"EP Method" of Intra-Ureteral Indocyanine Green Injection by Gynecologists: Strategy to Prevent Inadvertent Ureteral Injury in Complex Laparoscopic/Robotic Gynecologic Surgeries

Intraoperative ureteral injury is a known complication of gynecological surgery, which can lead to significant morbidity and legal implications if not detected during surgery.[ 1 2 ] A few studies have reported an overall incidence of 0.35%–1.5% in major pelvic operations.[ 3 4 ] 1.1%–1.5% during a hysterectomy,[ 5 6 ] 0.3%–0.5% after laparoscopic[ 3 4 ] and 0.4% with robotic surgery.[ 7 ] A 2018 systematic review, including 433 studies representing 140,444 gynecologic laparoscopic surgeries for benign indications, reported 458 lower urinary tract injuries, with an incidence of 0.33%.[ 8 ] In a retrospective review involving 3114 hysterectomies, the rate of ureteral injury of robotic hysterectomy (7/1088, 0.64%) was similar to laparoscopic (4/782, 0.51%), vaginal (1/304, 0.33%), and abdominal hysterectomy (5/940, 0.53%).[ 9 ] Complex pelvic surgery can render laparoscopic identification and dissection of the ureter difficult and risky. Risk factors for ureteral injury include cancer, hemorrhage, severe and deeply infiltrating endometriosis, adhesions, and large uterine mass.[ 7 10 ] The most common sites of injury are at the pelvic brim, where the ureter crosses the iliac arteries; the broad ligament, where the uterine artery crosses the ureter during hysterectomies; the cardinal ligament near the cervix; the ureterovesical junction, where the ureter enters the bladder, and the infundibulopelvic ligament during oophorectomy.[ 5 6 11 ] Types of injury include ligation, crush, laceration, avulsion, stretch, thermal, and devascularization.[ 6 11 ] In a 2018 systematic review,[ 8 ] the highest incidence of ureteral injury was found in endometriosis resection (0.4%, 95% CI 0.3–0.6), followed by laparoscopically assisted vaginal hysterectomy (0.2%, 95% CI 0.2–0.3) and laparoscopic hysterectomy not otherwise specified (0.2%, 95% CI 0.1–0.6). Thermal injuries from pelvic dissection with electrocautery were the most common cause of ureteral injury (33%), and lysis of adhesions was the most common cause of bladder injury (23%).[ 8 ] However, in over 40% of all ureteric injuries, no predisposing factors can be identified, and the surgery performed is described as routine.[ 12 ] Ureteric injury can lead to significant patient morbidity, including an irreversible loss of renal function, leading to chronic renal failure and the loss of a kidney. This is particularly true when the injury is not recognized and acted upon promptly. The diagnosis could be missed intraoperatively and detected late postoperatively, as it most commonly presents with loin pain, pyrexia, fistula, or nonspecific signs that might necessitate reoperation and risk of medical litigation.[ 11 ] Consequently, ureteral injury is invariably perceived by patients and their families as substandard surgical care, which provokes potential or actual ligation. Preoperatively, a careful evaluation of the patient’s gynecological disease and risk of genitourinary injury is paramount, especially in cases of deeply infiltrating endometriosis, large uterine mass, and those with previous surgery. Preoperative magnetic resonance imaging and pelvic ultrasound are equally sensitive and highly predictive.[ 13 ] They are beneficial in identifying the course of the ureters and detecting the involvement of the bladder and pelvic ureters in severe endometriosis. This information is essential in counseling the patient before surgery on the extent of the surgery, anticipating difficulty, and early multidisciplinary involvement. Intraoperatively, the most classic means of preventing advertent ureteral injury is observation using anatomic landmarks and vermiculating/peristaltic movement of the ureter through the peritoneum. However, the course of the ureter might not be readily visible when the pelvic anatomy is severely compromised due to the disease, adhesions, or bloody operative field. If pelvic dissection is anticipated, preoperative double-J stents are inserted to prevent ureteral damage.