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Indocyanine green fluorescence imaging in hepatobiliary surgery
Accepted Manuscript Title: Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery Author: Ali Majlesara Mohammad Golriz Mohammadreza Hafezi Arash Saffari Esther Wild Lena Maier-Hein Beat P. Muller-Stich ¨ Arianeb Mehrabi PII: DOI: Reference:
S1572-1000(16)30241-1 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.12.005 PDPDT 871
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
14-11-2016 14-12-2016 19-12-2016
Please cite this article as: Majlesara Ali, Golriz Mohammad, Hafezi Mohammadreza, Saffari Arash, Wild Esther, Maier-Hein Lena, Muller¨ Stich Beat P, Mehrabi Arianeb.Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.12.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
Short title: ICG imaging in hepatobiliary surgery Running title: ICG imaging in liver surgery Type of article: Review paper
Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery
Ali Majlesara a, * , Mohammad Golriz a, *, Mohammadreza Hafezi a, Arash Saffari a Esther Wild b, Lena Maier-Hein b, Beat P. Müller-Stich a Arianeb Mehrabi a, **
a
Department of General, Visceral, and Transplantation Surgery b
German Cancer Research Center (DKFZ)
University of Heidelberg; Heidelberg, Germany
**Corresponding author: Dr. med. A. Mehrabi, FEBS, FICS Attending General and Transplant Surgeon Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110 69120 Heidelberg, Germany Tel: 0049 – 6221 - 5636223 Fax: 0049 – 6221 - 567470 E-Mail: [email protected] *Both authors contributed equally to this work
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Highlights Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during liver surgery. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. Applications of ICG during liver surgery can be categorized into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy, avoids the drawbacks of conventional imaging and reduces post-operative complications without any known side effects.
Abstract Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during hepatobiliary surgery. ICG is injected intravenously, selectively taken up by the liver, and then secreted into the bile. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. We have characterized the applications of ICG during hepatobiliary surgery into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. In this literature review, we summarize the current understanding of ICG use during hepatobiliary surgery.
2
Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy and liver tumors. Intravenous administration of ICG is not toxic and avoids the drawbacks of conventional imaging. In addition, it reduces post-operative complications without any known side effects. ICG fluorescence imaging provides a safe and reliable contrast for extra-hepatic cholangiography when detecting intra-hepatic bile leakage following liver resection. In addition, liver tumors can be visualized and well-differentiated hepatocellular carcinoma tumors can be accurately identified. Moreover, vascular reconstruction and outflow can be evaluated following partial liver transplantation. However, since tissue penetration is limited to 5 to 10 mm, deeper tissue cannot be visualized using this method. Many instances of false positive or negative results have been reported, therefore further characterization is required. Key words: Indocyanine green, liver, surgery, liver resection, fluorescence imaging
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Introduction A major challenge in hepatobiliary surgery is performing a R0 resection with maximal preservation of the liver parenchyma. Tumor localization, identification of liver segments, and anatomical visualization of specific components are crucial to reduce post-operative morbidity and mortality. Real-time visualization of the liver and localization of hepatic lesions can help surgeons to perform R0 liver resections while preserving liver parenchyma, thereby reducing post-operative complications such as bile duct injury, which can cause bile leakage. Within the last decade, various intraoperative methods have been developed for this purpose [1, 2]. These methods are based on the use of traceable dyes that are taken up by the liver and excreted into the biliary tract. Indocyanine green (ICG) is the most commonly used dye in this method [3-6]. It is an anionic dye and has been used in retinal angiography and to calculate cardiac output and hepatic function [7]. ICG is injected intravenously, after which it binds to plasma proteins [8] and remains in the vascular space until selective uptake by the liver and excretion into the bile [9-11]. Its unique catabolic character makes ICG particularly suitable for visualizing anatomical and pathological structures in the liver. The aim of this study was to review the different applications of ICG in real-time hepatobiliary surgery.
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Fluorescence characteristics of ICG ICG is a disulfonated heptamethine indocyanine, which rapidly binds to plasma proteins and lipoproteins to form aggregated dye molecules in physiological environments [7, 12]. Binding of ICG to plasma proteins does not alter protein structure, [13] therefore intravenous administration of ICG is not toxic and is effective at lower doses. The absorption spectrum is in the infrared region and ICG emits fluorescence when excited by infrared light [13, 14]. Infrared light can penetrate living tissue, so the optical information from ICG is not limited to the tissue surface [15]. In the early 1970s, fluorescence imaging systems using ICG (FIS-ICG) were introduced as an intra-operative method for retinal angiography [16]. Since then, various studies have validated the use of FIS-ICG in intra-operative angiography [17], neurosurgery [18], cardiac surgery [19], vascular surgery [20], assessment of lymphatic function, and visualization of lymphatic sentinel nodes [21, 22].
5
ICG fluorescence imaging in hepatobiliary surgery ICG imaging has been used to test hepatic function and hepatic blood flow for 50 years [23], but has only been used during hepatobiliary surgery for ten years. Considerable advances were made in this field with the introduction of the Photo Dynamic Eye (PDE) imaging system, which was developed by Hamamatsu Photonic in Japan [3, 4, 10, 24]. Considering the characteristics and goals of ICG, we consider the four most important uses of FIS-ICG in hepatobiliary surgery to be: 1) liver mapping, 2) intra-operative cholangiography, 3) hepatic tumor visualization, and 4) partial liver transplantation (PLT). Liver mapping in liver resection To reduce post-operative complications following liver resection, the liver segments should be clearly defined. Real-time delineation of liver segments can help surgeons to perform resections based on the exact segmental anatomy of the liver [25, 26]. Intra-operative contrast-enhanced ultrasound remains the gold standard for liver mapping [27]. However, portal hypertension caused by liver cirrhosis might obstruct conventional liver mapping by ultrasonography. In contrast, fluorescence imaging allows accurate visualization even in the case of liver cirrhosis. Aoki et al. identified liver segments via FIS-ICG in 73 out of 81 patients (90.1%). Importantly, they reported no significant differences in the mapping of the liver segments between noncirrhotic and cirrhotic livers using ICG fluorescence [28]. Fluorescence imaging is a safe and sensitive method for identifying liver segments during liver resection [3, 28, 29].In addition, Miyata et al. reported that FIS-ISG significantly improved the identification of the boundaries of the hepatic segments compared with conventional staining technique [29]. They performed both FIS-ICG and indigo-carmine staining method for liver mapping on 30 patients who underwent anatomical liver resection.
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The hepatic transection line could be determined in full length along the hepatic segments, using FIS-ICG, in all the patients (100%). In comparison, conventional staining by indigo-carmine could not completely identify the hepatic segments in 13 Patient (43%). For this reason five mg of ICG (in solution) is intra-operatively injected into the portal vein branch under ultrasound guidance to illuminate and clearly delineate the segment of interest using a PDE camera (Figure 1). However, there are disadvantages to FIS-ICG. Tracking the stained plane during dissection of the liver parenchyma is difficult using FIS-ICG. The fluorescent dye within the target segment gradually disappears, and repeated injection of ICG or temporally clamping the hepatic artery is necessary for reducing washout of the dye and perpetual visualization of the segment. Additionally, a small amount of ICG circulates through the body after injection into the portal vein branch, which eventually stains the entire liver. To avoid these problems, intermittent periods of inflow clamping using the Pringle maneuver are recommended [27, 29]. This allows observation of the demarcation lines and continuous fluorescence imaging during the operation [3, 28] (Table 1). Intra-operative fluorescence cholangiography Cholangiography is often necessary for intra-operative visualization of the biliary tract to identify injuries. In 1996, fluorescence cholangiography was introduced [30] to: 1) avoid the multiple drawbacks of conventional X-ray methods, 2) simplify the intraoperative visualization of the biliary tract, and 3) be combined with other real-time assessments such as angiography or liver mapping. After 12 years, fluorescence cholangiography was modified and the use of ICG increased [10]. Like conventional fluorescence cholangiography, FIS-ICG is safe and efficient. It does not involve radiation, or require a large C-arm fluoroscopic machine [31]. However, the risk of adverse reactions following ICG is lower than conventional fluorescence imaging 7
(approximately 0.003% at doses above 0.5 mg/kg) [32]. Intra-operative fluorescence cholangiography with intravenous ICG administration can identify the cystic duct without dissection of Calot’s triangle [33]. Furthermore, the technique can easily delineate even the smallest biliary tract structures [34]. For intra-operative fluorescence cholangiography using the PDE system, 2.5 mg of ICG (in solution) must be injected intravenously 30 minutes before the patient enters the operating room [33]. ICG is excreted into the bile within a few minutes of intravenous injection and maximum concentration is reached within 2 hours. Verbeek et al. [35] recently reported that 10 mg ICG should be injected intravenously 24 hours before surgery for optimal fluorescence cholangiography using the Mini Fluorescence Assisted Resection and Exploration (Mini-FLARE) imaging system [36] (Figure 2). FIS-ICG cholangiography can be categorized as intra- and extra-hepatic cholangiography. Intra-hepatic cholangiography: FIS-ICG is limited by its depth of penetration (5 to 10 mm) [10], but ICG cholangiography can detect bile duct leakages that are missed by other conventional tests [37]. In a controlled trial from Keiburi et al., 102 patients who underwent hepatic resection without biliary reconstruction were randomized into two groups. In the control group (n = 50), bile duct leakages were detected using a standard test with dye alone. In the experimental group (n = 52), leakage was tested by FIS-ICG cholangiography using PDE. Any leakages in the remnant liver were sutured. After 8 weeks, the control group had a significantly higher rate of postoperative complications than the FIS-ICG group (16% vs. 4%, P = 0.039). Five patients developed post-operative bile leakage in the control group, while no bile leakage was detected in the FIS-ICG group (10% vs. 0%). The authors showed that the standard leakage test missed bile leakages that were easily detected by FIS-ICG cholangiography [37].
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Extra-hepatic cholangiography: Various studies have shown that ICG can be utilized to illuminate extra-hepatic bile ducts as well as the gallbladder [33, 38]. Schols et al. reported that FIS-ICG cholangiography visualized the common bile duct in 83% and the cystic duct in 97% of patients. In comparison, conventional imaging delineated the common bile duct in 73% and the cystic duct in 97% of patients [39]. FIS-ICG was unsuccessful in adipose patients (BMI > 26.35) or patients with chronic cholecystitis. In a separate study, the same team showed that FIS-ICG was significantly faster at visualizing the extra-hepatic ducts than conventional methods. The common bile duct was identified faster using FIS-ICG (22 minutes) compared with
conventional
methods
(32
minutes)
during
elective
laparoscopic
cholecystectomy [40]. Inserting a trans-cystic tube to inject contrast material or to dissect Calot’s triangle in a conventional extra-hepatic cholangiography is time consuming and may inflict bile duct injury or tumor dissemination [26]. FIS-ICG cholangiography identified the cystic duct in all examined patients without dissection of Calot’s triangle. Except for two cases with a thick fat layer on the common hepatic duct CHD, the CHD and cystic duct-CHD junction were clearly detected [33]. Furthermore, FIS-ICG delineated accessory hepatic ducts and unusual cystic duct junctions, which are at risk during cholecystectomy [41, 42]. It can also be used to evaluate primary sclerosing cholangitis [43]. Extra-hepatic FIS-ICG cholangiography can be performed concomitantly with angiography of the hepatic and cystic artery when evaluating ductal or vascular injuries. This is recommended to prevent bile duct stenosis and liver necrosis after reconstruction [44, 45]. An intravenous reinjection of ICG facilitates the identification of concomitant vascular and biliary injury and improves the safety of cholecystectomy [39, 46, 47]. Keneko et al. showed that the cystic artery and biliary tract could be visualized simultaneously in 89% of laparoscopic cholecystectomies. ICG is reinjected intravenously (2.5 mg) after the 9
fluorescence cholangiography [39, 46] and can be used during open and laparoscopic surgery, even when a conversion from laparoscopy to laparotomy is required [40, 48]. Extra-hepatic FIS-ICG cholangiography can also be performed during robotic cholecystectomy [49, 50]. Buchs et al. implemented a near infrared camera integrated to the da Vinci Si System to visualize the biliary anatomy in 12 cases of robotic single site cholecystectomy. The cystic duct was visualized in 91.7% of cases, the common bile duct in 50% of cases, and the CHD 33% of cases. At least one structure could be detected in every patient [49]. Various studies have revealed that detecting bile duct stones using FIS-ICG is challenging compared with conventional intra-operative methods [28, 51]. FIS-ICG detected cystic duct defects but not gallstones and common bile duct defects in 52 patients diagnosed pre-operatively by other methods. This was most likely due to the presence of fluorescing bile around the stone [33]. Visualization of the biliary anatomy depends on the rapid uptake of ICG by the liver and subsequent excretion into the bile, therefore visualization will be affected by impaired liver function or bile secretion. In patients with obstructive jaundice or liver dysfunction, (such as steatosis, fibrosis, ischemic/reperfusion injury, or porto-systemic shunt), detecting anatomical elements through FIS-ICG is complicated (Table 1) [10].
