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. 2023 Aug 24;18(8):e0290327. doi: 10.1371/journal.pone.0290327

Protective effect of propofol compared with sevoflurane on liver function after hepatectomy with Pringle maneuver: A randomized clinical trial

Junya Matsumi 1,*, Tetsufumi Sato 1
Editor: Hossam Eldien Ahmed Anis ElShamaa2
PMCID: PMC10449203  PMID: 37616308

Abstract

While the Pringle maneuver reduces intraoperative blood loss in hepatectomies, this technique can also be hepatotoxic. Hepatectomies require general anesthesia with propofol or volatile anesthetics like sevoflurane, agents known to offer multi-organ protection. However, their clinical effect after liver resection is unclear. We aimed to assess the effect of the two anesthetics on post-hepatectomy liver damage via measuring liver function tests. Fifty-six patients who underwent elective hepatectomies with the Pringle maneuver due to metastatic hepatic masses were preoperatively randomized to be anesthetized by sevoflurane or propofol. The primary and secondary outcomes were the postoperative peak levels of aspartate transaminase (AST) and alanine transaminase (ALT), respectively. Patients anesthetized by propofol exhibited significantly lower transaminases than those given sevoflurane (AST, p = 0.005; ALT, p = 0.006). The former agent significantly affected postoperative transaminases (AST hazard ratio -192.2, 95% confidence interval [-332.1 to -52.4], p = 0.00; ALT hazard ratio -140.2, 95% confidence interval [-240.0 to -40.7], p = 0.007). In conclusion, propofol had a greater hepatoprotective effect than sevoflurane as assessed by postoperative transaminases after hepatectomy with Pringle maneuver for metastatic liver tumors.

Introduction

A hepatectomy is crucial in treating various primary and secondary liver tumors. Despite the improvement in perioperative management and surgical technique, the mortality and morbidity rates after hepatectomy remain around 2–4% and 20–45%, respectively [1–4]. A main problem during liver resection is hemorrhage [5, 6]. Inflow occlusion by clamping the hepatoduodenal ligament, or the Pringle maneuver, is commonly done to reduce intraoperative blood loss [7]. However, this technique also induces liver damage.

Currently, there are protective strategies to prevent damage during a hepatectomy [8]. One established technique is ischemic preconditioning with intermittent Pringle maneuver [9]. Another is pharmacologic therapy. Some potentially effective drugs include propofol and volatile anesthetic agents, commonly used to maintain general anesthesia. These drugs have been shown to be hepatoprotective in experimental studies [10–12].

However, research on the two drugs has been conflicting. Some studies have demonstrated that propofol is more protective than volatile anesthetic agents during hepatectomies in humans [13, 14]. In contrast, there is also literature on the use of sevoflurane resulting in lower transaminase levels during a hepatectomy using the Pringle maneuver [15, 16]. Meanwhile, other studies show no difference between the effects of sevoflurane and propofol on postoperative transaminase levels [17, 18]. Moreover, some studies had different methodologies, such as pharmacologic postconditioning and ischemic preconditioning, from the usual clinical setting [15, 16]. Also, patients with cirrhosis were included in some studies, and the size of excised liver was also considered [15–18]; factors other than anesthetic agents might influence transaminases. Thus, there is a need to study the hepatoprotective effect of propofol versus sevoflurane in the typical clinical and more homogeneous setting.

This study aimed to assess the hypothesis that propofol-based anesthesia in patients without cirrhosis is more protective than sevoflurane-based anesthesia against liver damage as evaluated via liver transaminases during minor hepatectomy with the Pringle maneuver.

Materials and methods

Study design and settings

This randomized controlled trial was conducted at National Cancer Center Hospital (NCCH) in Tokyo, Japan. It was approved by the institutional review board for human clinical studies (no. 2017–504), and written informed consent was obtained from all patients. The study was carried out following the Declaration of Helsinki and registered in the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000034798) on December 12, 2018.

Inclusion and exclusion criteria

Between January 11, 2019, and November 19, 2020, we included patients diagnosed with metastatic or suspected metastatic hepatic masses undergoing elective liver resection with the Pringle maneuver at NCCH.

Exclusion criteria included patients aged more than 90 or under 18, a diagnosis of liver cirrhosis (LC), preoperative liver transaminases over 100 IU/L, more than five preoperatively diagnosed metastatic hepatic tumors, scheduled hepatic lesion resection in more than five Couinaud segments, concomitant additional therapy (such as the resection of the primary lesion and radiofrequency ablation) or biliary duct reconstruction, known allergies to the trial anesthetics, and patient refusal or withdrawal.

Randomization

Enrolled patients were preoperatively randomized to be anesthetized by either sevoflurane or propofol. Blocked randomization without stratification was performed by one of the authors not involved in informed consent acquisition and anesthetic administration.

Perioperative management

According to the predefined NCCH clinical protocol, all patients received similar perioperative treatment except for those who experienced postoperative complications. None received premedication for anesthesia. Continuous ropivacaine infusion via the thoracic epidural route was administered for postoperative pain management. In cases without epidural anesthesia or when the effect of epidural anesthesia was inadequate, fentanyl was given intravenously.