[ 14 ] A 2020 meta-analysis[ 15 ] reported lower ureteral injury rates for patients undergoing prophylactic ureteral catheterization than those without. However, this is expensive and too difficult for the gynecologist to perform, so a referral to the urologist is required. Furthermore, it is not without risk of complications, e.g., infection and postoperative discomfort, increased frequency, and hematuria. In addition, no evidence supports that stent insertion prevents ureteral damage in the gynecologic field. Therefore, their routine use as a prophylactic measure remains debatable. Indocyanine green (ICG) has been used for over 60 years in various medical applications and recently in gynaecologic conditions.[ 16 17 18 19 20 21 ] If injected intravenously, it can assess tissue vascularization. It has been proven a valuable tool to identify sentinel lymph nodes during surgical staging for several cancers (melanoma, prostate, rectal, or endometrial).[ 22 23 24 ] For benign conditions, ICG can be used as a guide during endometriosis surgery, facilitating intraoperative diagnosis of occult peritoneal and deep endometriotic lesions, evaluation for anastomotic perfusion assessment after resection of rectosigmoid or ureteric endometriosis, and assist the surgeon’s intraoperative decision. If injected into the ureter, it is helpful for the ureteral evaluation, allowing intraoperative ureteral visualization to reduce the risk of ureteral injury during gynecologic surgery.[ 25 26 27 ] ICG is a water-soluble tricarbocyanine dye that binds to lipoproteins and has a peak absorption wavelength of 805 nm, which makes it ideal for near-infrared (NIR) fluorescence imaging. ICG use is safe, with a dose of 0.1–0.5 mg/mL/kg for clinical use.[ 28 ] The dye is rapidly excreted by the liver into bile without known toxicity. The fluorescence released by the ICG can be detected intraoperatively almost immediately using a specifically NIR light-equipped camera system at the beginning of the surgery, and it typically lasts more than 5 h.[ 27 29 ] Its fluorescence effects allow real-time visualization of the anatomic location of both ureters and possibly reduce the risk of accidental injury in complex gynecological surgery. In most centers, ureter catheterization is considered a urological procedure and often requires a urologist’s presence, who is not always readily available. Conventional ureteral stents or illuminated ureteral catheters might not be cost-effective, time-consuming, or beneficial in some cases, especially for routine use in prophylaxis indications. If ureteral catheterization and intraurethral ICG injection could be made simple and safe for the gynecologist to perform, their routine use in complex procedures using the NIR imaging system could spare many ureters not only from the risk of advertent injury but also from delayed detection injury, which might result in loss of renal function and risk of medical litigation. Thus, this study aims to demonstrate the outcome of the simplified and safe retrograde intra-ureteral ICG injection by the gynecologic surgeon as a routine procedure in complex laparoscopic/robotic gynecological surgery. If the course of retroperitoneal ureters could be visualized in real-time and their limits of involvement could be readily identified during complex surgery, ureteral complications from complex pelvic surgery could be avoided.