Hepatic tumor visualization FIS-ICG can detect small liver tumors that cannot be identified using conventional intra-operative methods. This improves the accuracy of intra-operative tumor staging and atypical hepatectomy, both of which are challenging aspects of liver surgery. Hepatocellular carcinoma (HCC) and colorectal metastases are the most common primary and secondary malignant tumors of the liver [52, 53], and liver resection remains the therapy of choice [53, 54]. The aim of surgical treatment is to radically 10
resect the tumor with safe margins, while preserving as much of the liver as possible, [55, 56] and this is easier if the tumor can be visualized during surgery. In 2009, it was discovered that HCCs and colorectal metastases were detectable by infrared light after ICG was administered intravenously as part of a routine presurgical liver function test [3-5]. Moreover, fluorescence patterns were related to the type of cancer [57]. The expression of ICG transporters is consistent in welldifferentiated HCCs compared with poorly-differentiated HCCs and metastases [58, 59]. Impaired bile excretion in HCC tissue means that ICG is retained [24, 58], therefore well-differentiated HCCs can be detected by strong, homogenous fluorescence emissions. In contrast, ICG is retained in the parenchyma cytoplasm in poorly-differentiated HCCs and metastases because of pressure exerted by the tumor [58]. This means that poorly-differentiated HCCs and metastases produce rim type fluorescing patterns [24] (Figure 3). In support of these observations, welldifferentiated HCCs associated significantly with a homogenous pattern of fluorescence but not a rim type fluorescence pattern (P<0.001) [59]. A single dose of ICG (0.5 mg/kg) for routine liver function tests, administrated within 14 days prior to surgery, is sufficient to identify tumors by fluorescence imaging [24, 59]. A clinical study of 276 HCC tumors in 170 patients showed that FIS-ICG identified 273 HCCs (99%) in resected specimens. Moreover, 35 HCC tumors were visualized that were not diagnosed preoperatively; 14 were detected during liver resection and 21 were found by macroscopic examination of the resected specimen via intra-operative FISICG [59]. Ishizawa et al. reported a 100% positive predictive value of FIS-ICG in visualization of microscopically confirmed HCCs and liver metastases, even in resected tissue [24]. Uchiyama et al. reported a 98.1% sensitivity of FIS-ICG compared with 88.5% sensitivity using conventional imaging methods [60]. In another study of HCCs and liver metastases in 17 patients, 23 subcapsular tumors were 11
visualized via FIS-ICG, 17 of which were not identified by visual inspection of normal laparoscopic color images [61]. FIS-ICG can also detect other types of liver tumor. Harada et al. detected cholangio cell carcinoma (CCC) invasion by FIS-ICG [26]. CCC tumors can be detected as a result of cholestasis caused by bile duct obstruction. However, unlike HCC tumors, FIS-ICG cannot distinguish between specific types of CCC and CCC tumors can only be delineated by FIS-ICG cholangiography
[26].
Fluorescence
imaging
has
been
used
to
identify
hepatoblastoma, but its ability to distinguish between HCC and hepatoblastoma has not been confirmed [62, 63] (Figure 3). There are some limitations to visualizing tumors using FIS-ICG. These include limited depth of infrared light penetration and tissue thickness, both of which affect the fluorescence intensity. Infrared light can only penetrate 5 to 10 mm of tissue, therefore deeper lesions cannot be visualized by ICG excitation [4, 10]. Kudo et al. showed that tumors located 8 mm or more from the liver surface could not be identified in a study of 16 HCCs and 16 liver metastases resected from 17 patients. In this study, only HCCs and metastases that were 5 mm or closer to the liver surface were observable by FIS-ICG [61]. Moreover, in patients with impaired liver function, ICG removal from noncancerous tissue can be insufficient, creating false-positive nodules [59]. In a recent clinical study of ten cirrhotic explanted livers and 23 noncirrhotic resected livers, FIS-ICG had positive predictive value of 5.4% for malignant nodules in cirrhotic livers compared with 100% in non-cirrhotic resected specimens (P <0.0001) [64]. Because of the higher signal intensity of noncancerous parenchyma, it was suggested that the interval between the ICG injection and surgery should exceed 2 days for optimal tumor-to-liver contrast, especially in patients with advanced cirrhosis [24]. Furthermore, because ICG labeling is not specific, benign lesions may also emit fluorescence [4], making it difficult to 12
accurately determine the tumor free margin. In addition, benign lesions such as bile duct proliferations, expanding cysts or regenerating nodules may increase falsepositive results [65, 66] (Table 1). Partial liver transplantation Inflow evaluation: FIS-ICG can be used during PLT. Hepatic artery and portal vein thrombosis, insufficient anastomoses, and stenosis are associated with graft loss and early thrombectomy or reconstruction is required in these cases [67]. Kobuta et al. employed FIS-ICG to visualize flow turbulence in reconstructed vessels and to evaluate patency, kinking, and stenosis of vascular anastomoses following PLT [68]. They performed intra-operative doppler ultrasound and FIS-ICG in three PLT patients and compared the results. For intra-operative fluorescence imaging, 1.5 ml (3.75 mg) ICG was intravenously injected and flushed with 20 ml of saline following graft perfusion. Ten seconds later, the first images were recorded over a 30 second period. The same procedure was repeated after 2 minutes and a second round of imaging was performed. A final imaging was performed after 40 minutes without additional ICG injection. Fluorescence images were recorded using a SPY intraoperative imaging system previously developed for graft visualization during coronary bypass surgery [69]. The first image showed the hepatic artery and patency of the anastomosis. The second fluorescence recording evaluated the patency of the artery and portal vein anastomosis. After 40 minutes, the third recording showed the excretion of ICG into the bile duct. The authors concluded that FIS-ICG is safe and reproducible for evaluating the patency of reconstructed hepatic arteries and portal veins as well as demonstrating bile production in the transplanted graft during surgery [6, 68]. However, this approach was only semi quantitative, with flow assessments characterized as excellent, good, or poor. Moreover, due to poor penetration of infrared light, the flow patterns in large diameter vessels cannot be 13
completely visualized [10, 68]. Therefore, this method can only be used in addition to intra-operative doppler ultrasound. Organ outflow evaluation: The diagnosis of venous occlusion following PLT [70] and hepatectomy [71] is challenging. Portal uptake and sinusoidal perfusion are reduced in the venous occlusive region (VOR) [72]. Moreover, venous occlusion is associated with inadequate regeneration [73], post-operative complications [71, 74], and graft dysfunction [70]. The non-fluorescence characteristics of ICG have been used to estimate the VOR volume following PLT [72]. However, more recently Kawaguchi et al. used FIS-ICG to visualize the VOR and estimate the VOR volume according to ICG uptake [75] (Figure 4). In this clinical study, FIS-ICG was tested among 18 PLT donors, 23 PLT recipients, and 22 liver resections, using ICG concentrations in the liver parenchyma as a marker of portal uptake. ICG concentrations were significantly lower in the VOR compared with non-VOR in donors (0.69 µg/ml vs. 2.4 µg/ml, P <0.001), recipients (0.75 µg/ml vs. 1.8 µg/ml, P <0.001) and liver resection patients (0.75 µg/ml vs. 3.0 µg/ml, P <0.0001) [75]. The lower ICG concentrations caused by reduced portal uptake indirectly demonstrated outflow dysfunction in the related VOR. To perform this procedure, a single dose of ICG (0.0025 mg per ml of graft liver volume in PLT or remnant liver volume in donor surgery and liver resection) was injected intravenously after the liver graft was harvested (donor surgery), all hepatic vessels were reconstructed (recipient surgery) or the liver was resected. Fluorescence images of the liver surface were recorded for 300 seconds after intravenous injection of ICG [75, 76] (Figure 4), providing a differentiated real-time visualization of the VOR and non-VOR and estimating the volume of the liver with poor outflow. However, the liver surface must be monitored directly for the diagnosis of venous occlusion, therefore this method cannot be used to estimate post-operative
14
venous occlusion without laparotomy [76] (Table 1). Theoretically, this method is suitable for assessing liver outflow following any liver operation, although this must be confirmed by clinical studies.
15
Conclusions FIS-ICG is a visualization method based on fluorescence imaging that is feasible and suitable for hepatobiliary surgery. FIS-ICG is simple and safe compared with conventional systems. To date, FIS-ICG has been validated for liver mapping, intraoperative cholangiography, intra-operative tumor visualization, and flow evaluation following PLT. Despite the various benefits of FIS-ICG in hepatobiliary surgery, there are some drawbacks. These include limited tissue penetration and poor specificity. It remains unclear why FIS-ICG is not as popular in Europe and North America as it is in East Asia. One possible reason may be that ICG clearance is not routinely used as a liver function test in Western clinics. Further clinical studies are required to assess the sensitivity and specificity of FIS-ICG during hepatobiliary surgery.
Author contributions A. Majlesara, M. Golriz, and A. Mehrabi participated in the design of the study. A. Majlesara and M. Golriz participated in the collection of the data. M. Hafezi, A. Saffari, E. Wild, L. Maier-Hein, and B. P. Müller-Stich participated in the acquisition of data. M. Golriz and A. Majlesara drafted the manuscript. A. Majlesara, M. Golriz, and A. Mehrabi revised the manuscript. All authors read and approved the final manuscript.
Sources of financial support: None.
Funding This research did not receive any funding from the public, commercial, or not-profit sectors. 16
Conflicts of interest None.
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Refrences [1]
S. Beller, M. Hunerbein, S. Eulenstein, T. Lange, and P. M. Schlag, "Feasibility of navigated resection of liver tumors using multiplanar visualization of intraoperative 3-dimensional ultrasound data," Ann Surg, vol. 246, pp. 288-94, Aug 2007.
[2]
S. Beller, M. Hunerbein, T. Lange, S. Eulenstein, B. Gebauer, and P. M. Schlag, "Image-guided surgery of liver metastases by three-dimensional ultrasoundbased optoelectronic navigation," Br J Surg, vol. 94, pp. 866-75, Jul 2007.
[3]
T. Aoki, D. Yasuda, Y. Shimizu, M. Odaira, T. Niiya, T. Kusano, et al., "Imageguided liver mapping using fluorescence navigation system with indocyanine green for anatomical hepatic resection," World J Surg, vol. 32, pp. 1763-7, Aug 2008.
