Journal Pre-proof

A meta-analysis of indocyanine green fluorescence imaging-guided

laparoscopic cholecystectomy for benign gallbladder disease

Yu Liu, Yisheng Peng, Song Su, Cheng Fang, Shu Qin, Xuewen
Wang, Xianming Xia, Bo Li, Pan He

PII: S1572-1000(20)30302-1
DOI: https://doi.org/10.1016/j.pdpdt.2020.101948
Reference: PDPDT 101948

To appear in: Photodiagnosis and Photodynamic Therapy

Received Date: 28 April 2020

Revised Date: 27 July 2020
Accepted Date: 31 July 2020

Please cite this article as: Liu Y, Peng Y, Su S, Fang C, Qin S, Wang X, Xia X, Li B, He P, A
meta-analysis of indocyanine green fluorescence imaging-guided laparoscopic
cholecystectomy for benign gallbladder disease, Photodiagnosis and Photodynamic Therapy
(2020), doi: https://doi.org/10.1016/j.pdpdt.2020.101948

This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.

© 2020 Published by Elsevier.

A meta-analysis of indocyanine green fluorescence imaging-guided laparoscopic
cholecystectomy for benign gallbladder disease

Yu Liu1#;Yisheng Peng2#;Song Su2;Cheng Fang2;Shu Qin2,3;Xuewen Wang5,XianmingXia2,4;Bo

Li2,4*;Pan He2,3,4*

Author details
1
Department of Hepatobiliary Surgery, People's Hospital of Leshan,Sichuan Leshan
614000, China.
2
Department of General Surgery(Hepatobiliary Surgery),The Affiliated Hospital of

of
Southwest Medical University,Luzhou 646000, China.
3
Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province,

ro
Luzhou, 646000, China.
4
Academician（Expert）Workstation of Sichuan Province, Luzhou 646000, China.
5
-p
Department of Hepatobiliary surgery,Zigong Fourth People's Hospital,Zigong
643000,China.
re
# These authors contributed equally to this work
lP

* Corresponding author’s full contact details:

1.Name:Pan He;Address:Department of General Surgery(Hepatobiliary Surgery),The
na

Affiliated Hospital of Southwest Medical University,Luzhou 646000, China;E-mail

:18783096517@163.com.
2.Name:Bo Li;Address: Department of General Surgery(Hepatobiliary Surgery),The
ur

Affiliated Hospital of Southwest Medical University,Luzhou 646000, China;E-mail

:liboer2002@126.com.
Jo
Highlights

 Fluorescence molecular imaging is a very valuable research

hotspot in surgery in recent years.

 2.It is still remains unclear whether indocyanine green fluorescence

imaging technique can benefit from the laparoscopic

cholecystectomy for benign disease of the gallbladder. In addition,

the conclusions of the current research on the effect and safety of it

of
are not uniform.Therefore,whether it can improve the effect of

laparoscopic cholecystectomy is lack of high quality evidence at

ro
home and abroad.
-p
 This study firstly compare the effectiveness and safety of

indocyanine green fluorescence imaging guided laparoscopic

re
cholecystectomy for benign disease of the gallbladder by meta
lP

analysis base on currently available literature.This may represent

the largest body of information available for the effectiveness and

na

safety of indocyanine green fluorescence imaging guided

laparoscopic cholecystectomy for benign disease of the gallbladder.

ur

 4.The results not only could serve as a reference for clinical

Jo

practice,but also provide a large sample evidence for the

researchers of fluorescence molecular imaging.

Abstract
Background: This meta-analysis was conducted to evaluate the effectiveness and
safety of indocyanine green fluorescence imaging -guided laparoscopic
cholecystectomy for benign gallbladder disease.
Methods: Clinical studies were retrieved from PubMed, Embase, Cochrane Library,
Medline, and the Web of Science databases. Study-specific effect sizes and their 95%
confidence intervals (CIs) were combined to calculate the pooled values, using
fixed-effects or random-effects models.
Results: Eleven studies with combined total of 2,221 patients were included.
Compared to the control group, the indocyanine green fluorescence imaging-guided
group experienced shorter operative time (standardized mean difference [SMD] =
-0.30; 95% CI = -0.45 – -0.15; P < 0.001), shorter biliary anatomy identification time
(SMD = -2.34; 95% CI = -2.58 – -2.10; P < 0.001), lower blood loss (SMD = -0.14;

