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Received: 24 October 2024
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Accepted: 14 January 2025
Published: 16 January 2025
Citation: Pavulans, J.; Jain, N.; Zeiza,
K.; Sondore, E.; Cerpakovska, K.B.;
Opincans, J.; Atstupens, K.; Plaudis,
H. Fluorescence Cholangiography for
Extrahepatic Bile Duct Visualization
in Urgent Mild and Moderate Acute
Cholecystitis Patients Undergoing
Laparoscopic Cholecystectomy: A
Prospective Pilot Study. J. Clin. Med.
2025,14, 541. https://doi.org/
10.3390/jcm14020541
Copyright: © 2025 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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conditions of the Creative Commons
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(https://creativecommons.org/
licenses/by/4.0/).
Article
Fluorescence Cholangiography for Extrahepatic Bile
Duct Visualization in Urgent Mild and Moderate Acute
Cholecystitis Patients Undergoing Laparoscopic
Cholecystectomy: A Prospective Pilot Study
Janis Pavulans 1,2,3,*, Nityanand Jain 4, Kaspars Zeiza 1,3, Elza Sondore 3, Krista Brigita Cerpakovska 3,
Janis Opincans 1,3, Kristaps Atstupens 3and Haralds Plaudis 1,3
1Department of Surgery, Riga Stradinš University, 16 Dzirciema Street, LV-1007 Riga, Latvia;
kaspars.zeiza@rsu.lv (K.Z.); janis.opincans@rsu.lv (J.O.); hplaudis@gmail.com (H.P.)
2Department of Doctoral Studies, Riga Stradinš University, 16 Dzirciema Street, LV-1007 Riga, Latvia
3Department of General Surgery, Riga East Clinical University Hospital, LV-1038 Riga, Latvia;
017299@rsu.edu.lv (E.S.); kc13040@students.lu.lv (K.B.C.); kristofss@inbox.lv (K.A.)
4Statistics Unit, Riga Stradinš University, 16 Dzirciema Street, LV-1007 Riga, Latvia; nityapkl@gmail.com
*Correspondence: janis.pavulans@rsu.lv
Abstract: Background: Laparoscopic cholecystectomy for acute cholecystitis carries an
increased risk of biliovascular injuries. Fluorescence cholangiography (FC) is a valuable
diagnostic tool for identifying extrahepatic bile ducts (EHBD). The objective of this study
was to evaluate the efficacy of FC in delineating EHBD anatomy, both before and after
dissection, based on the critical view of safety (CVS) principles. Methods: Urgently
admitted patients were prospectively stratified into two groups, depending on whether
they had mild or moderate acute cholecystitis, in accordance with the 2018 Tokyo guidelines.
All patients were scheduled for an early laparoscopic cholecystectomy using FC and
were administered a fixed dose of indocyanine green (ICG) intravenously 12 h prior to
the surgical procedure. Results: A total of 108 patients—75 patients with mild acute
cholecystitis and 33 patients with moderate acute cholecystitis—were included. More than
four CVS steps were performed in 101 patients (93.5%). Less than four CVS steps were
performed only in seven patients—three (2.5%) patients with mild acute cholecystitis and
four (4%) patients with moderate acute cholecystitis. The achievement of the CVS principles
and the visualization rate using FC significantly increased in both patient groups, ranging
from 3% before CVS to 100% after CVS (p< 0.001). In both groups, the cystic duct was
visualized in most patients after CVS and FC, followed by the common bile duct and the
common hepatic duct. Conversely, even after using CVS and FC, the visualization of the
confluence of the cystic and common hepatic ducts remained less likely and challenging in
both groups (57.3% in mild patients vs. 33.3% in moderate patients; p= 0.022). Background
liver fluorescence disturbance was observed equally in both patient groups (6–11%), but
it did not reach statistical significance. The median operative time was 60
±
25 min in
patients with mild acute cholecystitis compared to 85
±
37 min in patients suffering from
moderate acute cholecystitis (p< 0.001). No postoperative complications or biliovascular
injuries were observed. Conclusions: FC is a convenient, safe, and efficacious procedure
for attaining CVS principles and identifying the EHBD anatomy in most patients. The
procedure showed superior results in mild acute cholecystitis patients in comparison to
moderate acute cholecystitis patients.
J. Clin. Med. 2025,14, 541 https://doi.org/10.3390/jcm14020541
J. Clin. Med. 2025,14, 541 2 of 17
Keywords: gallstone disease; laparoscopic cholecystectomy; fluorescence cholangiography;
critical view of safety; acute cholecystitis
1. Introduction
Gallstone disease is among the most frequently diagnosed gastrointestinal disorders,
with an estimated global prevalence of 9 to 20% [
1
–
3
]. The prevalence of the disease varies
according to gender and ethnicity, with a greater predisposition among women and an
inverse correlation with age [
2
,
3
]. A significant proportion of those affected, approximately
one-fifth, are reported to develop complications associated with the stones over the course
of their lifetime [
3
]. One of the most often observed gallstone-related complications is
acute cholecystitis, or inflammation of the gallbladder. While acalculous cholecystitis
represents approximately 10% of all acute cholecystitis cases, it is predominantly ischemic
and associated with an elevated risk of necrosis and perforation [4].
