Defining the ideal dose of indocyanine green dye for the identification of biliary structures during surgical treatment to remove the gallbladder
| ISRCTN | ISRCTN10190039 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10190039 |
| Secondary identifying numbers | 27 |
- Submission date
- 06/05/2022
- Registration date
- 30/05/2022
- Last edited
- 21/07/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Digestive System
Plain English Summary
Background and study aims
Cholecystectomy is a surgical procedure to remove the gallbladder: a small organ that sits below the liver on the upper right side of the abdomen. The gallbladder collects and stores bile, a digestive fluid produced by the liver. The gallbladder is connected to the liver and the bowel through small tubes that allow bile flow (biliary ducts or biliary tree). In case of common benign pathology like gallstones (cholelithiasis) and polyps (adenomyomatosis) the gallbladder should be removed. The cholecystectomy is commonly performed by inserting a video camera and surgical tools through four small incisions to see inside the abdomen and remove the gallbladder (laparoscopic cholecystectomy). It is a common surgical procedure, but it can be associated with some complications. The worst complications of cholecystectomy are injuries to the biliary tree. To date, the incidence of bile duct injury during laparoscopic cholecystectomy is about 0.3 %.
Over the last years, several techniques have been introduced into clinical practice to identify bile ducts. One of these techniques allows the identification of biliary structures after the administration of a green fluorescent dye called indocyanine green (ICG; indocyanine green fluorescent cholangiography). Dedicated surgical tools allow the identification of this fluorescent dye during surgery. Scientific studies demonstrated that this technique is better at identifying biliary structures compared to surgical procedures without the dye.
To date, the standard dose and timing of ICG administration for cholecystectomy have not been defined.
About 0.1-0.5 mg/kg of ICG are administered 3-12 hours before surgery. This dose allows visualization of biliary structures with intense green colour (high fluorescence intensity), but it is always associated with intense green colour in the liver parenchyma too (fluorescence hepatic background) with consequent reduction of biliary ducts identification. Recently, some studies tried to assess the correct dose and timing for this procedure, concluding that the ICG should be administered 3-10 hours before surgery. The first limit of this study is to assess a standard ICG dose for all patients, as in order to achieve a good visualization of biliary ducts weight-based dosing has to be defined. Furthermore, for routine clinical practice, administration of ICG several hours before surgery is unpractical, since most of the patients who undergo this surgical procedure are admitted the same day as surgery.
The primary aim of this study is to define the ideal range of ICG doses that should be administered in order to identify the biliary tree during the surgical procedure. The secondary aims are to define when the fluorescent dye should be administered and how the dye should be prepared for the administration.
Who can participate?
Patients aged 18 years and over requiring gallbladder removal (cholecystectomy) for gallbladder stones (cholelithiasis) or polyps (adenomyomatosis)
What does the study involve?
Participants undergo gallbladder removal with the use of a fluorescent dye injected into a vein before surgery (laparoscopic cholecystectomy with ICG fluorescent cholangiography). The study does not provide any change from the standard surgical procedure, apart from a reduction of the standard fluorescent dye dose. A follow-up visit is performed 30 days after surgery. Surgical procedures are anonymously recorded and images from the procedures are analysed.
What are the possible benefits and risks of participating?
The possible benefit of using a lower dose of the fluorescent dye is achieving a better visualization of the structures that connect the liver, gallbladder and bowel (biliary tree), reducing the risk of injury of these structures that would lead to further procedures. The only risk associated with the fluorescent dye indocyanine green is allergic reactions in patients with an allergy to iodides. Patients with a known allergy to iodides cannot be included in the study.
Where is the study run from?
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (Italy)
When is the study starting and how long is it expected to run for?
September 2020 to April 2022
Who is funding the study?
1. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Italy)
2. Arthrex GmbH (Germany)
Who is the main contact?
1. Ludovica Baldari, ludovica.baldari@policlinico.mi.it
2. Luigi Boni, luigi.boni@unimi.it
Contact information
Scientific
Via Francesco Sforza 35
Milan
20122
Italy
 ORCID ID |
0000-0002-7029-8485 |
|---|---|
| Phone | +39 (0)3391381687 |
| ludovica.baldari@policlinico.mi.it |
Principal Investigator
Via Francesco Sforza, 35
Milan
20122
Italy
| ORCID ID |
0000-0002-5906-3810 |
|---|---|
| Phone | +39 (0)255035610 |
| luigi.boni@unimi.it |
Study information
| Study design | Observational case series |
|---|---|
| Primary study design | Observational |
| Secondary study design | Case series |
| Study setting(s) | Hospital |
| Study type | Other |
| Scientific title | Defining the ideal indocyanine green dose for fluorescent cholangiography during laparoscopic cholecystectomy |
| Study acronym | INGreDo |
| Study hypothesis | The aim of the study is to define the ideal range of indocyanine green (ICG) doses (mg/kg) that should be administered intravenously in order to perform fluorescence cholangiography during laparoscopic cholecystectomy. The ideal dose is defined by the combination of evidence of high fluorescence intensity of biliary structures and the absence of fluorescence of the surrounding liver parenchyma. |
| Ethics approval(s) | Ethics approval not required: indocyanine green (ICG) is a dye approved for medical use by the Italian Medicine Agency (AIFA), as well as by the FDA, and is currently used in routine clinical practice for fluorescent cholangiography. ICG fluorescent cholangiography is daily used in every cholecystectomy as it has been demonstrated as able to reduce the number of complications during surgery (Tokyo Guidelines 2018). The study does not involve any change in standard surgical technique. Evaluation of the visualization of biliary structures is performed through surgical video analysis, which is not directly related to the health and illness of the patients. Preliminary consultation with the ethics committee was made and confirmation of not requiring approval was obtained |