of
95% CI = -0.26 – -0.01; P = 0.035), higher success rate of biliary tract imaging (odds
ratio [OR] = 2.37; 95% CI = 1.09 – 5.12; P = 0.029), lower rate of conversion to open

ro
surgery (OR = 0.10; 95% CI = 0.04 – 0.28; P < 0.001), shorter hospital stay (SMD =
-0.23; 95% CI = -0.39 – -0.06, P = 0.008), and lower biliary tract imaging costs (SMD
= -247.88; 95% CI, -274.31–-221.45, P = 0.000). Postoperative complications did
not differ between the groups. -p
Conclusion: This systematic review shows that indocyanine green fluorescence
biliary tract imaging is a safe and feasible new way for biliary tract identification in
re
laparoscopic cholecystectomy.

Keywords: Indocyanine green; Fluorescence imaging; laparoscopic cholecystectomy;

lP

Meta-analysis.
na
ur
Jo
1. Introduction
Cholecystectomy is one of the most common surgical procedures in the world [1]. It
has become the "gold standard" for treating benign lesions of the gallbladder [2]. Bile
duct injury is a severe but rare complication in cholecystectomy, with an incidence
rate of 0.3-0.7% [3-5]. Iatrogenic biliary tract injury is one of the main factors leading
to patients' dissatisfaction and doctor-patient disputes. There are many reasons for
intraoperative bile duct injury, among which the most common one is the failure to
identify the bile duct, especially when the region is complicated with inflammation,
edema, obesity, or biliary tract variations [6,7]. Intraoperative cholangiography can
help operators better identify the anatomy of the biliary tract to avoid biliary tract
injury.

In recent years, the application of near-infrared fluorescence imaging for

intraoperative navigation has received increasing attention from clinicians. Using

of
real-time intraoperative fluorescence imaging, surgeons can promptly grasp the
situation, endowing them with substantive guidance and help. Thus, it has become a

ro
highly desired surgical precision navigation method [8]. At present, in this field, more
research is called for on the indocyanine green fluorescence imaging technology [9].

-p
Indocyanine green fluorescence imaging is a new intraoperative imaging technique. It
has been widely used in liver resection and other kinds of surgery. According to
reports, the technique also helps surgeons map the components of the biliary tract
re
system by real-time biliary fluorescence imaging [10]. In recent years, real-time
biliary fluorescence imaging has also been applied to laparoscopic cholecystectomy
[11]. However, the technology is still in the development stage. A previous
lP

conventional systematic review has not provided enough evidence for short-term
outcomes and safety profile of the technique, as it included low-quality
non-randomized controlled studies and evaluated only a few parameters [12]. Until
recently, no meta-analysis study has evaluated the effectiveness and safety of
na

indocyanine green fluorescence imaging-guided laparoscopic cholecystectomy for

benign gallbladder disease. Therefore, the present meta-analysis was conducted to
systematically review the published literature and evaluate the effectiveness and
ur

safety of the technique. The results could serve as a reference in clinical practice.

2.1. Literature search

Jo

This study was conducted following the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines [13]. Three authors independently
searched PubMed, Embase, Cochrane Library, Medline, and the Web of Science
databases for studies that have compared fluorescence imaging-guided laparoscopic
cholecystectomy with traditional laparoscopic cholecystectomy (without fluorescence
imaging guidance) for benign gallbladder disease. The search terms included
cholecystectomy, indocyanine green, ICG, fluorescence dyes, laparoscopic,
robot-laparoscopic, minimally invasive, cholangiography, indocyanine green
cholangiography, near-infrared, near-infrared imaging, biliary tract visualization, and
intraoperative cholangiography. The reference lists of the included articles were also
reviewed for additional information on the topic. The literature search was limited to
articles written in English and dated through 31 February 2020.

2.2. Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) patients of any sex, age, race, or nationality
who underwent laparoscopic cholecystectomy for benign gallbladder disease; (2) the
experimental group (EG) underwent laparoscopic cholecystectomy guided by the
indocyanine green fluorescence imaging technology while the control group (TC) did
not; (3) studies reporting at least one of the following outcomes: operative time,
biliary anatomy identification time, blood loss, success rate of biliary tract imaging,
conversion to open surgery, hospital stay, biliary tract imaging costs, and
postoperative complications; and (4) studies that were either randomized controlled
trials (RCTs), retrospective cohort study (RCS), or comparative studies. Exclusion

of
criteria were as follows: (1) studies with no control group; (2) case reports, abstracts,
conference reports, or experiments; and (3) studies in which the full text was

ro
unavailable, and information from the abstract was insufficient.