All patients underwent radial arterial invasive blood pressure monitoring. General anesthesia, such as propofol, rocuronium, fentanyl, and remifentanil, was used for induction. After induction, propofol was infused by titrating for bispectral index (BIS) values between 30 to 70 in the propofol group. Sevoflurane was administered by titrating the end-tidal concentration of sevoflurane between 0.6–2% in the sevoflurane group. There were no limitations in perioperative management without using an anesthetic agent not assigned.

Surgical procedure

One of five surgeons certified in hepatobiliary surgery performed the hepatic resections in a standardized manner. The Pringle maneuver was intermittently performed (cycles of 15 to 30 min of ischemia followed by 5 min of reperfusion) using a large vascular clamp with rubber jaws or a vascular clip [9]. The forceps clamp-crush or cavitron ultrasonic surgical aspirator method was used for parenchymal transection. Further, the exposed vessels were ligated with silk threads or sealed with surgical instruments.

Outcomes

The primary outcome was the peak level of aspartate aminotransaminase (AST) during three postoperative days (POD), representing postoperative liver injury.

The secondary outcomes, measured during three POD, were peak alanine aminotransaminase (ALT) levels to measure liver injury and total bilirubin (tBil) to measure liver function. Another secondary outcome included postoperative serious adverse events (SAE) occurring within 28 POD. SAE was defined as Grades 3a, 3b, 4a, 4b, and 5 according to the Common Terminology Criteria for Adverse Events, version 4.0, of the Japan Clinical Oncology Group. A previous study at NCCH confirmed that AST, ALT, and tBil peaked within three POD [9].

Measurements

We prospectively collected perioperative parameters. The parameters collected were age, sex, American Society of Anesthesiologists Physical Status (ASA-PS), Charlson Comorbidity Index, LC and hepatic steatosis histopathologically proven by postoperative liver samples, treatment with chemotherapy within one year, the primary malignancy, duration of surgery (time between skin incision to closure), anesthesia time (time between the start of anesthesia induction to the patient leaving the operation room), the sum of the time in the Pringle maneuver during liver resection (total ischemic time [TIT]), intraoperative fluid balance, and weight of the resected liver.

Statistical analyses

We summarized the assessed variables using the mean and standard deviation or percentage (%) using Student’s t-test or Fisher’s exact test where appropriate. A multivariable linear regression using age, gender, TIT, and the anesthetic agent used was utilized to determine factors that affected postoperative peak levels of AST and ALT. Confidence intervals (CI) of hazard ratios (HR) were estimated at 95%. All outcomes were analyzed according to the intention-to-treat analysis.

Additionally, as a sub-analysis, all outcomes were analyzed according to the per-protocol effect. A p-value less than 0.05 was considered to be statistically significant.

All analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [19].

Sample size estimation

We preliminarily collected the data from 52 patients who underwent hepatectomy for metastatic masses at NCCH: the postoperative peak of AST was 658 [460] IU/L with sevoflurane and 351 [178] IU/L with propofol (S1 Table). As actual differences were 100 to 300 IU/L in previous studies and retrospective data at NCCH, and the standard deviation was 200 to 400 IU/L after hepatectomy, we set a difference of 300 IU/L in postoperative peak AST levels between the two groups as clinically significant. The standard deviation was determined to be 400 IU/L in postoperative peak AST levels [15–18]. Then, the sample size was calculated based on a difference of 300 IU/L in postoperative peak AST levels between the two groups and a standard deviation of 400 IU/L in postoperative peak AST levels with a type 1 error of 0.05, and a power of 0.8. This analysis showed that 28 patients were required in each group (56 patients).

Results

Patients

Fifty-six patients were included between January 11, 2019, and November 19, 2020. During this period, 117 patients underwent hepatectomies for metastatic tumors at NCCH. Fifty-three patients did not meet the inclusion criteria (37 patients had scheduled resection of other organs, 13 were preoperatively diagnosed with six or more tumors, and three had liver lesions involving more than five Couinaud segments). Eight patients refused to participate in this study (Fig 1). There were deviations from the study protocol in three patients: one patient in the sevoflurane group received another anesthetic agent perioperatively, and the Pringle maneuver could not be performed in one patient in each group due to adhesions from a previous surgery.

Fig 1. Enrollment and randomization.

Fig 1

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Sixty-one patients were excluded due to scheduled resection of other organs. Reasons for exclusion included being diagnosed with six or more tumors, liver lesions involving more than five Couinaud segments, and refusal to participate in the study.

Characteristics

Table 1 shows the patients’ characteristics. Colorectal cancer was the most frequent primary lesion. No LC was diagnosed histopathologically in the two groups. Anesthesia and operation times were long in the sevoflurane group. Additionally, none of the patients in this study underwent intraoperative revascularization procedures, such as portal vein or hepatic artery reconstruction, during liver resection. Also, none received continuous perioperative administration of vasopressors.

Table 1. Patients’ characteristics.