Regardless of the underlying etiology, the gold standard for the treatment of acute
cholecystitis is a laparoscopic cholecystectomy (LC). Since the early 1990s, laparoscopic
surgery has largely replaced the traditional open cholecystectomy, becoming the treatment
of choice for gallbladder disease [
5
]. The rates of LCs vary considerably across Europe, with
data indicating a range from 62 surgeries in Norway to 246 surgeries in Germany per 100,000
inhabitants annually [
3
]. Although generally considered relatively safe, the procedure has
an approximate mortality rate of 0.3 to 0.5% [
3
]. The incidence of complications remains
relatively high, with the probability of minor complications ranging from 2.6 to 5.5% and
the risk of major complications ranging from 5.6 to 8.9% [6].
The most significant complication of the procedure is an iatrogenic injury to the bile
duct, which typically necessitates additional surgical intervention for repair [
7
,
8
]. Bile
duct injury is estimated to occur in 0.2% to 1.5% of all cholecystectomies [
3
,
9
]. In most
cases, an erroneous interpretation of the biliary anatomy is the fundamental trigger for
the injury [
8
]. Such errors are primarily the result of the presence of complex or unclear
anatomic morphologies and dense adhesions. The heightened degree of inflammation and
fibrosis along the dissection planes, as well as adhesions from prior surgeries, represent
additional contributing factors that can increase the likelihood of a bile duct injury, conver-
sion to open surgery, postoperative complications, and the need for subsequent surgical
interventions [8].
To mitigate the risk of such iatrogenic complications, the critical view of safety (CVS)
technique was introduced and has since become a widely utilized method in laparoscopic
cholecystectomies. The CVS method involves removing adipose and fibrous tissue from the
Calot’s triangle, isolating the inferior aspect of the gallbladder from the cystic plane, and
visualizing at least two structures as they enter the gallbladder. This allows for an easier and
clearer identification of the cystic duct and cystic artery, which is crucial for ensuring the
safety and efficacy of the surgery [
8
]. Moreover, the recent advancements in intraoperative
imaging using indocyanine green fluorescence (ICG) imaging have demonstrated the value
of this modality in identifying vital structures during a laparoscopic cholecystectomy.
ICG imaging has been documented as a straightforward, viable, secure, and cost-
effective procedure that enables surgeons to map the components of the biliary tract
system in real time through biliary fluorescence imaging, thereby providing an enhanced,
uninterrupted, and augmented view of the anatomy [
10
–
12
]. ICG is generally well-tolerated
by patients, with a low rate of allergic reactions and other severe reactions [
13
]. Post-
injection, intravenous ICG binds to plasma albumin and is exclusively excreted from the
hepatocytes to the bile, making it an ideal dye for use in the fluorescence imaging of the
J. Clin. Med. 2025,14, 541 3 of 17
biliary tree [
14
]. It has been observed that the use of ICG during LC results in a reduction in
the surgical time and a lower risk of complications such as blood loss and bile duct injury,
while exhibiting a superior success rate of biliary tract imaging compared to traditional
modalities [
11
,
12
]. Hence, the aim of this study was to evaluate the effectiveness of ICG
fluorescence cholangiography (FC) for the detection of the biliary anatomy in urgently
admitted patients presenting with mild or moderate acute cholecystitis.
2. Methods
The present single-center, prospective, and comparative study was conducted from
October 2021 to April 2024 at the General and Emergency Surgery Department of Riga
East Clinical University Hospital (RAKUS), Riga, Latvia. RAKUS is one of the largest
tertiary care hospitals in the country, offering both elective and emergency care, with nearly
10,000 surgical procedures performed annually in our clinic. The study protocol adhered
to the principles established in the Helsinki Declaration of 2008, as revised in 2013, and
received approval from the Medical and Biomedical Research Ethics Committee of the
Riga East University Hospital Support Foundation (No. 9-A/20, dated 6 August 2020). All
patients provided written informed consent to participate in the study.
2.1. Patient Selection
The study population comprised adult patients (aged 18 to 90 years) who met the
criteria for mild or moderate acute cholecystitis, as recommended by the Tokyo guidelines,
2018 (Table 1) [
15
]. The included patients were admitted through the emergency department
and prepared for an early LC (defined as within 72 h according to the Tokyo Guidelines)
the next morning. The patients received ICG the previous evening. The diagnosis was
based on clinical assessments by trained surgeons, combined with laboratory findings
and imaging modalities such as a transabdominal ultrasound. Patients with complicated
gallstone disease, allergies, or a known adverse reaction to iodine, an abnormal thyroid
metabolism, thyroid malignancy, severe coagulopathy, suspected gallbladder malignancy,
or contraindications to laparoscopic surgery or general anesthesia were excluded from the
study. Patients who refused to provide or withdrew consent were also not included.
Table 1. Severity classification for acute cholecystitis patients based on the Tokyo guidelines, 2018.
Severity Grade Diagnostic Criteria
Acute Cholecystitis
Definite diagnosis: one item in A + one item in B + C.
Suspected diagnosis: one item in A + one item in B.
A. Local signs of inflammation—(1) Murphy’s sign or (2) right upper quadrant
mass/pain/tenderness.
B. Systemic signs of inflammation—(1) Fever, (2) elevated CRP, or (3) elevated
WBC count.
C. Imaging findings—Imaging findings characteristic of acute cholecystitis.
Mild (Grade I)
Acute cholecystitis patient meeting any of the following criteria:
•
Symptoms that do not meet the criteria of Grade III or Grade II acute cholecystitis.
