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Current status of indocyanine green fluorescent
angiography in assessing perfusion of gastric
conduit and oesophago-gastric anastomosis
Syed Nusrath, MS, DNB, DNBa, Prasanthi Kalluru, BScb, Srijan Shukla, MS, DNBa, Anvesh Dharanikota, MS, MCha,
Madhunarayana Basude, MS, DNBa, Pawan Jonnada, MS, MCha, Muayyad Abualjadayel, MDd,
Saleh Alabbad, MD, MBAd, Tanveer Ahmad Mir, PhDc, Dieter C. Broering, MD, PhDd, KVVN Raju, MS, MCha,
Thammineedi Subramanyeshwar Rao, MS, MCha, Yogesh Kumar Vashist, MD, PhDa,d,*
Abstract
Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA)
is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of
tissue perfusion and has demonstrated usefulness in oesophageal surgery. GC perfusion analysis by ICG-FA is crucial in con-
structing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to
potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of
patient and procedural factors to decrease AL rates. This review summarizes ICG-FA’s current applications in assessing esophago-
gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how
fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.
Keywords: anastomotic leak, oesophageal cancer surgery, gastric conduit, Indocyanine green fluorescent angiography, mor-
bidity, perfusion
Introduction
Surgical resection is the primary treatment approach for early and
locally advanced oesophageal cancer
[1]
. Despite advancements in
minimally invasive surgery (MIS) and improved postoperative
care, esophagectomy continues to exhibit a notable elevated
morbidity rate
[2]
. Among its complications, anastomotic leak
(AL) is one of the most significant occurring following Ivor Lewis
and McKeown esophagectomy. Its incidence remains substantial,
reaching upto 40%—depending on the site of the anastomosis—
even in high-volume centres
[3–6]
.
AL is not only linked to increased postoperative mortality but
also results in prolonged hospital stay and a diminished quality of
life (QoL) for patients
[7]
. In an analysis of the Society of Thoracic
Surgeons (STS) general thoracic surgery database, the 30-day
mortality rate for patients undergoing esophagectomy was
reported with 3.3% and besides respiratory distress syndrome,
reintubation and renal failure, AL was identified as one of the
most significant trigger for operative mortality. Notably, the
overall AL rate in this study was 12.8%
[8]
. However, in another
separate STS database study that examined AL rates based on the
site of the anastomosis, it was found that a cervical anastomosis
had a 12.3% anastomotic leak rate, while a thoracic anastomosis
had a slightly lower rate of 9.3% only. Despite these variations in
AL rates, both groups exhibited similar 30-day mortality rates of
3.6% and 2.7%, respectively
[9]
. From the clinical management
point of view the resulting condition of a mediastinal AL com-
pared to a AL in the neck area is different, hence many high-
volume centres prefer to perform an anastomosis in the neck
HIGHLIGHTS
•Anastomotic leakage is frequent in oesophageal cancer
surgery.
•Gastric conduit perfusion is dependent mainly on the right
gastroepiploic artery.
•About half to one-third of the gastric conduit has an
intramural blood supply.
•Indocyanine green fluorescent angiography is a useful tool
for assessing gastric conduit perfusion.
•Indocyanine green fluorescent angiography helps for
choice of anastomotic site.
•Indocyanine green fluorescent angiography can potentially
reduce anastomotic leak.
Departrments of
a
Surgical Oncology,
b
Clinical Research, Basavatarakam Indo
American Cancer Hospital and Research Institute, Hyderabad, India,
c
Tissue/Organ
Bioengineering & BioMEMS Laboratory, TR&I Department and
d
Organ Transplant
Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh,
Kingdom of Saudi Arabia
Sponsorships or competing interests that may be relevant to content are disclosed at
the end of this article.
Published online ■■
*Corresponding author. Address: Organ Transplant Center of Excellence, King Faisal
Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.
E-mail: yogesh.vashist@outlook.de (Y.K. Vashist).
Received 28 July 2023; Accepted 3 November 2023
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open access article distributed under the Creative Commons Attribution License 4.0
(CCBY), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
International Journal of Surgery (2023) 00:000–000
http://dx.doi.org/10.1097/JS9.0000000000000913
’
Review Article
1
rather than mediastinum. ALs are further associated with com-
plications such as arrhythmias, deep venous thrombosis, pneu-
monia, acute respiratory distress syndrome, the need for
ventilatory support, empyema, sepsis, stricture formation, and
renal failure. Furthermore, AL has been associated with local
recurrence and inferior long-term oncological outcomes
[10,11]
.
While several risk factors for AL have been discussed and those
may differ between mediastinal and neck anastomoses, one of the
most significant factors appears to be an insufficient perfusion of
the gastric conduit (GC). During esophagectomy, GC is the most
common used substitute for the esophageus. The blood supply to
the GC relies entirely on the right gastroepiploic artery (RGEA),
and the distal-most portion of the GC experiences relatively
reduced blood flow since the RGEA immerses into the gastric wall
and the entire proximal region of the GC has only an intramural
perfusion. Submucosal vessels are the primary source of blood
supply for this section of the GC. Therefore, placing the anasto-
mosis in well-perfused area of the GC appears to be critical to
reduce AL rates.