Sevoflurane n = 28 Propofol n = 28
Age (years) 66.3 [12.3]* 64.7 [10.1]
Male (%) 67.9 71.4
ASA-PS (%) 2 85.7 89.3
3 14.3 10.7
Charlson Comorbidity Index 6.5 [0.7] 6.6 [0.8]
Fatty liver (%) 14.3 7.1
Chemotherapy within 1 year (%) 28.6 25.0
Primary cancer site (%) Colorectal 75.0 78.6
Others 25.0 21.4
Preoperative AST level (IU/l) 27.4 [12.3] 26.4 [12.3]
Preoperative ALT level (IU/l) 24.9 [19.9] 24.0 [13.7]
Preoperative tBil level (mg/dl) 0.8 [0.4] 0.8 [0.2]
Laparoscopic surgery (%) 17.9 17.9
Use of epidural anesthesia (%) 96.4 100
Operation time (min) 290.4 [98.2] 237.4 [46.6]
Anesthesia time (min) 352.0 [106.1] 305.1 [54.1]
Total ischemic time (min) 68.5 [42.7] 59.7 [27.0]
Number of Pringle cycles (cycle) 4.3 [3.0] 3.5 [1.8]
Intraoperative bleeding (ml) 607.6 [594.0] 446.4 [370.7]
Intraoperative fluid balance (ml/kg/h) 7.1 [3.3] 6.8 [2.1]
Weight of resected liver (g) 121.5 [97.4] 158.9 [129.8]
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ASA-PS: American Society of Anesthesiologists Physical Status, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin.

* Data are presented as the % of the total number or mean [standard deviation].

Outcomes

The outcomes differed significantly between the two groups (Table 2). Both AST and ALT levels presented as mean (standard deviation), were significantly lower in the propofol group (AST: sevoflurane 510.3 [362.4] IU/L versus propofol 291.7 [151.2] IU/L; p = 0.005 and ALT: sevoflurane 422.1 [257.3] IU/L; propofol 264.3 [131.4] IU/L; p = 0.006).

Table 2. Outcome parameters at univariable analysis.

Sevoflurane n = 28 Propofol n = 28 p-value**
Peak AST level (IU/l) 510.3 [362.4]* 291.7 [151.2] 0.005
Peak ALT level (IU/l) 422.1 [257.3] 264.3 [131.4] 0.006
Peak tBil level (mg/dl) 1.24 [0.53] 1.16 [0.41] 0.55
SAE (%) 10.7 7.1 1
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AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin, SAE: serious adverse events.

* Data are presented as the % of the total number or mean [standard deviation].

** A p-value less than 0.05 was considered to be statistically significant.

The secondary outcomes were not significantly different between the two groups (tBil: sevoflurane 1.24 [0.53] mg/dL versus propofol 1.16 [0.41] mg/dL; p = 0.55. SAE: sevoflurane 10.7% versus propofol 7.1%; p = 1). SAE included four patients who developed bile fistula or intra-abdominal abscesses needing drainage (two patients per group) and one with urosepsis (in the sevoflurane group).

Postoperative peak values of AST and ALT were significantly affected by the choice of anesthetic agent (propofol p = 0.008 and 0.007, respectively) and TIT (p = 0.001 and p = 0.0004, respectively, Table 3).

Table 3. Multivariable linear regression of postoperative peak transaminase levels.

Factor AST ALT
Hazard ratio 95%CI P Hazard ratio 95%CI P value*
Age -0.9 -7.5 to 5.6 0.78 -1.9 -6.6 to 2.7 0.41
Female 39.3 -117.2 to 195.7 0.62 65.3 -46.0 to 176.6 0.24
TIT 3.3 1.4 to 5.3 0.001 2.6 1.2 to 4.0 0.0004
Propofol -192.2 -332.1 to -52.4 0.008 -140.2 -240.0 to -40.7 0.007
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AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, TIT: total ischemic time, CI: confidence interval.

*A p-value less than 0.05 was considered to be statistically significant.

Per-protocol analysis

The per-protocol analysis included 26 and 27 patients in the sevoflurane and propofol groups, respectively. The characteristics were similar to the original analysis (S2 Table), whereas the primary and secondary outcomes were the same as the original (S3 and S4 Tables)

Discussion

In this randomized control trial, we noted significantly lower postoperative peak transaminase levels in patients anesthetized by propofol than in those given sevoflurane after metastatic liver tumor resection with the Pringle maneuver.

Several studies have explored the protective effect of propofol against organ damage, including liver injury, in experimental models [20–24]. Additionally, some studies have shown that propofol has a more substantial protective effect than volatile anesthetics during human liver resection, as assessed by biomarkers not commonly used in a clinical setting [13, 14]. Based on these results, transaminases may be used to assess the protective effect of anesthetic agents against liver damage. However, our results are inconsistent with other studies’ findings.

A series of studies by Beck-Schimner and colleagues showed the beneficial effect of sevoflurane against liver damage after liver resection using the Pringle maneuver [15, 16]. The patients were mainly anesthetized with propofol, and sevoflurane was used only briefly before or after inducing ischemia. These anesthetic methods are not usually performed in a clinical setting. In turn, the anesthetic methods utilized in our study were the standard of care. One study included other ischemic methods that can affect postoperative transaminase levels [16]. Consequently, the effects seen in these studies might not reflect the impact of anesthetic agents on postoperative liver damage in the usual clinical setting.

Other studies by Song and Slankamenac showed no difference between sevoflurane and propofol [17, 18]. In contrast, this study did not include patients with LC. We thus speculate that these previous studies could not compare the effects of anesthetic agents against liver damage during hepatectomy with the Pringle maneuver without significant bias.