•Healthy patient with no organ dysfunction and mild inflammatory changes.
J. Clin. Med. 2025,14, 541 4 of 17
Table 1. Cont.
Severity Grade Diagnostic Criteria
Moderate (Grade II)
Acute cholecystitis patient presenting with any of the following symptoms:
•Leukocytosis (>18,000/mm3).
•Palpable tender mass in the right upper abdominal quadrant.
•Duration of complaints > 72 h.
•Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic
abscess, biliary peritonitis, emphysematous cholecystitis).
Severe (Grade III)
Acute cholecystitis patient presenting with dysfunction of any of the following organs/organ
systems:
•Cardiovascular dysfunction: hypotension requiring treatment with dopamine ≥5
µg/kg/min, or any dose of norepinephrine.
•Neurological dysfunction: decreased level of consciousness.
•Respiratory dysfunction: PaO2/FiO2ratio < 300.
•Renal dysfunction: oliguria, creatinine > 2.0 mg/dL.
•Hepatic dysfunction: PT-INR > 1.5.
•Hematological dysfunction: platelet count < 100,000/mm3.
2.2. Surgical Procedure
Laparoscopic cholecystectomy with FC under general anesthesia was performed for
the included patients. A dose of 12.5 mg of ICG dye with 10 cc of saline was administered
intravenously 12 h prior to the surgical procedure. The surgeries were performed by a team
of 2–3 certified hepato-pancreato-biliary (HPB) surgeons with expertise and confidence in
laparoscopic ICG visualization. The conventional four-trocar approach was used, with the
trocars placed at the 12 mm mark in the epigastrium proprium, the 10 mm mark in the
umbo, and two lateral 5 mm marks on the right side of the abdomen.
Once the pneumoperitoneum had been established, the gallbladder was retracted
cranially. Intraoperative scorings were performed both before and after the dissection
using the Systems Green ICG/near-infrared range fluorescence imaging platform (Richard
Wolf GmbH, Knittlingen, Germany). Hemoclips were used for both the cystic duct and
the cystic artery. The surgical procedures were video-documented using an endoscopic
camera inserted via the umbilical trocar. All patients, regardless of the surgical approach
employed, received standard care in accordance with local and international guidelines,
including the administration of antibacterial agents and pain management medications. A
comprehensive assessment of complications and symptomatic presentation was conducted
for all patients prior to their discharge from the hospital.
2.3. Assessment of CVS Principles
The laparoscopic cholecystectomies were performed in accordance with the CVS prin-
ciples [16] following the eight-step protocol (Figure 1; Table 2). The steps were performed
in a consecutive manner. The number of steps performed during the surgery was assessed
before and after FC.
Table 2. Overview of the critical view of safety (CVS) steps.
CVS Step CVS Step Description
I Cranial retraction of the fundus part of the gallbladder.
II Lateral retraction of the infundibulum part of the gallbladder.
III
Dissection of the visceral peritoneum with electrocoagulation, either
laterally or medially, from the infundibulum part, ascending to the fundus
part of the gallbladder.
J. Clin. Med. 2025,14, 541 5 of 17
Table 2. Cont.
CVS Step CVS Step Description
IV
Dissection of the medial adipose tissue of the gallbladder with
electrocoagulation, visualization and release of the cystic duct, and visualization
of its entry into the gallbladder.
VTotal dissection of adipose tissue and formation of a “critical safety triangle” by
separating cystic duct and cystic artery.
VI
Dissection of the infundibulum part of the gallbladder from adipose tissue and
mobilization in the anterior/posterior parts, creating the “Calot’s triangle”.
Visualization of the margin of the liver.
VII Clipping of the cystic duct (distal/proximal) from the gallbladder and its
resection. Clipping of cystic artery and its resection.
VIII Dissection of the gallbladder from the liver bed.
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 5 of 17
Figure 1. Pictorial representation of the eight steps performed as part of the critical view of safety
(CVS) principles in a mild acute cholecystitis patient undergoing a laparoscopic cholecystectomy.
For a detailed description of each step, refer to Table 1.
2.4. Intraoperative Assessment
Prior to the dissection of the visceral peritoneum, the visualization quality of the ex-
trahepatic bile duct (EHBD) structures was evaluated using both the white light mode
(WL) and FC modes. For the FC mode, the imaging platform detected fluorescence in the
wavelength of 800–850 nm (light source: LEDgreen, Richard Wolf GmbH, Germany),
where a single toggle switch enabled the transition between the WL and FC overlay
modes. The EHBD structures were then reassessed under both WL and FC modes follow-
ing the complete dissection of the cystic duct and the cystic artery. The FC visualization
quality was assessed using a Likert scale, with 1 indicating poor quality of the bile duct
visualization and 5 indicating excellent visual quality [17].
A four-point scale was employed to assess the extent to which fluorescence imaging
was perceived to be helpful in each case, with 0 indicating no helpfulness and 3 signifying
a high level of helpfulness. Additionally, the disturbance score was used to evaluate the
extent to which background fluorescence from the liver (liver-to-duct contrast when using
the ICG mode) interfered with the visualization of structures. This was achieved using a
Likert-point system, with 0 indicating no disturbance and 4 indicating an extreme disturb-
ance that made it nearly impossible to correctly visualize the biliary structures [17].
The veracity of the assigned scores was corroborated, both intraoperatively and post-
operatively, through a video review, and was assessed by a single certified surgeon. The
scoring scales demonstrated 100% concordance when comparing the intraoperative and
postoperative scoring.
