Evaluation of Long-Term Outcomes Utilizing Indocyanine Green to Decrease Ureteroenteric Anastomotic Stricture During Robotic Radical Cystectomy and Extracorporeal Urinary Diversion

Take Home Message

Our results demonstrate that the use of indocyanine green (ICG) during ureteroenteric anastomosis (UA) for urinary diversion was significantly associated with a lower risk of UA stricture. Our study represents the largest 1:1 comparison of ICG use in this setting with the longest follow-up to date.

Abstract

Background and objective

Intravenous indocyanine green (ICG) allows assessment of ureteral perfusion when performing ureteroenteric anastomosis. Our aim was to evaluate the impact of ICG use and clinical factors on the risk of ureteroenteric anastomotic stricture (UAS) following robot-assisted radical cystectomy (RARC) and extracorporeal urinary diversion (ECUD).

Methods

We conducted a retrospective review of patients who underwent RARC + ECUD with or without ICG use between 2011 and 2022 at a single tertiary center. For cases with a clinical suspicion of UAS, a nephrostomy tube was placed and an antegrade nephrostogram was performed for confirmation. Kaplan-Meier and logistic regression analyses were performed to estimate stricture rates and to identify risk factors for UAS incidence.

Results and limitations

A total of 392 consecutive cases were included. No ICG was used for the first 196 cases (50%), while ICG was used for the subsequent 196 cases (50%). ECUDs included 234 ileal conduits (60%), 110 neobladders (28%), and 48 Indiana pouches (12%). The risk of UAS was 2% at 6-months and 3% at 24-months in the ICG group, and 12% at 6-months and 14% at 24-months in the non-ICG group. No UAS occurred beyond 19-months. Multivariable analysis revealed that ICG use significantly reduced UAS risk (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.08–0.50; p < 0.001), whereas a history of diabetes mellitus significantly increased the risk of UAS (HR 3.07, 95%CI 1.47–6.41; p = 0.003). There were no adverse events related to ICG use.

Conclusions and clinical implications

ICG fluorescence imaging is a safe technique that can facilitate efforts to reduce the risk of UAS following RARC and ECUD.

Patient summary

Narrowing of the connection between the ureter and the segment of intestine used to create a new urinary reservoir is a serious complication after bladder removal for bladder cancer. We found that using a fluoroscent agent that identifies tissue blood supply at the time of urinary reconstruction may reduce the risk of this complication.

1. Introduction

Ureteroenteric anastomosis stricture UAS is a morbid complication following bladder extirpation and urinary diversion, with clinical consequences ranging from life-threatening infection to loss of renal function. The pathophysiology of UAS involves ischemia or inflammation of the ureteroenteric anastomosis, resulting in tissue necrosis and scar formation. UAS frequency ranges from 2.7% to 25%, and it is estimated that a stricture can develop within the first 6–18 months after surgery [1,2]. However, recent results from a high-volume center suggest that UAS risk can persist beyond 10-years [3], thus a high index of suspicion throughout the postoperative period is necessary. Prior studies suggested that the risk of UAS is not affected by the operative approach [4,5], the ureteroenteric anastomosis method [6], the anastomotic suturing technique [7], use of a ureteral stent, or whether the stent is internal or externalized [[8], [9], [10]]. While recommendations such as meticulous tissue handling and preservation of periureteric connective tissue exist, UAS prevention and surveillance have yet to be incorporated in guidelines and remain limited to expert opinion.

Indocyanine green (ICG) is a non-toxic fluorescent iodide dye approved by the US Food and Drug Administration for intravenous administration and is visualized using near-infrared fluorimetry. The majority (98%) of ICG travels in the intravascular space, yielding a short half-life of 3–4 minutes and a hepatic elimination latency that allows for multiple injections. A critical role of ICG in urologic surgery is to assess tissue perfusion, allow objective assessment of ureteral vascularity before ureteroenteric anastomosis [11]. Over the past decade, several centers have reported that ICG use lead to a significant reduction in UAS risk [12]. In line with these findings, we have included ICG administration as a critical surgical step for all ureteroenteric anastomoses since 2017.

