Chronological Course and Clinical Features after Denver Peritoneovenous Shunt Placement in Decompensated Liver Cirrhosis

Round 1

Reviewer 1 Report

This is an original retrospective observational study aiming to analyze clinical features of patients with decompensated liver disease, after the placement of the Denver Peritoneovenous Shunt. Unfortunately, the sample size is too small to reach statistically significant solutions.

Author Response

Thank you for the peer review and comments on our manuscript.

The small sample size was a serious problem for statistical analysis as suggested by 3 reviewers (Reviewer-1, Reviewer-2 (comment-1) and Reviewer-3 (comment-5,6,9) and Reviewer 4). Accordingly, we have removed the comparison between Child-Pugh B (n=10) and Child-Pugh C patients (n=4) and described the results of the 14 patients as a single group.

Reviewer 2 Report

Utsunomiya  et al.  aimed to evaluate the clinical features after PVS placement for refractory 70 ascites caused by decompensated cirrhosis, especially heart failure and DIC. 14 patients with refractory ascites associated with decompensated cirrhosis who underwent PVS placement between June 2011 and June 2023 were  included in this retrospective single centerde study.They reported no serious complication associated with the procedure occurred in any case.  They reported also The mean PVS patency was 345.4 days, and the median survival after PVS placement was 474.4 days. Although the patients with class B cirrhosis tended to have longer PVS patency, there was no significant difference between class B and C cirrhosis. The authors concluded as PVS placement for refractory ascites is a technically feasible palliative therapy.

1-Total Number of the  patients is low. I did not see any inclusion and exclusion criteria in method section. Generally, PVS is contraindicated in patients with end-stage renal failure on dialysis, septicemia, uncorrectable coagulopathy, morbidly obese patients, and patients with septation of the peritoneal cavity due to previous infection or surgery. Please give more information .

2-It would be a good idea to review the literature again and add the few studies that have been done on this subject to the discussion section.

Thank you for giving opportunity to review this  study.

Author Response

Thank you for your helpful comments. Our responses are as below.

Response to Comment 1

The small sample size was a serious problem for statistical analysis as suggested by all reviewers (Reviewer-1, Reviewer-2 (comment-1), Reviewer-3 (comment-5,6,9) and Reviewer 4). Accordingly, we have removed the comparison between Child-Pugh B (n=10) and Child-Pugh C patients (n=4) and described the results of the 14 patients as a single group.

In the Materials and Methods section, we have revised the sentences about the indications and contraindications of PVS placement in the section (2.1. Study Design and Patient Population) as follows:

“This was a single-center, retrospective, cohort study of patients with refractory ascites caused by decompensated cirrhosis who underwent PVS placement at our hospital between June 2011 and June 2023. This study enrolled patients who underwent placement of a PVS due to refractory ascites unresponsive to pharmacotherapy or necessitating frequent LVP on a weekly basis. The exclusion criteria were as follows: severe heart failure, end-stage renal failure without the initiation of dialysis, spontaneous bacterial peritonitis, sepsis, bloody ascites, intra-abdominal adhesions, hyperbilirubinemia (bilirubin levels > 2.0mg/dL), coagulation disorders (platelet count < 50 ×103/uL, INR > 2.0), untreated esophageal varices, and gastrointestinal bleeding. Fourteen patients with refractory ascites associated with decompensated cirrhosis who underwent PVS placement were enrolled in this study.”

Response to Comment 2

The following sentence and reference ([9]) have been added in the Discussion section: “In the patients with encapsulated ascites or intra-abdominal adhesions, the inability to adequately drain ascites may be considered to increase the risk of shunt occlusion. In such case, it is deemed contraindicated [9].”

[9]  Yarmohammadi, H.; Getrajdman, G.I. Symptomatic Fluid Drainage: Peritoneovenous Shunt Placement. Semin Intervent Radiol 2017, 34, 343-348, doi:10.1055/s-0037-1608705.