This study set careful selection criteria for its participants to avoid potential biases. As the size of the resected liver may affect postoperative transaminase levels, we only selected patients with a set number of metastatic liver tumors and liver lesions involving less than five Couinaud segments. Consequently, no significant difference in the size of the resected liver (assessed by resected liver weight) was noted in this study.

Second, TIT may also affect postoperative transaminase levels. Since we determined that the resected liver size was similar among the study participants, we speculated that the TIT during metastatic liver tumor resection would be similar. Further, the results revealed that the TIT was similar between the two groups.

Third, baseline liver function can also affect postoperative transaminase levels [24]. Since many patients with HCC also have varying degrees of LC, the liver function of patients with HCC varies widely. In contrast, patients with metastatic hepatic tumors may have similar liver function. As a result, none of our patients had LC, and the frequency of hepatic steatosis between the two groups was similar.

Overall, we think the homogenization of baseline characteristics that could affect the primary outcome was achieved. Thus, the comparison between the protective effect of anesthetic agents against liver damage could be elucidated.

This study has several limitations which should be considered when interpreting its results. First, as we usually use end-tidal sevoflurane concentration monitoring during sevoflurane anesthesia, BIS was not used for titration in the sevoflurane group. Nevertheless, end-tidal anesthetic concentration monitoring is as reliable as BIS; hence, the depth of anesthesia was compatible between groups [25]. Second, a large standard deviation was set at sample size estimation, which could lead to decreased power. However, the value of postoperative transaminase also varies widely in several studies [15–18], and this study’s achieved power was not very low (a power of 78.8%, calculated by the difference in mean values between groups 218.6 IU/L [SD 296.4 IU/L] and a type 1 error 0.05).

Third, in the sevoflurane group, anesthesia and operation times were long. The difference between the former and the latter was similar;and operation time was more influential in the difference noted. As the TIT, representing the duration of liver resection, was similar between the groups, the duration of liver resection and the influence of liver ischemia might similar. These times might concern with Adhesive detachment for previous surgeries including resection of the primary malignancy. Hence, the difference in these periods might not largely affect our results.

Fourth, we did not perform protocolized intraoperative management, such as maintaining a low central venous pressure. Such practices may affect intraoperative fluid volume and blood loss. However, the intraoperative fluid balance and blood loss differed between the two groups. Thus, this matter might not be significantly influential. Fifth, there was a deviation from the study protocol in three patients due to clinically justifiable causes. Nonetheless, as the predefined per-protocol analysis showed similar results, its effect was considered minimal.

Lastly, SAE incidence, the most critical measure for patients, was similar between groups in this study. Although this study aimed to assess anesthetic agents’ effects on liver damage during liver resection with the Pringle maneuver, we included only minor hepatectomies to maintain baseline characteristics’ homogenization. Therefore, the incidence of SAE in the patients included in this study was essentially low. Thus, the statistical power for evaluating the influence on SAE is very weak. Further research is needed to assess whether propofol-based anesthesia lowers the incidence of SAE compared with sevoflurane-based anesthesia after major liver resection with the Pringle maneuver.

In conclusion, our randomized controlled study indicates that propofol may have a more substantial protective effect during liver resection with the Pringle maneuver in a clinical setting.

Supporting information

S1 Checklist. CONSORT checklist.

(DOC)

Click here for additional data file. (196.7KB, doc)
S1 Table. The preliminary study’s data set.

This table contains the data set for the power calculation.

(XLSX)

Click here for additional data file. (9.8KB, xlsx)
S2 Table. Patients’ characteristics in a per-protocol analysis.

ASA-PS: American Society of Anesthesiologists Physical Status, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin. Data are presented as the % of the total number or mean [standard deviation], where appropriate.

(DOCX)

Click here for additional data file. (14.2KB, docx)
S3 Table. Outcome parameters at univariable analysis in a per-protocol analysis.

AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin, SAE: serious adverse events. Data are presented as the % of the total number or mean [standard deviation], where appropriate. A p-value less than 0.05 was considered to be statistically significant.

(DOCX)

Click here for additional data file. (11.9KB, docx)
S4 Table. Multivariable linear regression of postoperative peak transaminase levels in a per-protocol analysis.

AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, TIT: total ischemic time, 95%CI: 95% confidence interval. A p-value less than 0.05 was considered to be statistically significant.

(DOCX)

Click here for additional data file. (12.3KB, docx)
S5 Table. The study’s minimal underlying data set.

This table contains the data set underlying the results described in the manuscript.

(CSV)

Click here for additional data file. (5.4KB, csv)
S1 File. Study protocol (Japanese).

(DOCX)

Click here for additional data file. (82.1KB, docx)
S2 File. Study protocol (English).

(DOCX)

Click here for additional data file. (82.1KB, docx)

Acknowledgments

I wish to thank Dr. Kazuaki Shimada, Dr. Minoru Esaki, Dr. Satoshi Nara, Dr. Daisuke Ban, and Dr. Yoji Kishi for advice regarding the surgical technique for hepatectomy.

Data Availability

All relevant data are within the manuscript.

Funding Statement

This study was supported by The National Cancer Center Research and Development Fund (29-A-12). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Hossam Eldien Ahmed Anis ElShamaa

13 Jun 2023

PONE-D-23-10418

Protective effect of propofol compared with sevoflurane on liver damage during liver resection with Pringle maneuver: a randomized clinical trial

PLOS ONE

Dear Dr. Matsumi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: 

Kindly review my points that need to be corrected in the manuscript.