[4]
K. Gotoh, T. Yamada, O. Ishikawa, H. Takahashi, H. Eguchi, M. Yano, et al., "A novel image-guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation," J Surg Oncol, vol. 100, pp. 75-9, Jul 1 2009.
[5]
T. Ishizawa, Y. Bandai, and N. Kokudo, "Fluorescent cholangiography using indocyanine green for laparoscopic cholecystectomy: an initial experience," Arch Surg, vol. 144, pp. 381-2, Apr 2009.
[6]
M. Sekijima, T. Tojimbara, S. Sato, M. Nakamura, T. Kawase, K. Kai, et al., "An intraoperative fluorescent imaging system in organ transplantation," Transplant Proc, vol. 36, pp. 2188-90, Sep 2004.
[7]
R. C. Benson and H. A. Kues, "Fluorescence properties of indocyanine green as related to angiography," Phys Med Biol, vol. 23, pp. 159-63, Jan 1978.
18
[8]
M. L. Landsman, G. Kwant, G. A. Mook, and W. G. Zijlstra, "Light-absorbing properties, stability, and spectral stabilization of indocyanine green," J Appl Physiol, vol. 40, pp. 575-83, Apr 1976.
[9]
J. Hauptmann and J. Sturzebecher, "Influence of indocyanine green on plasma disappearance and biliary excretion of a synthetic thrombin inhibitor of the 3amidinophenyl-alanine piperazide-type in rats," Pharm Res, vol. 15, pp. 751-4, May 1998.
[10]
N. Mitsuhashi, F. Kimura, H. Shimizu, M. Imamaki, H. Yoshidome, M. Ohtsuka, et al., "Usefulness of intraoperative fluorescence imaging to evaluate local anatomy in hepatobiliary surgery," J Hepatobiliary Pancreat Surg, vol. 15, pp. 508-14, 2008.
[11]
S. Yoneya, T. Saito, Y. Komatsu, I. Koyama, K. Takahashi, and J. Duvoll-Young, "Binding properties of indocyanine green in human blood," Invest Ophthalmol Vis Sci, vol. 39, pp. 1286-90, Jun 1998.
[12]
K. J. Baker, "Binding of sulfobromophthalein (BSP) sodium and indocyanine green (ICG) by plasma alpha-1 lipoproteins," Proc Soc Exp Biol Med, vol. 122, pp. 957-63, Aug-Sep 1966.
[13]
V. I. Kochubey, T. V. Kulyabina, V. V. Tuchin, and G. B. Altshuler, "Spectral characteristics of indocyanine Green upon its interaction with biological tissues," Optics and Spectroscopy, vol. 99, pp. 560-566, 2005/10/01 2005.
[14]
S. Gioux, H. S. Choi, and J. V. Frangioni, "Image-guided surgery using invisible near-infrared light: fundamentals of clinical translation," Mol Imaging, vol. 9, pp. 237-55, Oct 2010.
19
[15]
T. Kitai, M. Miwa, H. Liu, B. Beauvoit, B. Chance, and Y. Yamaoka, "Application of near-infrared time-resolved spectroscopy to rat liver--a preliminary report for surgical application," Phys Med Biol, vol. 44, pp. 2049-61, Aug 1999.
[16]
R. W. Flower, "Injection technique for indocyanine green and sodium fluorescein dye angiography of the eye," Invest Ophthalmol, vol. 12, pp. 881-95, Dec 1973.
[17]
L. A. Yannuzzi, "Indocyanine green angiography: a perspective on use in the clinical setting," Am J Ophthalmol, vol. 151, pp. 745-751 e1, May 2011.
[18]
A. Raabe, P. Nakaji, J. Beck, L. J. Kim, F. P. Hsu, J. D. Kamerman, et al., "Prospective evaluation of surgical microscope-integrated intraoperative nearinfrared indocyanine green videoangiography during aneurysm surgery," J Neurosurg, vol. 103, pp. 982-9, Dec 2005.
[19]
L. Balacumaraswami, Y. Abu-Omar, B. Choudhary, D. Pigott, and D. P. Taggart, "A comparison of transit-time flowmetry and intraoperative fluorescence imaging for assessing coronary artery bypass graft patency," J Thorac Cardiovasc Surg, vol. 130, pp. 315-20, Aug 2005.
[20]
N. Unno, K. Inuzuka, M. Suzuki, N. Yamamoto, D. Sagara, M. Nishiyama, et al., "Preliminary experience with a novel fluorescence lymphography using indocyanine green in patients with secondary lymphedema," J Vasc Surg, vol. 45, pp. 1016-21, May 2007.
[21]
D. L. Morton, D. R. Wen, J. H. Wong, J. S. Economou, L. A. Cagle, F. K. Storm, et al., "Technical details of intraoperative lymphatic mapping for early stage melanoma," Arch Surg, vol. 127, pp. 392-9, Apr 1992.
[22]
C. P. Parungo, S. Ohnishi, S. W. Kim, S. Kim, R. G. Laurence, E. G. Soltesz, et al., "Intraoperative identification of esophageal sentinel lymph nodes with near-
20
infrared fluorescence imaging," J Thorac Cardiovasc Surg, vol. 129, pp. 844-50, Apr 2005. [23]
C. M. Leevy, C. L. Mendenhall, W. Lesko, and M. M. Howard, "Estimation of hepatic blood flow with indocyanine green," J Clin Invest, vol. 41, pp. 1169-79, May 1962.
[24]
T. Ishizawa, N. Fukushima, J. Shibahara, K. Masuda, S. Tamura, T. Aoki, et al., "Real-time identification of liver cancers by using indocyanine green fluorescent imaging," Cancer, vol. 115, pp. 2491-504, Jun 1 2009.
[25]
K. G. Billingsley, W. R. Jarnagin, Y. Fong, and L. H. Blumgart, "Segmentoriented hepatic resection in the management of malignant neoplasms of the liver," J Am Coll Surg, vol. 187, pp. 471-81, Nov 1998.
[26]
N. Harada, T. Ishizawa, A. Muraoka, M. Ijichi, K. Kusaka, M. Shibasaki, et al., "Fluorescence navigation hepatectomy by visualization of localized cholestasis from bile duct tumor infiltration," J Am Coll Surg, vol. 210, pp. e2-6, Jun 2010.
[27]
M. Makuuchi, H. Hasegawa, and S. Yamazaki, "Ultrasonically guided subsegmentectomy," Surg Gynecol Obstet, vol. 161, pp. 346-50, Oct 1985.
[28]
T. Aoki, M. Murakami, D. Yasuda, Y. Shimizu, T. Kusano, K. Matsuda, et al., "Intraoperative fluorescent imaging using indocyanine green for liver mapping and cholangiography," J Hepatobiliary Pancreat Sci, vol. 17, pp. 590-4, Sep 2010.
[29]
A. Miyata, T. Ishizawa, K. Tani, A. Shimizu, J. Kaneko, T. Aoki, et al., "Reappraisal of a Dye-Staining Technique for Anatomic Hepatectomy by the Concomitant Use of Indocyanine Green Fluorescence Imaging," Journal of the American College of Surgeons, vol. 221, pp. e27-e36, 8// 2015.
21
[30]
A. Oddi, V. Di Nicola, A. Panzini, A. Berni, S. Lucci, L. Greco, et al., "[The intraoperative visualization of the bile ducts by the use of fluorescent substances. A feasibility study]," G Chir, vol. 17, pp. 620-3, Nov-Dec 1996.
[31]
D. R. Flum, C. Flowers, and D. L. Veenstra, "A cost-effectiveness analysis of intraoperative cholangiography in the prevention of bile duct injury during laparoscopic cholecystectomy," J Am Coll Surg, vol. 196, pp. 385-93, Mar 2003.
[32]
R. Speich, B. Saesseli, U. Hoffmann, K. A. Neftel, and J. Reichen, "Anaphylactoid reactions after indocyanine-green administration," Ann Intern Med, vol. 109, pp. 345-6, Aug 15 1988.
[33]
T. Ishizawa, Y. Bandai, M. Ijichi, J. Kaneko, K. Hasegawa, and N. Kokudo, "Fluorescent cholangiography illuminating the biliary tree during laparoscopic cholecystectomy," Br J Surg, vol. 97, pp. 1369-77, Sep 2010.
[34]
J. Machi, T. Tateishi, A. J. Oishi, N. L. Furumoto, R. H. Oishi, S. Uchida, et al., "Laparoscopic ultrasonography versus operative cholangiography during laparoscopic cholecystectomy: review of the literature and a comparison with open intraoperative ultrasonography," J Am Coll Surg, vol. 188, pp. 360-7, Apr 1999.
[35]
F. P. Verbeek, B. E. Schaafsma, Q. R. Tummers, J. R. van der Vorst, W. J. van der Made, C. I. Baeten, et al., "Optimization of near-infrared fluorescence cholangiography for open and laparoscopic surgery," Surg Endosc, vol. 28, pp. 1076-82, Apr 2014.
[36]
F. P. Verbeek, J. R. van der Vorst, B. E. Schaafsma, M. Hutteman, B. A. Bonsing, F. W. van Leeuwen, et al., "Image-guided hepatopancreatobiliary surgery using near-infrared fluorescent light," J Hepatobiliary Pancreat Sci, vol. 19, pp. 626-37, Nov 2012.
22
[37]
M. Kaibori, M. Ishizaki, K. Matsui, and A. H. Kwon, "Intraoperative indocyanine green fluorescent imaging for prevention of bile leakage after hepatic resection," Surgery, vol. 150, pp. 91-8, Jul 2011.
[38]
A. Matsui, E. Tanaka, H. S. Choi, J. H. Winer, V. Kianzad, S. Gioux, et al., "Realtime intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts using clinically available contrast agents," Surgery, vol. 148, pp. 87-95, Jul 2010.
[39]
R. M. Schols, N. D. Bouvy, R. M. van Dam, A. A. Masclee, C. H. Dejong, and L. P. Stassen, "Combined vascular and biliary fluorescence imaging in laparoscopic cholecystectomy," Surg Endosc, vol. 27, pp. 4511-7, Dec 2013.
[40]
R. M. Schols, N. D. Bouvy, A. A. Masclee, R. M. van Dam, C. H. Dejong, and L. P. Stassen, "Fluorescence cholangiography during laparoscopic cholecystectomy: a feasibility study on early biliary tract delineation," Surg Endosc, vol. 27, pp. 1530-6, May 2013.
[41]
S. M. Strasberg, "Error traps and vasculo-biliary injury in laparoscopic and open cholecystectomy," J Hepatobiliary Pancreat Surg, vol. 15, pp. 284-92, 2008.
[42]
L. W. Way, L. Stewart, W. Gantert, K. Liu, C. M. Lee, K. Whang, et al., "Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and cognitive psychology perspective," Ann Surg, vol. 237, pp. 460-9, Apr 2003.
[43]
F. Ikeda, K. Yamamoto, S. Fujioka, R. Okamoto, K. Yabushita, M. Miyake, et al., "Laparoscopic findings in primary sclerosing cholangitis," Endoscopy, vol. 33, pp. 267-70, Mar 2001.
23
[44]
Y. Ashitate, A. Stockdale, H. S. Choi, R. G. Laurence, and J. V. Frangioni, "Realtime simultaneous near-infrared fluorescence imaging of bile duct and arterial anatomy," J Surg Res, vol. 176, pp. 7-13, Jul 2012.
[45]
S. M. Strasberg and W. S. Helton, "An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy," HPB (Oxford), vol. 13, pp. 1-14, Jan 2011.
