The ability to assess tissue perfusion and identify vital structures in the operating room in order to potentially decrease complication rates remains a key goal for surgeons. The introduction of immunofluorescence utilizing indocyanine green intraoperatively to evaluate areas such as an anastomosis, a free flap, biliary anatomy, or lymphatics has the possibility of decreasing postoperative complications by addressing identification and perfusion concerns at the time of surgery.
The use of laser induced immunofluorescence using indocyanine green relies on similar principles as fluorescein technique, which was first proposed in 1942. Fluorescein angiography was initially used to evaluate vascularity of the eye and skin. Fluorescein angiography did not become clinically significant, however, due to difficulties with the tracer. A second generation tracer, indocyanine green was developed in order to overcome the limitations of fluorescein. Indocyanine green (ICG) is a water-soluble lypophilized powder with a chemical formula of C43H47N2O6S2Na. It is a fluorophore that respondes to near infrared irradiation and absorbs light between wavelengths of 790 and 805 nm and re-emits it with an excitation wavelength of 835 nm. The compound is administered intravenously, and when injected it binds to plasma proteins. ICG binds nearly exclusively to albumin on electrophoresis, with only minor binding to other serum proteins, as seen in Figure 1.1
It is then taken up in the liver, and excreted in bile. The half-life of ICG is 3-5 minutes and excreted by the liver in 15-20 minutes. Its short half-life, hepatic excretion, and unique wavelength emission in tissue providing images of both circulation and lymphatics makes it well suited for use in the operative field. Contraindications for use of ICG are limited, but include patients with a known allergy or adverse reaction to ICG or iodine and those women who are pregnant or lactating. There have been reports of rare cases of anaphylactic shock and urticaria associated with ICG usage.
ICG and Near Infra-red (NIR) imaging modalities have been used in a wide array of surgical procedures. Minimally invasive colorectal surgery, encompassing both laparoscopic and robotic techniques, has employed the use of immunofluorescence to evaluate the perfusion of the anastomosis. This includes anastomoses for colorectal cancer of the right and left colon, as well as rectal cancer resections. Further immunofluorescence imaging has been used to assess blood supply of anastomoses following pancreaticoduodenectomy and esophagectomy. Additional uses of this technology in general surgery include lymphadenectomy, donor nephrectomy and liver resection to evaluate perfusion, and biliary anatomy during cholecystectomy. Fluorescence-guided surgery has been utilized in oncology surgery in attempts to achieve improved margin-negative status 27 although this analysis will not cover this use as it is outside of the focus of this evaluation. Finally, immunofluorescence has been used with some success in plastic surgery to evaluate the microvasculature of free flaps in attempts to improve free flap survival.
The cost of this technology is an important factor when considering its implementation into the clinical environment. The lowest cost portion of this technology is the ICG itself. A 25mg/Vial kit is approximately $70 with some variation in cost based on the company it is purchased from and specific institutional agreements on pricing.
There are multiple devices that can be used for intraoperative fluorescence imaging with ICG. These include Photodynamic Eye (Hamamatsu), SPY (Novadaq), FIREFLY robotic (Novadaq), FDPM imager (Texas), IC-View (Pulsion Medical), FLARE (Beth Israel Deaconess Hospital), and the AIM platform (Stryker). These devices vary in cost. An example of the price of these devices is the AIM platform by Stryker, which includes near-infrared immunofluorescence visualization amongst other visualization features. The cost of the system ranges from $56,000-87,000, depending on accessories. Many of the other devices in this category are comparable in price range. Another immunofluorescence platform is with robotic surgery. The cost of the FIREFLY system on the robot is dependent on the generation of the robot. The da Vinci Si model can be upgraded to include FIREFLY for roughly $80,000 if the system was not purchased with it already included. The newest model, Xi, has FIREFLY included as a component of the system with no additional charges for this imaging modality.
The following is a review of the current data on this technology, and a summary of the pros and cons of its use. Data on emerging technologies can be scarce, and while we have attempted to pull all relevant studies, more will come forth in the literature after the publication of this document. We will update when enough data accumulates to make a significant change necessary.
TAVAC Perfusion Assessment; Clinical Evidence
When reviewing the clinical evidence underpinning the use of near infrared fluorescence angiography (NIRFA) for the assessment of anastomotic perfusion, the primary questions and the ones most commonly addressed in the literature are:
- Does NIRFA reduce leak rate?
- Does NIRFA change resection margin?
- Can NIRFA safely reduce diversion (e.g. protective ileostomy) rate in colo-rectal procedures?