2.3. Study selection and data extraction

-p
Three reviewers independently read the full texts and extracted the following data:
first author, year, country, study design, surgical method, sample size, and outcomes.
The authors of the selected studies were contacted via e-mail to obtain any missing
re
information. When quantitative data was without means or standard deviations (SD),
and the missing information was unavailable from the authors, an alternative method
was used to estimate the mean and SD based on the median, range, and sample size
lP

[14,15].

2.4. Methodological quality assessment

The methodological quality of the included studies was assessed independently by
na

three researchers using the Newcastle-Ottawa Scale (NOS), which is widely used to
evaluate the quality of nonrandomized studies in meta-analyses [16]. This scale was
used to rate the included studies quality based on their population selection,
ur

comparability of the groups under study, and outcome assessment. The maximum
score on the scale is 9, and studies with scores > 5 were considered to have high
methodological quality. Disagreements were resolved by common consensus.
Jo

2.5. Statistical analysis

The study-specific odds ratio (OR) for categorical variables, standardized mean
difference (SMD) for continuous variables, and the 95% confidence intervals (CIs)
were combined to calculate the pooled value of each study using STATA 15.1 package
(Stata Corp, College Station, TX, USA). Cochran’s chi-square test and I2 were used to
examine the heterogeneity among the effect estimates. Statistical heterogeneity among
studies was defined as I2 statistic >50%. If heterogeneity existed, the data were
analyzed using a random-effects model. If heterogeneity was considered unimportant,
a fixed-effects model was used. Sensitivity analysis was performed by repeating the
analysis following sequential removal of each study. A funnel plot was used to
estimate potential publication bias. Asymmetry of the funnel plot was tested by the
Begg’s and Egger’s tests. Results of the two-sided tests were considered statistically
significant at P < 0.05.

3. Results
3.1. Search results, characteristics, and quality of included studies
The literature was selected using the designed strategy. Ninety-eight relevant citations
were identified after removing duplicates. Of these, 78 citations were excluded after
reviewing the titles and abstracts. The remaining 20 citations were assessed for
eligibility by reviewing the full text. Of these citations, nine were excluded. The
remaining 11 retrospective cohort studies [17-27] were used in this meta-analysis. Fig.
1 shows the literature selection process. Table 1 displays the characteristics of the

of
included studies. The NOS scores for these 11 retrospective cohort studies ranged
between seven and eight, indicating that the methodological quality of the included

ro
studies was high (Table 2).

3.2. Meta-analysis of the operative time (min)

-p
Data from eight trials were included. Heterogeneity among the trial results was found
to be unimportant (P = 0.184; I2 = 30.6%). Based on the fixed-effects model, the
operative time in the EG group was found to be slightly shorter than in the TC group
re
(SMD = -0.30; 95% CI = -0.45 – -0.15; P < 0.001; Fig. 2).

3.3. Meta-analysis of the biliary anatomy identification time (min)

lP

Data from three trials were included. Heterogeneity among the trial results was found
to be unimportant (P = 0.463; I2 = 0.0%). Based on the fixed-effects model, biliary
anatomy identification time was shorter in the EG group than in the TC group (SMD
= -2.34; 95% CI = -2.58 – -2.10; P < 0.001; Fig. 3).
na

3.4. Meta-analysis of blood loss volume (mL)

Data from three trials were included. Heterogeneity among the trial results was found
to be unimportant (P = 0.908; I2 = 0.0%). Based on the fixed-effects model, the blood
ur

loss volume was smaller in the EG group than in the TC group (SMD = -0.14; 95% CI
= -0.26 – -0.01; P = 0.035; Fig. 4).
Jo

3.5. Meta-analysis of biliary tract imaging success rate

Data from two trials were included. Heterogeneity among the trial results was
unimportant (P = 0.415; I2 = 0.0%). Based on the fixed-effects model, the success rate
of biliary tract imaging was higher in the EG group than the TC group (OR = 2.37;
95% CI = 1.09 – 5.12; P = 0.029; Fig. 5).