[46]
J. Kaneko, T. Ishizawa, K. Masuda, Y. Kawaguchi, T. Aoki, Y. Sakamoto, et al., "Indocyanine green reinjection technique for use in fluorescent angiography concomitant with cholangiography during laparoscopic cholecystectomy," Surg Laparosc Endosc Percutan Tech, vol. 22, pp. 341-4, Aug 2012.
[47]
N. Tagaya, M. Shimoda, M. Kato, A. Nakagawa, A. Abe, Y. Iwasaki, et al., "Intraoperative exploration of biliary anatomy using fluorescence imaging of indocyanine green in experimental and clinical cholecystectomies," J Hepatobiliary Pancreat Sci, vol. 17, pp. 595-600, Sep 2010.
[48]
R. M. Schols, N. J. Connell, and L. P. Stassen, "Near-infrared fluorescence imaging for real-time intraoperative anatomical guidance in minimally invasive surgery: a systematic review of the literature," World J Surg, vol. 39, pp. 1069-79, May 2015.
[49]
N. C. Buchs, M. E. Hagen, F. Pugin, F. Volonte, P. Bucher, E. Schiffer, et al., "Intra-operative fluorescent cholangiography using indocyanin green during robotic single site cholecystectomy," Int J Med Robot, vol. 8, pp. 436-40, Dec 2012.
[50]
D. Daskalaki, F. Aguilera, K. Patton, and P. C. Giulianotti, "Fluorescence in robotic surgery," J Surg Oncol, vol. 112, pp. 250-6, Sep 2015.
24
[51]
T. Ishizawa, S. Tamura, K. Masuda, T. Aoki, K. Hasegawa, H. Imamura, et al., "Intraoperative fluorescent cholangiography using indocyanine green: a biliary road map for safe surgery," J Am Coll Surg, vol. 208, pp. e1-4, Jan 2009.
[52]
H. B. El-Serag, J. A. Marrero, L. Rudolph, and K. R. Reddy, "Diagnosis and treatment of hepatocellular carcinoma," Gastroenterology, vol. 134, pp. 1752-63, May 2008.
[53]
S. Manfredi, C. Lepage, C. Hatem, O. Coatmeur, J. Faivre, and A. M. Bouvier, "Epidemiology and management of liver metastases from colorectal cancer," Ann Surg, vol. 244, pp. 254-9, Aug 2006.
[54]
J. M. Llovet, A. Burroughs, and J. Bruix, "Hepatocellular carcinoma," Lancet, vol. 362, pp. 1907-17, Dec 6 2003.
[55]
M. Golriz, A. Majlesara, S. El Sakka, M. Ashrafi, J. Arwin, N. Fard, et al., "Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure," Clin Res Hepatol Gastroenterol, Oct 26 2015.
[56]
Z. Morise, N. Kawabe, H. Tomishige, H. Nagata, J. Kawase, S. Arakawa, et al., "Recent advances in liver resection for hepatocellular carcinoma," Front Surg, vol. 1, p. 21, 2014.
[57]
C. Lim, E. Vibert, D. Azoulay, C. Salloum, T. Ishizawa, R. Yoshioka, et al., "Indocyanine green fluorescence imaging in the surgical management of liver cancers: current facts and future implications," J Visc Surg, vol. 151, pp. 117-24, Apr 2014.
[58]
C. Lim and E. Vibert, Fluorescent Imaging: Treatment of Hepatobiliary and Pancreatic Diseases vol. 31. Basel: Karger, 2013.
[59]
T. Ishizawa, K. Masuda, Y. Urano, Y. Kawaguchi, S. Satou, J. Kaneko, et al., "Mechanistic background and clinical applications of indocyanine green
25
fluorescence imaging of hepatocellular carcinoma," Ann Surg Oncol, vol. 21, pp. 440-8, Feb 2014. [60]
K. Uchiyama, M. Ueno, S. Ozawa, S. Kiriyama, Y. Shigekawa, and H. Yamaue, "Combined use of contrast-enhanced intraoperative ultrasonography and a fluorescence navigation system for identifying hepatic metastases," World J Surg, vol. 34, pp. 2953-9, Dec 2010.
[61]
H. Kudo, T. Ishizawa, K. Tani, N. Harada, A. Ichida, A. Shimizu, et al., "Visualization of subcapsular hepatic malignancy by indocyanine-green fluorescence imaging during laparoscopic hepatectomy," Surg Endosc, vol. 28, pp. 2504-8, Aug 2014.
[62]
T. Yamamichi, T. Oue, T. Yonekura, M. Owari, K. Nakahata, S. Umeda, et al., "Clinical application of indocyanine green (ICG) fluorescent imaging of hepatoblastoma," J Pediatr Surg, vol. 50, pp. 833-6, May 2015.
[63]
Y. Mitani, A. Kubota, M. Ueno, K. Takifuji, T. Watanabe, S. Hayami, et al., "Realtime identification of hepatoblastoma using a near infrared imaging with indocyanine green," Journal of Pediatric Surgery Case Reports, vol. 2, pp. 180183, 4// 2014.
[64]
T. Tanaka, M. Takatsuki, M. Hidaka, T. Hara, I. Muraoka, A. Soyama, et al., "Is a fluorescence navigation system with indocyanine green effective enough to detect liver malignancies?," J Hepatobiliary Pancreat Sci, vol. 21, pp. 199-204, Mar 2014.
[65]
M. Ishizuka, K. Kubota, J. Kita, M. Shimoda, M. Kato, and T. Sawada, "Intraoperative observation using a fluorescence imaging instrument during hepatic resection for liver metastasis from colorectal cancer," Hepatogastroenterology, vol. 59, pp. 90-2, Jan-Feb 2012.
26
[66]
S. Keereweer, J. D. Kerrebijn, P. B. van Driel, B. Xie, E. L. Kaijzel, T. J. Snoeks, et al., "Optical image-guided surgery--where do we stand?," Mol Imaging Biol, vol. 13, pp. 199-207, Apr 2011.
[67]
T. Kok, M. J. Slooff, C. J. Thijn, P. M. Peeters, R. Verwer, C. M. Bijleveld, et al., "Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation," Transpl Int, vol. 11, pp. 272-6, 1998.
[68]
K. Kubota, J. Kita, M. Shimoda, K. Rokkaku, M. Kato, Y. Iso, et al., "Intraoperative assessment of reconstructed vessels in living-donor liver transplantation, using a novel fluorescence imaging technique," J Hepatobiliary Pancreat Surg, vol. 13, pp. 100-4, 2006.
[69]
D. P. Taggart, B. Choudhary, K. Anastasiadis, Y. Abu-Omar, L. Balacumaraswami, and D. W. Pigott, "Preliminary experience with a novel intraoperative fluorescence imaging technique to evaluate the patency of bypass grafts in total arterial revascularization," Ann Thorac Surg, vol. 75, pp. 870-3, Mar 2003.
[70]
K. Sano, M. Makuuchi, K. Miki, A. Maema, Y. Sugawara, H. Imamura, et al., "Evaluation of hepatic venous congestion: proposed indication criteria for hepatic vein reconstruction," Ann Surg, vol. 236, pp. 241-7, Aug 2002.
[71]
T. Kakazu, M. Makuuchi, S. Kawasaki, S. Miyagawa, Y. Nakazawa, T. Kubota, et al., "Reconstruction of the middle hepatic vein tributary during right anterior segmentectomy," Surgery, vol. 117, pp. 238-40, Feb 1995.
[72]
T. Hashimoto, K. Miki, H. Imamura, K. Sano, S. Satou, Y. Sugawara, et al., "Sinusoidal perfusion in the veno-occlusive region of living liver donors evaluated
27
by indocyanine green and near-infrared spectroscopy," Liver Transpl, vol. 14, pp. 872-80, Jun 2008. [73]
N. Akamatsu, Y. Sugawara, J. Kaneko, K. Sano, H. Imamura, N. Kokudo, et al., "Effects of middle hepatic vein reconstruction on right liver graft regeneration," Transplantation, vol. 76, pp. 832-7, Sep 15 2003.
[74]
N. Akamatsu, Y. Sugawara, J. Kaneko, Y. Kishi, T. Niiya, N. Kokudo, et al., "Surgical repair for late-onset hepatic venous outflow block after living-donor liver transplantation," Transplantation, vol. 77, pp. 1768-70, Jun 15 2004.
[75]
Y. Kawaguchi, T. Ishizawa, Y. Miyata, S. Yamashita, K. Masuda, S. Satou, et al., "Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green," J Hepatol, vol. 58, pp. 247-53, Feb 2013.
[76]
Y. Kawaguchi, Y. Sugawara, T. Ishizawa, S. Satou, J. Kaneko, S. Tamura, et al., "Identification of veno-occlusive regions in a right liver graft after reconstruction of vein segments 5 and 8: application of indocyanine green fluorescence imaging," Liver Transpl, vol. 19, pp. 778-9, Jul 2013.
28
Figure legends
Figure 1. Liver mapping of segment 4: the liver surface after injection of ICG into the respective branch of the portal vein. (a) Without fluorescence imaging. (b) After fluorescence imaging with ICG [28]. ICG: Indocyanine green
Figure 2. Intra-operative cholangiography using FIS-ICG: (a) color video, (b) NIR fluorescence, and (c) a color-NIR overlay [36]. NIR: Near infrared; FIS-ICG: Fluorescence imaging system with indocyanine green
Figure 3. Liver tumor identification using fluorescence imaging (left) and gross tumor morphology (right). (a) Totally fluorescent type; well-differentiated hepatocellular carcinoma (HCC). (b) Partially fluorescent type; moderately differentiated HCC with well-differentiated components and hemorrhagic necrosis in the upper half of the tumor. (c) Rim fluorescent type; poorly-differentiated HCC.
(d)
Rim
fluorescent
type;
metastasis
of
colon
carcinoma.
(e)
Hepatoblastoma [24, 62]. HCC: Hepatocellular carcinoma
Figure 4. Fluorescence imaging following intravenous injection of ICG reveals the demarcation between veno-occlusive and non-veno-occlusive regions. (a) Gross morphology; (b) fluorescence images before ICG injection, and (c) fluorescence images after ICG injection [75]. ICG: Indocyanine green
29
fig 1
fig 2
fig 3
30
fig 4
31
Table 1. Different applications of fluorescence imaging using indocyanine green in liver surgery
Application
Method of ICG administration
Limitation(s)
Liver mapping
-
Segment demarcation Anatomical resection
-
Intra-operative 1 ml (5 mg/ml) Intra-portal ± Pringle maneuver
-
Impermanent visualization
Intra-operative cholangiography
-
-
Limited depth of visualization No characterization of intraductal mass
-
1 ml (2,5 mg/ml) / 30 min before operation [33] or 10 mg / 24 h before operation [35] Intravenous
-
-
Cholangiography Simultaneous cholangiography and angiography [46] Indirect demarcation of CCC
-
Atypical liver resection HCC (Identification) Liver metastases Hepatoblastoma
-
2 to 14 days before operation 0.5 mg/kg Intravenous
-
Limited depth of visualization False-positive nodules due to poor liver function Emission from benign lesions No identification of CCC Inaccurate in distinguishing between poorlydifferentiated HCC and metastases Semi quantitative evaluation Limited depth of penetration
Tumor visualization
-
-
PLT
-
-
Evaluation of the patency of vascular reconstructions Bile production in the transplanted graft Visualization of the veno-occlusive region
-
Intra-operative (after implantation) 1.5 ml (3.75 mg) flushed with 20 ml saline (reinjection after 2 min) Intravenous Intra-operative (after harvesting in donor or after reperfusion in recipient) 0.0025 mg/ml of the graft/remnant liver volume Intravenous
-
-
No post-operative evaluation without laparotomy
PLT: Partial liver transplantation; ICG: Indocyanine green; HCC: Hepatocellular carcinoma; CCC: Cholangio cell carcinoma
32
S1572-1000(16)30241-1 http://dx.doi.org/doi:10.1016/j.pdpdt.2016.12.005 PDPDT 871
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
14-11-2016 14-12-2016 19-12-2016
Please cite this article as: Majlesara Ali, Golriz Mohammad, Hafezi Mohammadreza, Saffari Arash, Wild Esther, Maier-Hein Lena, Muller¨ Stich Beat P, Mehrabi Arianeb.Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2016.12.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
Short title: ICG imaging in hepatobiliary surgery Running title: ICG imaging in liver surgery Type of article: Review paper
Indocyanine Green Fluorescence Imaging in Hepatobiliary Surgery
Ali Majlesara a, * , Mohammad Golriz a, *, Mohammadreza Hafezi a, Arash Saffari a Esther Wild b, Lena Maier-Hein b, Beat P. Müller-Stich a Arianeb Mehrabi a, **
a
Department of General, Visceral, and Transplantation Surgery b
German Cancer Research Center (DKFZ)
University of Heidelberg; Heidelberg, Germany
**Corresponding author: Dr. med. A. Mehrabi, FEBS, FICS Attending General and Transplant Surgeon Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110 69120 Heidelberg, Germany Tel: 0049 – 6221 - 5636223 Fax: 0049 – 6221 - 567470 E-Mail: [email protected] *Both authors contributed equally to this work
1
Highlights Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during liver surgery. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. Applications of ICG during liver surgery can be categorized into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy, avoids the drawbacks of conventional imaging and reduces post-operative complications without any known side effects.
