Laparoscopic Thermal Cholangiography: A novel technique for biliary imaging

Principal Investigator:

Jonathan Pearl, MD Assistant Professor Department of Surgery University of Maryland School of Medicine Baltimore, MD 21230 [email protected]

Total Funding Requested: $30,000

Statement of Funds

There are no funds for this or related projects pending or available through other sources.

Summary

There have been few recent advances in advanced imaging for laparoscopic surgery. Generating novel methods of defining anatomy and augmenting surgeons’ capabilities is critical to improving patient outcomes. This is especially germane in laparoscopic cholecystectomy where cholangiography has been shown to reduce bile duct injury rates by 50%, yet surgeons perform cholangiography in less than half of cases. Thermal imaging is an available technology that has not yet been employed in surgery. Using a thermal camera, we have performed a pilot project showing that thermal cholangiography clearly demonstrates biliary anatomy. The images are similar to fluoroscopic cholangiograms yet require only the injection of saline and a handheld thermal camera. We propose a series of ex vivo experiments to optimize the conditions of thermal cholangiography and compare the accuracy of thermal cholangiograms with fluoroscopic cholangiograms. We will use ex vivo porcine specimens in a temperature-controlled box trainer model. Specifics such as temperature of infusate and type of infusate will be tested. Next, thermal images will be compared to fluoroscopic images for the detection of choledocholithiasis and bile duct injury. The final set of experiments will examine whether motion detection software augments the surgeons’ ability to detect leaks or stones. These experiments will build on our pilot project and establish whether thermal cholangiography can yield information equivalent to fluoroscopy. Subsequent studies will test thermal cholangiography against fluoroscopic cholangiography in the clinical setting. The ultimate goal of these studies is to provide a simple and effective method for performing intraoperative cholangiography, thereby broadening its use and improving patient outcomes.

Background

Imaging is critical to the safe and effective conduct of laparoscopic operations. Current imaging technology uses high definition cameras with three charge coupled devices (CCDs). While high definition 3-CCD cameras provide reliable images, there have been few recent advances in laparoscopic imaging capabilities. Surgeons have a need for an imaging technique that augments their capability to delineate anatomy1,2. This is most evident for intraoperative cholangiography. In the United States there are over 750,000 laparoscopic cholecystectomies performed annually. Bile duct injury occurs in 0.4% of those cases3, mainly due to confusion regarding anatomy4,5. Biliary injury can be devastating to patients, surgeons, and the health care system. Patients who suffer bile duct injury require major reconstructive surgery, experience severe morbidity, and have a one-year mortality rate of 6%6. Bile duct injury is a frequent source of litigation against surgeons and hospitals, and the injury costs the United States health care system 1 billion dollars per year in patient care expenses and litigation costs7. By clarifying anatomy, intraoperative cholangiography reduces bile duct injury by 50%8-10, yet is it performed in less than half of laparoscopic cholecystectomies11. There are several barriers to pervasive intraoperative cholangiography12: Standard fluoroscopic cholangiography can be cumbersome, time consuming, and receives low reimbursement. Intraoperative ultrasound is an alternative, but this requires specialized training in image interpretation and has not been widely adopted. Near infrared fluorescence cholangiography is a newer technology, but it requires an expensive device and intravenous injection of a fluorescent agent. Thermal imaging is a solution to expand the use of intraoperative cholangiography during laparoscopic cholecystectomy. Thermal cameras detect differences in temperature to generate an image. Thermal imaging is simple to perform, inexpensive, and can be overlain with standard images to provide surgeons with augmented reality. Although widely used in the military, law enforcement, and environmental sciences, thermal technology has not yet impacted the field of medicine In conjunction with InnoVital Systems, Inc., we have developed a thermal endoscope for laparoscopic surgery. The thermal endoscope uses a commercially available thermal camera which has been modified to use in laparoscopy. The handheld device is controlled by the surgeon and requires no additional personnel to operate. A real-time image is projected onto a monitor for contemporaneous interpretation. We have performed thermal cholangiograms on porcine specimens and the results have been favorable (see figure below). To perform the thermal cholangiogram, we injected cold saline into the gallbladder. The thermal image clearly delineated the anatomy and detected a leak in the biliary tree. In our pilot project, thermal cholangiography was simple to perform and easy to interpret.

catheter

gallbladder leak

Bile duct

a b c

Figure. (a) Thermal cholangiogram in porcine specimen. Gallbladder and bile duct incompletely filled with cool saline (b) Thermal cholangiogram with complete filling of gallbladder and bile duct clearly demonstrating anatomy (c) Image after puncture of gallbladder clearly showing saline leaking from organ, indicating a breach in the integrity of the wall.