The answers to these questions are at least partially answered and discussed in detail in the following review of the literature. On the other hand, a number of other essential questions, are inadequately addressed by the current literature including:
- Does NIRFA reduce length of stay?
- Does NIRFA reduce or add to costs?
- Does NIRFA add to operative time?
- Does NIRFA require quantitative assessment to be useful?
- Is NIRFA more useful for a particular type of resection (i.e. right vs left vs rectal, gastric conduit vs colonic interposition vs jejunal)?
- Is NIRFA affected by neoadjuvant chemotherapy and/or radiotherapy?
Future research will hopefully not only definitively answer the primary questions but also address these secondary questions.
Near infrared fluorescence angiography (NIRFA) has been reported for use in the assessment of perfusion in both colorectal and esophageal anastomoses. Despite advances in surgical technique and perioperative management, anastomotic leaks remain one of the most devastating and costly complications following both colorectal and esophageal surgery. Rates of leak vary from 6 to 35% for esophageal anastomoses 2,3,4,5,6,7,8,9 and 1-30% in colorectal anastomoses with the leak rate increasing as the anastomosis approaches the anal verge. Complications of leak include increased length of stay, need for revisional surgery, permanent defunctioning stoma10, increased cancer recurrence rate11, reduced function, sepsis and even death. Additionally, protective diverting stomas routinely used prophylactically in cases of low rectal anastomoses are associated with significant morbidity and may be over-utilized.
Although many risk factors have been implicated as the causative etiology of anastomotic leaks, inadequate perfusion clearly plays a significant role12. Subjective evaluation of perfusion by the operating surgeon including; bleeding edges, tissue temperature, appearance of the tissue and palpable pulses have notoriously poor predictive value13,14. Multiple attempts at objective, reproducible anastomotic margin perfusion assessment have been described but have all failed to enter into common clinical practice.
By far the largest body of data exists for the use of NIRFA in colorectal anastomotic perfusion. First described by Kudszus et al in 2010, they describe a retrospective review of patients undergoing colon resection for colorectal cancer at a single institution. All of these pts were assessed using ICG and near infrared fluorescence. Over a 10 year period, a total of 332 patients had fluorescent evaluation of anastomotic perfusion. These patients were then matched with historical controls by age, BMI, type of resection, type of anastomosis, stoma, blood use, and emergent nature of surgery. A total of 402 patients were matched. Perfusion was rated by both visual assessment and by a software package which objectively assigned a value to the tissue in question.
In 13.9% of cases a change in anastomotic site was indicated by the NIRFA assessment. Of the 402 patients in both the study and control groups, 22 anastomotic leaks were identified, seven (3.5%) in the NIRFA group and 15 (7.5%) in the control group. Subgroup analysis further identified patient age over 70, hand sewn anastomosis and elective surgery as groups who benefited most from NIRFA. They also showed that length of stay was reduced in patients who had NIRFA assessment.
This publication was followed in 2012 by two papers describing the use of NIRFA transanally to assess colorectal anastomotic perfusion. In these studies, evaluation was accomplished with a NIR laparoscope introduced transanally via a rigid procto-sigmoidoscope mated to a 12mm laparoscopic trocar to maintain insufflation. An initial 7 patients undergoing LAR were enrolled and then followed by an additional 20 patients. In this study no changes were made based on NIRFA imaging but rather all decisions regarding a diverting ostomy and/or further resections were made based on clinical grounds.
Fluorescence was subjectively evaluated by comparing the anastomotic site to normally perfused distal rectum. The mean distance of the anastomosis from the anal verge was 11 (± 3) cm. Out of 20 patients, four exhibited abnormalities of flow on ICG evaluation. In two of the patients with hypo-fluorescence, the surgeon had already decided to perform a diverting loop ileostomy and both did well postoperatively. The other two hypo-fluorescent patients experienced delayed return of bowel function and febrile episodes, and CT scans performed revealed peri-anastomotic collections consistent with minor anastomotic leaks which did not require intervention.
Two papers reported on the use of NIRFA during robotic colorectal low anterior resections. In both studies the authors describe a significant number of revisions to the anastomotic margins based on the NIRFA imaging with a resultant significant decrease in anastomotic leaks. Jafari et al15 evaluated the results of 40 patients, 16 of whom had NIRFA assessment. These were ultralow rectal resections with a median level of anastomosis at 3.5 cm in the NIRFA group and 5.5 cm in the control group. 19% of the study patients had a revision of their resection margin based on NIRFA while the anastomotic leak rate was 6 and 18% in the study and control groups respectively. Hellan et al similarly described their experience in a prospective multicenter trial that evaluated 40 patients undergoing robotic or robotic assisted low anterior resections. 70% of patients had malignant disease and the majority received a diverting loop ileostomy. 40% (16/40) had a change in resection margin based on NIRFA evaluation with a mean additional proximal distance of 4 cm (±7.3 cm). Despite the change in resection margin 2 patients (5%) had anastomotic leaks requiring intervention. Of particular interest was the increased rate of revision in malignant disease likely related to the high ligation of the IMA and variable perfusion of the marginal circulation. Additionally of interest was that the leaks reported occurred very late at 15 and 40 days postoperatively.