2.5. Study Outcomes
The perioperative data were prospectively collected by certified surgeons from the
medical records and patient examinations. The curated dataset comprised the primary
outcomes, including the visualization rates of bile ducts and the quality of the visualiza-
tion. The secondary outcomes were bile duct injuries, the operation time, the postopera-
tive length of the hospital stay, and postoperative complications, assessed according to
the Clavien Dindo classification.
Figure 1. Pictorial representation of the eight steps performed as part of the critical view of safety
(CVS) principles in a mild acute cholecystitis patient undergoing a laparoscopic cholecystectomy. For
a detailed description of each step, refer to Table 1.
2.4. Intraoperative Assessment
Prior to the dissection of the visceral peritoneum, the visualization quality of the
extrahepatic bile duct (EHBD) structures was evaluated using both the white light mode
(WL) and FC modes. For the FC mode, the imaging platform detected fluorescence in
the wavelength of 800–850 nm (light source: LEDgreen, Richard Wolf GmbH, Germany),
where a single toggle switch enabled the transition between the WL and FC overlay modes.
The EHBD structures were then reassessed under both WL and FC modes following the
complete dissection of the cystic duct and the cystic artery. The FC visualization quality was
assessed using a Likert scale, with 1 indicating poor quality of the bile duct visualization
and 5 indicating excellent visual quality [17].
A four-point scale was employed to assess the extent to which fluorescence imaging
was perceived to be helpful in each case, with 0 indicating no helpfulness and 3 signifying
a high level of helpfulness. Additionally, the disturbance score was used to evaluate
the extent to which background fluorescence from the liver (liver-to-duct contrast when
using the ICG mode) interfered with the visualization of structures. This was achieved
using a Likert-point system, with 0 indicating no disturbance and 4 indicating an extreme
disturbance that made it nearly impossible to correctly visualize the biliary structures [
17
].
J. Clin. Med. 2025,14, 541 6 of 17
The veracity of the assigned scores was corroborated, both intraoperatively and post-
operatively, through a video review, and was assessed by a single certified surgeon. The
scoring scales demonstrated 100% concordance when comparing the intraoperative and
postoperative scoring.
2.5. Study Outcomes
The perioperative data were prospectively collected by certified surgeons from the
medical records and patient examinations. The curated dataset comprised the primary
outcomes, including the visualization rates of bile ducts and the quality of the visualization.
The secondary outcomes were bile duct injuries, the operation time, the postoperative
length of the hospital stay, and postoperative complications, assessed according to the
Clavien Dindo classification.
2.6. Statistical Analysis
A sample size estimation was not conducted due to the use of a purposive convenience
sampling method for the screening and selection of patients. Continuous numerical data
were checked for normality using the Shapiro–Wilk test and Q-Q plots. The data were
found to follow a non-Gaussian distribution, and hence, non-parametric tests were used
for comparison. For categorical independent variables, the chi-square test or Fisher’s exact
test was used for association testing. For categorical dependent variables, McNemar’s test
was used for 2
×
2 cross-tabulations. The Mann–Whitney U test was used to assess the
differences in the distribution of numerical variables. A two-tailed p< 0.05 was considered
statistically significant. The data analyses were performed using MS Excel 365 for Windows
11 and IBM SPSS v29.0.0 (IBM Corp, Armonk, NY, USA) for Windows 11.
3. Results
Our study cohort consisted of 108 patients, with 75 (69%) presenting with mild acute
cholecystitis and 33 (31%) presenting with moderate acute cholecystitis. There were notable
differences between the two groups in terms of their age and gender. The patients with
mild acute cholecystitis exhibited a younger demographic and were predominantly female,
while the patients with moderate acute cholecystitis demonstrated a more advanced age
and a male predominance. Upon admission, inflammatory marker levels, such as the white
blood cell count (WBC) and C-reactive protein (CRP), were elevated in both groups, with
higher values observed in patients with moderate acute cholecystitis (Table 3).
Table 3. Baseline patient characteristics.
Characteristics †Mild Acute Cholecystitis
(n = 75)
Moderate Acute Cholecystitis
(n = 33) p-Value
Patient gender
Male 23 (59%) 16 (41%) p= 0.076 **
Female 52 (75%) 17 (25%)
Age (years) 54 (24 to 85) 64 (24 to 86) p= 0.014 *
BMI (kg/m2)27.9 (7.1) 28.0 (6.6) p= 0.038 *
WBC count on admission
(109cells/L) 12.0 (4.0) 14.0 (5.5) p< 0.001 *
CRP on admission (mg/L) 16.5 (38.5) 42.0 (67.5) p< 0.001 *
†
Median and interquartile range (IQR) are reported. For age, median and range are reported. For gender, number
of patients and % are reported. * Mann–Whitney U test; ** chi-square test.
J. Clin. Med. 2025,14, 541 7 of 17
3.1. Intraoperative Findings
Patients with mild acute cholecystitis had a significantly lower rate of peri-vesical
infiltration (20% vs. 67%) and gallbladder empyema (13% vs. 55%) in comparison with the
moderate acute cholecystitis patients (Table 4).
Table 4. Summary of intraoperative findings.