An emerging method, near-infrared Indocyanine green fluor-
escence angiography (ICG-FA), helps in identifying well-perfused
region of GC for basing anastomosis and shows promise with
good intraoperative decision-making
[12,13]
.
This review summarizes the current applications of ICG-FA in
the perfusion assessment of esophago-gastric anastomosis (EGA)
after esophagectomy and reconstruction using a GC. We
attempted to include both qualitative and quantitative analyses
and reviews as well as available imaging systems to cover the
entire spectrum for successful ICG-FA usage in clinical routine.
Methods
In July 2023 we conducted a comprehensive systematic review
utilizing the PubMed database—the search was conducted in
conformity with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines in general, but
we opt not to exclude any full text report with original data
available in English language. The use of ICG fluorescence in
patients was identified through PubMed database search,
employing the medical-subject-headings terms “esophagectomy”
AND “Indocyanine green”OR “fluorescence guided”OR
“gastric tube”OR “gastric conduit”. Studies were included in the
analysis if full text manuscripts were published in English lan-
guage and only original data presented. Initial screening for
eligibility based on title and abstract was conducted by two
authors (S.N. and Y.K.V.). When potentially relevant articles
were found, both authors independently assessed the full texts to
determine which ones to include in the final review. Furthermore,
additional records were discovered by manually reviewing the
references cited in each selected article. In cases where there were
disagreements in study selection, consensus was reached through
a re-review process involving the two reviewers. Figure 1 sum-
marizes our selection process in form of a PRSIMA flowchart.
Results
Encounter the clinical challenge—a glimpse of light—green
light
Historically, evaluation of GC perfusion relied on the surgeon’s
visual and manual assessments, including factors such as
colour, bleeding from cut edges, peristalsis, and the pulse pal-
pation of the RGEA. Several studies have highlighted the limited
accuracy of clinical criteria based on intestinal colour, arterial
pulsation, and peristalsis for predicting AL in colorectal surgeries.
Additionally, these criteria are also less reliable for assessing
intestinal viability during acute intestinal ischaemia and esti-
mating GC perfusion in esophagectomy patients
[14–16]
.
Several strategies and techniques have been developed to assess
and enhance blood flow in the GC, aiming to minimize post-
operative complications. One such strategy involves gastric
ischaemic preconditioning before oesophageal surgery. This
approach seeks to redistribute gastric blood supply pre-
operatively, leading to improved tissue oxygenation at the distal
conduit for a better EGA site, ultimately reducing postoperative
AL rates. During ischaemic preconditioning, a portion of the
stomach’s blood supply is intentionally restricted by emboliza-
tion of either the left gastric artery or short gastric vessels or both
before surgery. This restriction encourages the formation of col-
lateral vessels, which in turn augment blood flow to the distal
regions of the GC
[17–19]
.
Although ischaemic preconditioning may seem like an
appealing strategy, multiple studies, including a randomized trial,
have failed to prove its effectiveness in reducing the rate of
ALs
[4,6]
. Despite various attempts to predict the risk of anasto-
motic complications by assessing GC perfusion during surgery
using a range of methods, none have yet been successfully
translated in clinical practice. These methods include intramu-
cosal pH, pulse-oxymetry, mucosal CO2, Doppler spectroscopy,
near-infrared and visible light spectro-photometry, infrared
imaging, laser Doppler flowmetry, and bowel wall contractility
measurements
[20–24]
.
However, a more recent and promising technique is the
fluorescent imaging, specifically the use of ICG. Fluorescence
imaging involves the injection of a small amount of fluorescent
dye into the patient at a precise point in the procedure. Typically,
this procedure employs a specialized camera equipped with a
dedicated fluorescent light source and sensor. The fluorescent
light source emits light at a specific wavelength designed to acti-
vate the fluorescent dye, causing it to emit light at a known
wavelength, which is then captured by the fluorescent sensor.
This fluorescence image can be observed either on its own or
overlaid onto a standard laparoscopic/ thoracoscopic image,
offering real-time visualization of organ perfusion. This techni-
que provides a wider view of tissue perfusion and has shown to be
valuable in both oesophageal and colorectal surgery for a better
intraoperative decision-making
[25–29]
.
By injecting ICG into the bloodstream, it fluoresces under near-
infrared light, enabling surgeons to view tissue blood flow in real-
time and make necessary adjustments to potentially reduce ALs
by highlighting ischaemic area. Figure 2A-D demonstrate the
intraoperative real-time ICG-FA of a GC at several time points
and clearly differentiates between the well-perfused area through
the RGEA, the submucosal perfused and non-perfused zone. The
efficacy of ICG-FA in predicting free flap necrosis by monitoring
the perfusion index was demonstrated in rat models by Giunta
and colleagues, and the findings were validated in humans by
Lamby and Prantl
[30–32]
. Additionally, Kudszus and colleagues
were the first to describe the usefulness of ICG-FA in assessing
perfusion in colorectal surgery, while Murawa and colleagues
first reported its value in evaluating perfusion in EGA
[13,33]
. The
safety, wider availability, and ease of use of fluorescent imaging
Nusrath et al. International Journal of Surgery (2023) International Journal of Surgery
2
using ICG have made it increasingly popular. ICG-FA can aid in
identifying well-perfused region of GC for basing EGA. This
especially applies when the anastomosis is performed in the neck
region due to the length of the GC.
