531661
research-article2014
SRIXXX10.1177/1553350614531661Surgical InnovationSchnelldorfer et al
In Context: Review
From Shadow to Light: Visualization of Extrahepatic Bile Ducts Using Image-Enhanced Laparoscopy
Surgical Innovation 2015, Vol. 22(2) 194–200 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1553350614531661 sri.sagepub.com
Thomas Schnelldorfer, MD1, Roger L. Jenkins, MD1, Desmond H. Birkett, MD1, and Irene Georgakoudi, PhD2
Abstract Background. Correct recognition of the extrahepatic bile ducts is thought to be crucial to reduce the risk of bile duct injuries during various laparoscopic procedures. Image-enhanced laparoscopy techniques, utilizing various optical modalities other than white light, may help in detecting structures “hidden” underneath connective tissue. Methods. A systematic literature search was conducted of studies describing image-enhanced laparoscopy techniques for visualization of the extrahepatic bile ducts. Results. In all, 29 articles met inclusion criteria. They describe various techniques in the animal or human setting, including autofluorescence imaging, drug-enhanced fluorescence imaging, infrared thermography, and spectral imaging. This review describes these various techniques and their results. Conclusion. Image-enhanced laparoscopy techniques for real-time visualization of extrahepatic bile ducts are still in its infancy. Out of the techniques currently described, indocyanine green–enhanced near-infrared fluorescence laparoscopy has the most mature results, but other techniques also appear promising. It can be expected that in the future, image-enhanced laparoscopy might become a routine adjunct to any white-light laparoscopic operation near the hepatic hilum. Keywords biomedical engineering, image-guided surgery, evidence-based medicine/surgery
Introduction Recognition of the correct location of the extrahepatic bile ducts is thought to reduce the risk of bile duct injuries during laparoscopic cholecystectomy and various other laparoscopic procedures. Extrahepatic bile ducts are almost always hiding from direct visualization underneath a sheath of soft tissue and are generally out of reach from palpation because of the limitations in tactile feedback with laparoscopy. Surgeons, therefore, use surrogate landmarks to estimate the correct location and avoid inadvertent injury. Intraoperative cholangiography and laparoscopic ultrasonography may add to the understanding of the anatomy, but do not provide real-time visualization of the bile ducts during dissection in proximity of the hepatic hilum. Image-enhanced laparoscopy techniques, defined as imaging of the peritoneal cavity utilizing various optical modalities other than white light, may help in detecting “hidden” structures. Conventional white-light laparoscopy only assesses for structure, contour, and color of objects. Image-enhanced laparoscopy has added capabilities, including visualization of biochemical properties, vascular
formations, and color outside of the visible spectrum, which in some cases leads to imaging of structures below the peritoneal surface.1 Image-enhanced laparoscopy, therefore, seems a compelling technique to visualize the generally hidden extrahepatic bile ducts. It includes techniques such as fluorescence imaging, which is based on illumination of the tissue with a set band of light, most commonly blue light, which will excite fluorophores within the tissue, resulting in fluorescence. These fluorophores can be naturally present like NADH or collagen (autofluorescence imaging) or are administered through an external vector (eg, drug-enhanced fluorescence imaging). Another technique is spectral imaging, which captures light at one or several defined wavelengths, resulting in an image that augments the display of objects with peak light 1
Lahey Hospital & Medical Center, Burlington, MA, USA Tufts University School of Engineering, Medford, MA, USA
2
Corresponding Author: Thomas Schnelldorfer, Department of General Surgery, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA. Email: [email protected]
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56 potentially relevant studies identified from the PubMed electronic database 11 studies excluded due to non-English language 45 studies retrieved for detailed evaluation 34 studies excluded, due to: 32 studies unrelated to operative imaging of extra-hepatic bile ducts 2 review articles without primary data 18 studies added from reference lists of retrieved studies 29 studies included in systematic review
Figure 1. Selection of articles for inclusion in the systematic review.
reflectance or fluorescence at the defined spectral window. Spectral imaging can utilize detection of light inside and outside the visible spectrum and sometimes can be enhanced with contrast agents. This review will cover the pertinent image-enhanced laparoscopic techniques described in the literature on investigational studies for visualization of the extrahepatic bile duct, with the goal to survey the various imaging techniques being used or under development for visualization of the biliary system.
Methods
Data Collection Of 56 publications identified from the electronic databases, 29 met inclusion criteria for the systematic review and were used for data collection, including 18 studies that were added from reference lists of retrieved studies (Figure 1).2-30 One investigator (TS) performed the systematic literature search and data collection. These 29 publications utilized the following imaging techniques: autofluorescence imaging, drug-enhanced fluorescence imaging, infrared thermography, and spectral imaging within the visible and near-infrared spectrum.
Systematic Literature Search A systematic literature search of the PubMed electronic database (National Library of Medicine) was conducted, with the last search carried out on March 6, 2013. The following search terms were used: bile duct(s) or biliary in combination with image-enhanced laparoscopy, fluorescence imaging, autofluorescence imaging, spectral imaging, hyperspectral imaging, narrow band imaging, near-infrared imaging, infrared imaging, thermography, or photoacoustic imaging. The literature search was limited to English language only without restriction to year of publication. The references within the selected studies were cross-searched for additional relevant literature. Any article was considered if the publication provided original data describing a method relevant for operative imaging of the extrahepatic bile ducts.