Over 1 year, from March 1, 2023 to March 30, 2024, a single surgeon at Gleneagles Hospital Johor performed 110 cases of ICG-guided complex gynecological surgery [ Table 1 ]. The mean age of the patients was 41.3 years, with a mean BMI of 26.4 kg/m 2 . About 63 cases were severe endometriosis of various spectrums, 40 were of large or complicated uterine mass, and eight were early cervical[ 2 ] and uterine[ 10 ] malignancies. More than one-third of the cases (44%) were complicated by adhesive disease from a previous surgery, and half of them were contributed to by exploratory laparotomy. Eighty-two cases were performed using 3D laparoscopy using Rubina® (Karl Storz) – 4K, 3D, NIR camera system, and another 28 cases were performed robotically using Da Vinci SI Surgical System. In all 110 cases, intra-ureteral ICG injection was performed by the primary operating gynecologist at the beginning of the complex laparoscopic or robotic-assisted surgery as a routine procedure. A total of 25 mg of ICG (5 mg/ml) was injected into the right and left ureters, respectively, using an epidural catheter at a depth of 150–200 mm from the ureteral orifice, with the tip positioned at the level of the pelvic brim. Patients’ characteristics ( n =110) *Additional procedures accomplished along with laparoscopic/robotic cystectomy or hysterectomy. DIE: Deeply infiltrating endometriosis, BMI: Body mass index, 3D: Three-dimensional, BSO: Bilateral salphingo-ophorectomy, PLND: Pelvic lymph node dissection In 107 cases (97%), the primary gynecologist successfully completed the procedure without difficulty, complications, or the need for a urologist’s assistance [ Table 2 ]. Excluding the three cases referred to a urologist for ureteric stenting and ICG injection, the mean duration of the ICG injection using the epidural catheter method by the gynecologist was 2.2 min, with a minimum time of 1.2 min and a maximum of 3.6 min. The procedure was described as straightforward and easy to learn. Surgical outcomes of retrograde Indocyanine green injection into the ureters ICG: Indocyanine green, SD: Standard deviation, EBL: Estimated blood loss, DOS: Duration of the surgery, LOS: Length of stay, NS: Not significant The visibility of the ureters using ICG was 100% throughout the surgeries. In a few cases where the ureter was not readily visible due to thickened peritoneum, extensive disease, or a bloody operative field, partial or complete ureterolysis was performed to enhance ureteral visibility. The procedure had no impact on the total operating time, EBL, or overall length of hospital stay. There were no difficulties or complications in the majority of cases. However, in three cases (3%), intraoperative referral to a urologist was required for ureteral stenting. One case involved failure of catheterization due to ureteric stricture, while the other two involved hydronephrosis and bladder endometriosis, necessitating ureteral double-J stenting by the urologist as part of a multidisciplinary approach. There were three cases of near-miss inadvertent ureteric injury [ Table 3 ]. Description of cases of near-miss ureteral injury DIE: Deeply infiltrating endometriosis, BMI: Body mass index, 3D: Three-dimensional The first case involved a hysterectomy for a large uterine mass. The ureter, highlighted by ICG fluorescence, was inadvertently caught in a tie with the left ascending branch of the uterine artery at a pedicle located where the artery crossed the ureter below the isthmus of the uterus. The issue was promptly identified and the tie was released before the pedicle was transacted. The second case involved a hysterectomy for severe endometriosis affecting the right ureter before it entered the ureteric tunnel. The ureter was displaced from its anatomical position, medially adhered to the lateral border of the right uterosacral ligament and paracervix. Using ICG guidance, complete ureterolysis was performed from the pelvic brim to the tunnel of Wertheim to mobilize the ureter laterally, away from the dissection field. This was done before dividing the right cardinal ligament and uterosacral ligament, followed by colpotomy. The ureter and its limits were clearly identified, safely mobilized, and protected from accidental injury during dissection, coagulation, and colpotomy. The third case was a robotic excision of deeply infiltrating endometriosis, where an extrinsic endometriotic fibrous band was found twisting and constricting the left ureter on the pelvic sidewall before it was crossed by the left uterine artery. This caused stricture and left a hydroureter. Guided by ICG fluorescence, the endometriotic fibrous band was meticulously dissected from the highlighted left ureter. The ureter was freed from the constriction without requiring resection or reimplantation. Of 22 cases that required ureterolysis, eight were of radical hysterectomy for early cervical cancer and uterine malignancy, and 14 were of laparoscopic/robotic cystectomy and hysterectomy for severe endometriosis involving the posterior compartment, the ureters, and the bowels. In most non-oncologic cases, partial ureterolysis was done at a specific area where dissection was necessary, unilateral or bilateral, instead of a complete ureterolysis from the pelvic brim down to the bladder and risking the perfusion to the adventitia layer of the ureter and its blood supply from dissection and thermal injury. In cases where complete ureterolysis was necessary, in particular, radical hysterectomy for malignancy, the perfusion of the ureters was readily checked and identified in real-time, and preventive measures were taken immediately. In addition, during complex or radical hysterectomy, ICG-guided fluorescence allowed precise identification of the ureter despite anatomical distortion. This facilitated the accurate localization of the uterine artery, making it significantly easier and faster to trace and ligate it at its origin. Furthermore, in cases with severe adhesions obliterating the ureterovesical fold, ICG fluorescence clearly delineated the bladder limits, enabling safe and effective dissection.