ICG is a hydrophilic, tri-carbocyanine fluorescent dye that has
become increasingly popular in various surgical fields due to its
ability to produce high-quality images with good tissue contrast
and sensitivity. ICG has a low inherent auto-fluorescence back-
ground, which makes it an excellent choice for imaging. Its
excitation spectrum ranges from 700 to 850 nm, while its emis-
sion spectrum peaks between 810 and 830 nm, which enables
easy detection and distinction from other tissues. The lyophilized
powder form of ICG is easily reconstituted in distilled water and
can be diluted with a saline solution before injection. Its ability to
penetrate deep into tissues makes it a popular choice for a variety
of surgical applications
[34]
.
In fluorescence angiography, ICG is typically injected as an
intravenous bolus through a peripheral intravenous line or a
central venous line, followed by a flush to ensure that the dye is
pushed into circulation as a bolus. The compound binds rapidly
to plasma proteins in the blood and is quickly cleared by the liver
and excreted in the biliary system. Its half-life is two to four
minutes, and it is usually cleared from the blood in 15 to
20 min
[12,27,35]
. Detection of the dye usually occurs within
seconds after injection, although the time to fluorescence after
injection may be affected by factors such as infusion type, injec-
tion site, ICG dose, haematocrit, and cardiac output
[27,35]
.
ICG was approved by the FDA for human use since 1956 and
has since than been a valuable tool in both clinical and research
settings. Initially, its applications were limited, gaining approval
for neurosurgical research in 2003 and cardiac vessel angio-
graphy in 2005. Approval for use with surgical microscopes
followed in 2006. ICG has also received approval for ophthalmic
angiography and has been widely used off-label for real-time
imaging across various fields, including abdominal and plastic
surgery, oncological staging, and perfusion assessment. Devices
employing ICG-FA have obtained FDA clearance based on their
similarity to previously approved ICG applications, without the
need for additional documentation of clinical effectiveness
[36]
.
Application, measurement, and stratification
Application, measurement, stratification, and outcome with ICG-
FA imaging systems that enable real-time fluorescence imaging
are available for both minimally invasive and open surgical
procedures. Certain imaging systems are equipped with software
that can measure the fluorescent intensity (FI) at specific regions
of interest. Table 1 provides a summary of the imaging systems
Figure 1. The PRISMA flowchart summarizes the comprehensive research and selection process. ICG, indocyanine green.
Nusrath et al. International Journal of Surgery (2023)
3
and software used for ICG-FA for EGA. Figure 3A-F exemplarily
reveals GC in different modes and also depicts measurement of
perfusion quantification by ICF-FA using Strykers Spy-phi device.
Besides the imaging system also the dose of ICG applied is of
importance, however there is no defined dose based on com-
parative clinical trials. The optimal ICG dose for evaluating the
GC varies in different studies, with ranges spanning from 1.25 to
25 mg per bolus (see Table 2). Due to the short half-life of ICG,
administration of repeated doses during same surgery is practical.
Generally, a bolus injection is given, and additional doses are
contemplated when the signal strength is insufficient or unclear.
To ensure accuracy in measurements, it is advisable to employ the
lowest effective ICG dose, as high doses may lead to background
signal interference, which could compromise the precision of the
readings
[57]
.
Aim of ICG-FA use in oesophageal surgery is to reflect the
difference between subjective visual inspection and objective
ICG-based assessment to identify the best site for EGA. Visual
assessment of tissue perfusion during an esophagectomy may not
consistently align with the adequacy of the blood supply. Data
clearly indicate that ICG-FA results can differ from visual
assessments. In few studies, ICG-FA revealed inadequate blood
supply to the GC’s tip, despite visual assessments suggesting
sufficient perfusion in 24–40% of the cases
[15,43]
. Figure 4A-D
exemplarily shows ICG-FA assessment of the GC using Stryker’s
1688 AIM High-Definition telescope, demonstrating the avas-
cular and dusky tip of the GC and oesophagus in overlay mode.
Changing the anastomotic site because of poor fluorescence at
the original location, necessitating a revision of the GC and
oesophageal stump is a challenging task but has been reported
in some studies, with rates ranging from 6 to 40%
[43,52,58]
.
A meta-analysis found that in the ICG-arm, the incidence of AL
and graft necrosis (GN) was 11%, with a pooled change in
management rate of 25%. This change in management included
the resection of poorly perfused portions of the GC and a change
in the anastomotic site. Subsequently, the ICG group exhibited a
reduced incidence of AL and GN compared to the non-ICG group
with a odds ratio of 0.30 (95% CI: 0.14–0.63)
[57]
.
Studies have reported the use of ICG in assessing reference
point of well-perfused area of GC during esophagectomy for
anastomosis. Campbell and colleagues utilized a reference point
10 cm from the pylorus and calculated FI 60 seconds after
injecting the ICG dye. They considered areas with FI at least 75%
of the reference point as well-vascularized and performed all
anastomoses in these zones after necessary revision with conse-
quently a reduced incidence of AL
[37]
. Kitagawa et al.
[44]
observed a decrease in AL rate from 17.9 to 4.4% by visualizing
the blood supply border of the RGEA using ICG-FA by the
HyperEye Medical System and accordingly changing the
anastomotic site.