Foppa et al looked at left, sigmoid and rectal resections and cases of small bowel ischemia. NIRFA and objective assessment software were used to obtain a perfusion index. 160 cases were included in this analysis of which 4 cases had a significant change in resection margin. They did not report on their overall leak rate but had no leaks in these 4 cases.
Ris et al reported on 30 consecutive patients undergoing colorectal resections and included both right and left resections. No change in resection margin was needed but they subjectively avoided performing diverting stomas in 3 patients in whom clinically they would have. No leaks were reported in this series.
The PILLAR II trial, is the largest multicenter prospective study to date and was designed to look at the effect of NIRFA on anastomotic leak rates. A total of 139 patients from 11 institutions undergoing left colorectal and low anterior resections with a planned anastomosis located 5 to 15 cm from the anal verge were evaluated. 86% underwent a laparoscopic resection and 14% robotic with a conversion rate of 7.8%. Forty-six percent had malignant disease. The mean level of anastomosis was 10 ± 4 cm from the anal verge. NIRFA was performed both from the serosal side and transanally via an introducer.
NIRFA affected the surgical plan in 11 (8%) patients, with the majority of changes at the proximal margin (7%). In one case, transanal identification of adequate perfusion precluded the need for formation of a diverting ileostomy. The anastomotic leak rate was 1.4% (n = 2) none of which were noted in the 11 patients who had a change in surgical plan based on intraoperative NIRFA. The authors concluded that NIRFA is safe and feasible and that this trial’s leak rate of 1.4% is lower than the reported rates in multiple recent large prospective randomized and cohort comparison studies in the literature (3% to 15%)16,17,18,19.
The authors recognized the following limitations of this study including lack of standardization of the operative technique and standard-of-care bowel viability assessment. Of note is that even in this group of highly experienced surgeons and with optimal perfusion (as confirmed by fluorescence), 2 leaks still occurred confirming that other factors in addition to perfusion contribute to anastomotic leaks.
Boni et al, reported on a cohort of 107 colectomies (40 right colectomies, 10 splenic flexure segmental resections, 35 left colectomies, and 22 anterior resections). They describe using intraoperative ICG-enhanced fluorescence to subjectively assess colon margins after resection, prior to and after completion of anastomosis. 107 patients were included, with the majority of cases (90.6%) done for malignancy. A protective ileostomy was performed in 17 patients (77.3 %) undergoing LAR.
Poor perfusion lead to “re-resection” in 3.7% (4/107) of cases (two anterior, one sigmoid and one segmental splenic flexure resections all for cancer). One patient undergoing a right colectomy ultimately had an anastomotic leak (.9%) which required reoperation. They concluded that ICG-enhanced fluorescent angiography provides useful intraoperative information about vascular perfusion during colorectal surgery and led to modifications in margin that possibly lowered anastomotic leak rate and resultant morbidity and mortality rates.
Watanabe et al reported on their experience with 119 patients undergoing colorectal surgery including; descending colon 2 (1.7 %), sigmoidectomy 38 (31.9 %), high anterior resection 23 (19.3 %), low anterior resection (LAR) 32 (26.9 %), super-low anterior resection (sLAR) 14 (11.8 %), Hartmann’s procedure 3 (2.5 %), and rectal amputation 7 (5.9 %). In all cases, it was difficult to visually identify the ischemic border macroscopically but on fluorescence enhanced imaging 68 patients (57.1 %) had adequate perfusion, 45 (37.8%) had delayed perfusion and 6 (5.0%) had no perfusion. The proximal margin of resection was changed based on these fluorescent images. The overall incidence of anastomotic leakage was 5.9 % and specifically in cases of LAR and sLAR was 6.5 %. The incidence of anastomotic stricture was 1.7 % in all cases, and was 4.3 % in the cases of LAR and sLAR. All of the cases in which an anastomotic stricture developed also experienced anastomotic leakage.