Results Autofluorescence Imaging Using autofluorescence imaging, Stiles et al2 demonstrated improved visualization of the extrahepatic biliary anatomy in an animal model. In this study, bile was harvested from mice, and the bile’s maximal autofluorescence emission spectrum was determined after illuminating the specimen with blue light at 475 nm. Spectrometry detected the maximal autofluorescence emission within the cyan/green range at 490 nm. Subsequently, mice underwent laparotomy, and the open abdominal cavity was inspected using a fluorescent stereomicroscope providing white-light images as well as fluorescence images at the same magnification and resolution. For autofluorescence imaging, light at 470 nm
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Figure 2. Visualization of the extrahepatic bile ducts under white light (left) and autofluorescence imaging (right) using a fluorescent stereomicroscope after laparotomy in a mouse model. Autofluorescence imaging provided improved delineation of the common bile duct (CBD) as well as the cystic duct (CD) joining the right hepatic duct; with permission from Stiles et al.2
was used for excitation and the corresponding fluorescence emission was captured at 500 nm, thereby visualizing the bile’s natural fluorescence (Figure 2). Images were shown to surgical trainees for survey. Evaluating white-light images, surgical trainees made errors in identifying the correct anatomy 22% of the time compared with only 2% with autofluorescence images. In addition, identification of the anatomy on autofluorescence images was achieved faster, only requiring half the time compared with white-light images. Next, similar fluorescent images were obtained using laparoscopy, which demonstrated feasibility of the concept; yet, the quality of autofluorescence laparoscopy images was inferior compared with that achieved with the fluorescent stereomicroscope, most likely as a result of the inferior intrinsic optical resolution of the laparoscope.
Drug-Enhanced Fluorescence Imaging Drug-enhanced fluorescence laparoscopy has been used to improve visualization of the extra-hepatic bile ducts. This has mainly been tested using indocyanine green (ICG)-enhanced near-infrared fluorescence imaging. Its feasibility was confirmed in various animal models, leading to its introduction into human studies.3-7 In human studies, standard doses of ICG were intravenously injected prior to laparoscopic cholecystectomy. During the operation, the hepatic hilum was examined with various near-infrared laparoscopic imaging systems that could shine light of either a wide spectrum (including light at 760 nm) or a narrow spectrum around 760 nm onto the target area. Through filtering of the emitted light, only images in the near-infrared spectrum above 810 nm were captured. With maximal excitation of ICG occurring at 760 nm and a maximal fluorescence emission being detected at 820 nm, these near-infrared laparoscopic imaging systems were able to visualize ICG excretion in bile.5,8-12
A total of 97 patients were examined in 6 studies using ICG-enhanced near-infrared fluorescence imaging during laparoscopic cholecystectomy. In these 6 studies, the common hepatic duct/common bile duct and the cystic duct were clearly visualized in 94% and 94% of patients, respectively (Figure 3).5,8-12 The confluence of the common hepatic and cystic duct was visualized without dissection of any connective tissue in 97% of 68 patients.5,8,10,12 However, the right and left hepatic duct junction was only recognized in 42% of 53 patients.8,12 In 9 patients, a replaced or accessory bile duct was identified under ICGenhanced near-infrared fluorescence imaging, which may not have been identified under white-light imaging.8,12 As expected, the gallbladder was not always visualized, likely because of cystic duct obstruction in some patients. Ishizawa et al8 assessed interobserver differences and found no differences in interpretation of the fluorescent images among various surgeons, demonstrating the ease of interpreting these images. Similar results have been obtained using ICGenhanced near-infrared fluorescence imaging with a 3D stereoscopic imaging system for robotic surgery. A total of 57 patients were examined in 2 studies. Before dissection of any connective tissues, the common hepatic duct/ common bile duct and the cystic duct were visualized in 84% and 93% of patients, respectively.13,14 The confluence of the common hepatic and cystic duct was visualized without tissue dissection in 75% of 57 patients.13,14 For open cholecystectomy, a similar technique using a near-infrared camera after intravenous injection of ICG was successful in identifying the common hepatic duct and cystic duct in 100% and 95% of 19 patients reported in 3 studies, respectively.5,6,15 Even in patients with inflammation in Calot’s triangle, the common bile duct was visible using the technique. Also, one study utilized ICG-enhanced near-infrared fluorescence imaging to visualize the extrahepatic bile ducts during open pancreatoduodenectomy.16
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Figure 3. Imaging of the triangle of Calot using white light (left) and indocyanine green–enhanced near-infrared fluorescence laparoscopy (right) in a human. Fluorescence imaging demonstrated improved visualization of the common hepatic duct (right arrow), cyst duct (arrowhead), and cystic artery (left arrow); with permission from Ishizawa et al.10
In all 8 patients, the common bile duct, cystic duct, and common hepatic duct could be identified. Besides ICG, other fluorescence dyes have been tested in animal models. These included fluorescein–bile acid conjugates,17,18 methylene blue,3,7 and the indocyanine derivatives VM674, IR-786, and CW800.4,19 Fluorescein itself has been tested in 1 human trial.20 Although these alternative dyes showed promising results, none of them have so far surpassed the results of ICG in terms of targetto-background ratios, duration of fluorescence, and safety in clinical use. Especially, the target-to-background ratio produced by ICG-enhanced near-infrared fluorescence imaging does provide benefits over the other dyes, which frequently fluoresce at lower wavelengths. The benefit of imaging at a higher wavelength is that of reduced tissue light scattering and reduced light absorption by hemoglobin, which allow better tissue penetration, thereby even revealing bile ducts covered under thick layers of connective tissue. Some of the drawbacks of ICG are being addressed by creating encapsulated ICG nanoparticles, which have been tested in ex vivo models, suggesting increase in fluorescence and delay in degradation.21 In addition, improvements in near-infrared camera systems are under way.22
Infrared Thermography Various tissues can be distinguished from each other by their differences in metabolism and subsequent temperature. Such differences in temperature—though frequently miniscule—provide differences in emission of infrared radiation. With the capability of infrared radiation to penetrate through deeper tissues, imaging using infrared cameras appears to be a logical approach for visualization of extrahepatic bile ducts.