Hence, we must assume that ICG-FA for assessing GC blood
supply during esophagectomy has yielded promising results in
reducing AL and GN incidence while aiding in optimal anasto-
motic site selection.
Assessment of the proximal oesophageal stump has also been
addressed in few studies since patency of the EGA also equally
depends on the oesophageal stump quality in determining
AL
[40,58]
. Thammineedi et al.
[58]
have demonstrated that ICG
plays a definitive role in assessing the perfusion of the proximal
oesophageal stump, necessitating revision in 40% of patients.
The use of ICG-FA has been proposed as a method to ensure
good blood perfusion at the anastomosis site during surgery.
Figure 2. Indocyanine green (ICG) fluorescence angiography of gastric conduit. (A) Perfusion of gastric conduit in white light. Note the part of conduit distal to inked
line is dusky with doubtful vascularity by visual inspection. (B). At 7 sec after IV injection in central venous catheter, the first appearance of ICG blush in gastric
conduit is seen along the gastroepiploic arterial arcade. (C) At 15 sec after injection almost 2/3
rd
of the gastric conduit demonstrate ICG colour. (D) At 25 sec post-
injection still the distal few cms of the gastric conduit is not enhancing with ICG fluorescence but the space between the black marking and the last arcade before
entering the gastric conduit wall, now demonstrates the submucosal perfusion.
Nusrath et al. International Journal of Surgery (2023) International Journal of Surgery
4
Table 1
Commonly used devices for ICG-FA imaging.
Manufacturer Imaging system Light source Utility Software Modes available
Mizuho Ikakogyo Co., Ltd, Tokyo,
Japan
HyperEye Medical System LED Portable hand held imaging
device for OP
LumiView 1.Superimposed fluorescence image on colour images
Hamamatsu Photonics K.K,
Hamamatsu, Japan
Photodynamic eye‐Neo II LED Portable hand held imaging
device for OP
ROIs 1. Colour and black and white fluorescent image 2. Fluorescence
mapping function 3. Focus adjustment (near ‐far)
Novadaq Technologies, Ontario,
Canada
SPY Elite Imaging System
(Integrated with Stryker’s)
Laser Laparoscopic, Thoracoscopic
surgery
SPY-Q
Da Vinci Surgical Systems Intuitive
Surgical, Sunnyvale, CA
Firefly camera systems
integrated into da
Vinci Si and Xi surgical robots
(Intuitive Surgical Inc)
3D LED illuminator Robotic surgery Da Vinci OS4 1. Firefly Si (camera at the end of a laparoscope) and Xi (chip ‐on—
a—tip arrangement)
2. Normal imaging and fluorescent modes
3. Firefly is an add ‐on feature with the Si robot and a standard
feature with the Xi robot
Karl Storz, Tuttlingen, Germany IMAGE1 S Rubina (Integrated 4 K
and 3D)
Laser-free LED (Xenon light
source)
Laparoscopic, Thoracoscopic
surgery
ROIs 1. Overlay mode—blue or green- regular white light image is
combined with the NIR/ICG data
2. Intensity map- Displays the intensity of the NIR/ICG signal using a
colour scale in an overlay image.
3. Monochromatic- NIR/ICG signal alone is displayed in white on a
black background
Karl Storz, Tuttlingen, Germany Image 1 S system HD xenon light source (D-light
P system)
Laparoscopic, Thoracoscopic
surgery
ROIs 1. Optical illumination and contrast enhancement with IMAGE1
S™CLARA and CHROMA
2. A foot switch between white light and ICG modes
3. No overlay mode
Stryker, Kalamazoo, MI, USA 1688 AIM (Advanced imaging
modality)
LED (L11 light source and
auto-light technology)
Laparoscopic, Thoracoscopic
surgery
SPY-Q 1. Green overlay mode (superimposed fluorescence on visible light
field)
2. SPY ‐ENV mode (grayscale and green imaging)
3. SPY ‐Contrast (High contrast visualization of 4K fluorescence in
black and white)
4. IRIS (for lighted ureteric stents)
Stryker, Kalamazoo, MI, USA SPY ‐PHI L11 with Auto-Light Portable hand held imaging
device for OP
SPY-Q 1. Green overlay mode
2. Colour-segmented fluorescence mode (gradient proportionate to
the intensity of fluorescence. Orange (maximum); Grey
(minimum)
3. SPY ‐Fluorescence mode (white fluorescence against a black
background)
Beth Israel Deaconess Medical
Center, Boston, MA, USA
Mini-FLARE™LED Portable cart based imaging
system for OP
Mini-FLARE
TM
Imaging
System Software
Colour Video, NIR Florescence image, Colour- NIR Merge
Fluoptics, Grenoble FRANCE Fluobeam Laser Portable hand held imaging
device for OP
.FLUSOFT imaging software 1. Florescence is depicted in black and white images.
2. FLUSOFT imaging software permits pseudo-colouring of
fluorescence intensities
Quest medical imaging, Middenmeer,
the Netherlands
Quest Spectrum Platform® LED Open and laparoscopic
procedures
Quest Research Framework® 1. Overlay mode
2. Intensity map
HD, high definition; ICG-FA, indocyanine green fluorescent angiography; LED, light emitting diode; OP, open procedures; ROI, region of interest.