Ureteric injury does not constitute negligence if it is demonstrated that the surgeon provided reasonable and accepted standards of care preoperatively, intraoperatively, and postoperatively. Intraoperative identification of the ureters is paramount in all cases. Retrograde ICG injection into the ureter enables real-time visualization of the ureter and its anatomical location and relationship with the surrounding tissues, thus reducing the risk of accidental ureteral injury in a complex gynecologic surgery by the 3D laparoscopic system or robotically. Our study has demonstrated that it is simple and safe for the gynecologic surgeon to do it as a routine practice. Sharifah Halimah J, Tan Ee Ping–Conceptualization, methodology, data collection, data curation; Sharifah Halimah J, Sufian H–writing, original draft preparation; Yi-Chen Chuang, Peng Teng Chua–writing, review, editing, supervision, and project administration. All authors have read and agreed to the final version of the manuscript. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. There are no conflicts of interest.

The objective of this study was to demonstrate the feasibility and safety of the simplified routine retrograde intra-ureteral ICG injection by the gynecologist without the need to call in the urologist to identify the ureter during laparoscopic/robotic gynecologic surgery for patients at high risk of ureteral injury due to complex pelvic pathologies. The referral to the urologist could be limited to those with some difficulty that requires their expertise, particularly in deeply infiltrating endometriosis directly involving the ureter or the bladder, necessitating resection of the ureter or bladder. Due to the close anatomical relationship between the ureter and the female reproductive organs, injuries to the ureter during complicated pelvic surgery, such as a hysterectomy or surgery for endometriosis, can occur.[ 16 18 19 ] The ureter can become embedded in or displaced by thick adhesions, making it more susceptible to injury during the dissection of the endometriotic tissue, clamping, or coagulating the nearby tissue or vessels.[ 16 20 ] Unilateral or bilateral ureterolysis is often necessary to isolate the ureter from the surrounding tissue, from the pelvic brim down to the ureteric tunnel, and the entrance into the bladder in radical hysterectomy for uterine or cervical malignancy. In our study, where ureterolysis was necessary for the visibility of the ureter by ICG, it was reduced to partial or segmental, where it was directly involved, hence minimizing the risk of necrosis from direct thermal injury or lateral spread and direct stripping of the adventitia and devascularization of the ureter from a complete dissection. It also spares the patient from a complete ureteral catheterization with related complications.[ 17 19 ] The ICG-highlighted ureter is highly distinctive from the surrounding tissue and readily identifiable and confirmed, even in the slightly bloody operative field. It could be helpful to guide the surgeon performing ureterolysis safely, coagulating, suturing, or transecting the uterine artery away from the ureter during hysterectomy, thus increasing the confidence level of the average surgeon performing a complex laparoscopic/robotic hysterectomy. The surgical outcome of our study is consistent with many studies that have investigated the safety and effectiveness of ICG for ureteric identification during laparoscopic/robotic gynaecological surgery.[ 17 22 26 27 29 ] No adverse event was reported from the gynecologist’s ureteric cannulation or the ICG injection. The procedure was fast, easy to replicate, and safe. Wong et al . found that using ICG significantly reduced the incidence of ureteric injury from 4.4% to 0.5%, with no adverse effects related to the use of the dye.[ 26 ] Similarly, in a prospective cohort study of 78 patients who underwent complex gynecological surgery, including sacrocolpopexy and radical hysterectomy, and received ICG for ureteric identification,[ 27 ] they found the use of ICG significantly reduced the risk of ureteric injury and did not cause any adverse events. The result of our study further supports the use of ICG as a valuable tool in complex gynecological surgery to prevent ureteric injury. In a recent analysis of 20 cases of ureteric injury during gynecological surgery in Canada, nine cases were contributed by laparoscopic hysterectomy for the large uterine mass and severe endometriosis. The most common mechanism of injury was from the accidental bite from stapling or ligation of the uterine artery and thermal burn by inadvertent direct coagulation of the ureter or by lateral spread of heat to the ureter.