Studies performed in pigs demonstrated that imaging systems detecting emitted light in the midinfrared range between 3000 and 5000 nm, capable of detecting differences up to 0.1°C, were able to reliably visualize the common hepatic duct and cystic duct in a small sample of animals undergoing laparoscopic23,24 or open operations.25,26 Because of limited spatial resolution and small differences in infrared radiation, the provided images were not as clear as would be preferred in the clinical setting. Current limitations in resolution, however, have a potential to resolve with upcoming newer technology. To improve imaging with infrared thermography, 2 studies additionally utilized contrast-enhanced infrared thermocholangiography during open operations to provide visualization of the extrahepatic biliary anatomy after intrabiliary injection with cold saline in a porcine model.25,26 Whereas visualization of the common hepatic ducts and cystic ducts were mildly improved by administering the contrast, there were again some limitations because of blurred images based on lower spatial resolution in infrared imaging compared with white-light imaging. The limited resolution was enhanced by fusing infrared and white-light images.25 However, the need for cannulation of bile ducts for contrast administration and its timely temperature equilibration limits the duration of contrast enhancement and, therefore, does not allow realtime imaging of the bile duct during dissection.
Spectral Imaging Within the Visible and NearInfrared Spectrum Although bile itself is a known chromophore, absorbing light within specific ranges of visible light, only a few studies evaluated these wavelength ranges for enhanced visualization of bile through the wall of extrahepatic bile
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ducts. Maitland et al27 demonstrated that human gallbladders, examined spectroscopically immediately after operative resection, have an absorption peak at 410 and 550 nm, which correlates with the absorption peaks of bilirubin as well as hemoglobin. Yet this has not been utilized to enhance visualization of extrahepatic bile ducts. Araki et al28 visualized bile ducts after intravenous injection of ICG in humans. The dye undergoes biliary excretion subsequently providing a blue color to the bile, which can be seen through the wall of the extrahepatic bile ducts under white-light imaging. This has not only the potential to enhance visualization under routine white-light laparoscopy but should even further augment visualization under spectral imaging, separate from the fluorescent properties of the dye utilized in fluorescent imaging. The intravenous administration of dye is also advantageous over the use of typical color dye cholangiography, which injects the dye directly into the biliary tree.29 Taking advantage of the different light absorption profiles of various tissue types in the near-infrared spectrum, Zuzak et al,30 using near-infrared hyperspectral imaging, demonstrated proof of principle in a porcine model. In this study, imaging within the range between 650 and 1100 nm provided good-resolution pictures of the common and hepatic bile duct underneath its coverage of soft tissue.
Discussion Image-enhanced laparoscopy has been around for more than 30 years in the form of isolated experiments.31,32 The true breakthrough has not occurred until very recently, with the rapid development of new imaging technologies, subsequently providing many opportunities for this new frontier to establish itself in routine clinical care. These advanced imaging techniques seem to be a good fit for the ongoing clinical problem of bile duct injury during laparoscopic cholecystectomy and during other operations near the hepatic hilum. Bile duct injuries during laparoscopic cholecystectomy are thought to occur after incorrect visual assumptions are being made on the underlying anatomy,33 a direct result of incomplete visualization of the extrahepatic bile ducts. Reliable visualization of bile ducts, therefore, seems imperative; image-enhanced laparoscopy has the potential to provide improvements. Despite the advances in technology, use of imageenhanced laparoscopy techniques for real-time visualization of extrahepatic bile ducts is still in its infancy. A lack of larger human trials is obvious across the board. From the available feasibility studies performed in animals or small human trials, there is currently no definitive technique available that is reliable and easy to use. ICGenhanced near-infrared fluorescence laparoscopy appears promising because it seems to have the most mature
results. The cumulative results from current reports, derived from smaller study populations, do show favorable results in correctly identifying the common hepatic, cystic, and common bile duct without the need for dissecting the tissues or cannulating the bile duct. However, difficulties seem to occur when trying to visualize the main hepatic ducts. Particularly, visualization of the right hepatic duct would be of benefit during laparoscopic cholecystectomy. Blood vessels are only vaguely visualized because the contrast has to clear from the blood stream before being excreted by bile, which is crucial because visualization of blood vessels could create confusion with the biliary system. The most important advantage of imaging in the near-infrared spectrum is its capability to penetrate much deeper through tissue than visible light, providing images of structures hidden below the surface. Laboratory models demonstrated that fluorescence of ICG detected at 830 nm can penetrate up to 3 cm of solution known to mimic tissue scattering properties.34 This depth of penetration is definitely more than the depth of soft tissue typically found surrounding the extrahepatic bile ducts in humans. However, because, in principle, near-infrared light can travel through a wide range of depths before being