Address all the points highlighted by the Reviewers.

==============================

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Hossam Eldien Ahmed Anis ElShamaa, M.D.

Academic Editor

PLOS ONE

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Additional Editor Comments:

Thank you for this well done manuscript, but I have minor points that need to be addressed;

1. Methodology: in perioperative management , titration of propofol and sevoflurane should be based both on the BIS value to have solid comparison based on np differences.

2. in the manuscript the author have to clarify both ( Anesthesia time surgery time ) , it should be stated from exactly when to when.

3. All tables should have a caption clearly stating the type of date and how is it expressed and the P value of statistical significance.

4. Figure 1 has neither title nor caption.

5. In the pre-protocol the author showed the operative time to be significantly longer in the Sevoflurane group,,, why ?

6. Discussion: paragraph 1, in the last line , the author said (anesthetic agent was significantly affected with postoperative peak levels of transaminase.) what is meant by this phrase?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

********** 

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

********** 

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

********** 

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: No

********** 

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. I look at the manuscript in/with statistical view point, other reviewer(s) look(s) at it with different angle so that in totality the review is very comprehensive. However, there should be efforts from authors side to improve (may be by taking clues from reviewer’s comments). Therefore, please do not limit the revision only (with respect) to comments made here.

COMMENTS: Although it is observed that this manuscript is well drafted [and the study is excellent with respect to most of the aspects], I have few observations/concerns (different opinion) which are given below:

I have few (minor/little) doubts regarding ‘Sample size estimation’. Firstly, you said “We set a difference of 300 IU/L in postoperative peak AST levels between the two groups” but the basis of this is not given. Though later as you specified since it is felt to be ‘clinically significant’ is perfectly alright but mind you that unless any reference is quoted, it is treated as ‘subjective’ [I am not a clinician, however, general opinion is expressed]. For standard deviation you said “was decided by referring to retrospective data of 52 patients” but the source of these data is not revealed. At the end of this section you said “this study was adequately powered with 28 patients per group (total 56 patients)” is doubtful because according to table-2 on page 158 of Jacob Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 [which is a sort of summary of the excellent book by Cohen himself titled ‘Statistical power analysis for the behavioral sciences’, Academic Press, 1977, New York] even for medium effect size you need n=64 per group (type-I error=0.05, power=80%). Fortunately, the power achieved in this trial is not very low (75.69% by referring to table-2 of this manuscript), however, here the comparison pertains only to ‘post’ values and baseline is not given any recognition [I am not sure regarding its clinical importance/relevance]. Look at the absolute values [both mead S.D.] in table-2 {Peak AST level (IU/l)� Sevoflurane group (n=28) 510.3 [362.4] Propofol group (n=28) }291.7 [151.2]}.

Any software or manual calculations will show that your ‘sample size’ results are definitely correct [as an example, a ‘Screen-shot’ of output from software called COMPARE2 is pasted below – which shows that I have no doubt about correctness of calculations], I doubt only about assumptions [assumed values of a difference of 300 IU/L and a standard deviation of 400 IU/L]. This implies that a very large effect size is assumed and that is doubtful.

Example: Screen-shot of output from COMPARE2

Note that the comparison of baseline characteristics when random allocation/assignment is used/done is not required [‘P’ values in last column 4 of Table 1 - Patients characteristics]. In this context, please read [though I am sure that the authors already know these things] a note which is pasted from one famous standard textbook on ‘Medical Research Methodology’:

To provide a description of baseline characteristics is entirely reasonable (since it is clearly important in assessing to whom the results of the trial can be applied), however, statistical comparison of baseline characteristics when random allocation/assignment is used/done [often for good/standard/leading journals these days] is not required, because even if P-value(s) turn(s) out to be significant (while comparing baseline characteristics despite random allocation), it is, by definition, a false positive as you then are supposed to be testing ‘randomization’ then, which in any single trial may not balance all baseline characteristics (particularly when sample sizes are small). Remember that ‘randomization’ is a sort of ‘insurance’ and not a guarantee scheme. Authors may please refer to following articles:

References:

1. Stuart J. Pocock, et al., ‘Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems’, Statistics in medicine, 2002; 21:2917–2930 [Particularly page 2927]

2. Harrington D, et al., ‘New guidelines for statistical reporting in the journal’, N Engl J Med 2019;381:285-6

[Important message (indirectly/ultimately indicated) from these articles: Never do any comparison with respect to ‘baseline’ characteristics {by applying statistical significance test(s)}, when allocation is done randomly].

However, Statistical comparison [only with respect to important/indicated variables] of baseline characteristics may be performed, to find out if analysis adjustment (say stratified analyses or else) is required with respect to these variables.

In ‘Abstract- Results’ section [and also in ‘outcome - Per-protocol analysis’ section later] there is a sentence “At multiple linear regression …..” which, in my opinion, is not grammatically correct {instead of At, it should be As shown by} . Please check. Later in ‘Randomization’ section, a sentence “A computer generated the blocked randomization with no stratification” appears to be incomplete. In section ‘Statistical analyses’, instead of “We expressed the assessed variables….” it could/should [desired] be “We summarised the assessed variables….”, I think.