Abstract Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during hepatobiliary surgery. ICG is injected intravenously, selectively taken up by the liver, and then secreted into the bile. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. We have characterized the applications of ICG during hepatobiliary surgery into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. In this literature review, we summarize the current understanding of ICG use during hepatobiliary surgery.
2
Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy and liver tumors. Intravenous administration of ICG is not toxic and avoids the drawbacks of conventional imaging. In addition, it reduces post-operative complications without any known side effects. ICG fluorescence imaging provides a safe and reliable contrast for extra-hepatic cholangiography when detecting intra-hepatic bile leakage following liver resection. In addition, liver tumors can be visualized and well-differentiated hepatocellular carcinoma tumors can be accurately identified. Moreover, vascular reconstruction and outflow can be evaluated following partial liver transplantation. However, since tissue penetration is limited to 5 to 10 mm, deeper tissue cannot be visualized using this method. Many instances of false positive or negative results have been reported, therefore further characterization is required. Key words: Indocyanine green, liver, surgery, liver resection, fluorescence imaging
3
Introduction A major challenge in hepatobiliary surgery is performing a R0 resection with maximal preservation of the liver parenchyma. Tumor localization, identification of liver segments, and anatomical visualization of specific components are crucial to reduce post-operative morbidity and mortality. Real-time visualization of the liver and localization of hepatic lesions can help surgeons to perform R0 liver resections while preserving liver parenchyma, thereby reducing post-operative complications such as bile duct injury, which can cause bile leakage. Within the last decade, various intraoperative methods have been developed for this purpose [1, 2]. These methods are based on the use of traceable dyes that are taken up by the liver and excreted into the biliary tract. Indocyanine green (ICG) is the most commonly used dye in this method [3-6]. It is an anionic dye and has been used in retinal angiography and to calculate cardiac output and hepatic function [7]. ICG is injected intravenously, after which it binds to plasma proteins [8] and remains in the vascular space until selective uptake by the liver and excretion into the bile [9-11]. Its unique catabolic character makes ICG particularly suitable for visualizing anatomical and pathological structures in the liver. The aim of this study was to review the different applications of ICG in real-time hepatobiliary surgery.
4
Fluorescence characteristics of ICG ICG is a disulfonated heptamethine indocyanine, which rapidly binds to plasma proteins and lipoproteins to form aggregated dye molecules in physiological environments [7, 12]. Binding of ICG to plasma proteins does not alter protein structure, [13] therefore intravenous administration of ICG is not toxic and is effective at lower doses. The absorption spectrum is in the infrared region and ICG emits fluorescence when excited by infrared light [13, 14]. Infrared light can penetrate living tissue, so the optical information from ICG is not limited to the tissue surface [15]. In the early 1970s, fluorescence imaging systems using ICG (FIS-ICG) were introduced as an intra-operative method for retinal angiography [16]. Since then, various studies have validated the use of FIS-ICG in intra-operative angiography [17], neurosurgery [18], cardiac surgery [19], vascular surgery [20], assessment of lymphatic function, and visualization of lymphatic sentinel nodes [21, 22].
5
ICG fluorescence imaging in hepatobiliary surgery ICG imaging has been used to test hepatic function and hepatic blood flow for 50 years [23], but has only been used during hepatobiliary surgery for ten years. Considerable advances were made in this field with the introduction of the Photo Dynamic Eye (PDE) imaging system, which was developed by Hamamatsu Photonic in Japan [3, 4, 10, 24]. Considering the characteristics and goals of ICG, we consider the four most important uses of FIS-ICG in hepatobiliary surgery to be: 1) liver mapping, 2) intra-operative cholangiography, 3) hepatic tumor visualization, and 4) partial liver transplantation (PLT). Liver mapping in liver resection To reduce post-operative complications following liver resection, the liver segments should be clearly defined. Real-time delineation of liver segments can help surgeons to perform resections based on the exact segmental anatomy of the liver [25, 26]. Intra-operative contrast-enhanced ultrasound remains the gold standard for liver mapping [27]. However, portal hypertension caused by liver cirrhosis might obstruct conventional liver mapping by ultrasonography. In contrast, fluorescence imaging allows accurate visualization even in the case of liver cirrhosis. Aoki et al. identified liver segments via FIS-ICG in 73 out of 81 patients (90.1%). Importantly, they reported no significant differences in the mapping of the liver segments between noncirrhotic and cirrhotic livers using ICG fluorescence [28]. Fluorescence imaging is a safe and sensitive method for identifying liver segments during liver resection [3, 28, 29].In addition, Miyata et al. reported that FIS-ISG significantly improved the identification of the boundaries of the hepatic segments compared with conventional staining technique [29]. They performed both FIS-ICG and indigo-carmine staining method for liver mapping on 30 patients who underwent anatomical liver resection.
6
The hepatic transection line could be determined in full length along the hepatic segments, using FIS-ICG, in all the patients (100%). In comparison, conventional staining by indigo-carmine could not completely identify the hepatic segments in 13 Patient (43%). For this reason five mg of ICG (in solution) is intra-operatively injected into the portal vein branch under ultrasound guidance to illuminate and clearly delineate the segment of interest using a PDE camera (Figure 1). However, there are disadvantages to FIS-ICG. Tracking the stained plane during dissection of the liver parenchyma is difficult using FIS-ICG. The fluorescent dye within the target segment gradually disappears, and repeated injection of ICG or temporally clamping the hepatic artery is necessary for reducing washout of the dye and perpetual visualization of the segment. Additionally, a small amount of ICG circulates through the body after injection into the portal vein branch, which eventually stains the entire liver. To avoid these problems, intermittent periods of inflow clamping using the Pringle maneuver are recommended [27, 29]. This allows observation of the demarcation lines and continuous fluorescence imaging during the operation [3, 28] (Table 1). Intra-operative fluorescence cholangiography Cholangiography is often necessary for intra-operative visualization of the biliary tract to identify injuries. In 1996, fluorescence cholangiography was introduced [30] to: 1) avoid the multiple drawbacks of conventional X-ray methods, 2) simplify the intraoperative visualization of the biliary tract, and 3) be combined with other real-time assessments such as angiography or liver mapping. After 12 years, fluorescence cholangiography was modified and the use of ICG increased [10]. Like conventional fluorescence cholangiography, FIS-ICG is safe and efficient. It does not involve radiation, or require a large C-arm fluoroscopic machine [31]. However, the risk of adverse reactions following ICG is lower than conventional fluorescence imaging 7
(approximately 0.003% at doses above 0.5 mg/kg) [32]. Intra-operative fluorescence cholangiography with intravenous ICG administration can identify the cystic duct without dissection of Calot’s triangle [33]. Furthermore, the technique can easily delineate even the smallest biliary tract structures [34]. For intra-operative fluorescence cholangiography using the PDE system, 2.5 mg of ICG (in solution) must be injected intravenously 30 minutes before the patient enters the operating room [33]. ICG is excreted into the bile within a few minutes of intravenous injection and maximum concentration is reached within 2 hours. Verbeek et al. [35] recently reported that 10 mg ICG should be injected intravenously 24 hours before surgery for optimal fluorescence cholangiography using the Mini Fluorescence Assisted Resection and Exploration (Mini-FLARE) imaging system [36] (Figure 2). FIS-ICG cholangiography can be categorized as intra- and extra-hepatic cholangiography. Intra-hepatic cholangiography: FIS-ICG is limited by its depth of penetration (5 to 10 mm) [10], but ICG cholangiography can detect bile duct leakages that are missed by other conventional tests [37]. In a controlled trial from Keiburi et al., 102 patients who underwent hepatic resection without biliary reconstruction were randomized into two groups. In the control group (n = 50), bile duct leakages were detected using a standard test with dye alone. In the experimental group (n = 52), leakage was tested by FIS-ICG cholangiography using PDE. Any leakages in the remnant liver were sutured. After 8 weeks, the control group had a significantly higher rate of postoperative complications than the FIS-ICG group (16% vs. 4%, P = 0.039). Five patients developed post-operative bile leakage in the control group, while no bile leakage was detected in the FIS-ICG group (10% vs. 0%). The authors showed that the standard leakage test missed bile leakages that were easily detected by FIS-ICG cholangiography [37].
8
Extra-hepatic cholangiography: Various studies have shown that ICG can be utilized to illuminate extra-hepatic bile ducts as well as the gallbladder [33, 38]. Schols et al. reported that FIS-ICG cholangiography visualized the common bile duct in 83% and the cystic duct in 97% of patients. In comparison, conventional imaging delineated the common bile duct in 73% and the cystic duct in 97% of patients [39]. FIS-ICG was unsuccessful in adipose patients (BMI > 26.35) or patients with chronic cholecystitis. In a separate study, the same team showed that FIS-ICG was significantly faster at visualizing the extra-hepatic ducts than conventional methods. The common bile duct was identified faster using FIS-ICG (22 minutes) compared with
conventional
methods
(32
minutes)
during
elective
laparoscopic
cholecystectomy [40]. Inserting a trans-cystic tube to inject contrast material or to dissect Calot’s triangle in a conventional extra-hepatic cholangiography is time consuming and may inflict bile duct injury or tumor dissemination [26]. FIS-ICG cholangiography identified the cystic duct in all examined patients without dissection of Calot’s triangle. Except for two cases with a thick fat layer on the common hepatic duct CHD, the CHD and cystic duct-CHD junction were clearly detected [33]. Furthermore, FIS-ICG delineated accessory hepatic ducts and unusual cystic duct junctions, which are at risk during cholecystectomy [41, 42]. It can also be used to evaluate primary sclerosing cholangitis [43]. Extra-hepatic FIS-ICG cholangiography can be performed concomitantly with angiography of the hepatic and cystic artery when evaluating ductal or vascular injuries. This is recommended to prevent bile duct stenosis and liver necrosis after reconstruction [44, 45]. An intravenous reinjection of ICG facilitates the identification of concomitant vascular and biliary injury and improves the safety of cholecystectomy [39, 46, 47]. Keneko et al. showed that the cystic artery and biliary tract could be visualized simultaneously in 89% of laparoscopic cholecystectomies. ICG is reinjected intravenously (2.5 mg) after the 9
fluorescence cholangiography [39, 46] and can be used during open and laparoscopic surgery, even when a conversion from laparoscopy to laparotomy is required [40, 48]. Extra-hepatic FIS-ICG cholangiography can also be performed during robotic cholecystectomy [49, 50]. Buchs et al. implemented a near infrared camera integrated to the da Vinci Si System to visualize the biliary anatomy in 12 cases of robotic single site cholecystectomy. The cystic duct was visualized in 91.7% of cases, the common bile duct in 50% of cases, and the CHD 33% of cases. At least one structure could be detected in every patient [49]. Various studies have revealed that detecting bile duct stones using FIS-ICG is challenging compared with conventional intra-operative methods [28, 51]. FIS-ICG detected cystic duct defects but not gallstones and common bile duct defects in 52 patients diagnosed pre-operatively by other methods. This was most likely due to the presence of fluorescing bile around the stone [33]. Visualization of the biliary anatomy depends on the rapid uptake of ICG by the liver and subsequent excretion into the bile, therefore visualization will be affected by impaired liver function or bile secretion. In patients with obstructive jaundice or liver dysfunction, (such as steatosis, fibrosis, ischemic/reperfusion injury, or porto-systemic shunt), detecting anatomical elements through FIS-ICG is complicated (Table 1) [10].