3.6. Meta-analysis of conversion to open surgery

Three studies explored the rate of conversion to open surgery. Unimportant
heterogeneity was found (P = 0.317; I2 = 12.9%). Based on the fixed-effects model,
the rate of conversion to open surgery was lower in the EG group when compared to
the TC group (OR = 0.10; 95% CI = 0.04 – 0.28; P < 0.001; Fig. 6).

3.7. Meta-analysis of the duration of hospital stay (days)

Data from six trials were included. Heterogeneity among the trial results was found to
be unimportant (P = 0.244; I2 = 25.3%). Based on the fixed-effects model, no
difference was observed between the two groups (SMD = -0.09; 95% CI, -0.19 – 0.02,
P = 0.102; Fig. 7).

3.8. Meta-analysis of the biliary tract imaging costs (US$)

Data from two trials were included. Unimportant heterogeneity was found (P = 0.893;
I2 = 0.0%). Based on the fixed-effects model, the biliary tract imaging costs were
lower in the EG group when compared to the TC group (SMD = -247.88; 95% CI,

of
-274.31 – -221.45, P = 0.000; Fig. 8).

ro
3.9. Meta-analysis of postoperative complications
Three studies explored the postoperative complications rate. Unimportant
heterogeneity was found (P = 0.742; I2 = 0.0%). No difference was observed between
-p
the two groups (OR = 1.01; 95% CI, 0.37 – 2.72,P = 0.320; Fig. 9).

3.10. Sensitivity analysis and publication bias

re
We conducted the sensitivity analysis by repeating the analysis after sequential
removal of each study to evaluate the stability of our results. Sensitivity analysis
showed that such a study-removal approach did not change the outcomes of almost all
lP

primary analyses. There was just one study [21] that might be the source of
heterogeneity for hospital stay duration (Fig. 10A). A less homogenous result (P =
0.688; I2 = 0.0%) was obtained, the pooled estimate changed, and the hospital stay
was significantly shorter in the EG group (SMD = -0.23; 95% CI = -0.39 – -0.06, P =
na

0.008) when analysis was performed without this trial (Fig. 10B).
Publication bias was tested by the Begg’s and Egger’s tests. Results suggest no
publication bias, and the funnel plot based on the analysis of operative time had a
symmetrical appearance (Begg’s test: P = 0.266; Egger’s test: P = 0.541; Fig. 11).
ur

4. Discussion
Jo

Cholecystectomy is one of the most common operations in general surgery.

Worldwide, more than one million patients undergo cholecystectomy every year to
treat benign gallbladder lesions [28]. It has been reported that the most severe
complication of laparoscopic cholecystectomy is bile duct injury. This happens
because of the small diameter of a normal bile duct and frequent physiological
pathway variations [5,29-30]. Many measures were employed to reduce the risk of
bile duct injury during laparoscopic cholecystectomy. These include anatomical safety
in the gallbladder triangle and application of intraoperative ultrasonography and
cholangiography [31-32]. These approaches can provide surgeons with anatomical
images of the bile duct. However, intestinal gas can easily interfere with the viewed
anatomy, requiring invasive examination. This complicates the operation, which
involves the use of special radiology technicians, and has the risk of radiation
exposure [33-34]. Therefore, in laparoscopic cholecystectomy, a convenient and
real-time accurate biliary tract visualization technique is urgently needed.

Such would be the new biliary tract visualization technique studied here. According to
one report, indocyanine green fluorescence biliary tract imaging can well show the
anatomical structure of the biliary tree, and prevent or reduce the risk for biliary tract
injury during the operation [35]. Therefore, biliary fluorescence imaging is
increasingly used in laparoscopic cholecystectomy. Some studies have reported that
this technique is safe and effective in animal models and clinical settings, and has an
excellent clinical value [36-38]. However, the technology is still in the development
stage, and its effectiveness and safety have not yet been verified. Therefore, the

of
present meta-analysis was conducted to systematically review the published literature
and evaluate the effectiveness and safety of indocyanine green fluorescence

ro
imaging-guided laparoscopic cholecystectomy for benign gallbladder disease.