scattered back out of the tissue and detected by the camera, the effective depth of field of the acquired images is very long, resulting in a decrease in the sharpness of the image features of interest. Future developments aimed at achieving some level of depth resolution could improve on the quality of these images.35 All the other image-enhanced techniques described for visualization of bile ducts do not seem to have been tested to the extent of ICG-enhanced near-infrared fluorescence laparoscopy. Autofluorescence imaging demonstrated very promising results. However, so far, it has only been tested in an animal model, which may not entirely represent the situation in humans. Particularly, the thickness of soft tissue surrounding the bile duct seems to be more extensive in humans, potentially making it more difficult to visualize the bile duct in humans. Also, laparoscopic imaging with its expected reduction in efficiency of exciting and/or detecting fluorescent light might provide different imaging properties from the open technique tested. Infrared thermography theoretically penetrates tissues deeper than any other method tested. But current methods relying on simple illumination/detection schemes have even more limited resolution than near-infrared-based imaging approaches because light in this wavelength regime can traverse even longer paths within the tissue before being detected. In addition, the sensitivity of the cameras is not very high in this spectral range, resulting in reduced signal-to-background ratio. And there is a potential of confusing blood vessels with bile ducts. Attempts have been made using contrast-enhanced infrared thermography trying to compensate for some of these
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Schnelldorfer et al limitations. The imaging results are improved, but cannulation of the bile duct is required to administer the thermal contrast, and there is timely temperature equilibration practically eliminating real-time imaging during the majority of surgical dissections. Spectral imaging has promising features but has not been tested enough to provide any conclusion. In summary, to minimize the risk of bile duct injury during laparoscopic operations through correct visual recognition of extrahepatic bile ducts “hidden” underneath connective tissue, it seems promising that, in the future, image-enhanced laparoscopy might become a routine adjunct to any white-light laparoscopic operation near the hepatic hilum. Apart from some minor additions to the existing equipment, image-enhanced laparoscopy usually does not require any major resources. Which specific technique will provide the best results is yet to be determined. In the currently available studies, the most advanced results available are for ICG-enhanced nearinfrared fluorescence laparoscopy, but other techniques also appear promising. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Schnelldorfer T. Image-enhanced laparoscopy: a promising technology for detection of peritoneal micrometastases. Surgery. 2012;151:345-350. 2. Stiles BM, Adusumilli PS, Bhargava A, Fong Y. Fluorescent cholangiography in a mouse model: an innovative method for improved laparoscopic identification of the biliary anatomy. Surg Endosc. 2006;20:1291-1295. 3. Matsui A, Tanaka E, Choi HS, et al. Real-time intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts using clinically available contrast agents. Surgery. 2010;148:87-95. 4. Tanaka E, Choi HS, Humblet V, Ohnishi S, Laurence RG, Frangioni JV. Real-time intraoperative assessment of the extrahepatic bile ducts in rats and pigs using invisible nearinfrared fluorescent light. Surgery. 2008;144:39-48. 5. Tagaya N, Shimoda M, Kato M, et al. Intraoperative exploration of biliary anatomy using fluorescence imaging of indocyanine green in experimental and clinical cholecystectomies. J Hepatobiliary Pancreat Sci. 2010;17:595-600. 6. Mitsuhashi N, Kimura F, Shimizu H, et al. Usefulness of intraoperative fluorescence imaging to evaluate local anatomy in hepatobiliary surgery. J Hepatobiliary Pancreat Surg. 2008;15:508-514.
7. Ashitate Y, Stockdale A, Choi HS, Laurence RG, Frangioni JV. Real-time simultaneous near-infrared fluorescence imaging of bile duct and arterial anatomy. J Surg Res. 2012;176:7-13. 8. Ishizawa T, Bandai Y, Ijichi M, Kaneko J, Hasegawa K, Kokudo N. Fluorescent cholangiography illuminating the biliary tree during laparoscopic cholecystectomy. Br J Surg. 2010;97:1369-1377. 9. Schols RM, Bouvy ND, Masclee AA, van Dam RM, Dejong CH, Stassen LP. Fluorescence cholangiography during laparoscopic cholecystectomy: a feasibility study on early biliary tract delineation. Surg Endosc. 2013;27:1530-1536. 10. Ishizawa T, Kaneko J, Inoue Y, et al. Application of fluorescent cholangiography to single-incision laparoscopic cholecystectomy. Surg Endosc. 2011;25:2631-2636 11. Aoki T, Murakami M, Yasuda D, et al. Intraoperative fluorescent imaging using indocyanine green for liver mapping and cholangiography. J Hepatobiliary Pancreat Sci. 2010;17:590-594. 12. Calatayud D, Milone L, Elli EF, Giulianotti PC. ICG fluorescence identification of a small aberrant biliary canaliculus during robotic cholecystectomy. Liver Int. 2012;32:602. 13. Spinoglio G, Priora F, Bianchi PP, et al. Real-time nearinfrared (NIR) fluorescent cholangiography in single-site robotic cholecystectomy (SSRC): a single-institutional prospective study. Surg Endosc. 2013;27:2156-2162. 14. Buchs NC, Hagen ME, Pugin F, et al. Intra-operative fluorescent cholangiography using indocyanin green during robotic single site cholecystectomy. Int J Med Robot. 2012;8:436-440. 15. Ishizawa T, Tamura S, Masuda K, et al. Intraoperative fluorescent cholangiography using indocyanine green: a biliary road map for safe surgery. J Am Coll Surg. 2009;208:e1-e4. 16. Hutteman M, van der Vorst JR, Mieog JSD, et al. Nearinfrared fluorescence imaging in patients undergoing pancreaticoduodenectomy. Eur Surg Res. 2011;47:90-97. 