Highlighting (listing/pointing out) the “Limitations” {with possible effects} is highly appreciable (although lower sample size is not included starting ‘Discussion’ with “In this adequately powered RCT is not agreed). However, mind you that as pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently [preferably by an expert surgeon in concerned field]. Some of these limitations may have significant influence on results.

Except these minor points, the article is acceptable. ‘Minor Revision’ is recommended.

Reviewer #2: In Manuscript PONE -D-23010418, Matsumi and Sato present their recent research examining the protective effect of propofol (P) vs sevoflurane (S) on liver damage during liver resection with a Pringle maneuver. This work was in part a further examination of these anesthetic agents on liver injury, which had previously been examined with conflicting results. I commend the authors for attempting to perform a more thorough randomized study to address this question. The collected data and results are presented in a similar to prior work, so direct comparisons are possible. Overall, the results are compelling however, the paper needs English editing as well as some stylistic editing as detailed below.

1. The Introduction discusses prior research in this area but should also include a better description of the differences in protocols between the prior study (See Discussion Page 22 “The patients were mainly anesthetized in…. usual clinical methods”). By including this discussion in the Introduction would better inform the reader about why this study is important. The authors used a protocol that more closely mimicked traditional anesthetic practice compared to prior work by others. This point should be emphasized more.

2. The authors excluded patients with liver cirrhosis, only included patients with similar tumor burdens etc. to produce a more homogenous patient population (see last paragraph in the Discussion). Such details should be emphasized in the introduction to build interest in the reader.

3. Propofol was titrated based upon bispectral index monitoring, but sevoflurane was titrated to end-tidal concentration. Why was bispectral index monitoring not used for sevoflurane? Could this influence anesthesia depth and hence outcome?

4. The authors state that the Pringle maneuver was used intermittently but do not include the duration of clamping and how many cycles were used between treatment groups. The Pringle maneuver has been shown to be protective (a form of ischemic pre-conditioning) so differences here could affect the outcomes measured. Were there any differences between the application of the Pringle maneuver?

5. Post-operative serious adverse events should be listed (supplemental would be fine) beyond their classification as grade 3a,4b etc. Not all readers will know what these various grades mean, so they should be included.

6. The authors present their data two ways, intention to treat (ITT) or “per-protocol” analysis. In the latter analysis, the authors drop 1-2 patients per treatment arm due to incomplete protocol implementation. The data/findings do not change, but the statistical data does change. In other words, it did not affect their interpretation, so why include it? The paper becomes much denser by the almost duplication of data without an effect on its interpretation. To make the paper more readable, I would suggest moving the “per-protocol” analysis to a supplemental figure.

7. The paper would benefit from English editing. Some sentences are non-sensical (“To reach AST, ALT and tBil peaks within 3 POD were confirmed by retrospective data analysis of 72 patients in liver resection for metastatic liver tumors at NCCH”).

********** 

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Reviewer #1: No

Reviewer #2: Yes: Timothy Angelotti MD PhD

**********

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Attachment

Submitted filename: renamed_2a3c7.docx

Click here for additional data file. (139.9KB, docx)
PLoS One. 2023 Aug 24;18(8):e0290327. doi: 10.1371/journal.pone.0290327.r002

Author response to Decision Letter 0

7 Jul 2023

Journal Requirements:

Thank you for point to note.

1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

→We are sorry about this matter. We change our manuscript to meet PLOS ONE style.

2.Please upload a new copy of Figure 1 as the detail is not clear.

→We are sorry about this matter. I uploaded a new copy of Figure 1.

3.Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

→We are sorry about this matter. We include captions for Supporting information files at the end of manuscript.

4.Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

→Thank you for pointing it out. We remove retracted paper and replace fixed paper.

Additional Editor Comments:

Thank you for your kindly check.

1. Methodology: in perioperative management , titration of propofol and sevoflurane should be based both on the BIS value to have solid comparison based on np differences.

→Thank you for pointing it out. As propofol can not use direct biological monitoring in clinical setting, anesthesia by propofol need to be used other non-direct monitoring like BIS. In turn, as volatile anesthetic agents can use end-tidal concentration which is direct biological monitoring, anesthesia by volatile anesthetic agent like sevoflurane does not necessarily need BIS in clinical settings. Consequently, we did not use BIS monitor at sevoflurane anesthesia. We add this matter at limitation in Discussion.

2. in the manuscript the author have to clarify both ( Anesthesia time surgery time ) , it should be stated from exactly when to when.

→Thank you for pointing it out. We state from when to when about anesthesia time and surgery time at measurement in Materials and Methods.

3. All tables should have a caption clearly stating the type of date and how is it expressed and the P value of statistical significance.

→Thank you for pointing it out. We state the type of data and how is it expressed and the P value of statistical significance at a caption in all tables

4. Figure 1 has neither title nor caption.

→Thank you for pointing it out. I wrote title and caption of Figure 1 at Patients in Results.

5. In the pre-protocol the author showed the operative time to be significantly longer in the Sevoflurane group,,, why ?

→Thank you for pointing it out. As according to the opinion from Reviewer#1, we canceled the statistical comparisons, the significant difference is dismissed. However as the operative time was long in the sevoflurane group, we address our consideration at Limitation in Discussion. As the difference between anesthesia time and operation time and total ischemic time which represented the duration of liver resection were similar, we assess the difference was mainly caused by the peering adhesion for previous surgery including primary cancer resection and did not largely affect the outcomes.