Characteristics †Mild Acute Cholecystitis
(n = 75)
Moderate Acute Cholecystitis
(n = 33) p-Value
Intraoperative detection of peri-vesicular infiltration
Yes 15 (20%) 22 (67%) p< 0.001 *
No 60 (80%) 11 (33%)
Gallbladder empyema
Yes 10 (13%) 18 (55%) p< 0.001 *
No 65 (87%) 15 (45%)
†For both categorical variables, number of patients and % are reported. * Chi-square test.
3.2. Number of CVS Steps Performed
To avoid bile duct injuries, it is crucial to perform at least the first four steps of the
CVS principles, including the dissection of fat and fibrous tissues out of Calot’s triangle,
the separation of the lowest part of the gallbladder, and the identification of two structures
entering the gallbladder (cystic duct and artery). Among our cohort, more than four CVS
steps were performed in 101 patients (93.5%). Fewer than four CVS steps were performed
only in seven patients—three (2.5%) patients with mild acute cholecystitis and four (4%)
patients with moderate acute cholecystitis (Table 5). The distribution of the number of CVS
steps performed was found to be statistically significant between the mild and moderate
acute cholecystitis patients, with the trend favoring mild acute cholecystitis patients.
Table 5. Distribution of patients (n, %) based on number of CVS steps performed.
No. of CVS Steps
Performed
Mild Acute
Cholecystitis
Moderate Acute
Cholecystitis p-Value *
0 steps 0 (0%) 1 (3%)
0.002
1 step 0 (0%) 1 (3%)
2 steps 1 (1%) 0 (0%)
3 steps 0 (0%) 0 (0%)
4 steps 2 (3%) 2 (6%)
5 steps 5 (7%) 6 (18%)
6 steps 16 (21%) 9 (27%)
7 steps 8 (11%) 5 (16%)
8 steps 43 (57%) 9 (27%)
*p-value derived from the Mann–Whitney test.
Accordingly, we observed that performing more than four CVS steps significantly
reduced the median operation time among patients with moderate acute cholecystitis
(Table 6). Among mild acute cholecystitis patients, although the median time increased
by 10 min when performing more than four CVS steps, the difference was not statistically
significant (p= 0.106).
J. Clin. Med. 2025,14, 541 8 of 17
Table 6. Operation time in minutes based on number of CVS steps performed.
No. of CVS Steps
Performed
Operation Time (min)
Mann–Whitney
p-Value
Mild Acute Cholecystitis Moderate Acute Cholecystitis
Median IQR Median IQR
0–4 steps (n = 7) 45.0 - 105.0 47.5 0.057
5–8 steps (n = 101) 55.0 25.0 75.0 30.0 <0.001
Mann–Whitney
p-value 0.106 0.009 -
3.3. Primary Outcomes: Visualization of Bile Ducts Using FC
Using the FC mode, it was observed that the rates of visualization were higher among
patients with mild acute cholecystitis in comparison to those with moderate acute cholecys-
titis (Figures 2and 3). Notable discrepancies in the visualization rates of the cystic duct
were evident between patients with mild and moderate acute cholecystitis, both prior to
(82.7% vs. 51.5%) and following (88.0% vs. 69.7%) CVS.
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 8 of 17
Figure 2. Effectiveness of CVS principles for the visualization of bile duct structures. The percent-
ages are calculated within different groups of acute cholecystitis. The p-values were derived from
the chi-square test.
Figure 2. Effectiveness of CVS principles for the visualization of bile duct structures. The percentages
are calculated within different groups of acute cholecystitis. The p-values were derived from the
chi-square test.
Moreover, the rate of visualization after CVS demonstrated significant differences in
the proportional distribution of patients with mild vs. moderate acute cholecystitis for the
J. Clin. Med. 2025,14, 541 9 of 17
confluence of the cystic and common hepatic ducts (57.3% vs. 33.3%) and the common
hepatic duct (70.7% vs. 45.5%).
Both in patients with mild and moderate acute cholecystitis, there was a notable
enhancement in the rate of visualization of the cystic duct when comparing the WL and FC
modes prior to CVS (Figure 4). The rate of visualization of the cystic duct in both groups
approached 100% following CVS with both WL and FC modes. Regarding the rate of
visualization of the common bile duct, a significant improvement was observed in both
patient groups when comparing the WL mode with the FC mode before CVS. Significant
differences in the visualization rates of bile ducts were observed when comparing before
and after the achievement of the CVS principles with the WL mode and WL + FC modes,
respectively. A similar tendency was observed when visualizing the common hepatic duct.
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 8 of 17
Figure 2. Effectiveness of CVS principles for the visualization of bile duct structures. The percent-
ages are calculated within different groups of acute cholecystitis. The p-values were derived from
the chi-square test.
Figure 3. Representational intra-operative pictures before and after CVS. Green fluorescence from the
ICG dye was visualized using the fluorescence cholangiography mode. The visualization of the cystic
duct, the common hepatic duct, the common bile duct, and the confluence of the cystic duct and
common hepatic ducts (A) before CVS and (B) after CVS in a patient with mild acute cholecystitis.
The visualization of the cystic duct, the common hepatic duct, and the confluence (C) before CVS and
(D) after CVS in a patient with moderate acute cholecystitis.
3.4. Usefulness of ICG for Visualization of Bile Ducts
There was a statistically significant association between the severity of acute chole-
cystitis and the usefulness of ICG for the visualization of extrahepatic bile ducts (Table 7).