[ 30 31 ] Six cases were litigated, and the rest were under review for potential litigation. In one of the cases, one expert opined that the failure to visually identify the ureter or dissect it before transecting pedicles constituted a breach of the standard of care. In another case, the gynecologists were found to be negligent for not identifying the ureter (either visually or by palpation) before dissecting a retroperitoneal cyst. In the third case, there were dense bowel adhesions and endometriosis scarring that made it more difficult/impossible to identify the ureters, and the case ended with a settlement – likely because of the notion that the gynecologist should have sought intraoperative urology assistance due to the high risk of injury due to adhesions. The lessons learned, and the author’s recommendations for good practice were intraoperative identification of the ureters, urologic consultation, and preoperative stenting to prevent or identify the ureteral injury.[ 30 ] While stenting the ureters is perhaps beneficial for conventional open hysterectomy, it is not only not valuable for the laparoscopic approach but also not cost-effective as a routine practice.[ 32 ] Moreover, it is not without side effects and needs a referral to the urologist, which could lengthen the operative time unnecessarily. Recently, the availability of advanced 3D imaging cameras and robotic systems equipped with NIR light technology has enabled the widespread application of ICG in gynecologic surgery and improved the precision and quality of surgery. Our study has demonstrated that routine intraurethral injection of ICG in a complex gynecologic surgery has averted 3 cases of iatrogenic ureteric injury to a near-miss tragedy. Economically, ICG is cheap and has been proven safe to be injected intra-ureterally or into the bloodstream. The procedure of intra-ureteral ICG injection using the method we referred to as the “EP Method,” as demonstrated in our study of 110 cases, is simple, fast, and easy to learn and to be carried out by the gynecologic surgeons as a routine procedure, and most importantly, it is proven beneficial to prevent inadvertent ureteral injury, replicable and was not associated with any adverse outcome. However, the limitation of this study is that it was single-surgeon data, and reporting bias could not be eliminated. Larger studies involving multiple surgeons from different centers would be invaluable for future research purposes.

The study was conducted in accordance with the Declaration of Helsinki. Institutional Review Board and ethics committee of Gleneagles Specialist Hospital, Iskandar Puteri, Johor, has exempted the ethics review process of this research in view that it involves retrospective analysis. The informed consent was waived by the IRB. This retrospective study focuses on complex laparoscopic and robotic gynecological surgeries performed by a single surgeon at Gleneagles Hospital, Johor, Malaysia. Complex cases were defined by the primary gynecologist as those involving large uterine masses, multiple fibroids, cervical or broad ligament fibroids, deeply infiltrating endometriosis affecting the posterior compartment, bowel, or ureters, endometriomas, a history of adhesive disease or previous pelvic surgery, and malignancies requiring radical hysterectomy. In addition to obtaining consent for the primary surgical procedure, patients were informed and consented to the possibility of an intra-ureteral ICG injection, which the gynecologist might perform preoperatively or intraoperatively as a prophylactic measure to prevent accidental ureteral injury. Referrals to a urologist for prophylactic ureteral stenting with intra-ureteral ICG injection were made preoperatively or intraoperatively under specific circumstances. These included the presence of hydronephrosis, ureteral stenosis, failure of ureteral