6. Discussion: paragraph 1, in the last line , the author said (anesthetic agent was significantly affected with postoperative peak levels of transaminase.) what is meant by this phrase?

→Thank you for pointing it out. We changed this sentence and used English editing service.

Reviewer #1: 

1. I have few (minor/little) doubts regarding ‘Sample size estimation’. Firstly, you said “We set a difference of 300 IU/L in postoperative peak AST levels between the two groups” but the basis of this is not given. Though later as you specified since it is felt to be ‘clinically significant’ is perfectly alright but mind you that unless any reference is quoted, it is treated as ‘subjective’ [I am not a clinician, however, general opinion is expressed]. For standard deviation you said “was decided by referring to retrospective data of 52 patients” but the source of these data is not revealed. At the end of this section you said “this study was adequately powered with 28 patients per group (total 56 patients)” is doubtful because according to table-2 on page 158 of Jacob Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 [which is a sort of summary of the excellent book by Cohen himself titled ‘Statistical power analysis for the behavioral sciences’, Academic Press, 1977, New York] even for medium effect size you need n=64 per group (type-I error=0.05, power=80%). Fortunately, the power achieved in this trial is not very low (75.69% by referring to table-2 of this manuscript), however, here the comparison pertains only to ‘post’ values and baseline is not given any recognition [I am not sure regarding its clinical importance/relevance]. Look at the absolute values [both mead S.D.] in table-2 {Peak AST level (IU/l)� Sevoflurane group (n=28) 510.3 [362.4] Propofol group (n=28) }291.7 [151.2]}. Any software or manual calculations will show that your ‘sample size’ results are definitely correct [as an example, a ‘Screen-shot’ of output from software called COMPARE2 is pasted below – which shows that I have no doubt about correctness of calculations], I doubt only about assumptions [assumed values of a difference of 300 IU/L and a standard deviation of 400 IU/L]. This implies that a very large effect size is assumed and that is doubtful. Example: Screen-shot of output from COMPARE2

→Thank you for pointing it out and kindly teaching about statistical matter. We are sorry but we can not recruit more participants in this study. Instead, we add the rationale about difference setting at Sample size estimation in Materials and Methods and the preliminary data set as supplemental data. And we erase the word ‘ adequately’ and add the wide range of standard deviation in sample size estimation (in addition, the power achieved in this study) at Limitation in Discussion.

2.Note that the comparison of baseline characteristics when random allocation/assignment is used/done is not required [‘P’ values in last column 4 of Table 1 - Patients characteristics]. In this context, please read [though I am sure that the authors already know these things] a note which is pasted from one famous standard textbook on ‘Medical Research Methodology’:To provide a description of baseline characteristics is entirely reasonable (since it is clearly important in assessing to whom the results of the trial can be applied), however, statistical comparison of baseline characteristics when random allocation/assignment is used/done [often for good/standard/leading journals these days] is not required, because even if P-value(s) turn(s) out to be significant (while comparing baseline characteristics despite random allocation), it is, by definition, a false positive as you then are supposed to be testing ‘randomization’ then, which in any single trial may not balance all baseline characteristics (particularly when sample sizes are small). Remember that ‘randomization’ is a sort of ‘insurance’ and not a guarantee scheme. Authors may please refer to following articles:

References:

1. Stuart J. Pocock, et al., ‘Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems’, Statistics in medicine, 2002; 21:2917–2930 [Particularly page 2927]

2. Harrington D, et al., ‘New guidelines for statistical reporting in the journal’, N Engl J Med 2019;381:285-6

[Important message (indirectly/ultimately indicated) from these articles: Never do any comparison with respect to ‘baseline’ characteristics {by applying statistical significance test(s)}, when allocation is done randomly].

However, Statistical comparison [only with respect to important/indicated variables] of baseline characteristics may be performed, to find out if analysis adjustment (say stratified analyses or else) is required with respect to these variables.

→Thank you for pointing it out and kindly teaching about statistical matter. We agree with your opinion. We erase statistical comparison.

3. In ‘Abstract- Results’ section [and also in ‘outcome - Per-protocol analysis’ section later] there is a sentence “At multiple linear regression …..” which, in my opinion, is not grammatically correct {instead of At, it should be As shown by} . Please check. Later in ‘Randomization’ section, a sentence “A computer generated the blocked randomization with no stratification” appears to be incomplete. In section ‘Statistical analyses’, instead of “We expressed the assessed variables….” it could/should [desired] be “We summarised the assessed variables….”, I think.

→Thank you for pointing it out. We correct these points and used English editing service for checking our English.

4. Highlighting (listing/pointing out) the “Limitations” {with possible effects} is highly appreciable (although lower sample size is not included starting ‘Discussion’ with “In this adequately powered RCT is not agreed). However, mind you that as pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently [preferably by an expert surgeon in concerned field]. Some of these limitations may have significant influence on results.

→Thank you for pointing it out. We correct these points and use English editing service..