17. Oddi A, Mills CO, Custureri F, DiNicola V, Elias E, DiMatteo G. Intraoperative biliary tree imaging with cholyl-lysyl-fluorescein: an experimental study in the rabbit. Surg Laparosc Endosc. 1996;6:198-200. 18. Holzinger F, Krahenbuhl L, Schteingart CD, Ton-Nu HT, Hofmann AF. Use of a fluorescent bile acid to enhance visualization of the biliary tract and bile leaks during laparoscopic surgery in rabbits. Surg Endosc. 2001;15: 209-212. 19. Figueiredo JL, Siegel C, Nahrendorf M, Weissleder R. Intraoperative near-infrared fluorescent cholangiography (NIRFC) in mouse models of bile duct injury. World J Surg. 2010;34:336-343. 20. Mohsen AA, Elbasiouny MS, Fawzy YS. Fluorescenceguided laparoscopic cholecystectomy: a new technique for visualization of biliary system by using fluorescein. Surg Innov. 2013;20:105-108. 21. Mitra K, Melvin J, Chang S, et al. Indocyanine-greenloaded microballoons for biliary imaging in cholecystectomy. J Biomed Opt. 2012;17:116025. 22. Patel NL, Lin ZJ, Rathore Y, Livingston EH, Liu H, Alexandrakis G. Relative capacities of time-gated versus
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continuous-wave imaging to localize tissue embedded vessels with increasing depth. J Biomed Opt. 2010;15: 016015. 23. Cadeddu JA, Jackman SV, Schulam PG. Laparoscopic infrared imaging. J Endourol. 2001;15:111-116. 24. Roberts WW, Dinkel TA, Schulam PG, Bonnell L, Kavoussi LR. Laparoscopic infrared imaging. Surg Endosc. 1997;11:1221-1223. 25. Hanna BV, Gorbach AM, Gage FA, et al. Intraoperative assessment of critical biliary structures with visible range/infrared image fusion. J Am Coll Surg. 2008;206: 1227-1231. 26. Liu JJ, Alemozaffar M, Mchone B, et al. Evaluation of realtime infrared intraoperative cholangiography in a porcine model. Surg Endosc. 2008;22:2659-2664. 27. Maitland DJ, Walsh JT, Prystowsky JB. Optical prop erties of human gallbladder tissue and bile. Appl Opt. 1993;32:586-591. 28. Araki K, Namikawa K, Mizutani J, et al. Indocyanine green staining for visualization of the biliary system during laparoscopic cholecystectomy. Endoscopy. 1992;24:803. 29. Sari YS, Tunali V, Tomaoglu K, Karagoz B, Guneyi A, Karagoz I. Can bile duct injuries be prevented? “A new
technique in laparoscopic cholecystectomy.” BMC Surg. 2005;5:14. 30. Zuzak KJ, Naik SC, Alexandrakis G, Hawkins D, Behbehani K, Livingston E. Intraoperative bile duct visualization using near-infrared hyperspectral video imaging. Am J Surg. 2008;195:491-497. 31. Jewett DA, Dukelow WR. Infrared photolaparographic techniques for ovulation studies in primates. J Med Primatol. 1972;1:193-195. 32. Polak M. Laparoscopic photography on infra-red sensitive film [in German]. Z Gastroenterol. 1975;13:679-680. 33. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparoscopic bile duct injuries. Ann Surg. 2003;237:460-469. 34. Houston JP, Thompson AB, Gurfinkel M, Sevick-Muraca EM. Sensitivity and depth penetration of continuous wave versus frequency-domain photon migration near-infrared fluorescence contrast-enhanced imaging. Photochem Photobiol. 2003;77:420-430. 35. Themelis G, Yoo JS, Soh KS, Schulz R, Ntziachristos V. Real-time intraoperative fluorescence imaging system using light-absorption correction. J Biomed Opt. 2009;14:064012.
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research-article2014
SRIXXX10.1177/1553350614531661Surgical InnovationSchnelldorfer et al
In Context: Review
From Shadow to Light: Visualization of Extrahepatic Bile Ducts Using Image-Enhanced Laparoscopy
Surgical Innovation 2015, Vol. 22(2) 194–200 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1553350614531661 sri.sagepub.com
Thomas Schnelldorfer, MD1, Roger L. Jenkins, MD1, Desmond H. Birkett, MD1, and Irene Georgakoudi, PhD2
Abstract Background. Correct recognition of the extrahepatic bile ducts is thought to be crucial to reduce the risk of bile duct injuries during various laparoscopic procedures. Image-enhanced laparoscopy techniques, utilizing various optical modalities other than white light, may help in detecting structures “hidden” underneath connective tissue. Methods. A systematic literature search was conducted of studies describing image-enhanced laparoscopy techniques for visualization of the extrahepatic bile ducts. Results. In all, 29 articles met inclusion criteria. They describe various techniques in the animal or human setting, including autofluorescence imaging, drug-enhanced fluorescence imaging, infrared thermography, and spectral imaging. This review describes these various techniques and their results. Conclusion. Image-enhanced laparoscopy techniques for real-time visualization of extrahepatic bile ducts are still in its infancy. Out of the techniques currently described, indocyanine green–enhanced near-infrared fluorescence laparoscopy has the most mature results, but other techniques also appear promising. It can be expected that in the future, image-enhanced laparoscopy might become a routine adjunct to any white-light laparoscopic operation near the hepatic hilum. Keywords biomedical engineering, image-guided surgery, evidence-based medicine/surgery
Introduction Recognition of the correct location of the extrahepatic bile ducts is thought to reduce the risk of bile duct injuries during laparoscopic cholecystectomy and various other laparoscopic procedures. Extrahepatic bile ducts are almost always hiding from direct visualization underneath a sheath of soft tissue and are generally out of reach from palpation because of the limitations in tactile feedback with laparoscopy. Surgeons, therefore, use surrogate landmarks to estimate the correct location and avoid inadvertent injury. Intraoperative cholangiography and laparoscopic ultrasonography may add to the understanding of the anatomy, but do not provide real-time visualization of the bile ducts during dissection in proximity of the hepatic hilum. Image-enhanced laparoscopy techniques, defined as imaging of the peritoneal cavity utilizing various optical modalities other than white light, may help in detecting “hidden” structures. Conventional white-light laparoscopy only assesses for structure, contour, and color of objects. Image-enhanced laparoscopy has added capabilities, including visualization of biochemical properties, vascular