This meta-analysis shows that when performing laparoscopic cholecystectomy with

-p
fluorescent biliary tract imaging, the operative time and biliary anatomy identification
time can be significantly reduced. It is suggested that fluorescence cholangiography
can significantly improve surgical efficiency in patients undergoing cholecystectomy.
re
The reason might be that the contrast agent used for the technique is injected through
the cubital vein, and thus not affected by the anatomy of the gallbladder. The time to
find the bile duct is thus shortened. In addition, the technique does not require an
lP

intraoperative injection of a contrast agent, so the operation time and blood loss can
correspondingly be reduced [39]. Furthermore, fluorescence biliary tract imaging can
improve the success rate of angiography and reduce the rate of conversion to open
surgery. It is also beneficial for the surgeons, who can better judge the anatomical
na

structure and identify the biliary tract variations, even when the gallbladder is
seriously inflamed and surrounded by heavy adhesion, congestion, and edema of the
Calot’s triangle, and when the anatomical structures are fuzzy. We also found that the
ur

technique can shorten hospital stay duration and lower biliary tract imaging costs.
This is consistent with previous research results. A possible explanation is that
fluorescence imaging technology can better display the biliary tract and thus reduce
Jo

the risk of intraoperative injury. As a result, the hospital stay is correspondingly

shorter. Moreover, the contrast agent used in fluorescence imaging is cheap and easy
to operate, so imaging costs are also lower. Despite these findings, there was no
difference between the groups in the postoperative complications rate. More research
is needed to confirm these results.

Since the studies included in this meta-analysis showed no apparent heterogeneity in

their outcomes, we can assume that the analysis results are reliable. Sensitivity
analysis was performed by removing one study at a time and repeating the
meta-analysis to assess whether any study significantly affected the pooled estimates.
The only parameter in which the estimates have completely changed was the duration
of hospital stay. Heterogeneity was lower when the study by Gangemi et al. [21] was
excluded. This indicates that this study might be the source of heterogeneity. Possible
explanations for heterogeneity are the different types of background diseases and the
study design.

This systematic review has some limitations. First, the number of included studies is
small, and the methodological quality was generally low in the sense that the included
studies were retrospective cohort studies. There is a lack of RCTs that have assessed
this technique. Second, most studies had a small sample size. Third, some outcome
indicators showed significant heterogeneity at the time of combination. This might
affect the reliability of the results owing to the lack of multifactor subgroup analyses.

of
In conclusion, this systematic review shows that indocyanine green fluorescence
biliary tract imaging is a safe and feasible new way for biliary tract visualization in

ro
cholecystectomy. However, considering the clinical and methodological heterogeneity
among the included studies, high-quality, consistent intervention, large-sample,
multicenter randomized controlled studies are required to verify the findings of this
study. -p
Conflict of interest: The authors declare that they have no conflict of interest.
re
Acknowledgments This work was supported by the nuclear medicine and molecular
imaging key laboratory of Sichuan Province open project (no. HYX18025), and the
lP

University level project of Southwest Medical University (no. 0903-00031341).

References
na

[1]Philip H,Pucher L,Michael B,et al.Outcome trends and safety measures after 30 years of
laparoscopic cholecystectomy:a systematic review and pooled data analysis[J].Surgical
Endoscopy,2018,32(5):2175-2183.
ur

[2]Sable SA,Nagra SN. Doctor, Single-incision laparoscopic cholecystectomy is associated with a

higher bile duct injury rate[J]. Ann Surg, 2015. 261(3):e79.
[3]Graggen ZK,Wehrli H, Metzger A,et al.Complications of laparoscopic cholecystectomy in
Jo