Reviewer #2:

1. The Introduction discusses prior research in this area but should also include a better description of the differences in protocols between the prior study (See Discussion Page 22 “The patients were mainly anesthetized in…. usual clinical methods”). By including this discussion in the Introduction would better inform the reader about why this study is important. The authors used a protocol that more closely mimicked traditional anesthetic practice compared to prior work by others. This point should be emphasized more.

→Thank you for your suggestion. We add the sentence to emphasize our strength at Introduction.

2. The authors excluded patients with liver cirrhosis, only included patients with similar tumor burdens etc. to produce a more homogenous patient population (see last paragraph in the Discussion). Such details should be emphasized in the introduction to build interest in the reader.

→Thank you for your suggestion. We add the sentence to emphasize our strength at Introduction.

3. Propofol was titrated based upon bispectral index monitoring, but sevoflurane was titrated to end-tidal concentration. Why was bispectral index monitoring not used for sevoflurane? Could this influence anesthesia depth and hence outcome?

→Thank you for pointing it out. As propofol can not use direct biological monitoring in clinical setting, anesthesia by propofol need to be used other non-direct monitoring like BIS. In turn, as volatile anesthetic agents can use end-tidal concentration which is direct biological monitoring, anesthesia by volatile anesthetic agent like sevoflurane does not necessarily need BIS in clinical settings. Consequently, we did not use BIS monitor at sevoflurane anesthesia. We assess this does not influence anesthesia depth and outcome. We add this matter at limitation.

4. The authors state that the Pringle maneuver was used intermittently but do not include the duration of clamping and how many cycles were used between treatment groups. The Pringle maneuver has been shown to be protective (a form of ischemic pre-conditioning) so differences here could affect the outcomes measured. Were there any differences between the application of the Pringle maneuver?

→Thank you for pointing it out. We assessed the duration of clamping as total ischemic time (TIT) and add the number of the cycle of Pringle maneuver at Measurement in Materials and Methods. Consequently, we assess the application of the Pringle maneuver is no difference between groups.

5. Post-operative serious adverse events should be listed (supplemental would be fine) beyond their classification as grade 3a,4b etc. Not all readers will know what these various grades mean, so they should be included.

→Thank you for pointing it out. We add the details of serious adverse event at Outcome in Results.

6. The authors present their data two ways, intention to treat (ITT) or “per-protocol” analysis. In the latter analysis, the authors drop 1-2 patients per treatment arm due to incomplete protocol implementation. The data/findings do not change, but the statistical data does change. In other words, it did not affect their interpretation, so why include it? The paper becomes much denser by the almost duplication of data without an effect on its interpretation. To make the paper more readable, I would suggest moving the “per-protocol” analysis to a supplemental figure.

→Thank you for your suggesting. We moved the per- protocol analysis to supplement files.

7. The paper would benefit from English editing. Some sentences are non-sensical (“To reach AST, ALT and tBil peaks within 3 POD were confirmed by retrospective data analysis of 72 patients in liver resection for metastatic liver tumors at NCCH”).

→Thank you for your suggestion. We use English editing service.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (39.4KB, docx)

Decision Letter 1

Hossam Eldien Ahmed Anis ElShamaa

4 Aug 2023

Protective effect of propofol compared with sevoflurane on liver function after hepatectomy with Pringle maneuver: a randomized clinical trial

PONE-D-23-10418R1

Dear Dr. Matsumi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Hossam Eldien Ahmed Anis ElShamaa, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Hossam Eldien Ahmed Anis ElShamaa

16 Aug 2023

PONE-D-23-10418R1

Protective effect of propofol compared with sevoflurane on liver function after hepatectomy with Pringle maneuver: a randomized clinical trial

Dear Dr. Matsumi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Dr. Hossam Eldien Ahmed Anis ElShamaa

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. CONSORT checklist.

    (DOC)

    Click here for additional data file. (196.7KB, doc)
    S1 Table. The preliminary study’s data set.

    This table contains the data set for the power calculation.

    (XLSX)

    Click here for additional data file. (9.8KB, xlsx)
    S2 Table. Patients’ characteristics in a per-protocol analysis.

    ASA-PS: American Society of Anesthesiologists Physical Status, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin. Data are presented as the % of the total number or mean [standard deviation], where appropriate.

    (DOCX)

    Click here for additional data file. (14.2KB, docx)
    S3 Table. Outcome parameters at univariable analysis in a per-protocol analysis.

    AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, tBil: total bilirubin, SAE: serious adverse events. Data are presented as the % of the total number or mean [standard deviation], where appropriate. A p-value less than 0.05 was considered to be statistically significant.

    (DOCX)

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    S4 Table. Multivariable linear regression of postoperative peak transaminase levels in a per-protocol analysis.

    AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, TIT: total ischemic time, 95%CI: 95% confidence interval. A p-value less than 0.05 was considered to be statistically significant.

    (DOCX)

    Click here for additional data file. (12.3KB, docx)
    S5 Table. The study’s minimal underlying data set.

    This table contains the data set underlying the results described in the manuscript.

    (CSV)

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    S1 File. Study protocol (Japanese).

    (DOCX)

    Click here for additional data file. (82.1KB, docx)
    S2 File. Study protocol (English).

    (DOCX)

    Click here for additional data file. (82.1KB, docx)
    Attachment

    Submitted filename: renamed_2a3c7.docx

    Click here for additional data file. (139.9KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (39.4KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript.

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