ICG was helpful in the visualization of the cystic duct in 83% of mildly severe patients
compared with 49% of moderately severe patients (p< 0.001). Similarly, ICG was helpful
in aiding the visualization of the common hepatic duct in 49% of mildly severe patients
compared with 27% of moderately severe patients (p= 0.033).
It is interesting to note that, for moderate acute cholecystitis patients, ICG demon-
strated a notably poor effectiveness across all structures. Since, during surgery, moderate
cholecystitis cases typically require the more precise identification of the biliary tree com-
J. Clin. Med. 2025,14, 541 10 of 17
pared to mild cases, ICG’s effectiveness in moderate acute cholecystitis patients needs to be
assessed further.
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 10 of 17
Figure 4. Effectiveness of CVS and FC for the improvement of the visualization of bile duct struc-
tures. The percentage of the patients visualized, stratified by the severity of the acute cholecystitis
before CVS using white light (WL), before CVS using fluorescence cholangiography (FC), and after
CVS using both modes (WL + FC). The percentages were calculated within different groups of acute
cholecystitis. The p-values were derived from McNemar’s test.
3.4. Usefulness of ICG for Visualization of Bile Ducts
There was a statistically significant association between the severity of acute chole-
cystitis and the usefulness of ICG for the visualization of extrahepatic bile ducts (Table 7).
ICG was helpful in the visualization of the cystic duct in 83% of mildly severe patients
compared with 49% of moderately severe patients (p < 0.001). Similarly, ICG was helpful
in aiding the visualization of the common hepatic duct in 49% of mildly severe patients
compared with 27% of moderately severe patients (p = 0.033).
It is interesting to note that, for moderate acute cholecystitis patients, ICG demon-
strated a notably poor effectiveness across all structures. Since, during surgery, moderate
cholecystitis cases typically require the more precise identification of the biliary tree
Figure 4. Effectiveness of CVS and FC for the improvement of the visualization of bile duct structures.
The percentage of the patients visualized, stratified by the severity of the acute cholecystitis before
CVS using white light (WL), before CVS using fluorescence cholangiography (FC), and after CVS
using both modes (WL + FC). The percentages were calculated within different groups of acute
cholecystitis. The p-values were derived from McNemar’s test.
J. Clin. Med. 2025,14, 541 11 of 17
Table 7. Assessment of usefulness of ICG (presented as n, %).
Structure
(n = 108)
Severity of Acute
Cholecystitis
Usefulness of ICG for CVS Chi-Square Test
p-Value
Not Helpful Helpful
Cystic duct Mild (n = 75) 13 (17%) 62 (83%) p< 0.001
Moderate (n = 33)
17 (52%) 16 (49%)
Common bile duct Mild (n = 75) 27 (36%) 48 (64%) p= 0.072
Moderate (n = 33)
18 (55%) 15 (45%)
Cystic and common hepatic duct confluence
Mild (n = 75) 53 (71%) 22 (29%) p= 0.054
Moderate (n = 33)
29 (88%) 4 (12%)
Common hepatic duct Mild (n = 75) 38 (51%) 37 (49%) p= 0.033
Moderate (n = 33)
24 (73%) 9 (27%)
Cystic duct connection to gallbladder Mild (n = 75) 52 (69%) 23 (31%) p= 0.312
Moderate (n = 33)
26 (79%) 7 (21%)
3.5. Assessment of Background Liver Fluorescence
The background liver fluorescence was assessed before and after the CVS principles.
Although a higher rate of disturbance in the background fluorescence was observed for
cystic ducts among mild acute cholecystitis patients when compared with moderate acute
cholecystitis patients, both before (10.7% vs. 6.1%; p= 0.720) and after CVS (10.7% vs. 9.1%;
p= 1.000), the difference was not statistically significant (Figure 5).
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 11 of 17
compared to mild cases, ICG’s effectiveness in moderate acute cholecystitis patients needs
to be assessed further.
Table 7. Assessment of usefulness of ICG (presented as n, %).
Structure
(n = 108)
Severity of Acute
Cholecystitis
Usefulness of ICG for CVS Chi-Square
Test p-Value
Not Helpful Helpful
Cystic duct Mild (n = 75) 13 (17%) 62 (83%) p < 0.001
Moderate (n = 33) 17 (52%) 16 (49%)
Common bile duct Mild (n = 75) 27 (36%) 48 (64%) p = 0.072
Moderate (n = 33) 18 (55%) 15 (45%)
Cystic and common hepatic
duct confluence
Mild (n = 75) 53 (71%) 22 (29%) p = 0.054
Moderate (n = 33) 29 (88%) 4 (12%)
Common hepatic duct Mild (n = 75) 38 (51%) 37 (49%) p = 0.033
Moderate (n = 33) 24 (73%) 9 (27%)
Cystic duct connection to
gallbladder
Mild (n = 75) 52 (69%) 23 (31%) p = 0.312
Moderate (n = 33) 26 (79%) 7 (21%)
3.5. Assessment of Background Liver Fluorescence
The background liver fluorescence was assessed before and after the CVS principles.
Although a higher rate of disturbance in the background fluorescence was observed for
cystic ducts among mild acute cholecystitis patients when compared with moderate acute
cholecystitis patients, both before (10.7% vs. 6.1%; p = 0.720) and after CVS (10.7% vs. 9.1%;
p = 1.000), the difference was not statistically significant (Figure 5).