Nusrath et al. International Journal of Surgery (2023)
5
Efforts have been undertaken to objectively stratify the ICG-FA
findings which is essential for not only reporting but also repli-
cation and clinical implementation of the technique.
One such attempt represents the 90 sec to 60 sec rule. Kumagai
et al.
[46]
proposed a 90-second rule to ensure good blood perfu-
sion at the anastomosis site during surgery. They created all
anastomoses in the area of the GC that enhanced within 90-sec
from the initial enhancement of the root of the RGEA. According
to this rule, the tip needed resection in 50% of the cases, and the
anastomotic site was changed in 52% (18 of 35 cases). None of
the patients underwent anastomosis at a site with delayed
enhancement after 90 seconds.
Yamaguchi and colleagues conducted a multicentric study and
observed that the AL rate was 4.1% when EGA site occurred
within 90 sec of enhancement and 2.4% when it happened within
60 sec using ICG-FA. They advocated the “90-to-60-second rule”
with ICG-FA to prevent AL from EGA
[53]
. Pather and colleagues
assessed the GC perfusion with ICG-FA under time constraints in
minimally invasive Ivor Lewis esophagectomy. Segments of the
GC that did not fully enhance within 60 sec were considered non-
perfusion zones and were transected. Anastomosis was then
performed between the distal native esophageus and the perfused
proximal stomach during the thoracoscopic part of the
procedure
[50]
.
Similar results have been published by Lou and colleagues in
McKeown minimally invasive esophagectomy with AL of only
1.2% when anastomosis had been carried out in ICG-FA visua-
lized zone within 60 sec. No vascular perfusion areas or perfusion
times exceeding 60 sec indicated a poor tissue perfusion and
presented higher AL rates of upto 10.4%
[47]
.
Since manual time measurement is subject to bias, hence
attempts were made to evaluate the GC perfusion based on flow
speed rate. ICG-FA was used by Koyanagi and colleagues to
measure blood flow speed in the GC during surgery. They found a
threshold of 1.76 cm/s for speed that predicted AL risk. Patients
were divided into two groups based on the ICG flow speed—a
simultaneous group and a delayed group. The simultaneous
group had similar speeds in the GC wall and greater curvature
vessels, while the delayed group had slower speed in the GC wall
compared to the greater curvature vessels. None of the patients in
the simultaneous group developed a AL, while 46.7% of the
patients in the delayed group presented clinical evident ALs hence
the group concluded that the ICG-FA using blood flow speed in
GC is a useful tool to predict the risk of AL in oesophageal
surgery
[45]
.
Interpretation of ICG-FA results remains a challenge as mea-
surements can be subjective (evaluating FI and time to adequate
fluorescence) or objective (assessing flow patterns, velocity, and
inflow/outflow patterns via software analysis). Although desir-
able, objective measurements can be time-consuming due to cal-
culations or software analysis. Van Den Hoven et al.
[59]
identified
11 software programs for quantifying tissue perfusion via ICG
near-infrared fluorescence imaging and stressed the importance
of standardization for reliable results. The group categorized
fluorescence studies into three types:
(1) Static fluorescence analysis measures ICG fluorescence inten-
sity in a specific region of interest to assess tissue perfusion
but relies on camera settings and timing.
(2) Dynamic fluorescence analysis with absolute intensity is
valuable for objectively tracking changes in tissue perfusion
over time.
Figure 3. Quantification perfusion analysis. (A) A reference point on well-vascularized part of gastric conduit is selected. Here 10 cms from pylorus on conduit is
marked as 100% (Seen in overlay mode). (B) Relative perfusion of 61% (in relation to reference point) 2 cm proximal to inked line (visual boundary of poor perfusion).
Seen in overlay mode. (C) Perfusion distal to inked line with 19% relative perfusion. Seen in overlay mode. (D) Borderline perfusion of conduit (46%) just proximal to
inked line as seen in fluorescent mode. (E) Borderline perfusion of conduit (47%) just proximal to inked line in colour-segmented fluorescent (CSF) mode. Grey colour
indicates avascular zone. Blue poorly perfused zone. Green and Red or pink indicate well perfused. (F) Perfusion of oesophageal stump at the tip (35%) in
overlay mode.
Nusrath et al. International Journal of Surgery (2023) International Journal of Surgery
6
(3) Dynamic normalized fluorescence expresses fluorescence
intensity as a percentage change from maximum intensity
over time.
Ishikawa and colleagues performed a post hoc analysis and
compared the FI curves at the antrum to the FI curves at the tip of
the GC and an area 5 cm distal/ caudad to the GC tip. They found
a significantly lower max FI at the tip and 5 cm distal/ caudad to
the tip were associated with AL, and time to max FI at 5 cm distal
to the tip was associated with AL
[42]
.
Time-fluorescence intensity curves graphically display the
intensity of fluorescence over time and are an effective tool for
evaluating tissue perfusion and detecting abnormal pattern,
particularly delayed ICG fluorescence flow, which can indicate
inflow or outflow issues. Recent research has shown that blood
flow decreases significantly over time from the GC creation phase
to the anastomotic phase, and tension or compression from
pulling up the GC through the posterior mediastinal or retro-
sternal route may also affect blood perfusion. Time-fluorescence
intensity curves can thus offer valuable insights into tissue per-
fusion and help surgeons detect potential issues during proce-
dures. Recently Galema and colleagues demonstrated three
pattern using ICG-FA for GC evaluation - 1 (steep inflow, steep
outflow); 2 (steep inflow, minor outflow); and 3 (slow inflow, no
outflow). Major finding of that study was to outline the poor
inter-observer agreement
[41]
. Yukaya et al.