Switzerland A prospective 3-year study of 10,174 patients. Swiss Association of Laparoscopic and
Thoracoscopic Surgery[J]. Surg Endosc, 1998. 12(11): 1303-10.
[4]Fletcher DR, Hobbs MS, Tan P,et al.Complications of cholecystectomy:risks of the
laparoscopic approach and protective effects of operative cholangiography: a population-based
study[J]. Ann Surg, 1999. 229(4): 449-57.
[5]Giger U,Ouaissi M,Schmitz SF,et al. Bile duct injury and use of cholangiography during
laparoscopic cholecystectomy[J]. Br J Surg, 2011, 98(3): 391-6.
[6]Stewart L.Iatrogenic biliary injuries: identification, classification, and management[J].Surg
Clin North Am,2014, 94(2):297-310.
[7]Fortunato AA, Gentile JK, Caetano DP, et al.Comparativeanalysis of iatrogenic injury of biliary
tract in laparotomic and laparoscopic cholecystectomy[J]. Arq Bras Cir Dig ,2014,72(4):272-274.
[8]He P, Su S, Fang C,et al.Residual cancerous lesion and vein tumour thrombus identified
intraoperatively using a fluorescence navigation system in liver surgery[J]. ANZ J Surg, 2019
,89(7-8):E308-E314.
[9]Hu Z, Qu Y, Wang K, et al. In vivo nanoparticle-mediated radiopharmaceutical-excited
fluorescence molecular imaging[J]. Nature Communications,2015, 6:7560.
[10]Ishizawa T, Bandai Y, Ijichi M,et al. Fluorescent cholangiography illuminating the biliary tree
during laparoscopic cholecystectomy[J]. Br J Surg, 2010, 97(9): 1369-77.
[11]Hozo SP,Djulbegovic B,Hozo I.Estimating the mean and variance from the median, range,
and the size of a sample[J].. BMC Med Res Methodol, 2005. 5:13.
[12]Vlek SL, van Dam DA, Rubinstein SM, et al.Biliary tract visualization using near-infrared
imaging with indocyanine green during laparoscopic cholecystectomy: results of a systematic
review[J]. Surg Endosc,2017,31(7):2731-2742.

of
[13]Liberati A, Altman DG, Tetzlaf J, et al. The PRISMA statement for reporting systematic
reviews and meta-analyses of studies that evaluate health care interventions: explanation and

ro
elaboration.Ann Intern Med. 2009;151:W65-W94.
[14]Hou XW, Shi JP, Chen X. How to estimate the mean and standard deviation based on the
median, range and sample size when conducting meta-analysis. Chin J Evid Based Med.
2015;15:484–487. -p
[15]Hozo SP, Djubegovic B, Hozo I. Estimating the mean and variance from the median, range
and the size of a simple. BMC Med Res Methodol. 2005;5:13.
re
[16]Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of
nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9)
:603e605.
lP

[17]Nicolas C , Pugin F, Azagury DE,et al.Real-time near-infrared fluorescent cholangiography could

shorten operative time during robotic single-site cholecystectomy[J]. Surgical Endoscopy, 2013. 27(10):
3897-3901.
[18]Fernando D, Asbun D, Rosales VA,et al.Cost analysis and effectiveness comparing the routine
na

use of intraoperative fluorescent cholangiography with fluoroscopic cholangiogram in patients

undergoing laparoscopic cholecystectomy[J]. Surgical Endoscopy, 2014. 28(6):1838-1843.
[19]Yoshiya S, Minagawa R, Kamo K,et al.Usability of Intraoperative Fluorescence Imaging
ur

with Indocyanine Green During Laparoscopic Cholecystectomy After Percutaneous Transhepatic

Gallbladder Drainage[J].World J Surg. 2019 ;43(1):127-133.
[20]Sharma S, Huang R, Hui S,et al.The utilization of fuorescent cholangiography during robotic
Jo

cholecystectomy at an inner-city academic medical center[J].J Robot Surg.2018 ;12(3):481-485.

[21]Gangemi A, Danilkowicz R, Elli FE,et al. Could ICG-aided robotic cholecystectomy reduce
the rate of open conversion reported with laparoscopic approach? A head to head comparison of
the largest single institution studies[J]. J Robot Surg.2017;11(1):77-82.
[22]Spinoglio G, Priora F, Bianchi PP,et al.Real-time near-infrared (NIR) fluorescent
cholangiography in single-site robotic cholecystectomy (SSRC):a single-institutional prospective
study[J] .Surg Endosc. 2013;27(6):2156-62.
[23]Fernando D,Roy M, Lo Menzo E,et al.Routine use of fluorescent incisionless
cholangiography as a new imaging modality during laparoscopic cholecystectomy[J].Surg
Endosc. 2015;29(6):1621-6.
[24]Sylvester N, Wendling MR, Drosdeck JM,et al.Near-infrared fluorescent cholangiography
facilitatesidentification of biliary anatomy during laparoscopic cholecystectomy[J].Surg
Endosc. 2015;29(2):368-75.
[25]Viktoria P, Schneider-Koriath S, Scholz M,et al.Fluorescence Cholangiography in Comparison
to Radiographic Cholangiography During Laparoscopic Cholecystectomy[J] .Zentralbl Chir.2018;
143(1):35-41.
[26]Peter C, Plambeck J, Fernandez-Jesberg V,et al.The role of indocyanine green fluoroscopy
for intraoperative bile duct visualization during laparoscopic cholecystectomy: an observational
cohort study in 70 patients[J].Patient Saf Surg. 2019 ; 13:2.
[27] Quaresima S, Balla A, Palmieri L, et al.Routine near infra-red indocyanine green fluorescent
cholangiography versus intraoperative cholangiography during laparoscopic cholecystectomy: a
case-matched comparison[J].Surg Endosc. 2019 Jul 15. doi: 10.1007/s00464-019-06970-0.
[28]Deziel DJ, Millikan KW, Economou SG,et al.Complications of laparoscopic cholecystectomy:

