicated the association between postoperative ascites and pleural effusion. The postoperative hospital stay duration was significantly longer in patients with ascites than in those without ascites.

It is important to note that there were some limitations to the present study. The main limitation was the small sample size and retrospective non-matched design, making the results susceptible to bias in data selection and analysis. Moreover, some variables were different between patients with and without postoperative ascites, such as the diuretic dose and amount of fluid therapy. Thus, a well-designed prospective study with a larger population is needed to evaluate the predictors of postoperative ascites.

In conclusion, postoperative ascites was more frequent among patients with poor liver functional reserve. Notably, postoperative ascites is significantly associated pleural effusion. The appearance of both pleural effusion and ascites might make postoperative management difficult and significantly prolong postoperative hospital stay duration.