Reviewer 3 Report

Dear Authors

I read with great interest your work entitled "Chronological Course of Ascites and Clinical Features after the Denver Peritoneovenous Shunt Placement in Patients with Decompensated Liver Cirrhosis". As treatment options to reduce the ascites burden for patients with refractory ascites are limited, and with only a few advancements during the past three decades, this work is important. However, I believe some major concerns must be addressed before publication is justified. Please find below my specific comments on the manuscript.

1. The title is unnecessarily long. Please shorten.

2. Regarding the introduction, I suggest more emphasis on the fact that refractory ascites is the end-stage of cirrhotic ascites. Hence, these patients have passed a crucial tipping point and face a gloomy prognosis. Therefore, we must invest our resources in preventing patients from progressing to this advanced stage of ascites. Yet, optimized palliative management of ascites is of course desired for the patients that anyhow progress to refractory ascites.

3. Also concerning the introduction, the authors must comment on the permanent drain insertion; another and more widely used palliative treatment of ascites. Why was this treatment not considered for the 14 patients included here?

4. I understand, that the study is retrospective. However, I was surprised that the Denver shunt remained in use. Please report the specific indications for this choice of treatment for the 14 patients and why liver transplantation or TIPS was not considered. According to Table 2, no patients had alcohol-related liver disease, which usually is prohibitive of liver transplantation.

5. My main concern relates to the presentation of the results: The authors chose to compare Child-Pugh B patients with Child-Pugh C patients. This is arbitrary and not relevant, e.g. bilirubin differs between these groups as it is part of the Child-Pugh score. Moreover, I do not understand the selection of variables: why not include clinical variables such as time with cirrhosis, time with ascites, number of paracenteses before PVS insertion, diuretic treatments, earlier hepatic encephalopathy, etc.? I don't understand why the ALBI score is included.

6. P-values must be removed throughout the manuscript!

7. The time course is not clear to me. Did the patients undergo more, less, or no paracentesis after PVS insertion? 

8. Kaplan-Meier analyses are allowed for non-survival outcomes only if none of the patients die during the analysis time.

9. I suggest that a revised manuscript reports the 14 cases as one group, and focuses on describing the safety and clinical palliative efficacy of PVS insertion, reducing the use of statistical tests to an absolute minimum.

Kind regards.

The quality of English is acceptable.

Author Response

Thank you for reviewing and advising on our manuscript. We revised the content of the manuscript based on your valuable comments. We kindly request that you review it once again.

Response to Comment 1

We have shortened the title as follows: “Chronological Course and Clinical Features After the Denver Peritoneovenous Shunt Placement in Decompensated Liver Cirrhosis”

Response to Comment 2

We have added the following sentence and references ([6],[7]) in the Introduction section:  Approximately 10% of patients with liver cirrhosis have refractory ascites [6], and the mortality rate is reported to exceed 20% within 1 year [7].

[6]  Wong, F. Management of refractory ascites. Clin Mol Hepatol 2023, 29, 16-32, doi:10.3350/cmh.2022.0104.

[7]  Jepsen, P.; Watson, H.; Macdonald, S.; Vilstrup, H.; Jalan, R. MELD remains the best predictor of mortality in outpatients with cirrhosis and severe ascites. Aliment. Pharmacol. Ther. 2020, 52, 492-499, doi:10.1111/apt.15882.

Response to Comment 3

Thank you for the important suggestion. As one of the treatment options for refractory ascites, we added information on the indwelling peritoneal catheter. The indwelling peritoneal catheter is widely used as a palliative treatment for refractory ascites, but in Japan, it is currently not covered by insurance and cannnot be used.