Hepatic tumor visualization FIS-ICG can detect small liver tumors that cannot be identified using conventional intra-operative methods. This improves the accuracy of intra-operative tumor staging and atypical hepatectomy, both of which are challenging aspects of liver surgery. Hepatocellular carcinoma (HCC) and colorectal metastases are the most common primary and secondary malignant tumors of the liver [52, 53], and liver resection remains the therapy of choice [53, 54]. The aim of surgical treatment is to radically 10
resect the tumor with safe margins, while preserving as much of the liver as possible, [55, 56] and this is easier if the tumor can be visualized during surgery. In 2009, it was discovered that HCCs and colorectal metastases were detectable by infrared light after ICG was administered intravenously as part of a routine presurgical liver function test [3-5]. Moreover, fluorescence patterns were related to the type of cancer [57]. The expression of ICG transporters is consistent in welldifferentiated HCCs compared with poorly-differentiated HCCs and metastases [58, 59]. Impaired bile excretion in HCC tissue means that ICG is retained [24, 58], therefore well-differentiated HCCs can be detected by strong, homogenous fluorescence emissions. In contrast, ICG is retained in the parenchyma cytoplasm in poorly-differentiated HCCs and metastases because of pressure exerted by the tumor [58]. This means that poorly-differentiated HCCs and metastases produce rim type fluorescing patterns [24] (Figure 3). In support of these observations, welldifferentiated HCCs associated significantly with a homogenous pattern of fluorescence but not a rim type fluorescence pattern (P<0.001) [59]. A single dose of ICG (0.5 mg/kg) for routine liver function tests, administrated within 14 days prior to surgery, is sufficient to identify tumors by fluorescence imaging [24, 59]. A clinical study of 276 HCC tumors in 170 patients showed that FIS-ICG identified 273 HCCs (99%) in resected specimens. Moreover, 35 HCC tumors were visualized that were not diagnosed preoperatively; 14 were detected during liver resection and 21 were found by macroscopic examination of the resected specimen via intra-operative FISICG [59]. Ishizawa et al. reported a 100% positive predictive value of FIS-ICG in visualization of microscopically confirmed HCCs and liver metastases, even in resected tissue [24]. Uchiyama et al. reported a 98.1% sensitivity of FIS-ICG compared with 88.5% sensitivity using conventional imaging methods [60]. In another study of HCCs and liver metastases in 17 patients, 23 subcapsular tumors were 11
visualized via FIS-ICG, 17 of which were not identified by visual inspection of normal laparoscopic color images [61]. FIS-ICG can also detect other types of liver tumor. Harada et al. detected cholangio cell carcinoma (CCC) invasion by FIS-ICG [26]. CCC tumors can be detected as a result of cholestasis caused by bile duct obstruction. However, unlike HCC tumors, FIS-ICG cannot distinguish between specific types of CCC and CCC tumors can only be delineated by FIS-ICG cholangiography
[26].
Fluorescence
imaging
has
been
used
to
identify
hepatoblastoma, but its ability to distinguish between HCC and hepatoblastoma has not been confirmed [62, 63] (Figure 3). There are some limitations to visualizing tumors using FIS-ICG. These include limited depth of infrared light penetration and tissue thickness, both of which affect the fluorescence intensity. Infrared light can only penetrate 5 to 10 mm of tissue, therefore deeper lesions cannot be visualized by ICG excitation [4, 10]. Kudo et al. showed that tumors located 8 mm or more from the liver surface could not be identified in a study of 16 HCCs and 16 liver metastases resected from 17 patients. In this study, only HCCs and metastases that were 5 mm or closer to the liver surface were observable by FIS-ICG [61]. Moreover, in patients with impaired liver function, ICG removal from noncancerous tissue can be insufficient, creating false-positive nodules [59]. In a recent clinical study of ten cirrhotic explanted livers and 23 noncirrhotic resected livers, FIS-ICG had positive predictive value of 5.4% for malignant nodules in cirrhotic livers compared with 100% in non-cirrhotic resected specimens (P <0.0001) [64]. Because of the higher signal intensity of noncancerous parenchyma, it was suggested that the interval between the ICG injection and surgery should exceed 2 days for optimal tumor-to-liver contrast, especially in patients with advanced cirrhosis [24]. Furthermore, because ICG labeling is not specific, benign lesions may also emit fluorescence [4], making it difficult to 12
accurately determine the tumor free margin. In addition, benign lesions such as bile duct proliferations, expanding cysts or regenerating nodules may increase falsepositive results [65, 66] (Table 1). Partial liver transplantation Inflow evaluation: FIS-ICG can be used during PLT. Hepatic artery and portal vein thrombosis, insufficient anastomoses, and stenosis are associated with graft loss and early thrombectomy or reconstruction is required in these cases [67]. Kobuta et al. employed FIS-ICG to visualize flow turbulence in reconstructed vessels and to evaluate patency, kinking, and stenosis of vascular anastomoses following PLT [68]. They performed intra-operative doppler ultrasound and FIS-ICG in three PLT patients and compared the results. For intra-operative fluorescence imaging, 1.5 ml (3.75 mg) ICG was intravenously injected and flushed with 20 ml of saline following graft perfusion. Ten seconds later, the first images were recorded over a 30 second period. The same procedure was repeated after 2 minutes and a second round of imaging was performed. A final imaging was performed after 40 minutes without additional ICG injection. Fluorescence images were recorded using a SPY intraoperative imaging system previously developed for graft visualization during coronary bypass surgery [69]. The first image showed the hepatic artery and patency of the anastomosis. The second fluorescence recording evaluated the patency of the artery and portal vein anastomosis. After 40 minutes, the third recording showed the excretion of ICG into the bile duct. The authors concluded that FIS-ICG is safe and reproducible for evaluating the patency of reconstructed hepatic arteries and portal veins as well as demonstrating bile production in the transplanted graft during surgery [6, 68]. However, this approach was only semi quantitative, with flow assessments characterized as excellent, good, or poor. Moreover, due to poor penetration of infrared light, the flow patterns in large diameter vessels cannot be 13
completely visualized [10, 68]. Therefore, this method can only be used in addition to intra-operative doppler ultrasound. Organ outflow evaluation: The diagnosis of venous occlusion following PLT [70] and hepatectomy [71] is challenging. Portal uptake and sinusoidal perfusion are reduced in the venous occlusive region (VOR) [72]. Moreover, venous occlusion is associated with inadequate regeneration [73], post-operative complications [71, 74], and graft dysfunction [70]. The non-fluorescence characteristics of ICG have been used to estimate the VOR volume following PLT [72]. However, more recently Kawaguchi et al. used FIS-ICG to visualize the VOR and estimate the VOR volume according to ICG uptake [75] (Figure 4). In this clinical study, FIS-ICG was tested among 18 PLT donors, 23 PLT recipients, and 22 liver resections, using ICG concentrations in the liver parenchyma as a marker of portal uptake. ICG concentrations were significantly lower in the VOR compared with non-VOR in donors (0.69 µg/ml vs. 2.4 µg/ml, P <0.001), recipients (0.75 µg/ml vs. 1.8 µg/ml, P <0.001) and liver resection patients (0.75 µg/ml vs. 3.0 µg/ml, P <0.0001) [75]. The lower ICG concentrations caused by reduced portal uptake indirectly demonstrated outflow dysfunction in the related VOR. To perform this procedure, a single dose of ICG (0.0025 mg per ml of graft liver volume in PLT or remnant liver volume in donor surgery and liver resection) was injected intravenously after the liver graft was harvested (donor surgery), all hepatic vessels were reconstructed (recipient surgery) or the liver was resected. Fluorescence images of the liver surface were recorded for 300 seconds after intravenous injection of ICG [75, 76] (Figure 4), providing a differentiated real-time visualization of the VOR and non-VOR and estimating the volume of the liver with poor outflow. However, the liver surface must be monitored directly for the diagnosis of venous occlusion, therefore this method cannot be used to estimate post-operative
14
venous occlusion without laparotomy [76] (Table 1). Theoretically, this method is suitable for assessing liver outflow following any liver operation, although this must be confirmed by clinical studies.
15
Conclusions FIS-ICG is a visualization method based on fluorescence imaging that is feasible and suitable for hepatobiliary surgery. FIS-ICG is simple and safe compared with conventional systems. To date, FIS-ICG has been validated for liver mapping, intraoperative cholangiography, intra-operative tumor visualization, and flow evaluation following PLT. Despite the various benefits of FIS-ICG in hepatobiliary surgery, there are some drawbacks. These include limited tissue penetration and poor specificity. It remains unclear why FIS-ICG is not as popular in Europe and North America as it is in East Asia. One possible reason may be that ICG clearance is not routinely used as a liver function test in Western clinics. Further clinical studies are required to assess the sensitivity and specificity of FIS-ICG during hepatobiliary surgery.
Author contributions A. Majlesara, M. Golriz, and A. Mehrabi participated in the design of the study. A. Majlesara and M. Golriz participated in the collection of the data. M. Hafezi, A. Saffari, E. Wild, L. Maier-Hein, and B. P. Müller-Stich participated in the acquisition of data. M. Golriz and A. Majlesara drafted the manuscript. A. Majlesara, M. Golriz, and A. Mehrabi revised the manuscript. All authors read and approved the final manuscript.
Sources of financial support: None.
Funding This research did not receive any funding from the public, commercial, or not-profit sectors. 16
Conflicts of interest None.
17
Refrences [1]
S. Beller, M. Hunerbein, S. Eulenstein, T. Lange, and P. M. Schlag, "Feasibility of navigated resection of liver tumors using multiplanar visualization of intraoperative 3-dimensional ultrasound data," Ann Surg, vol. 246, pp. 288-94, Aug 2007.
[2]
S. Beller, M. Hunerbein, T. Lange, S. Eulenstein, B. Gebauer, and P. M. Schlag, "Image-guided surgery of liver metastases by three-dimensional ultrasoundbased optoelectronic navigation," Br J Surg, vol. 94, pp. 866-75, Jul 2007.
[3]
T. Aoki, D. Yasuda, Y. Shimizu, M. Odaira, T. Niiya, T. Kusano, et al., "Imageguided liver mapping using fluorescence navigation system with indocyanine green for anatomical hepatic resection," World J Surg, vol. 32, pp. 1763-7, Aug 2008.
