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Abstract
Introduction Bile leakage (BL) after hepatectomy cannot always be detected with conventional methods; moreover, BL cannot be completely prevented. Recently, navigation procedures with indocyanine green (ICG) have been reported. Furthermore, we previously reported the possibility of detecting BLs with high sensitivity during hepatectomy by administering ICG into the bloodstream, which is quickly excreted in the bile. This study aims to verify whether detecting and addressing ICG leakage from the hepatic dissection plane using an ICG camera can reduce the bilirubin concentration in the drainage fluid, and consequently, the incidence of BL.
Methods and analysis This prospective single-centre non-randomised single-arm trial will be conducted with historical controls. Overall, 85 patients will be enrolled, including 40 and 45 in the ICG and historical control groups, respectively. In the ICG group, 10 mg/2 mL of ICG will be transvenously or transportally administered during liver surgery. After its uptake by liver cells and excretion into bile, it will be visualised using a camera following the completion of hepatectomy, and the site of ICG leakage will be sutured. Moreover, we will record the number of bile leak spots detected by the naked eye and ICG camera. The primary endpoint of the study will be the total bilirubin concentration in the drain fluid on postoperative day 3, and we will determine whether the concentration differs significantly between the ICG and historical control groups. The results of our study will be used to suggest whether intraoperative ICG administration and evaluation at the hepatic dissection plane can be widely used in liver surgery for more reliable detection of BL and consequent reduction of biliary fistula.
Ethics and dissemination The protocol was approved by the Certified Review Board of Tottori University Hospital (approval number: 21C002). Findings from this trial will be published in peer-reviewed journals and presented at academic conferences.
Trial registration number jRCTs061210043.
- surgery
- hepatobiliary surgery
- clinical trial
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Indocyanine green (ICG) administered into the bloodstream is quickly excreted into bile, and bile leakage from the hepatic dissection plane can be detected with high sensitivity using an ICG camera, which enables the prevention of biliary fistulas during hepatectomy.
To the best of our knowledge, this will be the first trial of the effect of systemic administration of ICG in the hepatic dissection plane in the prevention of posthepatectomy biliary fistula.
Levels of bilirubin in the drainage fluid on postoperative day 3 in a group of patients prospectively treated with ICG will be compared with those in a group of patients who underwent hepatectomy at the time when ICG was not used intraoperatively (the historical control group) in order to determine the effectiveness of intraoperative ICG administration and evaluation in preventing biliary fistulas.
The inclusion of a historical control group has the inherent disadvantages of non-randomisation and non-blinding; therefore, we cannot exclude the possibility of selection, attrition, performance or detection bias.
Introduction
Posthepatectomy biliary fistula is caused by bile leakage (BL) and is a complication of hepatectomy, and its incidence ranges from 4% to 10%.1 2 Although it generally resolves spontaneously with drainage, occasionally, biliary fistula is persistent. Notably, persistent BL and biliary fistula can cause severe complications owing to intra-abdominal infection.3 4 According to the diagnostic criteria proposed by the International Study Group of Liver Surgery (ISGLS) in 2011, posthepatectomy BL5 is defined by a drainage fluid bilirubin concentration ≥3 times the serum bilirubin concentration on or after postoperative day (POD) 3 or the need for one radiological or surgical intervention for bile accumulation or biliary peritonitis. The severity of BL is classified into four levels: none; grade A leakage, necessitating no or little change in patients’ clinical management; grade B leakage, necessitating active therapeutic intervention but not repeat laparotomy; and grade C leakage, necessitating relaparotomy.
Although intraoperative cholangiography is an established technique for preventing postoperative BLs,6 it has various disadvantages, including the inability to detect BLs from small bile duct injuries; the inability to address BLs from bile ducts that do not communicate with the common bile duct, such as those caused by Nagano’s type D7 or Strasberg’s type C bile duct injuries;8 and the inconvenience of using intraoperative radiographic equipment. In contrast, during the BL test, a catheter is placed through the cystic duct into the common bile duct, and a dye solution injected into the catheter reveals the site of the leakage. The BL test has the advantages of directly confirming the damaged bile ducts and enabling immediate repair.9 Wang et al performed a meta-analysis of two randomised controlled trials and three controlled clinical trials investigating BL test frequency and BL repair.10 They confirmed that the BL test decreased the frequency of BL.