formations, and color outside of the visible spectrum, which in some cases leads to imaging of structures below the peritoneal surface.1 Image-enhanced laparoscopy, therefore, seems a compelling technique to visualize the generally hidden extrahepatic bile ducts. It includes techniques such as fluorescence imaging, which is based on illumination of the tissue with a set band of light, most commonly blue light, which will excite fluorophores within the tissue, resulting in fluorescence. These fluorophores can be naturally present like NADH or collagen (autofluorescence imaging) or are administered through an external vector (eg, drug-enhanced fluorescence imaging). Another technique is spectral imaging, which captures light at one or several defined wavelengths, resulting in an image that augments the display of objects with peak light 1
Lahey Hospital & Medical Center, Burlington, MA, USA Tufts University School of Engineering, Medford, MA, USA
2
Corresponding Author: Thomas Schnelldorfer, Department of General Surgery, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA. Email: [email protected]
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56 potentially relevant studies identified from the PubMed electronic database 11 studies excluded due to non-English language 45 studies retrieved for detailed evaluation 34 studies excluded, due to: 32 studies unrelated to operative imaging of extra-hepatic bile ducts 2 review articles without primary data 18 studies added from reference lists of retrieved studies 29 studies included in systematic review
Figure 1. Selection of articles for inclusion in the systematic review.
reflectance or fluorescence at the defined spectral window. Spectral imaging can utilize detection of light inside and outside the visible spectrum and sometimes can be enhanced with contrast agents. This review will cover the pertinent image-enhanced laparoscopic techniques described in the literature on investigational studies for visualization of the extrahepatic bile duct, with the goal to survey the various imaging techniques being used or under development for visualization of the biliary system.
Methods
Data Collection Of 56 publications identified from the electronic databases, 29 met inclusion criteria for the systematic review and were used for data collection, including 18 studies that were added from reference lists of retrieved studies (Figure 1).2-30 One investigator (TS) performed the systematic literature search and data collection. These 29 publications utilized the following imaging techniques: autofluorescence imaging, drug-enhanced fluorescence imaging, infrared thermography, and spectral imaging within the visible and near-infrared spectrum.
Systematic Literature Search A systematic literature search of the PubMed electronic database (National Library of Medicine) was conducted, with the last search carried out on March 6, 2013. The following search terms were used: bile duct(s) or biliary in combination with image-enhanced laparoscopy, fluorescence imaging, autofluorescence imaging, spectral imaging, hyperspectral imaging, narrow band imaging, near-infrared imaging, infrared imaging, thermography, or photoacoustic imaging. The literature search was limited to English language only without restriction to year of publication. The references within the selected studies were cross-searched for additional relevant literature. Any article was considered if the publication provided original data describing a method relevant for operative imaging of the extrahepatic bile ducts.
Results Autofluorescence Imaging Using autofluorescence imaging, Stiles et al2 demonstrated improved visualization of the extrahepatic biliary anatomy in an animal model. In this study, bile was harvested from mice, and the bile’s maximal autofluorescence emission spectrum was determined after illuminating the specimen with blue light at 475 nm. Spectrometry detected the maximal autofluorescence emission within the cyan/green range at 490 nm. Subsequently, mice underwent laparotomy, and the open abdominal cavity was inspected using a fluorescent stereomicroscope providing white-light images as well as fluorescence images at the same magnification and resolution. For autofluorescence imaging, light at 470 nm
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Figure 2. Visualization of the extrahepatic bile ducts under white light (left) and autofluorescence imaging (right) using a fluorescent stereomicroscope after laparotomy in a mouse model. Autofluorescence imaging provided improved delineation of the common bile duct (CBD) as well as the cystic duct (CD) joining the right hepatic duct; with permission from Stiles et al.2
was used for excitation and the corresponding fluorescence emission was captured at 500 nm, thereby visualizing the bile’s natural fluorescence (Figure 2). Images were shown to surgical trainees for survey. Evaluating white-light images, surgical trainees made errors in identifying the correct anatomy 22% of the time compared with only 2% with autofluorescence images. In addition, identification of the anatomy on autofluorescence images was achieved faster, only requiring half the time compared with white-light images. Next, similar fluorescent images were obtained using laparoscopy, which demonstrated feasibility of the concept; yet, the quality of autofluorescence laparoscopy images was inferior compared with that achieved with the fluorescent stereomicroscope, most likely as a result of the inferior intrinsic optical resolution of the laparoscope.