[5]
also differentiated
three curves (normal, inflow delayed, outflow delayed) and their
association with AL rates. Although no significant correlation
could be established between AL and blood flow pattern in that
study with only 27 patients, they were able to produce a repro-
ducible quantitative measurement tool. The study by Ishige
et al.
[60]
reported no AL in 20 patients but outlined the impor-
tance of multiple quantitative measurements as they could clearly
show a decrease between quantitative FI between the time of GC
creation and anastomosis while macroscopically no obvious
difference was notable.
In recent years robotic-assisted minimally invasive esopha-
gectomy (RAMIE) has gained much popularity hence it is
necessary to address the role of ICG-FA in RAMIE as well
although the current available data with focus on this topic is very
limited. De Groot et al.
[39]
reported in a prospective study change
of anastomotic site in 14% (9 out of 63). Sakaria and colleagues
assessed ICG-FA during RAMIE and reliably identified the vas-
cular arcade termination in all 30 study patients. Furthermore,
they reported on even previously unseen small transverse vessels
becoming visible with ICG-FA in RAMIE. ICG-FA also aided in
determining the vascular arcade’s position during greater curve
and omentum mobilization, enhancing surgical precision and
safety
[51]
. Hodari et al.
[40]
investigated the effectiveness of Firefly
Table 2
ICG-FA assessment of perfusion of GC.
Author (Ref.) Year
Study
design Country N AL in ICG-arm (%)
AL in non-ICG-arm
(%)
Operative
technique
Timing of ICG
Injection Dose(mg)
Imaging
system AS
Campbell
[37]
2015 R USA 90 0/30 (0)a 12/60(20) MI-ILE After GC 5 SPY Elite T
Dalton
[38]
2017 R USA 40 2/20 (10) 0/20 MI-ILE After GC 7.5 PINPOINT T
DeGroot
[39]
2022 P NL 63 14/63(22.2) —RA-ILE After GC 7.5 FireflyT
Hodari
[40]
2015 R USA 54 0/39 (0) 3/15 (20) RA-ILE After GC NS FireflyT
Galema
[41]
2023 P NL 20 3/20 (15) —NS After GC 5 Quest N
Ishikawa
[42]
2021 R USA 304 70/304 (23) —ILE/THE After GC 5 SPY Elite N
Karampinis
[43]
2017 R Germany 90 1/35(3) 10/55(20) MKE/IVE After GC 7.5 PINPOINT T/N
Kitagawa
[44]
2017 R Japan 72 7/72 (9.7) —MIE Before & After GC 5 HEMS N
Koyanagi
[45]
2016 R Japan 40 7/40 (17.5) —Open After GC 1.25/2.5 PDE N
Kumagai
[46]
2018 R Japan 70 1/70 (1.43) —TTE After GC 2.5 PDE N
Luo
[47]
2021 R China 192 1/86 (1.16) 11/106 (10.3) M K MIE After GC 0.5 mg/kg Novadaq N
Murawa
[13]
2012 R Poland 15 1/15 (6.7) —THE After GC 25 IC-VIEW N
Noma
[48]
2017 R(PS) Japan 136 6/68 (8.7) 15/68 (22) MIE/Open After GC 12.5 PDE N
Ohi
[49]
2017 R Japan 120 1/59 (1.7) 9/61 (14.75) MIE/Open After GC 2.5 PDE N
Pather
[50]
2021 R USA 100 6/100 (6) —MI-ILE After GC 7.5 PINPOINT T
Rino
[28]
2018 R Japan 33 5/33 (15) —3flnd After GC 2.5 PDE T
Sarkaria
[51]
2014 P USA 30 2/30 (6.7) —RAMIE Before GC 10 Firefly T/N
Schlottman
[15]
2017 R USA 5 0/5 (0) —Hybrid ILE After GC 5 STORZ T
Shimada
[29]
2011 R Japan 40 3/40 (7.5) —TTE After GC 12.5 PDE N
Slooter
[52]
2020 P NL 84 12/84 (14) —MI-ILE After GC 0.05 mg/kg Pinpoint/ spy N/T
Talavera-Urquijo
[4]
2020 P Italy 100 32/100 (32) —MI-ILE Before & After GC 0.3 mg/kg Olympus T
Thammineedi
[34]
2020 P India 13 0/13 (0) —MIE After GC 2.5-15 PINPOINT N
Von Kroge
[3]
2020 R Germany 20 7/20 (35) —Open After GC 0.02 mg/kg SPY Elite T/N
Yamaguchi
[53]
2021 P Japan 129 4/129 (3) —Open/MIE After GC 2.5 PDE N
Yukaya
[5]
2015 R Japan 27 9/27 (33) —NS After GC 0.1 mg/kg HEMS N
Zehetner
[54]
2015 R USA 144 24/144 (16.7) —MIE After GC 2.5 SPY N
LeBlanc
[55]
2023 R USA 312 4/61 (6,6) 13/251(5,2) RAMIE After GC ——T
Shishido
[56]
2022 R Japan 39 7/39 —MIE After GC 10 PDE/ FireflyN
AL, anastomotic leak; AS, anastomotic site; GC, gastric conduit; Inj, Injection; M K MIE, Mc Keown minimally invasive esophagectomy; MIE, minimally invasive esophagectomy; MI-ILE, minimally invasive Ivor lewis
esophagectomy; MKE/ILE, Mc Keown esophagectomy/ Ivor Lewis Esophagectomy; N, neck; N, total numbers; NL, Netherland; NS, not specified; P, prospective; PDE- PhotoDynamic Eye; PS, Propensity Score
Matching; R, retrospective; RA-ILE, Robotic-assisted Ivor Lewis Esophagectomy; SPY Elite System; T, thorax; LifeCell, Bridgewater, NJ, USA, IC-VIEW
R
Pulsion Medical System, Munich, Germany; Hamamatsu
Photonics K.K, Firefly- Intuitive Surgical, Sunnyvale, CA, USA. PINPOINT- (Novadaq Technologies Inc. Richmond, Canada, 4CMOS laparoscopi c fluorescence imaging system, Opman Mandi Company,
Guangdong, China, Quest V2 Fluorescence imaging platform (Quest Medical Imaging), Middenmeer, The Netherlands, HyperEye Medical System (Mizuho Ikakogyo Co., Ltd, Tokyo, Japan, SPY Imaging System
Novadaq, Ontario, Canada), laparoscopic camera (Olympus, Tokyo, Japan).