Figure 5. The percentage of patients with a disturbed background, stratified based on the severity
of acute cholecystitis before and after CVS. The percentages were calculated within different groups
of acute cholecystitis. The p-values were derived from Fisher’s exact test.
Figure 5. The percentage of patients with a disturbed background, stratified based on the severity of
acute cholecystitis before and after CVS. The percentages were calculated within different groups of
acute cholecystitis. The p-values were derived from Fisher’s exact test.
J. Clin. Med. 2025,14, 541 12 of 17
3.6. Secondary Outcomes
The operation time was significantly shorter in mild acute cholecystitis patients,
with no patient requiring conversion to an open approach. However, three patients with
moderate acute cholecystitis required conversion to an open approach due to the presence
of severe peri-vesicular infiltration. The WBC count and CRP at discharge were significantly
higher in patients with moderate acute cholecystitis (Table 8). All the patients were classified
as Grade I Clavien Dindo in terms of postoperative complications, with no cases of dropout.
No differences in the length of the hospital stay were observed between the two groups.
No iatrogenic bile duct injuries were reported in either group.
Table 8. Overview of surgical outcomes.
Characteristics †
Mild Acute Cholecystitis
(n = 75)
Moderate Acute Cholecystitis
(n = 33) p-Value
Operation time (min) 60.0 (25.0) 85.0 (37.5) p< 0.001 *
Conversion to open approach
Yes 0 (0%) 3 (9%)
p= 0.027 **
No 75 (100%) 30 (91%)
WBC count on discharge (109cells/L) 7.0 (3.0) 10.0 (4.5) p= 0.002 *
CRP on discharge (mg/L) 30.0 (53.0) 60.0 (105.5) p= 0.002 *
Hospitalization length (days) 6.0 (3.0) 6.0 (4.5) p= 0.437 *
Length of postoperative stay (days) 2.0 (2.0) 3.0 (2.0) p< 0.001 *
Biliovascular injuries (No. of patients) 0 (0) 0 (0) -
Mortality (No. of patients) 0 (0) 0 (0) -
†
Median and interquartile range (IQR) are reported. For categorical variables, raw count (%) is reported.
* Mann–Whitney U test; ** Fisher’s exact test due to violation of assumptions for chi-square test.
4. Discussion
FC has gained considerable traction in recent years and has been demonstrated to
enhance the visualization rate of EHBD structures while concurrently reducing the intraop-
erative risk of bile duct injuries [
18
–
21
]. Primarily, the enhanced visualization facilitates
the navigation of surrounding structures and the identification of vital vasculature and
bile ducts that are challenging to discern in patients presenting with acute cholecystitis.
Advanced peri-vesical inflammation, peri-cholecystic adhesions, a high BMI, and anatomi-
cal variations often present challenges to the precise identification of the EHBD structures,
even for experienced surgeons, contributing to an increased risk of iatrogenic biliovascular
injuries [22,23].
Such injuries have the potential to lead to late complications such as anastomotic
strictures, recurrent cholangitis, and secondary biliary cirrhosis, necessitating prolonged
hospitalizations and repeated surgical interventions [
22
,
24
,
25
]. Our study showed that
the frequency of bile duct visualization using FC was higher in patients with mild acute
cholecystitis in comparison to patients with moderate acute cholecystitis.
These discrepancies may be attributed to the inflammation of the gallbladder and the
surrounding tissues [
26
,
27
], with higher rates of gallbladder inflammation and empyema
noted in patients with moderate acute cholecystitis. The degree of intra-abdominal fatty
tissue and adiposity in the hepatoduodenal ligament are other factors that can affect the
quality of the fluorescence effect [
28
]. The visualization rate of EHBD structures using FC
may be attributed to the limited tissue penetration of the ICG fluorescent light, which has
been estimated to be approximately 5–10 mm [
29
,
30
]. In patients with substantial peritoneal
adiposity or peritoneal scarring due to inflammation, the light may not effectively penetrate
the tissues [
30
]. The stepwise usage of the CVS protocol under FC effectively allows a
J. Clin. Med. 2025,14, 541 13 of 17
surgeon to visualize the bile duct anatomy and complete the dissection of the cystic duct
from the surrounding tissues.
Additionally, the visualization of the bile ducts can be altered not only by localized
inflammation and peritoneal adiposity, but also by the inflammation of liver. An animal
study that mimicked acute and chronic liver injury in rats demonstrated that the inter-
nalization of the ICG dye by hepatocytes was markedly compromised, resulting in the
incomplete visualization of the liver lobes and a significant reduction in the spectral inten-
sities for yellow and green hues [
31
]. It seems reasonable to hypothesize that a comparable
process may occur in humans, whereby a hepatocytic injury resulting from inflammatory
infiltration in the context of acute cholecystitis could potentially impair ICG metabolism
and the subsequent secretion into the bile [
32
,
33
]. Further research is required to investigate
this relationship between the ICG plasma disappearance rate (ICG-PDR) and the EHBD
visualization rate and quality.
A higher rate of visualization of extrahepatic bile ducts with FC has been documented
in the literature than observed in our study [
17
,
20
,
34
,
35
]. Similar observations have been
reported in patients with acute cholecystitis who underwent FC-assisted robotic surgery.
When using the FC mode during the robotic cholecystectomy, a rise in the rate of the
identification of the cystic duct, common bile duct, and common hepatic duct was reported,
both before and after Calot’s triangle dissection [
36
–
38
]. For example, the FALCON trial
showed a higher rate of CBD detection. However, it is noteworthy that the FALCON
trial patients underwent an elective LC [
39
], in contrast to our study, where the patients
underwent an urgent LC.