Gröne et al evaluated 18 patients undergoing LAR for cancer. A high ligation of the inferior mesenteric artery and mobilization of the mesocolon including the splenic flexure was performed. As in the PILLAR II trial the proximal margin was assessed by white light and an appropriate margin was marked by the operating surgeon. This margin was then evaluated by NIRFA and the adequacy of fluorescence evaluated subjectively by the surgeon. The proximal margin was then adjusted based on these findings, the anastomosis was formed and then reassessed by fluorescence. A decision was then made regarding a diverting ostomy. Perfusion imaging influenced surgical decision making in 28% of all cases (5/18). In 2 cases the margin was moved proximally, in 1 case the margin was moved distally and in 2 cases a diversional ostomy was averted. Re-laparotomy was required in one patient (6%) with anastomotic leakage 10 days after low colorectal anastomosis. No anastomotic leakage was detected in the five patients with changes of the surgical plan based on the results of fluorescence angiography. This compared favorably with this group’s 15% historical leak rate.
A report by Protyniak et al evaluated 77 patients undergoing colorectal resections. Assessment was carried out objectively using an assessment software package. 4 LAR patients had additional segments of descending colon resected based on visual assessment despite adequate absolute perfusion. 2 patients experienced a leak both following right sided surgery despite adequate perfusion by NIRFA.
Kin et al performed NIRFA on 173 patients undergoing colo-colonic, colorectal, and colo-anal anastomoses. The NIRFA group was then compared to case matched historical controls. Matching was based on sex, age (±5 years), level of anastomosis (±1 cm), history of neoadjuvant pelvic radiation therapy, and use of a diverting loop ileostomy. The primary outcome measure was anastomotic leak occurring within 60 days of the initial operation.
Although 5% of cases who underwent NIRFA had adjustments to resection margin, the leak rate in this series was 7.5% and 6.4% in the control and NIRFA groups respectively. This difference was not statistically significant (p = 0.67). The authors therefore concluded that the value of NIRFA in colorectal anastomotic perfusion assessment was equivocal. An example is shown in the next four images (Image 1-4)
Of note in this study is that NIRFA was not used routinely in the study period, but rather used in only a “proportion” of cases. The authors do not provide a description of the algorithm they used to decide on whether or not to use NIRFA. Another shortcoming of this study is that only the proximal colon was analyzed using NIRFA. No imaging of rectal stump perfusion, final post-anastomotic perfusion or mucosal transana perfusion was performed.
In summary, ICG NIRFA in virtually all studies impacted the site of resection in colorectal surgery. This was true even though the initial site was deemed well perfused by an expert and even on re-evaluation by a blinded observer in one study. This change also appeared to decrease the reported anastomotic leak rate. Also, inadequate perfusion is not the exclusive cause of leak as indicated by a reduced but not zero leak rate reported in most of these studies. None of the studies reported any complications related to the use of ICG or fluorescence imaging. None of the studies to date evaluated costs associated with the use of this technology but did note only a small increase in operative time (4-6 minutes).
Pacheco et al20 reported on a feasibility study in which they retrospectively reviewed 11 patients undergoing a transhiatal esophagectomy for cancer. One patient was identified as subjectively having reduced perfusion but despite this had their anastomosis formed in this area. 2 patients experienced leaks, one of whom was the patient identified as having poor perfusion.
Yukaya et al21 prospectively evaluated 27 esophagectomy cases. An objective evaluation of 2 points on the gastric conduit was analyzed for inflow or outflow delays in perfusion. The two points chosen were the last branch of the right gastroepiploic artery and an arbitrary point 3cm proximally. They found 9 leaks (3 normal flow, 2 outflow delay, 4 inflow delay) but had no fatalities.
The authors concluded that ICG angiography can be used to quantitatively measure arterial blood flow and venous return of the reconstructed gastric tubes; may help choose the appropriate surgical strategy such as supercharging, superdrainage or the use of other reconstructed organs and that blood flow type was statistically unrelated to anastomotic leakage in this study.
Due to the clearly flawed nature of the authors’ arbitrary quantification parameters and arbitrary points of analysis (versus for example the actual site of anastomosis) no conclusions can be reached from this study.
Shimada et al22 prospectively evaluated, 40 patients undergoing esophagectomy for cancer. The majority of reconstructions were performed using a gastric conduit in a retrosternal position, but cases of free jejunal, colonic and combined cases in a subcutaneous and a posterior-mediastinal positions were also included.
They used ICG fluorescence to subjectively decide whether additional arterial anastomosis or venous drainage was likely to be effective at improving perfusion. Although this study identified 2 minor and 1 major anastomotic leaks, there were no leaks in cases where they observed “small vessels” in the reconstructed organ’s wall.