of
a national survey of 4,292 hospitals and an analysis of 77,604 cases[J]. Am J Surg, 1993. 165(1):
9-14.

ro
[29]Flum DR, Dellinger EP, Cheadle A,et al.Intraoperative cholangiography and risk of common bile
duct injury during cholecystectomy[J]. JAMA, 2003. 289(13): 1639-44.
[30]Strasberg SM,Brunt LM.Rationale and use of the critical view of safety in laparoscopic
cholecystectomy[J]. J Am Coll Surg, 2010,211(1): 132-8. -p
[31]Traverso LW.Intraoperative cholangiography lowers the risk of bile duct injury during
cholecystectomy[J]. Surg Endosc, 2006. 20(11):1659-61.
re
[32]Ford JA, Soop M, Du J,et al.Systematic review of intraoperative cholangiography in
cholecystectomy[J]. Br J Surg, 2012. 99(2): 160-7.
[33]Silva AA,Camara CA,Martins AJr,et al.Intraoperative cholangiography during elective
lP

laparoscopic cholecystectomy: selective or routine use?[J] .Acta Cir Bras, 2013. 28(10): 740-3.
[34]Törnqvist B, Strömberg C, Persson G,et al.Effect of intended intraoperative cholangiography and
early detection of bile duct injury on survival after cholecystectomy: population based cohort study[J].
BMJ, 2012. 345: e6457.
na

[35]Machi J, Johnson JO, Deziel DJ,et al.The routine use of laparoscopic ultrasound decreases bile
duct injury: a multicenter study[J]. Surg Endosc, 2009. 23(2): 384-8.
[36]Machi J,Johnson JO, Deziel DJ,et al.The routine use of laparoscopic ultrasound decreases bile duct
ur

injury: a multicenter study[J]. Surg Endosc, 2009. 23(2): 384-8.

[37]Liu YY, Kong SH, Diana M,et al.Near-infrared cholecysto-cholangiography with indocyanine
green may secure cholecystectomy in difficult clinical situations: proof of the concept in a porcine
Jo

model[J]. Surg Endosc, 2016. 30(9):4115-23.

[38]Liu YY,Liao CH,Diana M,et al.Near-infrared cholecystocholangiography with direct
intragallbladder indocyanine green injection: preliminary clinical results[J]. Surg Endosc, 2018. 32(3):
1506-1514.
[39]Quaresima S, Balla A, Guerrieri M, et al. A 23 year experience with laparoscopic common bile
duct exploration[J]. HPB , 2017. 19(1):29-35.
Figure legends:

Fig. 1: Flow diagram of the literature selection process. PubMed, Embase, Cochrane
Library, Medline and Web of Science databases were searched for the literature using
specific searching terms. After screening the titles, abstracts, and then the full texts for
relevance, in a step-by-step approach, eleven studies were considered suitable to be
included in this meta-analysis.

Fig. 2. Forest plot of the meta-analysis on operative time.

Fig. 3. Forest plot of the meta-analysis on biliary anatomy identification time.

of
Fig. 4. Forest plot of the meta-analysis on blood loss volume.

ro
Fig. 5. Forest plot of the meta-analysis on biliary tract imaging success rate.

Fig. 6. Forest plot of the meta-analysis on conversion to open surgery.