Furthermore, these studies did not stratify patients according to the severity of their
acute cholecystitis, which could explain the differences. Notable discrepancies were also
identified in the ICG administration protocols implemented across the studies, particu-
larly with reference to the dosage, timing, and frequency of repeated doses. While our
protocol involved the administration of a higher dosage (12.5 mg) than observed in other
studies [12,40]
, previous studies have opted to administer the contrast agent less than an
hour before the incision and/or to utilize repeated doses with the aim of improving visu-
alization [
17
,
20
,
34
–
38
]. This is of particular importance, given that multivariate analyses
have demonstrated that both the timing and dosage of ICG can have a significant impact on
the quality of visualization [
17
]. Nonetheless, we do acknowledge that the administration
of ICG 12 h before an LC may prove to be challenging in cases of indicated early surgery,
regardless of how much time has passed since the onset of symptoms, as recommended by
the Tokyo guidelines.
In our clinics, the extended CVS protocol is used, comprising of eight steps starting
from visceral peritoneum dissection to gallbladder removal from the liver bed [
16
]. The
CVS steps were performed with the help of FC, and the results showed that, in all cases,
the cystic duct was successfully identified, which is a critical aspect of performing a safe
cholecystectomy. Other studies have concurred with the observation that, to achieve the
CVS principles, the dissection of fat and fibrous tissues out of Calot’s triangle, the separation
of the lowest part of the gallbladder, and the identification of two structures entering the
gallbladder (cystic duct and artery) are essential to avoid bile duct injuries [
41
]. Clearly, FC
enhances the visualization of extrahepatic bile ducts, allowing CVS to be safely achieved,
even in patients with moderately severe acute cholecystitis.
All operations in our study were performed by 2–3 trained hepato-pancreato-biliary
surgeons that strictly followed the extended CVS principles. The extended CVS protocol
began with the preoperative administration of ICG and concluded with the evaluation
of the liver bed to exclude bile leaks [
42
]. The extended CVS principles, together with
strict ICG administration protocols, can be considered as strengths of our study. It is
J. Clin. Med. 2025,14, 541 14 of 17
noteworthy that, in moderate acute cholecystitis patients, the achievement of the CVS could
be counter-indicated, as complications can occur during the dissection. In our study as well,
we achieved a few CVS steps only in this group of patients to lower the risk of biliovascular
injuries [43].
It is important to note that our study is subject to certain limitations. The study popu-
lation was rather limited, and the obtained results require further validation and replication
in larger, multi-center cohorts. Our study groups were disproportionately distributed in a
2:1 ratio (mild/moderate acute cholecystitis patients), a reflection of the general trend of
patient hospitalization patterns encountered in our department. Furthermore, an overall
small sample size limited the possible generalizability of the p-values so obtained in our
analyses. Similarly, diversifying the demographic pool of patients in terms of gender,
age groups, and BMI could further refine the results. A video-archive review by a single
certified surgeon also leaves room for subjectivity and the need for inter-rater agreement
in future studies. Nonetheless, our study shows that FC improves the visualization of
EHBD structures in most patients with mild or moderate acute cholecystitis when a step-
wise extended CVS protocol is used. Both CVS and FC help surgeons to perform a “safe
cholecystectomy”.
5. Conclusions
Fluorescence cholangiography (FC) was found to be an effective method for the visual-
ization of extrahepatic bile ducts during urgent laparoscopic cholecystectomy, especially for
patients with mild acute cholecystitis. However, our findings also highlight the significant
limitations of FC in moderate acute cholecystitis patients. In moderate acute cholecystitis
patients, we experienced lower visualization rates of critical structures such as cystic and
common hepatic ducts, longer operative times, and procedural challenges, even after ad-
herence to the critical view of safety (CVS) protocol. Factors such as increased peri-vesical
inflammation, gallbladder empyema, and tissue adiposity likely contributed to the lower ef-
fectiveness of FC in such patients. While no iatrogenic biliovascular injuries were observed,
the findings highlight the need to optimize the FC protocols to improve their efficacy in
acute cholecystitis patients. Future research should validate our observations in larger,
multi-center cohorts to ensure patient safety and procedural success.
Author Contributions: J.P. and H.P. conceptualized the present study and were responsible for the
methodology. Data collection and investigations were conducted by J.P., K.Z., E.S., K.B.C., J.O., K.A.
and H.P., while J.P. and N.J. were responsible for data coding and validation. N.J. was responsible for
the formal analyses and visualizations. Supervision and project administration was performed by
H.P., while J.P. was responsible for resources and funding acquisition. J.P., N.J. and H.P. wrote the
initial draft, while all the authors were responsible for critically revising the manuscript. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study protocol adhered to the principles established in
the Helsinki Declaration of 2008 and received approval from the Medical and Biomedical Research
Ethics Committee of the Riga East University Hospital Support Foundation (No. 9-A/20, dated 6
August 2020).
Informed Consent Statement: All the participants provided informed consent prior to participating
in the study.
Data Availability Statement: The underlying dataset is available for non-commercial purposes from
the corresponding author upon reasonable request.
Conflicts of Interest: The authors declare no conflicts of interest.
J. Clin. Med. 2025,14, 541 15 of 17
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