In a larger study also supporting the use of NIRFA in esophageal reconstruction, Zehetner et al23 retrospectively reviewed 150 patients undergoing a minimally invasive esophagectomy. A standardized method of gastric pullup with a handsewn single-layer cervical anastomosis was used in all cases. The indication for esophagectomy was cancer in 133 patients and end-stage benign disease in 17 patients. The type of esophagectomy was en-bloc in 88 patients, transhiatal in 26, minimally invasive in 24 and vagal-sparing in 12 (open 10, laparoscopic 2). 24 patients experienced a minor or major leak (16/8).
NIRFA with subjective perfusion assessment was used intraoperatively to evaluate the gastric conduit. The entire graft was noted to have good perfusion in 66 of 150 patients (44%), whereas in 84 (66%) patients, an area of slower, less robust perfusion was noted in the proximal stomach. Out of necessity, an anastomosis to an area identified as having less than optimal perfusion was formed in 55 patients.
Patients in whom the anastomosis was placed in an area of reduced perfusion as identified by NIRFA were signiﬁcantly more likely to have a leak compared to those with good perfusion (45% vs 2%, P < 0.0001). In addition, no major leaks occurred when the anastomosis was created to well perfused stomach and thus required no re-intervention.
The authors concluded that the use of NIRFA may lead to an altered surgical plan in some patients and contribute to reduced anastomotic morbidity and better overall patient outcomes.
In summary, there is a sparsity of data regarding NIRFA assessment of the gastric conduit following esophagectomy. There does however appear to be a reduction in leak rate and/or severity when the anastomosis is created in a well perfused area of stomach as identified subjectively by NIRFA.
Indocyanine Green Usage for Biliary Visualization:
Laparoscopic cholecystectomy is widely accepted as the standard of care for cholecystectomy. It is currently the most commonly performed procedure performed by general surgeons in the United States 28. Bile duct injuries, in the era of laparoscopic cholecystectomy range from 0.4% to 0.5% 37,46,29. Their incidence decreases with increased surgeon experience40, and, while infrequent, they represent a significant patient and healthcare burden when present.
Indocyanine Green Fluorescence Cholangiography Background:
Intravenous injection of indocyanine green (ICG) to visualize the biliary tree was described in open and laparoscopic cholecystectomy in 200833 and 200932, respectively. After administration of ICG, near-infrared illumination is applied, the fluorescent image is visualized through the use of a specifically-designed fluorescence-imaging capable laparoscope and light source, allowing real-time imaging without disrupting surgical workflow while easily switching between bright-light and fluorescence mode imaging. (Images 5 & 6)
Image 5: (Cystic Duct and Common Bile Duct visualization prior to dissection)
Image 6: (Cystic Duct and Common Bile Duct visualization during Critical View dissection)
Function assessment of different organs can be targeted with various ICG intravenous doses. For example, cardiac output studies require doses of up to 5mg/kg body weight, while hepatic function imaging studies require lower doses, of 0.5 mg/kg body weight24. When biliary tree imaging is solely sought, an even lower intravenous dose, of approximately 0.025-0.05mg/kg is routinely used. A unique property of ICG is that repeated dosing can be utilized intra-operatively, with low risk of harm or allergic reaction. Biliary excretion of indocyanine green occurs within minutes following intravenous injection, and peak concentrations of ICG occur between 120 and 240 minutes following intravenous injection, as shown in Figure 2 1.
Indocyanine Green Fluorescence Cholangiography as a Roadmap in Cholecystectomy:
Appropriate pre-operative ICG injection can provide an augmented cholangiographic map. This technique allows surgeons to identify either the normal anatomy or any anatomic variation present prior to, or even during dissection. In the presence of significant inflammation, it also allows surgeons to establish and protect areas of critical importance, until further dissection allows better delineation of structures. Ishizawa et al. reported 100% common hepatic duct visualization and 90% cystic duct visualization using a pre-operative ICG injection, 1-hour prior to open cholecystectomy33, with inflammation being the limiting factor for visualization in the single patient in whom the cystic duct was not seen. The same group later described their laparoscopic experience with pre-operative ICG injection for cholangiography during cholecystectomy, demonstrating a 100% visualization of the cystic duct and 96% visualization of the common hepatic duct prior to any dissection, which improved to 100% visualization of both structures with dissection32. Several other groups have demonstrated similar findings34,32,45,44,35,38 during laparoscopic cholecystectomy as well as during robotic-assisted laparoscopic cholecystectomy43,26. Several studies also demonstrated that earlier identification of the extrahepatic bile ducts during dissection is possible with fluorescence cholangiography when compared with dissection without the fluorescent visual aid39,38,44.