As a high-volume tertiary referral center with considerable experience in radical cystectomy and both continent and incontient urinary diversion, our objectives were to evaluate the efficacy of ICG in preventing UAS in a cohort of patients with extended follow-up, to explore pertinent clinical factors affecting UAS risk, and to understand the impact of UAS on the patient and our healthcare system.

2. Patients and methods

2.1. Study population

We reviewed an institutional review board–approved (IRB#05148) prospective database of 409 consecutive patients who underwent robot-assisted radical cystectomy (RARC) and extracorporeal urinary diversion (ECUD) at a single tertiary referral center between October, 2011 and August, 2022. RARC and ECUD were performed as previously described [13]. ICG was first introduced in our practice on March 31, 2016, however, consistent ICG use for all cases did not occur until May, 2017. All ECUDs were performed by a single surgeon (K.G.C.). Patients with malignant UAS (n = 5) and those who died before or had incomplete postoperative upper-tract imaging (n = 12) were excluded.

2.2. Surgical procedure

Following RARC and negative ureteral margin(s), an infraumbilical 6–8-cm incision was made and the ureter(s) were inspected. The limit of nonviable ureter was marked with suture, using white light for patients who did not receive ICG or using infrared light for those patients that received ICG, before preparing the bowel for ECUD. This order of operations ensured a tailored bowel segment for a tension-free ureteroenteric anastomosis. All excised ureteral segments were sent for formalin fixation and pathology analysis at the time of ECUD. Each ureteroenteric anastomosis was completed over a 7 Fr stent that was externalized through the abdominal wall.

For patients who did not receive ICG, the ureter was transected up to the point of perceived viability for a tension-free anastomosis. Bricker ureteroenteric anastomoses were then performed using a “no-touch” technique and ten 4-0 polygalactin interrupted sutures. For patients who received ICG, 3 ml of intravenous ICG was administered, followed by 10 ml of normal saline. Ureteral perfusion was assessed using an infrared laparoscope (PINPOINT; Stryker, Portage, MI, USA) or a handheld infrared camera (SPY-PHI; Stryker). If good distal perfusion was observed, the ureter was divided at an appropriate length for a tension-free anastomosis. A simple suture was used to mark the distal extent of ureteral perfusion (Fig. 1A). The ureter was then divided proximal to the marking suture. Bricker ureteroenteric anastomoses were completed using a “no-touch” technique and a 4-0 polygalactin interrupted suture. A second 3-ml aliquot of intravenous ICG was administered for final perfusion assessment of each ureteroenteric anastomosis (Fig. 1B). This assessment was performed extracorporeally for ileal conduits and continent cutaneous urinary diversions. For neobladders, the final anastomotic perfusion assessment was completed intracorporeally using an infrared laparoscope or a Firefly device (Intuitive Surgical Systems, Sunnyvale, CA, USA).

Fig. 1.

(A) Intraoperative multiwavelength infrared and white-light images showing the distal extent of ureteral perfusion that is then marked with a simple suture following administration of 3 ml of intravenous indocyanine green. (B) Intraoperative multiwavelength infrared and white-light images showing intact perfusion following completion of ureteroenteric anastomosis after administration of 3 ml of intravenous indocyanine green.

2.3. Postoperative care

Postoperative care followed an enhanced recovery after surgery pathway [13]. Renal ultrasound imaging was performed approximately 6-weeks after surgery. Surveillance imaging was performed according to National Comprehensive Cancer Network guidelines. If clinically significant hydronephrosis was identified, a fluoroscopic loopogram or pouchogram and a diuretic nuclear medicine renal scan were recorded. If no ureteroenteric reflux was detected and/or a diuretic renal scan demonstrated obstruction, a percutaneous nephrostomy tube was placed and an antegrade nephrostogram was recorded to determine if a UAS was present.