Drug-Enhanced Fluorescence Imaging Drug-enhanced fluorescence laparoscopy has been used to improve visualization of the extra-hepatic bile ducts. This has mainly been tested using indocyanine green (ICG)-enhanced near-infrared fluorescence imaging. Its feasibility was confirmed in various animal models, leading to its introduction into human studies.3-7 In human studies, standard doses of ICG were intravenously injected prior to laparoscopic cholecystectomy. During the operation, the hepatic hilum was examined with various near-infrared laparoscopic imaging systems that could shine light of either a wide spectrum (including light at 760 nm) or a narrow spectrum around 760 nm onto the target area. Through filtering of the emitted light, only images in the near-infrared spectrum above 810 nm were captured. With maximal excitation of ICG occurring at 760 nm and a maximal fluorescence emission being detected at 820 nm, these near-infrared laparoscopic imaging systems were able to visualize ICG excretion in bile.5,8-12
A total of 97 patients were examined in 6 studies using ICG-enhanced near-infrared fluorescence imaging during laparoscopic cholecystectomy. In these 6 studies, the common hepatic duct/common bile duct and the cystic duct were clearly visualized in 94% and 94% of patients, respectively (Figure 3).5,8-12 The confluence of the common hepatic and cystic duct was visualized without dissection of any connective tissue in 97% of 68 patients.5,8,10,12 However, the right and left hepatic duct junction was only recognized in 42% of 53 patients.8,12 In 9 patients, a replaced or accessory bile duct was identified under ICGenhanced near-infrared fluorescence imaging, which may not have been identified under white-light imaging.8,12 As expected, the gallbladder was not always visualized, likely because of cystic duct obstruction in some patients. Ishizawa et al8 assessed interobserver differences and found no differences in interpretation of the fluorescent images among various surgeons, demonstrating the ease of interpreting these images. Similar results have been obtained using ICGenhanced near-infrared fluorescence imaging with a 3D stereoscopic imaging system for robotic surgery. A total of 57 patients were examined in 2 studies. Before dissection of any connective tissues, the common hepatic duct/ common bile duct and the cystic duct were visualized in 84% and 93% of patients, respectively.13,14 The confluence of the common hepatic and cystic duct was visualized without tissue dissection in 75% of 57 patients.13,14 For open cholecystectomy, a similar technique using a near-infrared camera after intravenous injection of ICG was successful in identifying the common hepatic duct and cystic duct in 100% and 95% of 19 patients reported in 3 studies, respectively.5,6,15 Even in patients with inflammation in Calot’s triangle, the common bile duct was visible using the technique. Also, one study utilized ICG-enhanced near-infrared fluorescence imaging to visualize the extrahepatic bile ducts during open pancreatoduodenectomy.16
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Figure 3. Imaging of the triangle of Calot using white light (left) and indocyanine green–enhanced near-infrared fluorescence laparoscopy (right) in a human. Fluorescence imaging demonstrated improved visualization of the common hepatic duct (right arrow), cyst duct (arrowhead), and cystic artery (left arrow); with permission from Ishizawa et al.10
In all 8 patients, the common bile duct, cystic duct, and common hepatic duct could be identified. Besides ICG, other fluorescence dyes have been tested in animal models. These included fluorescein–bile acid conjugates,17,18 methylene blue,3,7 and the indocyanine derivatives VM674, IR-786, and CW800.4,19 Fluorescein itself has been tested in 1 human trial.20 Although these alternative dyes showed promising results, none of them have so far surpassed the results of ICG in terms of targetto-background ratios, duration of fluorescence, and safety in clinical use. Especially, the target-to-background ratio produced by ICG-enhanced near-infrared fluorescence imaging does provide benefits over the other dyes, which frequently fluoresce at lower wavelengths. The benefit of imaging at a higher wavelength is that of reduced tissue light scattering and reduced light absorption by hemoglobin, which allow better tissue penetration, thereby even revealing bile ducts covered under thick layers of connective tissue. Some of the drawbacks of ICG are being addressed by creating encapsulated ICG nanoparticles, which have been tested in ex vivo models, suggesting increase in fluorescence and delay in degradation.21 In addition, improvements in near-infrared camera systems are under way.22
Infrared Thermography Various tissues can be distinguished from each other by their differences in metabolism and subsequent temperature. Such differences in temperature—though frequently miniscule—provide differences in emission of infrared radiation. With the capability of infrared radiation to penetrate through deeper tissues, imaging using infrared cameras appears to be a logical approach for visualization of extrahepatic bile ducts.
Studies performed in pigs demonstrated that imaging systems detecting emitted light in the midinfrared range between 3000 and 5000 nm, capable of detecting differences up to 0.1°C, were able to reliably visualize the common hepatic duct and cystic duct in a small sample of animals undergoing laparoscopic23,24 or open operations.25,26 Because of limited spatial resolution and small differences in infrared radiation, the provided images were not as clear as would be preferred in the clinical setting. Current limitations in resolution, however, have a potential to resolve with upcoming newer technology. To improve imaging with infrared thermography, 2 studies additionally utilized contrast-enhanced infrared thermocholangiography during open operations to provide visualization of the extrahepatic biliary anatomy after intrabiliary injection with cold saline in a porcine model.25,26 Whereas visualization of the common hepatic ducts and cystic ducts were mildly improved by administering the contrast, there were again some limitations because of blurred images based on lower spatial resolution in infrared imaging compared with white-light imaging. The limited resolution was enhanced by fusing infrared and white-light images.25 However, the need for cannulation of bile ducts for contrast administration and its timely temperature equilibration limits the duration of contrast enhancement and, therefore, does not allow realtime imaging of the bile duct during dissection.