Thermal imaging may be a means of increasing use of intraoperative cholangiography, with the attendant improved patient outcomes. It is a simple and inexpensive technology which can augment surgeons’ visualization. Expanding the penetrance of intraoperative cholangiogram will reduce the incidence of bile duct injury, improve outcomes, and reduce health care costs.

Hypothesis

This study will investigate the capabilities of the thermal endoscope for laparoscopy to image the biliary tree using an ex vivo porcine model. Thermal imaging will be compared to the current gold-standard, fluoroscopy. This study will focus on one hypothesis: Thermal cholangiography is equivalent to fluoroscopic cholangiography for defining biliary anatomy, detecting filling defects, and identifying leaks in the biliary tree.

Methods

This study will build on the proof-of-principle study we conducted showing the feasibility of thermal cholangiography. The goal of the current study is to optimize the technique of thermal cholangiography and determine its ability to provide clinically relevant information prior to embarking on large animal studies and a clinical trial. Per scientific standards, these laboratory experiments will be completed in quintuplicate to ensure their validity. Post hoc image analysis will be independently performed in triplicate. Power analysis and sample size assessment are not essential for these laboratory experiments. Aim 1: To establish the basic principles of thermal cholangiography using an ex vivo porcine model.

Rationale: Thermal imaging in laparoscopy is a novel technology which has not been thoroughly investigated. Establishing the basic principles is therefore needed to advance the technique. The optimal temperature differential between target tissue and infusate, fluid type for infusate, and distance between target tissue and scope will be determined in this aim. Methods: An ex vivo porcine cholangiogram model will be used. Intact porcine biliary trees will be secured in an enclosed laparoscopic box trainer. An air- warming device will maintain the system at a constant 37°. The thermal endoscope for laparoscopy will be used to obtain the images. Establishing optimal temperature differential: Thermal imaging relies on temperature differentials to generate an image. The most distinct image is produced when the temperature variances are large. This may not be practical in the clinical setting when infusing fluids to establish the temperature differential. Excessively cold fluids may induce hypothermia and hot fluids may cause injury. Thermal cholangiograms will be conducted using saline at various temperatures with the goal of determining precisely how much variance between body temperature (37°) and fluid temperature is necessary to generate an adequate image. Five cholangiograms will be performed with each of the following saline temperatures: 10°, 15°, 20°, 22° (room temperature), 25°, 30°, 32°, 34°, 36°, 38°, 40°, 45°, and 50°. The thermal images will be captured and scored post hoc by 3 surgeons using a 5-point Likert scale for the following data points: visualization of gallbladder, visualization of cystic duct, visualization of hepatic ducts, visualization of common bile duct, visualization of duodenal filling. A rating of 5 on the Likert scale will be equivalent to a clear, well-performed fluoroscopic cholangiogram. Such an image will be provided to reviewers to use as a benchmark. Establishing optimal fluid for infusate: One of the long-term goals of thermal imaging is as an imaging method in austere environments. Establishing if simple fluids, such as tap water, are adequate for thermal cholangiography is important for such conditions. In this experiment we will determine whether type of fluid influences quality of the thermal image. The above model will be used with fluid at the optimal temperature, as established above. Five cholangiograms will be performed using each of the following fluids: 0.9% normal saline, 3% saline, lactated ringers, tap water. The cholangiograms will be scored by 3 surgeons, as noted above. Establishing optimal distance between thermal laparoscope and target tissue: The standard practice in cholangiography is to collect the image with the entire biliary tree in view. At times, a focused image is required to scrutinize certain findings. In this experiment we will establish whether these techniques are practicable in thermal imaging. We will use the above model. 5 thermal cholangiograms will be performed with the endoscope at the 1 cm intervals from the target tissue. The images will be scored by 3 surgeons on a 5 point Likert scale for image clarity. Aim 2: To compare the results of thermal cholangiography with fluoroscopic cholangiography using an ex vivo model.