2.4. Study outcomes

The primary endpoint was the UAS rate in each group. Secondary endpoints included the rate of unplanned return visits and Clavien-Dindo grade IV complications. The study groups were defined according to whether or not ICG was used during the ECUD procedure. The date of UAS diagnosis was defined as the date of the confirmatory antegrade nephrostogram. Symptomatic UAS was defined as abdominal or flank pain, or fever with or without hydronephrosis that prompted further evaluation.

We recorded the frequency of Clavien-Dindo grade IV adverse events [14] and unplanned return visits for patients diagnosed with UAS that were specifically related to genitourinary complications. An unplanned return visit was defined as an in-person visit to an external emergency department or our urgent care clinic, admission to our facility or an external hospital, or an unplanned outpatient visit.

2.5. Statistical analysis

Results for categorical variables are presented as the frequency and proportion. Results for continuous variables are reported as the median and interquartile range (IQR). Pearson’s χ² test or Fisher’s exact test and Wilcoxon rank-sum tests were used to compare baseline characteristics between patients or renal units in the ICG and non-ICG groups. Survival rates by UAS status from the date of surgery to the date of UAS diagnosis were estimated using the Kaplan-Meier method, and differences between the ICG and non-ICG groups were compared using a log-rank test. For patients with multiple stricture events, we analyzed the time to the first event. Patients who died without a documented UAS, those lost to follow-up, and patients who were still alive without a documented UAS at their last visit or contact were censored. Cox regression analyses were performed to characterize the risk factors for UAS. Variables significantly associated with UAS incidence on univariable analysis were entered into a multivariable model. There was a difference in body mass index (BMI) between the ICG and non-ICG groups at baseline, so the multivariable model was further adjusted for BMI. A Cochran-Armitage test for trends was used to assess differences in UAS incidence over time. A two-tailed p value of <0.05 was considered significant. Data management and statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria).

3. Results

3.1. Study cohort

A total of 392 patients with median follow-up of 34.9 months (IQR 16.7–74.9) were included in the final analysis (Table 1). There were 158 (40%) continent ECUDs, of which 110 (70%) were neobladders and 48 (30%) were continent cutaneous urinary diversions. The ICG group consisted of 196 (50%) patients with 387 (50%) renal units, while the non-ICG group consisted of 196 (50%) patients with 385 (50%) renal units.

Table 1.

Baseline clinical characteristics by study group^a

Parameter	Group		p valueb
	ICG (n = 196)	Non-ICG (n = 196)
Median follow-up, mo (IQR)	27.7 (17–44)	73.2 (17–97)	–
Median age, yr (IQR)	73.0 (66–80)	72.3 (65–79)	0.3
Male, n (%)	161 (82)	155 (79)	0.4
Median body mass index, kg/m2 (IQR)	25.7 (23-29)	26.8 (25-30)	0.002
Diabetes mellitus, n (%)c	50 (26)	36 (18)	0.08
Current smoker, n (%)	131 (67)	138 (70)	0.4
Clinical T stage, n (%)			0.6
cTa	8 (4)	8(4)
cTis	11 (6)	5 (3)
cT1	45 (23)	49 (25)
cT2	95 (48)	104 (53)
cT3	23 (12)	18 (9)
cT4	14 (7)	12 (6)
Clinical N stage, n (%)			0.065
cNx	9 (5)	5 (3)
cN0	159 (81)	150 (77)
cN1	12 (6)	8 (4)
cN2	7 (4)	19 (10)
cN3	9 (5)	14 (7)
Diversion type, n (%)			0.6
Ileal conduit	122 (62)	112 (57)
Indiana pouch	23 (12)	25 (13)
Neobladder	51 (26)	59 (30)
Neoadjuvant chemotherapy, n (%)d	92 (47)	75 (38)	0.08
Median operative time, min (IQR)	419 (358-483)	430 (359-477)	0.6

ICG = indocyanine green; IQR = interquartile range.

^aFour patients in the ICG group and 13 in the non-ICG group were symptomatic at the time of ureteroenteric anastomosis stricture presentation.

^bWilcoxon rank-sum test or Pearson’s χ² test.