Spectral Imaging Within the Visible and NearInfrared Spectrum Although bile itself is a known chromophore, absorbing light within specific ranges of visible light, only a few studies evaluated these wavelength ranges for enhanced visualization of bile through the wall of extrahepatic bile
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ducts. Maitland et al27 demonstrated that human gallbladders, examined spectroscopically immediately after operative resection, have an absorption peak at 410 and 550 nm, which correlates with the absorption peaks of bilirubin as well as hemoglobin. Yet this has not been utilized to enhance visualization of extrahepatic bile ducts. Araki et al28 visualized bile ducts after intravenous injection of ICG in humans. The dye undergoes biliary excretion subsequently providing a blue color to the bile, which can be seen through the wall of the extrahepatic bile ducts under white-light imaging. This has not only the potential to enhance visualization under routine white-light laparoscopy but should even further augment visualization under spectral imaging, separate from the fluorescent properties of the dye utilized in fluorescent imaging. The intravenous administration of dye is also advantageous over the use of typical color dye cholangiography, which injects the dye directly into the biliary tree.29 Taking advantage of the different light absorption profiles of various tissue types in the near-infrared spectrum, Zuzak et al,30 using near-infrared hyperspectral imaging, demonstrated proof of principle in a porcine model. In this study, imaging within the range between 650 and 1100 nm provided good-resolution pictures of the common and hepatic bile duct underneath its coverage of soft tissue.
Discussion Image-enhanced laparoscopy has been around for more than 30 years in the form of isolated experiments.31,32 The true breakthrough has not occurred until very recently, with the rapid development of new imaging technologies, subsequently providing many opportunities for this new frontier to establish itself in routine clinical care. These advanced imaging techniques seem to be a good fit for the ongoing clinical problem of bile duct injury during laparoscopic cholecystectomy and during other operations near the hepatic hilum. Bile duct injuries during laparoscopic cholecystectomy are thought to occur after incorrect visual assumptions are being made on the underlying anatomy,33 a direct result of incomplete visualization of the extrahepatic bile ducts. Reliable visualization of bile ducts, therefore, seems imperative; image-enhanced laparoscopy has the potential to provide improvements. Despite the advances in technology, use of imageenhanced laparoscopy techniques for real-time visualization of extrahepatic bile ducts is still in its infancy. A lack of larger human trials is obvious across the board. From the available feasibility studies performed in animals or small human trials, there is currently no definitive technique available that is reliable and easy to use. ICGenhanced near-infrared fluorescence laparoscopy appears promising because it seems to have the most mature
results. The cumulative results from current reports, derived from smaller study populations, do show favorable results in correctly identifying the common hepatic, cystic, and common bile duct without the need for dissecting the tissues or cannulating the bile duct. However, difficulties seem to occur when trying to visualize the main hepatic ducts. Particularly, visualization of the right hepatic duct would be of benefit during laparoscopic cholecystectomy. Blood vessels are only vaguely visualized because the contrast has to clear from the blood stream before being excreted by bile, which is crucial because visualization of blood vessels could create confusion with the biliary system. The most important advantage of imaging in the near-infrared spectrum is its capability to penetrate much deeper through tissue than visible light, providing images of structures hidden below the surface. Laboratory models demonstrated that fluorescence of ICG detected at 830 nm can penetrate up to 3 cm of solution known to mimic tissue scattering properties.34 This depth of penetration is definitely more than the depth of soft tissue typically found surrounding the extrahepatic bile ducts in humans. However, because, in principle, near-infrared light can travel through a wide range of depths before being scattered back out of the tissue and detected by the camera, the effective depth of field of the acquired images is very long, resulting in a decrease in the sharpness of the image features of interest. Future developments aimed at achieving some level of depth resolution could improve on the quality of these images.35 All the other image-enhanced techniques described for visualization of bile ducts do not seem to have been tested to the extent of ICG-enhanced near-infrared fluorescence laparoscopy. Autofluorescence imaging demonstrated very promising results. However, so far, it has only been tested in an animal model, which may not entirely represent the situation in humans. Particularly, the thickness of soft tissue surrounding the bile duct seems to be more extensive in humans, potentially making it more difficult to visualize the bile duct in humans. Also, laparoscopic imaging with its expected reduction in efficiency of exciting and/or detecting fluorescent light might provide different imaging properties from the open technique tested. Infrared thermography theoretically penetrates tissues deeper than any other method tested. But current methods relying on simple illumination/detection schemes have even more limited resolution than near-infrared-based imaging approaches because light in this wavelength regime can traverse even longer paths within the tissue before being detected. In addition, the sensitivity of the cameras is not very high in this spectral range, resulting in reduced signal-to-background ratio. And there is a potential of confusing blood vessels with bile ducts. Attempts have been made using contrast-enhanced infrared thermography trying to compensate for some of these
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Schnelldorfer et al limitations. The imaging results are improved, but cannulation of the bile duct is required to administer the thermal contrast, and there is timely temperature equilibration practically eliminating real-time imaging during the majority of surgical dissections. Spectral imaging has promising features but has not been tested enough to provide any conclusion. In summary, to minimize the risk of bile duct injury during laparoscopic operations through correct visual recognition of extrahepatic bile ducts “hidden” underneath connective tissue, it seems promising that, in the future, image-enhanced laparoscopy might become a routine adjunct to any white-light laparoscopic operation near the hepatic hilum. Apart from some minor additions to the existing equipment, image-enhanced laparoscopy usually does not require any major resources. Which specific technique will provide the best results is yet to be determined. In the currently available studies, the most advanced results available are for ICG-enhanced nearinfrared fluorescence laparoscopy, but other techniques also appear promising. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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