Rationale: For thermal cholangiography to have clinical utility, its results should be equivalent to the most commonly used intraoperative cholangiography technique: fluoroscopy. For this aim, the ability of thermal cholangiography to define biliary anatomy, detect filling defects, and detect injuries to the biliary tree will be compared to fluoroscopic cholangiography. An ex vivo model is an appropriate initial platform to compare thermal to fluoroscopic cholangiography, as it eliminates the use of live animals and provides similar data. Methods: The box trainer cholangiogram model used in Aim 1 will be used for Aim 2, and the principles of thermal cholangiography established in Aim 1 will be applied. Fluoroscopic cholangiograms will be performed using an iodine-based positive contrast agent and a C-arm. The images will be compared. Defining biliary anatomy: Five separate ex vivo specimens will be used for both thermal and fluoroscopic cholangiograms. The images will be captured and post hoc evaluation will be performed by 3 surgeons. The images will be scored for the following metrics using a 5 point Likert scale: visualization of cystic duct, intrahepatic ducts, common duct; and flow into duodenum. Visualization of filling defects: Simulated gallstones will be inserted into the biliary trees of 5 separate specimens. Different size stones in various locations will be used. Thermal and fluoroscopic cholangiograms will be performed and captured for each specimen. Post hoc evaluation will be performed as above and scored for accuracy in location and size of filling defects. Detecting biliary injuries: The following biliary injuries will be created in 5 ex vivo specimens: lateral injury to the common duct, transection of the right hepatic duct, transection of the left hepatic duct, transection of the common duct, and clip application to the common duct without transection. Thermal and fluoroscopic images will be obtained. Post hoc evaluation will be scored for ability to accurately define biliary injuries. Aim 3: To determine whether motion detection software aids in detection of bile duct stones and biliary injuries during thermal cholangiography.

Rationale: InnoVital Systems, Inc. produces commercially available motion detection software. Its principal use is during military surveillance. Motion detection software may augment the capabilities of surgeons by detecting subtle changes not visible to the human eye. This may be an additional tool in augmenting surgical capabilities through imaging technology. Methods: The ex vivo porcine cholangiogram model with stones and bile leaks will be used. Five different stone models and 5 different bile leak models will be used. Thermal cholangiograms will be performed under optimal conditions as established in Aim 1. Thermal imaging will be supplemented with motion detection software. The software will identify areas of motion and stasis, equivalent to leaks and stones. The images will be stored and evaluated post hoc by 3 separate surgeons for presence and location of stones, and presence and location of bile injuries. The results of computer detected stones and leaks will be compared with surgeon interpretation of images to determine reliability of motion detection software for aiding the detection of biliary pathology. Milestones

Item Description M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 Develop temperature-controlled 1 box trainer Temperature, fluid and distance 2 testing Image review and data 3 interpretation for Aim 1 Thermal vs fluoro 4 cholangiography experiments Image review and data 5 interpretation for Aim 2

6 Motion detection experiments Image review and data 7 interpretation forAim 3

8 Presentation preparation Manuscript prepration and 9 submission Potential Obstacles and Strategies for Mitigation

Thermal imaging is a novel strategy for bile duct imaging that has not yet been used clinically. However, thermal imaging may simply replicate the findings of near-infrared fluorescence cholangiography. We believe that thermal imaging holds several advantages over near-IR fluorescence: it is less expensive, can be directly incorporated into a laparoscope without additional equipment, and does not require injection of a fluorophobe. Furthermore, near-IR technology has been available for several years, and fluorescence cholangiography is rarely employed today. As with any experiment, there is the risk that the results will not be favorable. In this case, we have performed a pilot project which shows the feasibility of thermal cholangiography. We have not yet tested whether stones will be detectable on thermal imaging. It is possible that filling defects will be not visible on thermal imaging, which will negate the clinical utility of the technology. We are prepared to find other clinical uses of the technique, such as thermal enterography or tumor detection, should cholangiography be ill-suited for thermal imaging.

Budget

NAME POSITION TITLE TIME/EFFORT SALARY FRINGE BENEFITS SUB-TOTALS % Hrs/ Week Jonathan Pearl Principal Investigator* 5 4 Sheree Carter Chase Simulation Trainer 5 2 70,000 28,700 4935 CONSULTANT COSTS

EQUIPMENT Thermal endoscope for laparoscopy (InnoVital Systems, Inc); Motion detection (List all Items&Total Equipment Cost) software (Innovital Systems, Inc) 18,000 SUPPLIES Porcine specimens, contrast agents, air warmer, (List all Items&Total Supplies Cost) 5065 TRAVEL** 1000 PATIENT CARE COSTS CONSORTIUM/CONTRACTUAL COSTS OTHER EXPENSES Fluoroscopy time (10 hours at $100/hour) (List all Items & Total Cost) 1000 TOTAL DIRECT COSTS 30,000