-p
Fig. 7. Forest plot of the meta-analysis on hospital stay.
re
Fig. 8. Forest plot of the meta-analysis on biliary tract imaging costs.

Fig.9. Forest plot of the meta-analysis on postoperative complications.

lP

Fig.10. A. Sensitivity analysis for hospital stay; B. Forest plot of the meta-analysis on
hospital stay when one study [21] was removed.
na

Fig.11. Funnel plot of the included studies for overall analysis of operative time
(Begg’s test: P = 0.266; Egger’s test: P = 0.541).
ur
Jo
Jo
ur
na
lP
re
-p
ro
of
 Fig 2

Jo
ur
na
lP
re
-p
ro
of
 Fig 3

Jo
ur
na
lP
re
-p
ro
of
 Fig4

Jo
ur
na
lP
re
-p
ro
of
 Fig5

Jo
ur
na
lP
re
-p
ro
of
 Fig 6

Jo
ur
na
lP
re
-p
ro
of
 Fig 7

Jo
ur
na
lP
re
-p
ro
of
 Fig 8

Jo
ur
na
lP
re
-p
ro
of
 Fig 9

Jo
ur
na
lP
re
-p
ro
of
 Fig 10

Jo
ur
na
lP
re
-p
ro
of
 Fig 11

Jo
ur
na
lP
re
-p
ro
of
 References Year Country Study Surgical style Sample Size Outcomes
Design Total EG TC
Nicolas et al 2013 Swiss RCS Robot-assisted 44 23 21 ①③⑥⑦
laparoscopy
Fernando et al 2014 USA RCS Lparoscopic 86 43 43 ①④
Yoshiya et al. 2019 Japan RCS Lparoscopic 130 39 91 ①③⑤⑥⑦
Sharma et al. 2018 USA RCS Robot-assisted 287 96 191 ⑤⑥
laparoscopy
Gangemi et al. 2017 USA RCS Robot-assisted 965 676 289 ③⑤
laparoscopy
Spinoglio et al. 2013 Italy RCS Lparoscopic 70 45 25 ①
Fernando et al 2015 USA RCS Lparoscopic 87 45 42 ①②

of
Sylvester et al. 2015 USA RCS Lparoscopic 164 82 82 ①②④
Viktoria et al 2018 Germany RCS Lparoscopic 230 170 60 ②

ro
Peter et al 2019 Germany RCS Lparoscopic 70 29 41 ①⑥
Quaresima et al 2019 Italy RCS Lparoscopic 88 44 44 ①⑥⑦
-p
RCS:retrospective cohort study .EG:experimental group. TC: traditional control.①operative time②
identification of biliary anatomy time③ blood loss ④success rate of biliary tract
imaging⑤conversion to open⑥hospital stay⑦postoperative complications.
re
lP

Table 1. Characteristics of included studies

na
ur
Jo
 TABLE 2. The Quality of Retrospective Cohort Studies With Newcastle-Ottawa Scale Scores

Studies Selection Comparability Outcome Scores

1 2 3 4 5 6 7 8
Nicolas et al ★ ★ ★ ★ ★★ ★ ★ - 8
Fernando et al ★ ★ ★ ★ ★ ★ ★ - 7
Yoshiya et al ★ ★ ★ ★ ★ ★ ★ - 7
Sharma et al. ★ ★ ★ ★ ★★ ★ ★ - 8
Gangemi et al. ★ ★ ★ ★ ★ - ★ - 6
Spinoglio et al. ★ ★ ★ ★ ★ ★ ★ ★ 8
Fernando et al ★ ★ ★ ★ ★ ★ ★ - 7
Sylvester et al. ★ ★ ★ ★ ★★ ★ ★ - 8
Viktoria et al ★ ★ ★ ★ ★★ ★ ★ - 8
★ ★ ★ ★ ★★ ★ ★

of
Peter et al - 8
Quaresima et al ★ ★ ★ ★ ★★ ★ ★ - 8
★ indicates one point .1. Representativeness of exposed cohort; 2.Selection of non-exposed cohort;

ro
3.Ascertainment of exposure; 4. Outcome of interest was not present at start of study; 5. Comparability
of cohorts on the basis of the design or analysis; 6.Assessment of outcomes;7. Follow-up long enough
for outcomes to occur;8. Adequacy of follow-up.
-p
re
lP
na
ur
Jo