[4]
K. Gotoh, T. Yamada, O. Ishikawa, H. Takahashi, H. Eguchi, M. Yano, et al., "A novel image-guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation," J Surg Oncol, vol. 100, pp. 75-9, Jul 1 2009.
[5]
T. Ishizawa, Y. Bandai, and N. Kokudo, "Fluorescent cholangiography using indocyanine green for laparoscopic cholecystectomy: an initial experience," Arch Surg, vol. 144, pp. 381-2, Apr 2009.
[6]
M. Sekijima, T. Tojimbara, S. Sato, M. Nakamura, T. Kawase, K. Kai, et al., "An intraoperative fluorescent imaging system in organ transplantation," Transplant Proc, vol. 36, pp. 2188-90, Sep 2004.
[7]
R. C. Benson and H. A. Kues, "Fluorescence properties of indocyanine green as related to angiography," Phys Med Biol, vol. 23, pp. 159-63, Jan 1978.
18
[8]
M. L. Landsman, G. Kwant, G. A. Mook, and W. G. Zijlstra, "Light-absorbing properties, stability, and spectral stabilization of indocyanine green," J Appl Physiol, vol. 40, pp. 575-83, Apr 1976.
[9]
J. Hauptmann and J. Sturzebecher, "Influence of indocyanine green on plasma disappearance and biliary excretion of a synthetic thrombin inhibitor of the 3amidinophenyl-alanine piperazide-type in rats," Pharm Res, vol. 15, pp. 751-4, May 1998.
[10]
N. Mitsuhashi, F. Kimura, H. Shimizu, M. Imamaki, H. Yoshidome, M. Ohtsuka, et al., "Usefulness of intraoperative fluorescence imaging to evaluate local anatomy in hepatobiliary surgery," J Hepatobiliary Pancreat Surg, vol. 15, pp. 508-14, 2008.
[11]
S. Yoneya, T. Saito, Y. Komatsu, I. Koyama, K. Takahashi, and J. Duvoll-Young, "Binding properties of indocyanine green in human blood," Invest Ophthalmol Vis Sci, vol. 39, pp. 1286-90, Jun 1998.
[12]
K. J. Baker, "Binding of sulfobromophthalein (BSP) sodium and indocyanine green (ICG) by plasma alpha-1 lipoproteins," Proc Soc Exp Biol Med, vol. 122, pp. 957-63, Aug-Sep 1966.
[13]
V. I. Kochubey, T. V. Kulyabina, V. V. Tuchin, and G. B. Altshuler, "Spectral characteristics of indocyanine Green upon its interaction with biological tissues," Optics and Spectroscopy, vol. 99, pp. 560-566, 2005/10/01 2005.
[14]
S. Gioux, H. S. Choi, and J. V. Frangioni, "Image-guided surgery using invisible near-infrared light: fundamentals of clinical translation," Mol Imaging, vol. 9, pp. 237-55, Oct 2010.
19
[15]
T. Kitai, M. Miwa, H. Liu, B. Beauvoit, B. Chance, and Y. Yamaoka, "Application of near-infrared time-resolved spectroscopy to rat liver--a preliminary report for surgical application," Phys Med Biol, vol. 44, pp. 2049-61, Aug 1999.
[16]
R. W. Flower, "Injection technique for indocyanine green and sodium fluorescein dye angiography of the eye," Invest Ophthalmol, vol. 12, pp. 881-95, Dec 1973.
[17]
L. A. Yannuzzi, "Indocyanine green angiography: a perspective on use in the clinical setting," Am J Ophthalmol, vol. 151, pp. 745-751 e1, May 2011.
[18]
A. Raabe, P. Nakaji, J. Beck, L. J. Kim, F. P. Hsu, J. D. Kamerman, et al., "Prospective evaluation of surgical microscope-integrated intraoperative nearinfrared indocyanine green videoangiography during aneurysm surgery," J Neurosurg, vol. 103, pp. 982-9, Dec 2005.
[19]
L. Balacumaraswami, Y. Abu-Omar, B. Choudhary, D. Pigott, and D. P. Taggart, "A comparison of transit-time flowmetry and intraoperative fluorescence imaging for assessing coronary artery bypass graft patency," J Thorac Cardiovasc Surg, vol. 130, pp. 315-20, Aug 2005.
[20]
N. Unno, K. Inuzuka, M. Suzuki, N. Yamamoto, D. Sagara, M. Nishiyama, et al., "Preliminary experience with a novel fluorescence lymphography using indocyanine green in patients with secondary lymphedema," J Vasc Surg, vol. 45, pp. 1016-21, May 2007.
[21]
D. L. Morton, D. R. Wen, J. H. Wong, J. S. Economou, L. A. Cagle, F. K. Storm, et al., "Technical details of intraoperative lymphatic mapping for early stage melanoma," Arch Surg, vol. 127, pp. 392-9, Apr 1992.
[22]
C. P. Parungo, S. Ohnishi, S. W. Kim, S. Kim, R. G. Laurence, E. G. Soltesz, et al., "Intraoperative identification of esophageal sentinel lymph nodes with near-
20
infrared fluorescence imaging," J Thorac Cardiovasc Surg, vol. 129, pp. 844-50, Apr 2005. [23]
C. M. Leevy, C. L. Mendenhall, W. Lesko, and M. M. Howard, "Estimation of hepatic blood flow with indocyanine green," J Clin Invest, vol. 41, pp. 1169-79, May 1962.
[24]
T. Ishizawa, N. Fukushima, J. Shibahara, K. Masuda, S. Tamura, T. Aoki, et al., "Real-time identification of liver cancers by using indocyanine green fluorescent imaging," Cancer, vol. 115, pp. 2491-504, Jun 1 2009.
[25]
K. G. Billingsley, W. R. Jarnagin, Y. Fong, and L. H. Blumgart, "Segmentoriented hepatic resection in the management of malignant neoplasms of the liver," J Am Coll Surg, vol. 187, pp. 471-81, Nov 1998.
[26]
N. Harada, T. Ishizawa, A. Muraoka, M. Ijichi, K. Kusaka, M. Shibasaki, et al., "Fluorescence navigation hepatectomy by visualization of localized cholestasis from bile duct tumor infiltration," J Am Coll Surg, vol. 210, pp. e2-6, Jun 2010.
[27]
M. Makuuchi, H. Hasegawa, and S. Yamazaki, "Ultrasonically guided subsegmentectomy," Surg Gynecol Obstet, vol. 161, pp. 346-50, Oct 1985.
[28]
T. Aoki, M. Murakami, D. Yasuda, Y. Shimizu, T. Kusano, K. Matsuda, et al., "Intraoperative fluorescent imaging using indocyanine green for liver mapping and cholangiography," J Hepatobiliary Pancreat Sci, vol. 17, pp. 590-4, Sep 2010.
[29]
A. Miyata, T. Ishizawa, K. Tani, A. Shimizu, J. Kaneko, T. Aoki, et al., "Reappraisal of a Dye-Staining Technique for Anatomic Hepatectomy by the Concomitant Use of Indocyanine Green Fluorescence Imaging," Journal of the American College of Surgeons, vol. 221, pp. e27-e36, 8// 2015.
21
[30]
A. Oddi, V. Di Nicola, A. Panzini, A. Berni, S. Lucci, L. Greco, et al., "[The intraoperative visualization of the bile ducts by the use of fluorescent substances. A feasibility study]," G Chir, vol. 17, pp. 620-3, Nov-Dec 1996.
[31]
D. R. Flum, C. Flowers, and D. L. Veenstra, "A cost-effectiveness analysis of intraoperative cholangiography in the prevention of bile duct injury during laparoscopic cholecystectomy," J Am Coll Surg, vol. 196, pp. 385-93, Mar 2003.
[32]
R. Speich, B. Saesseli, U. Hoffmann, K. A. Neftel, and J. Reichen, "Anaphylactoid reactions after indocyanine-green administration," Ann Intern Med, vol. 109, pp. 345-6, Aug 15 1988.
[33]
T. Ishizawa, Y. Bandai, M. Ijichi, J. Kaneko, K. Hasegawa, and N. Kokudo, "Fluorescent cholangiography illuminating the biliary tree during laparoscopic cholecystectomy," Br J Surg, vol. 97, pp. 1369-77, Sep 2010.
[34]
J. Machi, T. Tateishi, A. J. Oishi, N. L. Furumoto, R. H. Oishi, S. Uchida, et al., "Laparoscopic ultrasonography versus operative cholangiography during laparoscopic cholecystectomy: review of the literature and a comparison with open intraoperative ultrasonography," J Am Coll Surg, vol. 188, pp. 360-7, Apr 1999.
[35]
F. P. Verbeek, B. E. Schaafsma, Q. R. Tummers, J. R. van der Vorst, W. J. van der Made, C. I. Baeten, et al., "Optimization of near-infrared fluorescence cholangiography for open and laparoscopic surgery," Surg Endosc, vol. 28, pp. 1076-82, Apr 2014.
[36]
F. P. Verbeek, J. R. van der Vorst, B. E. Schaafsma, M. Hutteman, B. A. Bonsing, F. W. van Leeuwen, et al., "Image-guided hepatopancreatobiliary surgery using near-infrared fluorescent light," J Hepatobiliary Pancreat Sci, vol. 19, pp. 626-37, Nov 2012.
22
[37]
M. Kaibori, M. Ishizaki, K. Matsui, and A. H. Kwon, "Intraoperative indocyanine green fluorescent imaging for prevention of bile leakage after hepatic resection," Surgery, vol. 150, pp. 91-8, Jul 2011.
[38]
A. Matsui, E. Tanaka, H. S. Choi, J. H. Winer, V. Kianzad, S. Gioux, et al., "Realtime intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts using clinically available contrast agents," Surgery, vol. 148, pp. 87-95, Jul 2010.
[39]
R. M. Schols, N. D. Bouvy, R. M. van Dam, A. A. Masclee, C. H. Dejong, and L. P. Stassen, "Combined vascular and biliary fluorescence imaging in laparoscopic cholecystectomy," Surg Endosc, vol. 27, pp. 4511-7, Dec 2013.
[40]
R. M. Schols, N. D. Bouvy, A. A. Masclee, R. M. van Dam, C. H. Dejong, and L. P. Stassen, "Fluorescence cholangiography during laparoscopic cholecystectomy: a feasibility study on early biliary tract delineation," Surg Endosc, vol. 27, pp. 1530-6, May 2013.
[41]
S. M. Strasberg, "Error traps and vasculo-biliary injury in laparoscopic and open cholecystectomy," J Hepatobiliary Pancreat Surg, vol. 15, pp. 284-92, 2008.
[42]
L. W. Way, L. Stewart, W. Gantert, K. Liu, C. M. Lee, K. Whang, et al., "Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and cognitive psychology perspective," Ann Surg, vol. 237, pp. 460-9, Apr 2003.
[43]
F. Ikeda, K. Yamamoto, S. Fujioka, R. Okamoto, K. Yabushita, M. Miyake, et al., "Laparoscopic findings in primary sclerosing cholangitis," Endoscopy, vol. 33, pp. 267-70, Mar 2001.
23
[44]
Y. Ashitate, A. Stockdale, H. S. Choi, R. G. Laurence, and J. V. Frangioni, "Realtime simultaneous near-infrared fluorescence imaging of bile duct and arterial anatomy," J Surg Res, vol. 176, pp. 7-13, Jul 2012.
[45]
S. M. Strasberg and W. S. Helton, "An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy," HPB (Oxford), vol. 13, pp. 1-14, Jan 2011.
[46]
J. Kaneko, T. Ishizawa, K. Masuda, Y. Kawaguchi, T. Aoki, Y. Sakamoto, et al., "Indocyanine green reinjection technique for use in fluorescent angiography concomitant with cholangiography during laparoscopic cholecystectomy," Surg Laparosc Endosc Percutan Tech, vol. 22, pp. 341-4, Aug 2012.