References

1. Hughes-Hallett A, Mayer EK, Marcus HJ, et al. Augmented Reality Partial Nephrectomy: Examining the Current Status and Future Perspectives. Urology. Oct 19 2013. 2. Marzano E, Piardi T, Soler L, et al. Augmented reality-guided artery-first pancreatico-duodenectomy. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. Nov 2013;17(11):1980-1983. 3. Waage A, Nilsson M. Iatrogenic bile duct injury: a population-based study of 152 776 cholecystectomies in the Swedish Inpatient Registry. Archives of surgery. Dec 2006;141(12):1207-1213. 4. Strasberg SM. Avoidance of biliary injury during laparoscopic cholecystectomy. Journal of hepato-biliary-pancreatic surgery. 2002;9(5):543-547. 5. Strasberg SM. Error traps and vasculo-biliary injury in laparoscopic and open cholecystectomy. Journal of hepato-biliary-pancreatic surgery. 2008;15(3):284-292. 6. Sinha S, Hofman D, Stoker DL, et al. Epidemiological study of provision of cholecystectomy in England from 2000 to 2009: retrospective analysis of Hospital Episode Statistics. Surgical endoscopy. Jan 2013;27(1):162-175. 7. Carroll BJ, Birth M, Phillips EH. Common bile duct injuries during laparoscopic cholecystectomy that result in litigation. Surgical endoscopy. Apr 1998;12(4):310-313; discussion 314. 8. Buddingh KT, Nieuwenhuijs VB, van Buuren L, Hulscher JB, de Jong JS, van Dam GM. Intraoperative assessment of biliary anatomy for prevention of bile duct injury: a review of current and future patient safety interventions. Surgical endoscopy. Aug 2011;25(8):2449-2461. 9. Buddingh KT, Weersma RK, Savenije RA, van Dam GM, Nieuwenhuijs VB. Lower rate of major bile duct injury and increased intraoperative management of common bile duct stones after implementation of routine intraoperative cholangiography. Journal of the American College of Surgeons. Aug 2011;213(2):267-274. 10. Sheffield KM, Riall TS, Han Y, Kuo YF, Townsend CM, Jr., Goodwin JS. Association between cholecystectomy with vs without intraoperative cholangiography and risk of common duct injury. JAMA : the journal of the American Medical Association. Aug 28 2013;310(8):812-820. 11. Sheffield KM, Han Y, Kuo YF, Townsend CM, Jr., Goodwin JS, Riall TS. Variation in the use of intraoperative cholangiography during cholecystectomy. Journal of the American College of Surgeons. Apr 2012;214(4):668-679; discussion 679-681. 12. Massarweh NN, Devlin A, Elrod JA, Symons RG, Flum DR. Surgeon knowledge, behavior, and opinions regarding intraoperative cholangiography. Journal of the American College of Surgeons. Dec 2008;207(6):821-830.

Local/Institution Review Board

This study will not require approval from the IRB. Since it is using ex vivo specimens, rather than live animals, IACUC approval is not necessary. Available Resources

All research will be conducted at the University of Maryland Medical Center in the Maryland Advanced Simulation, Training, Research, and Innovation (MASTRI) Center. The MASTRI Center is a 3500 square foot facility used for simulation training, education, and research at the University of Maryland School of Medicine and Medical Center. The facility consists of four decommissioned operating rooms that can be reconfigured to meet the needs of learners and researchers. The decommissioned operating rooms are lead-lined to support fluoroscopy and are authorized for training and research on ex vivo animal models. Personnel at the MASTRI Center include a simulation educator, a simulation training specialist, and two simulation technicians. A full array of laparoscopic box trainers and instrumentation are available for use. The principal investigator serves as the Medical/Surgical Director of the MASTRI Center.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME POSITION TITLE Jonathan P. Pearl, MD Assistant Professor of Surgery eRA COMMONS USER NAME (credential, e.g., agency login) jpearl EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION (if applicable) MM/YY FIELD OF STUDY Wayne State University School of Medicine, MD 06/99 Medicine Detroit, MI

Residency 06/05 General Surgery National Naval Medical Center, Bethesda, MD

Advanced laparoscopy Case Western Reserve University School of Fellowship 06/07 and endoscopy Medicine, Cleveland, OH

A. Personal Statement

The goal of the proposed research is to examine the capabilities of a thermal laparoscope to image the biliary tree. The research will be performed in a simulation laboratory with ex vivo porcine models. I have vast experience in biliary imaging and simulation. During my fellowship in advanced laparoscopy and endoscopy I performed over 200 cholangiograms. I have continued with the practice of cholangiography during the next 6 years of surgical practice. While I am facile with the technique, I have observed surgeons in several institutions struggling with cholangiography. It is my goal to simplify the procedure and increase the use of routine cholangiography.

I currently serve as the Medical Director of the Maryland Advanced Simulation, Training, Research, and Innovation Center. The MASTRI Center is well prepared to conduct the type of research proposed. The supplies and equipment are readily available, and the necessary personnel are in place.