catheterization, bladder or intrinsic ureteral pathology, or deeply infiltrating endometriosis involving the bladder or ureters that required resection or reimplantation. The urologist was informed to stand by or be called in when necessary. Method: The simplified retrograde intra-ureteral ICG injection procedure is named the “EP Method” (a technique referred to as the EP method, named after the epidural catheter). We used a Betocchi hysteroscope (Karl Storz, 2.9 mm × 5 mm), an epidural catheter (BBraun Perifix®, 0.85 mm × 1000 mm), and ICG (Aurogreen, AUROLAB) [ Figure 1 ]. We used an epidural catheter because its diameter is smaller, 0.85 mm with a soft tip, hence less traumatic, and it has a measuring guide or marking, easily visible through the scope, from the tip; 50 mm (1 line), 100 mm (2 lines), 150 mm (3 lines), and 200 mm (4 lines) to guide the surgeon on the depth or level of entry on the catheter from the ureteral opening [ Figure 2 ]. We used a hysteroscope instead of a cystoscope because it has a smaller operating channel (inner diameter 2.9 mm) and smaller in diameter (outer diameter 5 mm, thus better stability for advancing the epidural catheter into the channel and the ureter without coiling and less patient, discomfort after surgery. The materials and tools for the “EP Method” of retrograde intraureteral indocyanine green (ICG) injection by the gynecologist: the hysteroscope (Karl Storz), and the (BBraun Perifix ® , 0.85 mm × 1000 mm). The proximal tip of the epidural catheter is inserted through the operative channel of the hysteroscope, and the syringe filled with ICG is attached to its distal end. The tip of the epidural catheter is advanced into the ureteral orifice under the view of the hysteroscope to 150 mm–200 mm marking, and 5cc ICG is injected into the ureter The marking reference on the epidural catheter (BBraun Perifix ® , 0.85 mm × 1000 mm In most cases, the procedure was performed after the patient was under general anesthesia and before starting the surgery. A hysteroscope was gently inserted through the urethral meatus and advanced into the bladder to inspect the bladder mucosa and locate the ureteral orifices bilaterally. An epidural catheter was introduced into the operating channel of the scope and advanced into each ureteral orifice under direct visualization, reaching approximately 150 mm from the orifice where the ureter crosses the pelvic brim. Sterile ICG dye powder (25 mg) was reconstituted with 5 ml of water in a syringe, and 2.5 mls was injected into each ureter via the catheter. After the injection, the catheter was withdrawn from the ureter under direct vision, and the same procedure was repeated for the other ureter. The time required for intraureteral ICG injection, from the introduction of the scope into the bladder to the withdrawal of the catheter from the ureter, was video-recorded. Subsequently, the planned laparoscopic or robotic gynecologic procedures were carried out. During the surgery, the course of the ureters was identified and traced from the pelvic brim down to the ureteric tunnel. For laparoscopy, a three-dimensional (3D) 4K RUBINA™ camera system with NIR light was used to visualize the fluorescently highlighted ureter in real-time. For robotic procedures, the DaVinci™ Xi system with the Firefly function was utilized [ Figure 3a and b ]. Outcome measures: Pre-determined primary outcome measures were visibility of the ureter during the surgery, estimated blood loss (EBL), duration of the surgery, length of stay postoperatively, and the complications, which include failure of catheterization of the ureter and retrograde intra-ureteral ICG injection, frank hematuria, injury to ureter or bladder, allergic incidence, postoperative urinary retention, the incidence of postoperative urinary tract infection, the incidence of ureteric stricture up to 6 weeks follow up. The independent personnel collected data from the patient’s admission record, the operating record, the video recording of the surgery, and the follow-up record after each case from hospitalization until she completed the follow-up to 2 months postoperatively and entered it into the predetermined survey sheet. (a) ICG-highlighted ureter using 3D 4K RUBINA™ NIR system. (b) ICG-highlighted ureter using Da Vinci Xi ‘Firefly’ mode”