[47]
N. Tagaya, M. Shimoda, M. Kato, A. Nakagawa, A. Abe, Y. Iwasaki, et al., "Intraoperative exploration of biliary anatomy using fluorescence imaging of indocyanine green in experimental and clinical cholecystectomies," J Hepatobiliary Pancreat Sci, vol. 17, pp. 595-600, Sep 2010.
[48]
R. M. Schols, N. J. Connell, and L. P. Stassen, "Near-infrared fluorescence imaging for real-time intraoperative anatomical guidance in minimally invasive surgery: a systematic review of the literature," World J Surg, vol. 39, pp. 1069-79, May 2015.
[49]
N. C. Buchs, M. E. Hagen, F. Pugin, F. Volonte, P. Bucher, E. Schiffer, et al., "Intra-operative fluorescent cholangiography using indocyanin green during robotic single site cholecystectomy," Int J Med Robot, vol. 8, pp. 436-40, Dec 2012.
[50]
D. Daskalaki, F. Aguilera, K. Patton, and P. C. Giulianotti, "Fluorescence in robotic surgery," J Surg Oncol, vol. 112, pp. 250-6, Sep 2015.
24
[51]
T. Ishizawa, S. Tamura, K. Masuda, T. Aoki, K. Hasegawa, H. Imamura, et al., "Intraoperative fluorescent cholangiography using indocyanine green: a biliary road map for safe surgery," J Am Coll Surg, vol. 208, pp. e1-4, Jan 2009.
[52]
H. B. El-Serag, J. A. Marrero, L. Rudolph, and K. R. Reddy, "Diagnosis and treatment of hepatocellular carcinoma," Gastroenterology, vol. 134, pp. 1752-63, May 2008.
[53]
S. Manfredi, C. Lepage, C. Hatem, O. Coatmeur, J. Faivre, and A. M. Bouvier, "Epidemiology and management of liver metastases from colorectal cancer," Ann Surg, vol. 244, pp. 254-9, Aug 2006.
[54]
J. M. Llovet, A. Burroughs, and J. Bruix, "Hepatocellular carcinoma," Lancet, vol. 362, pp. 1907-17, Dec 6 2003.
[55]
M. Golriz, A. Majlesara, S. El Sakka, M. Ashrafi, J. Arwin, N. Fard, et al., "Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure," Clin Res Hepatol Gastroenterol, Oct 26 2015.
[56]
Z. Morise, N. Kawabe, H. Tomishige, H. Nagata, J. Kawase, S. Arakawa, et al., "Recent advances in liver resection for hepatocellular carcinoma," Front Surg, vol. 1, p. 21, 2014.
[57]
C. Lim, E. Vibert, D. Azoulay, C. Salloum, T. Ishizawa, R. Yoshioka, et al., "Indocyanine green fluorescence imaging in the surgical management of liver cancers: current facts and future implications," J Visc Surg, vol. 151, pp. 117-24, Apr 2014.
[58]
C. Lim and E. Vibert, Fluorescent Imaging: Treatment of Hepatobiliary and Pancreatic Diseases vol. 31. Basel: Karger, 2013.
[59]
T. Ishizawa, K. Masuda, Y. Urano, Y. Kawaguchi, S. Satou, J. Kaneko, et al., "Mechanistic background and clinical applications of indocyanine green
25
fluorescence imaging of hepatocellular carcinoma," Ann Surg Oncol, vol. 21, pp. 440-8, Feb 2014. [60]
K. Uchiyama, M. Ueno, S. Ozawa, S. Kiriyama, Y. Shigekawa, and H. Yamaue, "Combined use of contrast-enhanced intraoperative ultrasonography and a fluorescence navigation system for identifying hepatic metastases," World J Surg, vol. 34, pp. 2953-9, Dec 2010.
[61]
H. Kudo, T. Ishizawa, K. Tani, N. Harada, A. Ichida, A. Shimizu, et al., "Visualization of subcapsular hepatic malignancy by indocyanine-green fluorescence imaging during laparoscopic hepatectomy," Surg Endosc, vol. 28, pp. 2504-8, Aug 2014.
[62]
T. Yamamichi, T. Oue, T. Yonekura, M. Owari, K. Nakahata, S. Umeda, et al., "Clinical application of indocyanine green (ICG) fluorescent imaging of hepatoblastoma," J Pediatr Surg, vol. 50, pp. 833-6, May 2015.
[63]
Y. Mitani, A. Kubota, M. Ueno, K. Takifuji, T. Watanabe, S. Hayami, et al., "Realtime identification of hepatoblastoma using a near infrared imaging with indocyanine green," Journal of Pediatric Surgery Case Reports, vol. 2, pp. 180183, 4// 2014.
[64]
T. Tanaka, M. Takatsuki, M. Hidaka, T. Hara, I. Muraoka, A. Soyama, et al., "Is a fluorescence navigation system with indocyanine green effective enough to detect liver malignancies?," J Hepatobiliary Pancreat Sci, vol. 21, pp. 199-204, Mar 2014.
[65]
M. Ishizuka, K. Kubota, J. Kita, M. Shimoda, M. Kato, and T. Sawada, "Intraoperative observation using a fluorescence imaging instrument during hepatic resection for liver metastasis from colorectal cancer," Hepatogastroenterology, vol. 59, pp. 90-2, Jan-Feb 2012.
26
[66]
S. Keereweer, J. D. Kerrebijn, P. B. van Driel, B. Xie, E. L. Kaijzel, T. J. Snoeks, et al., "Optical image-guided surgery--where do we stand?," Mol Imaging Biol, vol. 13, pp. 199-207, Apr 2011.
[67]
T. Kok, M. J. Slooff, C. J. Thijn, P. M. Peeters, R. Verwer, C. M. Bijleveld, et al., "Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation," Transpl Int, vol. 11, pp. 272-6, 1998.
[68]
K. Kubota, J. Kita, M. Shimoda, K. Rokkaku, M. Kato, Y. Iso, et al., "Intraoperative assessment of reconstructed vessels in living-donor liver transplantation, using a novel fluorescence imaging technique," J Hepatobiliary Pancreat Surg, vol. 13, pp. 100-4, 2006.
[69]
D. P. Taggart, B. Choudhary, K. Anastasiadis, Y. Abu-Omar, L. Balacumaraswami, and D. W. Pigott, "Preliminary experience with a novel intraoperative fluorescence imaging technique to evaluate the patency of bypass grafts in total arterial revascularization," Ann Thorac Surg, vol. 75, pp. 870-3, Mar 2003.
[70]
K. Sano, M. Makuuchi, K. Miki, A. Maema, Y. Sugawara, H. Imamura, et al., "Evaluation of hepatic venous congestion: proposed indication criteria for hepatic vein reconstruction," Ann Surg, vol. 236, pp. 241-7, Aug 2002.
[71]
T. Kakazu, M. Makuuchi, S. Kawasaki, S. Miyagawa, Y. Nakazawa, T. Kubota, et al., "Reconstruction of the middle hepatic vein tributary during right anterior segmentectomy," Surgery, vol. 117, pp. 238-40, Feb 1995.
[72]
T. Hashimoto, K. Miki, H. Imamura, K. Sano, S. Satou, Y. Sugawara, et al., "Sinusoidal perfusion in the veno-occlusive region of living liver donors evaluated
27
by indocyanine green and near-infrared spectroscopy," Liver Transpl, vol. 14, pp. 872-80, Jun 2008. [73]
N. Akamatsu, Y. Sugawara, J. Kaneko, K. Sano, H. Imamura, N. Kokudo, et al., "Effects of middle hepatic vein reconstruction on right liver graft regeneration," Transplantation, vol. 76, pp. 832-7, Sep 15 2003.
[74]
N. Akamatsu, Y. Sugawara, J. Kaneko, Y. Kishi, T. Niiya, N. Kokudo, et al., "Surgical repair for late-onset hepatic venous outflow block after living-donor liver transplantation," Transplantation, vol. 77, pp. 1768-70, Jun 15 2004.
[75]
Y. Kawaguchi, T. Ishizawa, Y. Miyata, S. Yamashita, K. Masuda, S. Satou, et al., "Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green," J Hepatol, vol. 58, pp. 247-53, Feb 2013.
[76]
Y. Kawaguchi, Y. Sugawara, T. Ishizawa, S. Satou, J. Kaneko, S. Tamura, et al., "Identification of veno-occlusive regions in a right liver graft after reconstruction of vein segments 5 and 8: application of indocyanine green fluorescence imaging," Liver Transpl, vol. 19, pp. 778-9, Jul 2013.
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Figure legends
Figure 1. Liver mapping of segment 4: the liver surface after injection of ICG into the respective branch of the portal vein. (a) Without fluorescence imaging. (b) After fluorescence imaging with ICG [28]. ICG: Indocyanine green
Figure 2. Intra-operative cholangiography using FIS-ICG: (a) color video, (b) NIR fluorescence, and (c) a color-NIR overlay [36]. NIR: Near infrared; FIS-ICG: Fluorescence imaging system with indocyanine green
Figure 3. Liver tumor identification using fluorescence imaging (left) and gross tumor morphology (right). (a) Totally fluorescent type; well-differentiated hepatocellular carcinoma (HCC). (b) Partially fluorescent type; moderately differentiated HCC with well-differentiated components and hemorrhagic necrosis in the upper half of the tumor. (c) Rim fluorescent type; poorly-differentiated HCC.
(d)
Rim
fluorescent
type;
metastasis
of
colon
carcinoma.
(e)
Hepatoblastoma [24, 62]. HCC: Hepatocellular carcinoma
Figure 4. Fluorescence imaging following intravenous injection of ICG reveals the demarcation between veno-occlusive and non-veno-occlusive regions. (a) Gross morphology; (b) fluorescence images before ICG injection, and (c) fluorescence images after ICG injection [75]. ICG: Indocyanine green
29
fig 1
fig 2
fig 3
30
fig 4
31
Table 1. Different applications of fluorescence imaging using indocyanine green in liver surgery
Application
Method of ICG administration
Limitation(s)
Liver mapping
-
Segment demarcation Anatomical resection
-
Intra-operative 1 ml (5 mg/ml) Intra-portal ± Pringle maneuver
-
Impermanent visualization
Intra-operative cholangiography
-
-
Limited depth of visualization No characterization of intraductal mass
-
1 ml (2,5 mg/ml) / 30 min before operation [33] or 10 mg / 24 h before operation [35] Intravenous
-
-
Cholangiography Simultaneous cholangiography and angiography [46] Indirect demarcation of CCC
-
Atypical liver resection HCC (Identification) Liver metastases Hepatoblastoma
-
2 to 14 days before operation 0.5 mg/kg Intravenous
-
Limited depth of visualization False-positive nodules due to poor liver function Emission from benign lesions No identification of CCC Inaccurate in distinguishing between poorlydifferentiated HCC and metastases Semi quantitative evaluation Limited depth of penetration
Tumor visualization
-
-
PLT
-
-
Evaluation of the patency of vascular reconstructions Bile production in the transplanted graft Visualization of the veno-occlusive region
-
Intra-operative (after implantation) 1.5 ml (3.75 mg) flushed with 20 ml saline (reinjection after 2 min) Intravenous Intra-operative (after harvesting in donor or after reperfusion in recipient) 0.0025 mg/ml of the graft/remnant liver volume Intravenous
-
-
No post-operative evaluation without laparotomy
PLT: Partial liver transplantation; ICG: Indocyanine green; HCC: Hepatocellular carcinoma; CCC: Cholangio cell carcinoma
32