In conjunction with InnoVital Systems, I have developed a thermal endoscope for laparoscopy. While currently in its pre-commercial phase, the thermal endoscope is slated to be available for purchase within 2 years.

As a practicing surgeon with a keen interest in patient safety, I am always looking for techniques that would improve patient outcomes. The thermal endoscope has the potential to augment surgical imaging capabilities and improve patient outcomes. This grant will help to establish thermal cholangiography as a useful tool and allow it to proceed into clinical trials.

B. Positions and Honors

Positions and Employment 1999-2005 Resident, General Surgery, National Naval Medical Center, Bethesda, MD 2005-2006 Ship’s Surgeon, USS GEORGE WASHINGTON, Norfolk, VA 2006-2007 Fellow, Advanced Laparoscopy and Endoscopy, Case Western Reserve School of Medicine, Cleveland, OH 2007-2012 Assistant Professor of Surgery, Uniformed Services University, Bethesda, MD 2007-2012 Staff Surgeon, National Naval Medical Center, Bethesda, MD 2012-present Assistant Professor of Surgery, University of Maryland School of Medicine, Baltimore MD 2012-present Chief, Perioperative Services, VA Medical Center, Baltimore, MD 2013-present Chief, General Surgery, VA Medical Center, Baltimore, MD

Other Experience and Professional Memberships 2008-2011 Councilor, Washington, DC Chapter, American College of Surgeons 2008-2011 Chair, Young Surgeons Committee, DC Chapter, American College of Surgeons 2008-present Member, SAGES FES Task Force and SAGES Guidelines Committee 2009-present Ad hoc reviewer, Surgical Endoscopy 2013 Member, Association of Academic Surgeons Publications Committee

Honors 1995 Phi Beta Kappa, University of Michigan 2004 First Prize, Surgical Residents Competitive Forum, DC Chapter, ACS 2005 Winner, Harry B Zehner Traveling Fellowship, DC Chapter, ACS 2013 Resident Teaching Award, University of Maryland Dept of Surgery

C. Selected Peer-Reviewed Publications Most relevant to the current application

1. Ritter EM, Cox TC, Trinca KD, Pearl JP. Simulated colonoscopy objective performance evaluation (SCOPE): a non-computer-based tool for assessment of endoscopic skills. Surg Endosc. 2013. 2. Crane NJ, McHone B, Hawksworth J, Pearl JP, DeNobile J, Tadaki D, Pinto PA, Levin IW, Elster EA.Enhanced surgical imaging: Laparoscopic vessel identification and assessment of tissue oxygenation. J Am Coll Surg. 2008 Jun;206(3):1159-66.

3. Pearl JP, Wind GG, Ritter EM. A meandering external iliac artery: Potential doom outside the triangle. J Am Coll Surg 2009. 208(3): 478-9.

Selected peer-reviewed publications

1. Pearl JP, Ponsky JL. Natural Orifice Translumenal Endoscopic Surgery: A critical review. J Gastrointest Surg 2007;

2. Pearl JP, Marks JM. The future of teaching surgical endoscopy. Surg Innov. 2006; 13(4)

3. Nikfargam M, McGee MF, Trunzo JA, Onders RP, Pearl JP, Poulose BK, Chak A, Ponsky JL, MarksJM. Transgastric natural orifice transluminal endoscopic surgery peritoneoscopy in humans: a pilot study in efficacy and gastrotomy site selection by using a hybrid technique. Gastrointest Endoscopy. 2010; 72(2): 279-83.

4. Marks JM, Ponsky JL, Pearl JP, McGee MF. PEG Rescue—A practical NOTES technique. Surg Endosc 2007. 21(5): 816-9.

5. Ponsky LE, Poulose BK, Pearl J, Ponsky JL. Natural orifice translumenal endoscopic surgery: reality or myth? J Endourol. 2009; 23(5); 733-5.

D. Research Support

None

Participation in SAGES

The principal investigator, Jonathan Pearl, has been a member of SAGES since 2005. He has been a member of the Guidelines Committee and the FES Taskforce since 2008. Jonathan has served as faculty at the SAGES basic laparoscopy course in Cincinnati and the fellows’ endoscopy course in Cleveland. In addition, Jonathan has given both oral and poster presentations at SAGES annual meetings. His dedication to SAGES is evident in his participation in the upcoming annual meeting as lead for the FES section in the Learning Center and faculty for the Laparoscopic CBD exploration course.

Disclaimer

Jonathan Pearl has no financial interest in InnoVital Systems, Inc. There is a patent pending for the thermal endoscope for laparoscopy. The provisional patent is held by the University of Maryland, Baltimore.