However, similar to intraoperative cholangiography, BL from bile ducts that are not in contact with the common bile duct cannot be detected using the BL test. Moreover, it is difficult to cannulate a catheter and inject a dye solution into the cystic duct of patients who do not undergo cholecystectomy. Therefore, a new simpler testing method is required to reveal all types of BLs.
Indocyanine green (ICG) is recognised as a reagent used to evaluate preoperative liver function. Notably, ICG administered into the bloodstream is rapidly excreted into the bile after its uptake by hepatocytes.11 Moreover, it has been used to evaluate blood flow during navigation studies,12 and as ICG administrated into the bloodstream is excreted in bile, it may help reveal BLs. Our previous retrospective study reported that because of the use of ICG and the intraoperative detection and treatment of ICG leakage in the bile during hepatectomy, the levels of bilirubin in the drainage fluid were reduced (figure 1).13 The presence or absence of BL after the completion of liver resection was conventionally confirmed only with the naked eye, and the leaks that could not be visually confirmed occasionally became BLs later, resulting in biliary fistula. In this study, we will systemically administer ICG intraoperatively to observe the hepatic dissection plane, which, in addition to intraoperative visual confirmation of BL, may allow for more accurate detection and treatment of BL. Thus, the increase in bilirubin concentration in the drainage fluid will be reduced and BL—a major complication occurring after hepatectomy—will be prevented.
Observation of the hepatic dissection plane. On naked‐eye observation (A), the gauze pressed against the hepatic dissection plane did not appear to be stained yellow with bile. Near-infrared observation of the same gauze (B) revealed indocyanine green fluorescence, indicating contamination due to bile leakage that could not be observed with the naked eye (arrowheads) and the corresponding Glisson that caused the bile leakage was identified (arrow) (B). A Z-shaped suture was added to the Glisson, and the contamination of the gauze was later eliminated.
Methods and analysis
Study design
In this clinical prospective single-centre non-randomised single-arm study, we will compare the drainage fluid bilirubin levels in a group of patients prospectively receiving systemic ICG during liver resection whose liver dissection planes will be assessed using an ICG camera with a group of historical controls who had undergone hepatectomy at a time when ICG was not used. The selection flowchart for this study is shown in figure 2. The study was started in September 2021 at Tottori University Hospital, Yonago, Japan, and will continue until December 2023, and the analysis is expected to be completed by December 2024. This study protocol is based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement (online supplemental material 1).14
Supplemental material
Flow chart of selection for the trial. ICG, indocyanine green.
Study participants
Potential members of the ICG group are patients scheduled for hepatectomy for primary liver cancer, metastatic liver cancer and benign liver lesions during the study period. The study will include the following patients: (1) those undergoing open or laparoscopic hepatectomy for elective surgery for primary liver cancer, metastatic liver cancer or benign liver lesions; (2) those with an Eastern Cooperative Oncology Group (ECOG) Performance Status scores of ≤1; (3) males and females aged ≥20 years at the time of obtaining consent; (4) those without severe preoperative complications and (5) those who received a full explanation of the content of this study from the principal investigator, understood the purpose of the study and voluntarily provided their written consent to participate in the study. The trial will exclude the following patients: (1) those undergoing emergency hepatectomy, (2) those with a history of hypersensitivity to any component of ICG, (3) those with a history of iodine hypersensitivity, (4) those who are or may be pregnant, (5) those who are breastfeeding, (6) those who participated in other clinical trials or studies and used unapproved or off-label drugs within 3 months before enrolment in this study and (7) those whose participation in this trial is judged to be inappropriate by the investigators.