Nusrath et al. International Journal of Surgery (2023)
7
and ICG-FA in identifying perfusion demarcation during
RAMIE. Integrated Firefly accurately pinpointed perfusion zones
in all included 54 patients, especially near the oesophageal stump.
The use of ICG-FA reduced AL rates from 20% to 0%, under-
scoring its value in improving patient outcomes utilizing robotic
platform. In line with this is a most recent report by LeBlanc and
colleagues outlining the impact of ICG-FA in RAMIE as it directly
impacts surgeon’s decision-making (80%!) for additional resec-
tion of the GC. In addition, they demonstrated a correlation
between elevated time to initial perfusion and maximum perfu-
sion with ALs
[55]
.
ICG-FA and reduction in anastomotic leaks
ICG-FA has become an increasingly valuable tool for assessing
tissue perfusion during esophagectomy. Its use in evaluating GC
perfusion before anastomosis has been shown to significantly
reduce the risk of AL. Efforts have been made to position the
anastomotic site in a well-perfused area to decrease AL rates.
ICG-FA has been shown to be an independent risk factor for
AL
[49]
. Placing the anastomosis in an area of good perfusion, also
referred to as the “optizone,”has been proven to decrease the rate
of AL. When the anastomotic site was positioned within the
optizone as defined by ICG-FA several authors reported reduc-
tion of AL rates in upto 45%
[37,50,54]
. In addition, Noma et al.
[48]
not only noted a significant reduction in the incidence but also
severity of AL with the use of ICG-FA.
Two meta-analyses found a 70% overall risk reduction for AL
with the use of ICG-FA
[57,61]
. In addition, a meta-analysis by
Slooter reported even 70% risk reduction in GC necrosis with
ICG-FA
[57]
. These findings are also supported by a recent a sys-
tematic review by Van Dele et al.
[62]
. In addition a propensity
score matched study by Shishido et al.
[56]
clearly outlined the
benefit of ICG-FA with AL rate of 9% in the ICG-FA group.
On the contrary we must also acknowledge reports question-
ing the efficacy of ICG-FA in terms of reducing ALs. A meta-
analysis by Casas et al.
[63]
suggested that using ICG-FA does not
appear to reduce AL rates in patients undergoing minimally
invasive esophagectomy with intrathoracic anastomosis. Another
meta-analysis by Zhang and colleagues reached to a similar
conclusion. ICG-FA was declared by the group only to be useful
for reduction in ALs and consequently shorter postoperative
hospital stay for patients undergoing cervical anastomosis only.
However, it was not found to be effective for patients undergoing
intrathoracic anastomosis as reported by Cases and colleagues
too. Additionally, the application of ICG fluorescence both
before and after GC creation was more effective in preventing
AL
[64]
.
Despite the adoption of ICG-FA, the risk of AL persists as other
factors contributing to ALs remain as potential morbidity factors.
Various meta-analyses have reported AL incidence rates ranging
from 11% to 14% following intraoperative ICG-FA
[52,61]
.
Management strategies regarding post-ICG assessment have
involved resecting poorly perfused GC and changing the anasto-
motic site. However, despite these interventions, the rates of ALs
and GN remain elevated in general. In fact, one meta-analysis
found that the pooled incidence of AL and GN increased after
management changes, potentially due to anastomotic tension and
selection bias among patients with poor vascularization or vas-
culature status
[57]
.
Figure 4. Indocyanine green (ICG) Fluorescence Angiography Assessment of Gastric Conduit Using Stryker’s 1688 AIM High-Definition Laparoscope.
(A) Enhancement of the gastric conduit is observed after 7 sec of ICG injection in overlay mode. (B) Further enhancement is seen after 20 sec. (C) A close-up view
reveals the avascular and dusky tip of the gastric conduit, along with the distal end of the divided oesophagus in overlay mode. (D) The gastric conduit is displayed in
Spy env mode.