^cDiabetes mellitus was defined as serum hemoglobin A1c level ≥6.5%.

^dNeoadjuvant chemotherapy was given to eligible patients with ≥cT2 disease.

3.2. UAS incidence

The overall UAS rate during the study period was 7.6%. There was a 4% increase in the UAS rate from 2011 to 2017, which was the portion of the study period before consistent ICG use, but there was no difference in UAS incidence between the ICG and non-ICG groups during this time (p = 0.2). The risk of UAS was 2% at 6-months and 3% at 24-months in the ICG group, and 12% at 6-months and 14% at 24-months in the non-ICG. Nineteen (56%) of the UASs identified occurred in the left renal unit. Four patients in the non-ICG group had bilateral UAS. The median time to UAS incidence was 3.6-months (IQR 2.5–5.5). Open revision was performed for 32 of the 34 UASs. The remaining two patients with unilateral UAS were poor surgical candidates and were managed with a nephrostomy tube. ICG use was significantly associated with a lower UAS rate per renal unit, with a rate of 1.6% in the ICG group versus 7.3% in the non-ICG group (p < 0.001). Furthermore, ICU use resulted in greater excised non-viable ureteral length than ECUDs performed without ICG, 2.6 cm (IQR 2-3.8) vs. 2.5 cm (IQR1.6-3.5), respectively, p = 0.023. UAS incidence rates for the two groups are shown in Fig. 2. Importantly, ICG use reduced the incidence of UAS irrespective of the urinary diversion type (Fig. 3).

Fig. 2.

Kaplan-Meier analysis of stricture incidence from the time of extracorporeal urinary diversion to ureteroenteric anastomotic stricture for the groups with and without indocyanine green (ICG) during ureteroenteric anastomosis. A total of 362 patients had no stricture over median follow-up of 34.4 mo (IQR 15.7–74.4). In the non-ICG group, 172 patients had no stricture over median follow-up of 74.1 mo (IQR 14.0–97.9). In the ICG group, 190 patients had no stricture over median follow-up of 27.7 mo (IQR 16.4–45.0). IQR = interquartile range.

Fig. 3.

Kaplan-Meier analysis of the cumulative incidence of ureteroenteric anastomotic stricture in the indocyanine green (ICG) and non-ICG groups stratified by type of urinary diversion.

Multivariable analysis revealed that ICG use significantly reduced the risk of UAS (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.08–0.50; p < 0.001), whereas diabetes mellitus was associated with significantly higher UAS risk (HR 3.07, 95% CI 1.47–6.41; p = 0.003; Table 2).

Table 2.

Cox regression results for the relationship between preclinical and intraoperative factors and the risk of ureteroenteric anastomosis stricture

Parameter	Events	Univariable analysis		Multivariable analysis
	(n)	HR (95% CI)	p value	HR (95% CI)	p value
ICG use
No ICG	24	Reference		Reference
ICG	6	0.23 (0.09–0.56)	0.001	0.20 (0.08–0.50)	<0.001
Age in years	30	0.98 (0.95–1.01)	0.17
Sex
Female	3	Reference
Male	27	2.08 (0.63–6.86)	0.23
Body mass index in kg/m2	30	1.01 (0.99–1.03)	0.24
Diabetes
No	18	Reference		Reference
Yes	12	2.48 (1.20–5.16)	0.015	3.07 (1.47–6.41)	0.003
Smoking status
Never/former smoker	7	Reference
Current smoker	23	1.59 (0.68–3.70)	0.29
Neoadjuvant chemotherapy	30	0.92 (0.44–1.90)	0.82
Diversion type
Ileal conduit	14	Reference
Indiana pouch	5	1.63 (0.59–4.52)	0.35
Neobladder	11	1.56 (0.71–3.45)	0.27

CI = confidence interval; HR = hazard ratio; ICG = indocyanine green.