The historical control group will include patients who underwent hepatectomy between April 2018 and July 2020, that is, the period when ICG was not used to evaluate the intraoperative hepatic dissection plane. This group will include ≤45 patients who meet the following criteria: (1) those who underwent hepatectomy for primary liver cancer, metastatic liver cancer, or benign liver tumours as well as underwent drainage at Tottori University Hospital before July 2020, regardless of whether the operation was open or laparoscopic; (2) those with ECOG Performance Status scores of ≤1; (3) males and females aged ≥20 years at the time of surgery; (4) those whose data include total bilirubin concentration in drainage fluid on POD 3 and (5) those without preoperative severe complications.
Schedule of the study
Informed consent for participation in this study will be obtained from each patient in the ICG group after reviewing the inclusion/exclusion criteria, participant’s background and ECOG Performance Status score. Within 28 days before surgery, we will evaluate and record blood test values, such as complete blood cell count; levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, alkaline phosphatase, total and direct bilirubin, total cholesterol, albumin, blood urea nitrogen, creatinine, C reactive protein, serum sodium and serum potassium; results of blood coagulation and ICG tests; and urinalysis results and radiological findings. Further, the collected samples (blood and urine) will be examined on admission, 2 days before surgery, and on specific days after surgery (PODs 1, 2, 3, 5 and 7). The following intraoperative information will be documented: surgical approach (laparoscopic vs open), area of liver resection, type of liver resection (anatomical vs nonanatomical), weight of resected specimen, position of inserted drain, length of operation, amount of intraoperative blood loss, whether blood transfusion is performed, and number of BL spots (seen by the naked eye vs under near-infrared light). The bilirubin concentration of the drainage fluid will be measured on PODs 1 and 3 (and on PODs 5 and 7 if the drain is retained), and the drainage fluid will be cultured simultaneously. We will also record the number of days from surgery to discharge. The presence of BL or biliary fistula based on physical examination of drainage fluid, volume of drainage effluent, and postoperative complications will be evaluated on each day of hospitalisation and at the first outpatient visit after discharge (between PODs 21 and 35). Any adverse event occurring during the study period will be recorded. The schedule of activities in this study is summarised in online supplemental table 1 and online supplemental material 2.
Supplemental material
Intervention
Liver resection (open or laparoscopic) will be performed according to the usual practice. At the start of hepatic parenchymal dissection (approximately 1–2 hours before the completion of hepatic dissection), 10 mg/2 mL of ICG (Daiichi Sankyo Company Limited, Tokyo, Japan) will be administered intravascularly. After hepatic resection is completed, the abdominal cavity will be thoroughly flushed with saline solution, and the presence and number of BL spots will be observed with the naked eye. A Stryker 1588 AIM system (Stryker, Kalamazoo, Michigan, USA) will then be used to irradiate the area of the hepatic dissection plane with near-infrared light, and the near-infrared light excitation will be observed to record the presence or absence of ICG fluorescence on the gauze at the site of liver resection, which is used to determine contamination by bile, as well as the number of leakage spots. If bile or ICG in bile is confirmed on the gauze, the leaking bile duct will be sutured and treated. Further, we will diagnose postoperative BL according to the ISGLS definition of BL using biochemical methods to measure the total bilirubin level in the serum and drainage fluid from the abdominal cavity on POD 3. If possible, the drain will be removed on POD 3 according to the usual practice. If the postoperative course is uneventful, the patient will be discharged based on the decisions within the scope of routine care. Subsequently, BL will be evaluated in the outpatient clinic between PODs 21 and 35.
If any of the following conditions occur after starting the administration of the research drug, the principal investigator or research assistant will stop the study and conduct an examination at the time of discontinuation: (1) if the participant declines to participate in the research or withdraws consent; (2) if the participant is found to be ineligible after enrolment; (3) if the continuation in the study is considered undesirable due to deterioration of the primary disease; (4) if it is difficult to continue the study owing to worsening complications; (5) if it is difficult to continue the research because of adverse events; (6) if it is impossible to continue the research owing to the inconvenience of the research participant, such as moving to a new place of residence; (7) if pregnancy is detected; (8) if there is a failure of the research equipment; (9) if the overall research is discontinued and (10) if, for other reasons, the principal investigator or research assigning physician decides that it is appropriate to discontinue the research.