Nusrath et al. International Journal of Surgery (2023) International Journal of Surgery
8
It is important to note that most studies evaluating EGA with
ICG assessment are retrospective and involve small sample sizes.
Very few have included a control group without ICG
assessment
[37,38,43]
. To provide a more robust evaluation of ICG-
FA effectiveness in reducing AL incidence, larger prospective
randomized controlled trials are needed.
In addition, AL following esophagectomy depends not only on
adequate perfusion but also on factors like anastomotic tension,
location, and surgical approach and patient overall condition.
Numerous studies have uncovered various risk factors associated
with ALs. Kassis et al.
[9]
linked ALs to obesity and comorbidities
like congestive heart failure, hypertension, and renal insuffi-
ciency, as well as the type of anastomosis performed. Similarly,
Hall et al.
[65]
identified increased operative time, elevated pre-
operative white blood cell count, pre-existing diabetes, and
perioperative transfusion as independent AL risk factors. With
regard to the GC Pather et al.
[50]
highlighted the non-perfusion
areas as independent AL risk factors. However, some authors, as
Yamaguchi et al.
[53]
did not find any significant differences in AL
rates and reconstruction route, anastomotic method, tumour
location, or the administration of preoperative chemotherapy or
radiation therapy.
Table 2 summarizes various studies on ICG-FA conducted to
date and their outcomes, providing a comprehensive overview on
the research in this field.
The complexity of anastomosis healing does not allow to cover
all aspects in a single review article hence we need to address the
limitations that need to be acknowledged. Firstly, it is essential to
note that this is not a meta-analysis or a systematic review; rather,
it offers a summary of the existing literature on the subject.
Systematic reviews and meta-analyses are undoubtedly a tool to
overcome sample size, heterogeneity, and outcome reporting.
Both allow to evaluate an information available for decision-
making. On the other hand, the quality of systematic reviews and
meta-analyses depend to greatest extent upon the addressed
question with inevitable selection bias and loss of information.
The systematic reviews and meta-analyses we have included in
this paper for example report on outcomes based upon 9–25
studies. Furthermore, many of the articles included in those sys-
tematic reviews and meta-analyses were characterized by very
small sample sizes, retrospective designs, and a potential for
publication bias (type of reconstruction!). Additionally, the
absence of control groups in most studies limits the ability to
draw definitive conclusions. Moreover, variations in ICG dosa-
ges, techniques, and imaging systems used among the studies add
another layer of complexity to the interpretation of the findings.
Finally, it is important to highlight that high-quality RCTs on this
subject are lacking. These limitations emphasize the need for
further research to establish more robust evidence regarding the
effectiveness of ICG-FA in the context of GC and EGA perfusion
assessment. At present majority of the data available pinpoints
towards a benefit of ICG-FA in oesophageal resection with GC
reconstruction. Although many qualitative and quantitative tests
have been evaluated to objectively stratify ICG-FA results in GC
and EGA perfusion assessment, none can be designated as the
gold-standard since each one has only been tested in a single study
and comparative analysis are missing till date. However, this is
ultimately to be happen, especially within the frame of robotic
platforms with included ICG-FA tools becoming more and more
popular.
We aimed here to cover the entire topic related to ICG-FA—
from applied dosage, imaging systems, assessment and stratifi-
cation tools, and outcome—in GC and EGA perfusion
assessment.
Conclusion
In summary, ICG-FA stands as a safe and valuable tool for
assessing GC and EGA perfusion during esophagectomy. It fur-
nishes crucial information to guide GC construction and ana-
stomotic site selection, potentially reducing the occurrence of AL.
However, it’s essential to recognize that AL development is
influenced by various factors. Therefore, ICG-FA should be
employed in conjunction with other strategies to optimize both
patient-specific and procedural factors, ultimately minimizing AL
rates. Altogether, the utilization of ICG-FA represents a promis-
ing advancement in enhancing the safety and effectiveness of
oesophageal surgery.
Ethical approval
None.
Consent
None.
Source of funding
None.
Author contribution
S.N.: design - literature search, data extraction, writing—final
proof. P.K.: - literature search, data extraction, writing—final
proof. S.S.: design—data extraction, writing—final proof. A.D.:
literature search, data extraction, final proof. M.B.: literature
search, data extraction—final proof. P.J.: literature search, data
extraction, final proof. M.A.: revision literature research, data
extraction, final proof. S.A.: literature search, data extraction, final
proof. T.A.M.: data extraction, final proof. D.C.B.: revision, final
proof. K.V.V.N.R.: writing, final proof. T.S.R.: design, writing,
final proof. Y.K.V.: design, literature search, data extraction,
writing, final proof.
Conflicts of interest disclosure
Not invited.
Research registration unique identifying number
(UIN)
Not invited.
Guarantor
Syed Nusrath. Yogesh Vashist.
Nusrath et al. International Journal of Surgery (2023)
9
Data availability statement
Not invited.
Provenance and peer review
Not invited.
Data statement
This is a review based on available data in the literature. We have
summarized the results of the studies published in this paper. We
can provide that data upon requirement. Also, data from our own
institute can be provided to the extent of this review. Due to
copyright issues, we cannot provide the full-length articles, but
the reference list of the paper, represents the literature from which
data is included.
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