We have revised the Introduction as below:

“Other therapeutic options for refractory ascites include large-volume paracentesis (LVP) with albumin substitution, indwelling peritoneal catheter, transjugular intrahepatic portosystemic shunt placement (TIPS), automated low-flow ascites pump implantation, and peritoneovenous shunt (PVS) placement. “ (paragraph 1) ; “The indwelling peritoneal catheter is widely used as a palliative treatment for refractory ascites [2], although a high incidence of infection was reported [12]. In Japan, it is currently not covered by insurance, and it is clinically unavailable.” (paragraph 2)

[2]  Fukui, H.; Kawaratani, H.; Kaji, K.; Takaya, H.; Yoshiji, H. Management of refractory cirrhotic ascites: challenges and solutions. Hepat. Med. 2018, 10, 55-71, doi:10.2147/hmer.S136578.

[12]  Reinglas, J.; Amjadi, K.; Petrcich, B.; Momoli, F.; Shaw-Stiffel, T. The Palliative Management of Refractory Cirrhotic Ascites Using the PleurX (©) Catheter. Can. J. Gastroenterol. Hepatol. 2016, 2016, 4680543, doi:10.1155/2016/4680543.

Response to Comment 4

TIPS was reported to be indicated for patients with refractory ascites who require frequent LVP, and it was suggested to have long-term efficacy compared to PVS placement. However, in Japan, TIPS is not covered by insurance and is therefore not commonly performed. Regarding liver transplantation, the potential necessity for PVS placement is relatively higher than in Western countries due to the limited availability of liver donors.

We have revised the sentences in Discussion section as follows: ”TIPS was reported to be indicated for patients with refractory ascites who require frequent LVP [20], and it was suggested to have a long-term efficacy compared to PVS placement [21]. However, in Japan, the insurance coverage of other shunt technique (e.g., TIPStransjugular intrahepatic portosystemic shunt placement) and the availability of liver donors is limited; therefore, the potential necessity of PVS placement has been relatively higher than western countries [18,19,22].”   

Response to Comment 5,6,8,9

As suggested, we changed our approach to conduct a statistical examination of the 14 cases as one group, without dividing them into Child-Pugh B patients and Child-Pugh C patients throughout the manuscript. We also removed the mention of the ALBI score and related references. (Johnson, P.J. et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J. Clin. Oncol. 2015, 33, 550-558, doi:10.1200/jco.2014.57.9151.)

Accordingly, we have removed the P-values from the manuscript and minimized statistical analysis. In the 14 cases, we have plotted the survival rate using Kaplan-Meier curves, but deleted the curve of PVS patency in the revised version.

Information on the frequency of abdominal paracentesis before and after PVS placement and the dosage of diuretics used, was included in Table2.

Hepatic encephalopathy was observed in no patients. It was difficult to ascertain the duration of cirrhosis and the period of ascites because our patients were referred from other institutions and their precise information regarding the duration of cirrhosis and the period of ascites was limited before the referral.

Response to Comment 7

In all cases, abdominal paracentesis was required once every 1 to 2 weeks before PVS placement. In 2 out of the 14 cases, several paracenteses were required even after PVS placement, while in the 12 cases, paracentesis was not performed the period of shunt patency. We have added the changes in abdominal paracentesis before and after PVS placement in Table2.

Reviewer 4 Report

This is a very interesting research concentrated on PVS treatment in patients with decompensated liver cirrhosis. This is a single centre, retrospective, cohort study. However, the time span of this study is too long.  Only 14 patients were enrolled in the study cohort in 12 years.  Only limited data were collected. I think more patients were needed for this study. 

Author Response

Thank you for reviewing our manuscript and positive suggestions. Although our study had a small sample size of only 14 patients, we believe that our results have shown the important aspects regarding the patient management of the liver cirrhosis with ascites. We have added the following sentence in the study limitations (Discussion section): “We plan to accumulate more patients with PVS in the several hospitals and conduct further studies.”

Round 2

Reviewer 3 Report

Dear authors

I think you have done a good job improving the manuscript. I wish you the best of luck in this and future endeavors.