If a safety problem, such as the occurrence of an adverse event, occurs and the study is discontinued, the principal investigator or research assistant physician will immediately take appropriate measures and conduct follow-up investigations until recovery as far as possible.
Outcomes
Primary endpoint
The primary endpoint of this study is the decreased total bilirubin concentration in drainage fluid on POD 3.
Secondary endpoints
The secondary endpoints are as follows: (1) incidence of postoperative BL after hepatectomy (according to the definition by ISGLS), (2) presence and number of BL spots on the hepatic dissection plane after hepatectomy, (3) changes in total bilirubin concentration in drainage fluid from PODs 1–3, (4) total estimated bilirubin concentration on POD 1, (5) presence/absence and type of bacteria in drainage fluid with effluent culture, (6) length of postoperative hospitalisation and (7) adverse events, adverse effects and postoperative complications during the whole observation period (according to the Clavien-Dindo classification).15
Sample size calculation
The mean values of total bilirubin concentration in drainage fluid on POD 3 in 22 ICG-treated patients and 50 historical controls who did not receive ICG at Tottori University Hospital were 1.377 mg/dL (SD, 0.596 mg/dL) and 2.476 mg/dL (SD, 2.266 mg/dL), respectively. According to the evidence and a relatively conservative estimate of the differences between the two groups, with a mean total bilirubin concentration of 1.3 mg/dL (SD, 1.1 mg/dL) in the group receiving the study drug, a sample size of 40 cases was required to achieve 80% power. Therefore, the sample size of the ICG group in this trial was 40.
Statistical analysis
Patients’ baseline characteristics
The summary of statistical values will be obtained from the baseline characteristics data. For categorical variables, frequencies and proportions will be calculated, whereas for continuous variables, the number of participants, mean values, SDs, minimum values, medians and maximum values will be calculated.
Efficacy analysis
For the statistical analysis of the primary endpoint, we will use propensity score weighting analysis to compare the decrease in total bilirubin concentration in drainage fluid on POD 3 between the ICG and historical control groups.16 Notably, propensity score weighting enables balancing of the potential confounding factors between the two groups as well as adjusts the resultant bias effectively.16 Further, to estimate the propensity score, we will use a logistic regression model in which the outcome variable is the group indicator variable (intervention or control) and the explanatory variables are age, sex, body mass index, degree of fibrosis in the background liver tissue (Inuyama class F0–F4),17 preoperative blood test results (total bilirubin concentration, albumin level, platelet count and prothrombin time (percentage)), and the weights of the resected liver specimens. Further, we will use the estimated propensity scores to calculate the inverse probability of treatment weighting (IPTW) estimator of the mean difference and its 95% CI. We will also perform a statistical test for the null hypothesis to ensure that the mean difference is 0 according to the IPTW method, with a significance level of 5% (two sided).
Further, for the analyses of secondary endpoints, we perform the IPTW analysis to compare the incidences of postoperative BL after hepatectomy. For the presence and number of BL spots on the hepatic dissection plane after hepatectomy, we will summarise the outcome data in terms of means and SDs and will perform a paired t-test to compare the mean values of changes in the numbers of BL spots before and after hepatectomy. We will also summarise descriptive statistical values for changes in total bilirubin concentration in drain fluid between PODs 1 and 3, estimated total bilirubin on POD 1, presence/absence and type of bacteria in drainage fluid based on effluent culture, length of postoperative hospital stay, adverse events, adverse effects and postoperative complications throughout the observation period.
Data management and monitoring
All study-related information will be securely stored at the study site. Moreover, to maintain participant confidentiality, participants will be identified only by a coded number that will be stored securely at the study site. Participant confidentiality will be maintained. All participant information will be stored in a locked file cabinet at the Department of Gastrointestinal and Pediatric Surgery, Tottori University, with restricted access. All records containing names or additional personally identifiable information will be stored separately from research records identified by code numbers. A password-protected access system will be used to protect all local databases. Participant research information will not be released outside the study without obtaining written permission from the participant. All authors take responsibility for the integrity of the data and accuracy of the data analysis. The study will not involve a data management committee because we will not perform any interim analysis.