Advantages of Indocyanine Green Fluorescence Cholangiography:
Fluorescent cholangiography has several potential advantages over conventional radiographic intra-operative cholangiography (IOC). First, fluorescent cholangiography can save time and operative costs associated with traditional radiographic IOC with respect to cannula insertion and contrast injection for biliary imaging. Second, the technique is often viewed as more versatile than traditional radiographic IOC: via a single pre-operative intravenous ICG injection, the surgeon can obtain fluorescent imaging at any point during the procedure, without requiring the assistance of a radiology technician or C-arm. Third, repeated imaging with repeat ICG injections is possible throughout the surgical procedure to help delineate concomitant vascular anatomy. Fourth, the imaging can be viewed from several angles, in real-time, with real-time tissue manipulation, to better understand anatomic relationships. Fifth, proper use of this technology can make obsolete the argument of routine versus selective IOC, and give more options to the surgeon for biliary visualization at a minimal additional cost per case. In centers for education, it can be a good adjunct to assist surgical trainees in understanding anatomy in real time. Lastly, the use of fluorescence cholangiography is safe and does not involve radiation exposure and the technique can be safely used in patients with traditional iodine contrast-related allergies.
Limitations of Indocyanine Green Fluorescence Cholangiography:
Despite its safety and value as a road-map in cholecystectomy, fluorescence cholangiography with ICG has some limitations. It adds costs, requiring a light source, camera with specific filters for near-infrared imaging, and fluorescent dye. Fluorescence IOC cannot visualize deep structures – deep laying intrahepatic ducts or extrahepatic ducts covered by surrounding organs, fat, or inflamed tissue. Also, the ability to detect small bile duct stones with fluorescence cholangiography is also questionable as the small defects from small stones are likely lost in the fluorescing bile present around it. In order to alleviate some of these limitations, some authors used an animal model to perform direct injection of the ICG dye into the gallbladder36. This yielded superior results in visualization of the biliary anatomy when compared with intravenous ICG injection; however the study has not been replicated in humans to date.
To our knowledge, there are only two studies to date to compare near-infrared cholangiography with traditional IOC38,31. In the latest study38, the authors evaluated the two modalities in patients with BMI>30 and concluded that near-infrared cholangiography was faster and superior in identifying the extrahepatic biliary structures. However, the study has limitations, particularly the inability of performing IOC in 24% of the patients studied, due to technical difficulties.
NIF angiography and fluorescent cholangiography both appear to be promising technologies. The ability to visualize structures and assess perfusion can have a great benefit to the surgeon and may help prevent complications in the surgical patient.
NIF angiography may help reduce the leak rate in both colorectal and esophageal anastomoses, but studies to date on this subject have many shortcomings including small numbers and their retrospective nature. In the future, large, multi-center studies should be undertaken to show benefit of this technology to further its common place use. We see promise in the use of NIF angiography in cases where perfusion margin or resection line blood flow is questionable and the surgeon requires more data before creating an anastomosis. Not to be ignored is the cost of these systems. These can be upwards of $60,000 to $80,000 for the visualization system and then ongoing costs for the drug itself. This cost can be offset with the possible prevention of complications, with a leak in an LAR or a common duct injury cost equaling the one time cost of the equipment.47
NIFFC has many benefits to the minimally invasive surgeon when compared with standard IOC. The ability to visualize the biliary system without the use of external beam radiation and the technologic and skill set required to perform IOC is the first. It can also be used several times during the surgical dissection to enhance visualization of critical biliary structures before any clips or ductotomies are made with the ability to manipulate the enhanced tissue in real-time. However, NIFFC is currently not equivalent to IOC in visualizing small stones within the duct, nor can it identify anatomy in thick or inflamed tissues. NIFFC’s ability to visually enhance the anatomy alone may offer benefit in surgeries involving the gallbladder, as enhanced NIFR imaging and biliary mapping improve accurate identification of the biliary structures, which should make the surgical procedures safer, and thus, reducing adverse outcomes. It must be noted that the dosage of ICG must be given up to one hour before optimal visualization of the biliary tree. With this in mind, careful consideration by the surgeon must be used to decide which patients with which to use this technology before the case starts. Further studies of clinical effectiveness, development of reliable and reproducible quantitative assessment of tissue perfusion, and improvements in biliary visualization including stones, paired with reduction in cost of the devices, will encourage wider adoption of this technology.
- Cherrick GR, S. S. (1960). Indocyanine green: Observations on its physical properties, plasma decay, and hepatic extraction. J Clin Invest , 39, 592-600.
- Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg. 2000;232:225–32.