Grade IV complications among those with UAS occurred in 6/24 patients (25%) in the non-ICG group and 0/6 (0%) in the ICG group. All grade IV complications were due to sepsis from a urinary source. Two patients also had a urine leak and one patient had a delayed bowel perforation. Of the 42 unplanned return visits, 34 (81%) were in the non-ICG group and eight (19%) were in the ICG group.

4. Discussion

Our results demonstrate that ICG use during ECUD reduced UAS to a rare occurrence (1.6%). This finding is derived from the largest study of ICG use in relation to UAS incidence (>700 renal units evaluated) with the longest median follow-up (∼3-years) in the literature to date and included a high proportion of continent urinary diversions (40%). ICG use resulted in excision of more non-viable ureter prior to anastomosis, although the clinical relevance of this difference is small. The median time to UAS was 3–4 months, and most patients (57%) were symptomatic at presentation. Our analysis of stricture rates revealed divergence of UAS risk within the first 3-months after surgery and throughout the follow-up period between the two groups. Multivariable analysis showed that ICG use was associated with significantly lower UAS risk (HR 0.20), while diabetes mellitus was associated with higher UAS risk (HR 3.07). Importantly, patients in the ICG group who developed UAS had fewer grade IV complications requiring critical care and unplanned return visits.

The pathophysiology and clinical manifestation of UAS reveal variability in the incidence, timing, and multifactorial nature of this challenging condition. Shah et al [1] analyzed data for 1964 patients who underwent open radical cystectomy (ORC) and urinary diversion with more than a decade of follow-up and found a UAS rate of 2.6% at a median of 10-months after surgery. The authors attributed their results to a meticulous “no-touch” approach for ureteral manipulation and close follow-up. Amin et al [15] observed a UAS rate of 4.3% among 2888 consecutive ORC cases; the UAS was symptomatic in the majority of cases (76%). Multivariable analysis revealed that male sex (HR 1.8), BMI (HR 1.04), American Society of Anesthesiologists score ≥3 (HR 1.8), lymph node positivity (HR 1.6), and prior abdominal surgery (HR 3.4) were associated with time to UAS. The strong association between UAS and prior abdominal surgery led the authors to hypothesize that intra-abdominal adhesions may affect ureteroenteric anastomosis healing [15]. Other factors with a negative impact on healing include preoperative nutritional status, urinary tract infection, and postoperative urinary anastomosis leakage [16]. Goh et al [17] reviewed 332 RARC and 1449 ORC cases and found that UAS incidence rates at 6-months (12.1% vs 7.0%; p < 0.01) and 12-months (15.0% vs 9.5%; p = 0.01) were greater for RARC versus ORC. Their multivariable analyses showed that RARC (HR 1.6) and preoperative hydronephrosis (HR 1.5) were associated with higher risk of UAS formation. A recent systematic review involving more than 5500 patients evaluated UAS risk for RARC versus ORC and ECUD versus intracorporeal urinary diversion (ICUD) [12]. The overall UAS rate was 9.2%, with a greater risk following RARC in comparison to ORC (odds ratio [OR] 1.4). The authors also found a difference in UAS risk between ECUD and ICUD using nonrandomized data, yet the quality of the evidence precluded any conclusions regarding a clear clinical difference between the approaches. In our study, 40% of patients overall received a continent ECUD; the overall neobladder and continent cutaneous urinary diversion rates were 28% and 12%, respectively. Among prior studies assessing UAS risk, the rate of orthotopic bladder use ranged from 8% to 15% [4,[17], [18], [19], [20]]. An evaluation of UAS risk in relation to ICG use in one high-volume center revealed an overall continent urinary diversion rate of 28% and a relative orthotopic bladder rate of 27% [21]. Importantly, our analysis shows that diversion type did not affect the risk of UAS, which is in agreement with findings from other studies [10,18].

We found that diabetes mellitus was associated with UAS risk. Lee et al [22] reviewed 388 patients who underwent robot-assisted ureteroplasty to determine predictors of a successful repair. Their analysis revealed that the odds of success was threefold lower for patients with diabetes mellitus. It is evident from the literature that multiple intrinsic and extrinsic factors affect perfusion of the ureteroenteric anastomosis, the disruption of or lack of anastomotic healing, and thus UAS formation. ICG use should be considered as a potential additional step to mitigate the risk of UAS occurrence after surgery.