| Condition | Benign gallbladder diseases: cholelithiasis, adenomyomatosis |
| Intervention | The study defines the ideal range of ICG dose (mg/kg), timing of administration and dilution for fluorescent cholangiography and is divided into two parts: the first one identifies the best four ICG doses in a group of 14 patients by applying the bisection method; then these four doses are tested in four groups (four patients for each group) to confirm the defined range of ICG dose; in the second part of the study the ICG dose is tested in a series of 50 consecutive cholecystectomies to confirm the optimal dose, dilution and administration timing. Enrolled patients undergo laparoscopic cholecystectomy with fluorescent cholangiography with intravenous administration of ICG before surgery due to cholelithiasis or adenomyomatosis. Starting from the current ICG dose used in routine clinical practice, the ICG dose is gradually reduced until the identification of good visualization fluorescence into the biliary tree with the absence of fluorescence in the liver parenchyma. Fluorescence intensity of biliary structures and liver parenchyma is measured through two evaluations: 1. Subjective evaluation by the operating surgeon and ranked as 1(absent), 2 (poor) 3 (medium), 4 (high) 2. Objective evaluation performed using ImageJ software(*) on selected pictures captured on recorded surgical procedures The evaluation through the ImageJ software is performed: 1. On cystic duct and on common bile duct if visible, in order to define the fluorescence intensity 2. On liver parenchyma: on the left/right side of the infundibulum (next to the cystic duct), in order to define the liver background. The range of ICG dose is defined by the best balance between the highest fluorescence intensity of biliary structure associated with the lowest liver parenchyma background achievable. Data obtained by objective evaluation (through the ImageJ software) are used to define the signal to background ratio (SBR) = mean signal of biliary structures fluorescence intensity / mean signal of liver background to strengthen data. A follow-up visit is performed 30 days after surgery. |
| Intervention type | Procedure/Surgery |
| Primary outcome measure | The definition of the ideal range of ICG dose (mg/kg) for fluorescent cholangiography. Fluorescence intensity of biliary structures and liver parenchyma is measured through two evaluations twice for each patient during the same surgical procedure (before and after dissection of Calot's triangle): 1. Subjective evaluation by the operating surgeon and ranked as 1 (absent), 2 (poor) 3 (medium), 4 (high) 2. Objective evaluation performed using ImageJ software(*) on selected pictures captured on recorded surgical procedures Evaluation is performed using the ImageJ software: 1. On cystic duct and on common bile duct if visible, in order to define the fluorescence intensity 2. On liver parenchyma: on the left/right side of the infundibulum (next to the cystic duct), in order to define the liver background. The range of ICG dose is defined by the best balance between the highest fluorescence intensity of biliary structure associated with the lowest liver parenchyma background achievable. Data obtained by objective evaluation (through the ImageJ software) are used to define the signal to background ratio (SBR) = mean signal of biliary structures fluorescence intensity / mean signal of liver background to strengthen data. |
| Secondary outcome measures | 1. Best timing for IV ICG administration measured in minutes before surgery. The pre-established administration timing is 1 hour before surgery, and it is eventually modified according to the results of the first part of the study 2. Best dilution of ICG measured in milliliters. Starting from 10 ml dilution with sterile water, it is increased according to the dose identified at the end of the first part of the study |
| Overall study start date | 10/09/2020 |
| Overall study end date | 30/04/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 80 |
| Total final enrolment | 80 |
| Participant inclusion criteria | 1. Age ≥18 years old 2. Indication for cholecystectomy (gallstones disease; adenomyomatosis) 3. Ability to understand and follow study procedures 4. Having provided signed consent |
| Participant exclusion criteria | 1. Known allergy to iodides 2. Coagulopathy 3. Pre-existing liver disease 4. Pregnancy 5. Acute cholecystitis 6. BMI ≥40 kg/m² |
| Recruitment start date | 30/09/2020 |
| Recruitment end date | 28/03/2022 |
Locations
Countries of recruitment
- Italy
Study participating centre
Milan
20122
Italy
Sponsor information
Hospital/treatment centre
via Francesco Sforza 35
Milan
20122
Italy
| Phone | +39 (0)25503 5610 |
|---|---|
| anna.banfi@unimi.it | |
| Website | https://www.policlinico.mi.it |
"ROR" |
https://ror.org/016zn0y21 |
Funders
Funder type
Hospital/treatment centre
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Policlinico of Mila, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, "Ca' Granda Ospedale Maggiore Policlinico" Foundation, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico
- Location
- Italy
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Arthrex Medizinische Instrumente GmbH
- Location
- Germany
Results and Publications
| Intention to publish date | 30/09/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Baldari Ludovica (ludovica.baldari@policlinico.mi.it). Each subject provides written consent with knowledge of the procedures involved. Hard copy documents are retained for the duration of the study until data entry. All hard copy documents are kept in a locked cabinet. Data entry (data from image analysis) is completed in an Excel secure database (password protected), which covers all the created case report forms (CRFs). Only de-identified data are used for data analysis. All hard copy documents will be stored for a maximum of 10 years after completion of the study and then they will be shredded upon Sponsor approval. The Principal Investigator will be responsible for data handling and keeping before, during and after the present study. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 1 | 13/02/2021 | 29/12/2022 | No | No |
| Results article | 20/07/2023 | 21/07/2023 | Yes | No |
Additional files
Editorial Notes
21/07/2023: Publication reference added.
29/12/2022: Protocol file uploaded.
12/07/2022: The intention to publish date was changed from 30/07/2022 to 30/09/2022.
10/05/2022: Trial's existence confirmed by the Research Office of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan.