An independent monitor at Tottori University Hospital will review the source documents, as needed, to determine whether the data reported in the electronic data are complete and accurate. Source documents are defined as medical charts and associated reports.
Patient and public involvement statement
Patients and members of the public were involved in this study. Three lay representatives were involved in the protocol design and ethical approval. The study protocol and patient-related trial documents, including the information sheets and consent forms, have been reviewed by the trial’s lay representatives.
Ethics and dissemination
This study is being conducted according to the 1964 Declaration of Helsinki and the Clinical Trials Act in Japan. The Certified Review Board of Tottori University Hospital approved the study protocol on 27 September 2021 (approval number: 21C002, see protocol data set in online supplemental material 3). In the case of an adverse event caused by the administration of ICG, this trial will provide compensation. Moreover, the compensation for adverse events caused by participation in this study is also described in the informed consent form.
Supplemental material
The results of this study will be published in respected peer-reviewed journals and findings will be presented at scientific conferences in the field of surgery.
Protocol changes
Any further amendments to the protocol will be recorded by the Japan Registry of Clinical Trials according to the SPIRIT guidelines. Any changes in the trial protocol (ie, changes in eligibility criteria, outcomes or analyses) will be implemented via a new version of the full trial protocol, and tracked with the date of the update and the version number of the trial protocol. A list summarising the changes made in each protocol revision will be included at the end of each protocol. The updated protocol will be sent to the Certified Review Board of Tottori University Hospital for tracking before the implementation of the protocol change.
Discussion
BL is widely recognised as a problem in liver resection. Moreover, the study by Hayashi et al reported the relationship between the intraoperative detection of BL and the incidence of biliary fistula.18 Despite various attempts to prevent BL and biliary fistula, they continue to occur in many cases. As previously reported, cholangiography and BL tests effectively detect damaged bile ducts, but these methods necessitate the administration of a drug into the bile duct. Notably, the administration of dye or contrast medium into the bile duct is an essential step before detecting bile duct injury points; however, an excessive dose of contrast medium can cause barotrauma, resulting in new bile duct injury whose management requires professional skill.19 ICG, which is spontaneously excreted into the bile duct after its administration into the bloodstream, can be detected at the site of bile duct injury on the hepatic dissection plane without the concern of new injury from injection pressure, which is noted in cholangiography or BL testing.
In addition, because the detection of BL with ICG involves the step of excretion from hepatocytes, ICG administration is effective to identify injuries to bile duct that connect to the common bile/hepatic duct as well as to identify other types of injuries to bile duct that have no such connections.11
Based on the abovementioned findings, we are conducting this trial considering that the detection of leaking ICG with an ICG camera will help expose BLs that are not detected by the naked eye. The bilirubin levels in drainage fluid on POD 3 in a group of patients prospectively treated with ICG will be compared with those in a group of patients who underwent hepatectomy at a time when ICG was not used intraoperatively in order to evaluate the efficacy of intraoperative ICG administration and evaluation in preventing biliary fistula. To the best of our knowledge, this will be the first trial to evaluate the effects of systemic administration of ICG on the hepatic dissection plane for preventing posthepatectomy biliary fistula, although bias cannot be completely eliminated owing to the design of the study (ie, a relatively small number of participants and a prospective single-arm clinical trial with a historical control group).
Although the use of ICG in this study will be off-label according to Japanese health insurance in 2022, the dose of ICG (10 mg/2 mL) is lower than that used in preoperative liver function tests (0.5 mg/kg) for adults with average physique. We believe that this dose is safe and acceptable for patients. The results of this study will help establish the procedure for ICG assessment and treatment in hepatectomy, which can help liver surgeons to more sensitively detect intraoperative BL and thereby prevent postoperative biliary fistula. This study will provide foundational data to optimise ICG administration to be used as a prerequisite for planning subsequent confirmatory studies or to provide additional evidence for insurance coverage for the use of ICG in hepatectomy.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors TaH, NT, YE, HS, HN and YF substantially contributed to the study design. TaH, KG, TepS, YM, TM and MY drafted the manuscript. TerS, ToH and YF were involved in supervising the manuscript. All authors critically reviewed and provided final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.