Our results indicate that ICG use may reduce the risk of UAS and build on previous findings. Doshi et al [23] compared non-ICG (n = 30) versus ICG (n = 31) ORC cases and found a significantly lower UAS rate with ICG use (16.7% vs 3.2%, respectively). Shen et al [24] reviewed data for 94 patients who underwent RARC and ECUD and found UAS rates of 0% for the ICG group versus 9.5% for the non-ICG group. A similar review of 179 RARC and ICUD cases by Ahmadi et al [21] revealed that none of the 47 ICG patients and 14/132 (10.6%) non-ICG patients experienced UAS after median follow-up of >1-year. Importantly, there were no differences in 90-day readmission or complication rates between the groups; however, the frequency of Clavien-Dindo high-grade events was greater in the non-ICG group (23%) than in the ICG group (9%). In addition, the non-viable ureteral segment that was removed was significantly longer in the ICG group than in the non-ICG group. Narita et al [25] reported a 30% decrease in UAS incidence after implementation of ICG use during RARC and ICUD. Lastly, evaluation of 366 urinary diversions performed in a single tertiary center showed that the non-viable ureteral length removed was inversely associated with UAS risk (OR 0.73) and time to stricture formation (HR 0.78) [26]. On the other hand, a review of 221 RARC and ICUD cases with median follow-up of 21-months by Carbonell et al [27] showed no difference in UAS rate (18% vs 19%) for non-ICG (n = 142) versus ICG (n = 79) procedures. These findings are hypothesis-generating, contradict the literature, and suggest further study is required to substantiate the results. In summary, the evidence available suggests a high likelihood that there is more non-viable ureter present than that identified with conventional white light alone [28]. Thus, the improved outcomes for urinary diversions completed using ICG may be attributable to precise visualization of ureteral perfusion during the procedure.

Our study is limited by its single-center, nonrandomized, and largely single-surgeon design. Our results also may be subject to time bias and generalized only to other tertiary referral centers with similar sub-specialty expertise and workflow. Importantly, given the adoption of intracorporeal diversion at other high-volume centers, a comparison between extracorporeal “no-touch” and intracorporeal techniques would provide valuable insights. Furthermore, initiation of ICG use occurred relatively late in the experience of the single surgeon performing ECUD procedures. However, given the scale of the present study, we believe that our results speak to the potential benefits of intravenous ICG use during urinary diversion surgery. Therefore, a prospective randomized trial to confirm our findings is warranted.

5. Conclusions

ICG use can reduce the risk of UAS and improve the probability of a durable ureteroenteric anastomosis. Given patients with diabetes mellitus had a higher risk of UAS, there may be additional clinical factors that contribute to UAS development. Our results support a rationale for a prospective randomized study of intravenous ICG use as a possible standardized technique to optimize ureteroenteric anastomotic outcomes following bladder extirpation and urinary diversion.



Author contributions: Daniel J. Lama had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



Study concept and design: Lama, Hudnall, Yuh, Chan.

Acquisition of data: Lama, Jaime-Casas, Hudnall, Okunowo.

Analysis and interpretation of data: Lama, Okunowo, Yamzon, Zhumkhawala, Lau, Yuh, Chan.

Drafting of the manuscript: Lama, Jaime-Casas, Hudnall, Okunowo, Yuh, Chan.

Critical revision of the manuscript for important intellectual content: Lama, Jaime-Casas, Okunowo, Lau, Yuh, Chan.

Statistical analysis: Lama, Okunowo, Yuh, Chan.

Obtaining funding: None.

Administrative, technical, or material support: Yamzon, Zhumkhawala, Villareal, Lau, Yuh, Chan.

Supervision: Yuh, Chan.

Other: None.



Financial disclosures: Daniel J. Lama certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.



Funding/Support and role of the sponsor: None.

Associate Editor: M. Carmen Mir