- Tachimori Y, Kanamori N, Uemura N, Hokamura N, Igaki H, Kato H. Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2009;137:49–54.
- Lee Y, Fujita H, Yamana H, Kakegawa T. Factors affecting leakage following esophageal anastomosis. Surg Today. 1994;24:24–9.
- Sarela AI, Tolan DJ, Harris K, Dexter SP, Sue-Ling HM. Anastomotic leakage after esophagectomy for cancer: a mortality-free experience. J Am Coll Surg. 2008;206:516–23.
- Korst R, Port JL, Lee PC, Altorki NK. Intrathoracic manifestations of cervical anastomotic leaks after transthoracic esophagectomy for carcinoma. Ann Thorac Surg. 2005;80:1185–90.
- Atkins BZ, Shah AS, Hutcheson KA, Mangum JH, Pappas TN, Harpole DH, et al. Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg. 2004;78:1170–6.
- Udagawa H, Akiyama H. Surgical treatment of esophageal cancer: Tokyo experience of the three-field technique. Dis Esophagus. 2001;14:110–4.
- Nederlof N, Tilanus HW, Tran TC, et al. End-to-end versus end-to-side esophagogastrostomy after esophageal cancer resection: a prospective randomized study. Ann Surg. 2011;254:226–233.
- Lindgren R, Hallbook O, Rutegard J, Sjodahl R, Matthiessen P (2011) What is the risk for a permanent stoma after low anterior resection of the rectum for cancer? A six-year follow-up of a multicenter trial. Dis Colon Rectum 54:41–47
- Kingham TP, Pachter HL. Colonic anastomotic leak: risk factors, diagnosis, and treatment. J Am Coll Surg 2009;208: 269e278.
- Reavis K. The esophageal anastomosis: how improving blood supply affects leak rate. J Gastrointest Surg 2009;13:1558–60.
- Markus PM, Martell J, Leister I, Horstmann O, Brinker J, Becker H (2005) Predicting postoperative morbidity by clinical assessment. Br J Surg 92:101–106
- Karliczek A, Harlaar NJ, Zeebregts CJ, Wiggers T, Baas PC, van Dam GM (2009) Surgeons lack predictive accuracy for anastomotic leakage in gastrointestinal surgery. Int J Colorectal Dis 24:569–576
- Jafari MD, Lee KH, Halabi WJ, Mills SD, Carmichael JC, Stamos MJ, Pigazzi A. The use of indocyanine green fluorescence to assess anastomotic perfusion during robotic assisted laparoscopic rectal surgery. Surg Endosc. 2013 Aug;27(8):3003-8.
- Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 2005;365:1718e1726.
- Senagore A, Lee EC, Wexner SD, et al. Bioabsorbable staple line reinforcement in restorative proctectomy and anterior resection: a prospective randomized study. Dis Colon Rectum 2014;57:324e330.
- Pigazzi A, Luca F, Patriti A, et al. Multicentric study on robotic tumor-specific mesorectal excision for the treatment of rectal cancer. Ann Surg Oncol 2010;17:1614e1620.
- Sauer R, Fietkau R,Wittekind C, et al. Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: theGerman trial CAO/ARO/AIO-94. Colorectal Dis 2003;5:406e415.
- Pacheco PE1, Hill SM, Henriques SM, Paulsen JK, Anderson RC. The novel use of intraoperative laser-induced fluorescence of indocyanine green tissue angiography for evaluation of the gastric conduit in esophageal reconstructive surgery. Am J Surg. 2013 Mar;205(3):349-52; discussion 352-3.
- Yukaya et al Indocyanine Green Fluorescence Angiography for Quantitative Evaluation of Gastric Tube Perfusion in Patients Undergoing Esophagectomy. JACS; Aug 2015: 221
- Shimada et al Usefulness of blood supply visualization by indocyanine green fluorescence for reconstruction during esophagectomy –, Esophagus; 2011:8:259-266.
- Intraoperative Assessment of Perfusion of the Gastric Graft and Correlation With Anastomotic Leaks After Esophagectomy. Zehetner J, DeMeester SR, Alicuben ET, Oh DS, Lipham JC, Hagen JA, DeMeester TR. Ann Surg. 2015 Jul;262(1):74-8.
- A Review of Indocyanine Green Fluorescent Imaging in Surgery. Alander JT, K.I. International Journal of Biomedical Imaging, 2012 (940585), 1-26
- Routine Cholangiography Reduces Sequelae of Common Bile Duct Injuries. Carroll BJ, F.R., Surgical Endoscopy, (1996) 10, 1194-1197
- Indocyanine Green (ICG) Fluorescent Cholangiography During Robotic Cholecystectomy: Results of 184 Consecutive Cases in a Single Institution. Daskalaki D, F. E., Surgical Innovation, (2014) 21 (6), 615-621
- Current Status and Future Perspectives of Fluorescence-Guided Surgery for Cancer. DeLong JC H.R. Expert Review of Anticancer Therapy, (2016), 16 (1), 71-81
- Bile Duct Injury During Laparoscopic Cholecystectomy and Survival in Medicare Beneficiaries. Flum DR, C.A. Journal of the American Medical Association, (2003) 290 (2), 2168-2173
- Intraoperative Cholangiogram and Risk of Common Bile Duct Injury During Cholecystectomy. Flum DR, D. E. Journal of the American Medical Association, (2003) 289, 1639-1644
- Systematic Review of Intraoperative Cholangiography in Cholecystectomy. Ford JA, S.M. British Journal of Surgery, (2012), 99, 160-167
- Fluorescent Cholangiography Illuminating the Biliary Tree During Laparoscopic Cholecystectomy. Ishizawa T Bandai Y, I.M. British Journal of Surgery, (2010), 97, 1269-1377
- Fluorescent Cholangiography Using Indocyanine Green for Laparoscopic Cholecystectomy: an Initial Experience. Ishizawa T, B.Y., Archives of Surgery, (2009), 144, 381-382
- Intraoperative Fluorescent Cholangiography Using Indocyanine Green: A Biliary Road Map for Safe Surgery. Ishizawa T, T.S. Journal of the American College of Surgeons, (2008), 208, e1-e4
- Indocyanine Green Re-injection Technique for use in Fluorescent Angiography Concomitant with Cholangiography During Laparoscopic Cholecystectomy. Kaneko J, I.T., Surg Laparosc Endosc Percutan Tech, (2012), 22 (4), 341-344
- Techniques of Fluorescence Cholangiography During Laparoscopic Cholecystectomy for Better Delineation of the Bile Duct Anatomy. Kono Y, I.T., Medicine. (2015), 94 (25), e1005
- Near-Infrared Cholecysto-Cholangiography with Indocyanine Green May Secure Cholecystectomy in Difficult Clinical Situations: Proof of the Concept in a Porcine Model. Liu YY, K. S. Surgical Endoscopy, (2015), PMID 26511116
- Bile Duct Injury During Laparoscopic Cholecystectomy: Results of an Italian National Survey on 56,591 Cholecystectomies. Nuzzo G, G.F. Archives of Surgery (2005), 140, 986-992
- Near-Infrared Fluorescent Cholangiography Facilitates Identification of Biliary Anatomy During Laparoscopic Cholecystectomy. Osayi SN, W.M.-R. Surgical Endoscopy (2015), 29, 368-375
- Combined Vascular and Ciliary Fluorescence Imaging in Laparoscopic Cholecystectomy. Schols RM, B.N. Surgical Endoscopy (2013), 27, 4511-4517
- Threefold Increased Bile Duct Injury Rate is Associated with Less Surgeon Experience in an Insurance Claims Database. Schwaitzber SD, S.D. Surgical Endoscopy (2014), 28, 3068-2073
- Variation in the Use of Intraoperative Cholangiography During Cholecystectomy. Sheffield KM, J.Y. Journal of the American College of Surgeons (2012) 214, 668-679
- Anaphylactoid Reaction after Indocyanine-green Administration. Speich R, S.B. Annals of Internal Medicine (1988) 109, 345,346
- Real-time Near-infrared (NIR) Fluorescent Cholangiography in Single Site Robotic Cholecystectomy (SSRC): A Single Institutional Study. Spinoglio G, P.F. Surgical Endoscopy (2013) 27, 2156-2162
- Comparing Near-infrared Imaging with Indocyanine Green to Conventional Imaging During Laparoscopic Cholecystectomy: A Prospective Cross-over Study. Van Dam D, A.M. Journal of Laparoendoscopic & Advanced Surgical Techniques (2015), 25 (6), 486-492
- Optimization of Near-infrared Fluorescence Cholangiography for Open and Laparoscopic Surgery. Vertbeek F, S.B. Surgical Endoscopy (2014) 28 (4), 1076-1082
- Iatrogenic Bile Duct Injury: A Population-based Study of 152,776 Cholecystectomies in the Swedish Inpatient Registry. Waage A, M.M. Archives of Surgery (2006) 141, 1207-1213
- Iatrogenic Bile Duct Injury – a Cost Analysis. Tingstedt B. HPB (2008) 10(6), 416-419