Intraoperative Imaging of the Common Bile Duct: A Systematic Review

Authors

Julie Hong¹, Sunjay Kumar², Intekhab Akram³, Sharif Rauf Khan³, Lawrence N. Cetrulo⁴, Romeo Ignacio⁵, Jeffrey Chiu⁶, Brian Davis⁷, Marian McDonald⁸, Subhashini Ayloo⁹, Ali Kchaou¹⁰, David Overby¹¹, Dena G. Shehata¹², Eduardo Moreno‑Paquentin¹³, Bethany J. Slater¹⁴, Emily Miraflor¹⁵

ABSTRACT

Background: Benign biliary disease is a common gastrointestinal condition often requiring surgical intervention. Serious complications during minimally invasive cholecystectomy, such as bile duct injury (BDI) and retained common bile duct stones, must be minimized to improve outcomes and optimize resource use. This systematic review summarizes data comparing intraoperative cholangiography (IOC), fluorescent imaging (FI) with indocyanine green (ICG), and laparoscopic ultrasound (LUS) during laparoscopic cholecystectomy.

Methods: A systematic review was conducted to address key questions (KQs) on the use of intraoperative common bile duct imaging to prevent BDI and retained stones. Comparisons included routine IOC (KQ1 routine versus selective IOC (KQ1b) in adult and pediatric populations (KQ1p), as well as IOC versus FI with ICG (KQ2) and IOC versus LUS (KQ3). Searches were conducted in PubMed, Embase, Clinicaltrials.gov, ICTRP, and Cochrane databases. Meta-analyses were performed using random effects models (inverse variance and Mantel–Haenszel), and risk of bias was assessed using the Cochrane Risk of Bias tool and a modified Newcastle–Ottawa Scale.

Results: Of 1,981 unique publications, 46 studies met inclusion criteria (KQ1 n = 19, KQ1b n = 7, KQ1p n = 5, KQ2 n = 6, KQ3 n = 9). IOC was associated with increased operative time (Mean difference 22.61 min [95% CI 16.87, 28.34]) and technical failure (OR 8.28 [1.02, 67.47]). Routine IOC showed trends toward reduced bile duct injury (RR 0.66 [0.08, 5.36]) and increased intraoperative stone detection (RR 2.83 [1.08, 7.41]). Compared to FI with ICG, IOC showed a trend toward fewer bile duct injuries (RR 0.33 [0.01, 8.02]) and more frequent stone identification (RR 5.00 [0.25, 102.00]). IOC also reduced the need for second imaging modalities. No differences were found in postoperative stone detection across techniques.

Conclusions: Routine IOC may offer advantages over selective IOC, FI with ICG, and LUS in reducing complications, but is also associated with higher technical failure and longer operative time.

Keywords: Gallbladder · Hepatobiliary · Intraoperative cholangiography · Fluorescent imaging · Indocyanine green · Laparoscopic ultrasound

INTRODUCTION

Gallbladder disease impacts 20 million people in the United States [1], and is one of the most prevalent gastrointestinal conditions. Of this population, approximately 600,000 patients undergo laparoscopic cholecystectomy each year [2]. Bile duct injuries (BDI) are estimated to occur in 0.2–0.5% of cases [3, 4], and retained stone occurs in 0.5% of cases [5]. Given the prevalence of gallbladder disease and surgical treatment, relatively low incidence rates for two costly unexpected outcomes still place an undue burden on healthcare.

The risk of BDI has been attempted to be reduced with preoperative imaging, attention to anatomy, and the use of the critical view of safety [5]. However, biliary anatomic variations and significant inflammation of the hepatocystic triangle can render patients susceptible to injury [6, 7]. Similarly, common bile duct stones can be anticipated preoperatively with imaging and laboratory values, however, small stones may not be identified on imaging, and bilirubin takes time to accumulate. Additionally, stones that drop into the common bile duct during the operation cannot be prevented. After bile duct injury or retained stone occurs, postoperative imaging methods such as magnetic resonance cholangio-pancreatography (MRCP) or endoscopic ultrasound (US) can reliably detect both choledocholithiasis and bile duct injury [8–11]. However, these methods are solely diagnostic, and management requires subsequent invasive interventions such as endoscopic retrograde cholangiopancreatography (ERCP), which carries risks of pancreatitis and bleeding.

Intraoperative imaging is therefore a valuable adjunct that allows for early identification and intervention for BDI and retained stones [12], and may reduce the risk of BDI by clarifying the anatomy [13]. Of intraoperative imaging modalities, intraoperative cholangiography (IOC) has been studied the most. However, IOC use is not universal. Newer techniques that do not require radiation or cystic duct cannulation, such as fluorescent imaging (FI) with indocyanine green (ICG) or laparoscopic ultrasound (LUS), could potentially be more effective, less technically challenging, or more cost-effective [14–18]. While studies have been published comparing two or three of these methods, to our knowledge, there are currently no systematic reviews that summarize these findings. This systematic review and meta-analysis compare the modern and established options for intraoperative imaging of the CBD during cholecystectomy.

Methods and materials

Key Questions 

The SAGES guidelines committee developed key questions of interest that were identified by project leads. Key questions were represented in the PICO format (Population, Intervention, Comparator, and Outcomes) and evaluated via systematic review and meta-analysis according to PRISMA guidelines [19]. Five key questions were developed, but two were later excluded due to insufficient literature. The remaining three key questions were expanded to five key questions. Three key questions addressed IOC, and two key questions compared IOC with FI and LUS:

• KQ1: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to standard surgical technique?
• KQ1b: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, should IOC be used routinely or selectively?
• KQ1p: In pediatric patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to standard surgical technique?
• KQ2: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to fluorescent imaging with indocyanine green?
• KQ3: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to laparoscopic ultrasound?

Literature Search and Eligibility Criteria

A professional librarian performed a literature search for each key question on PubMed, Embase, Clinicaltrials.gov, International Clinical Trials Registry (ICTRP), and Cochrane Library databases. Search strategies as well as years covered by each database are included in Supplemental 1. Studies were limited to human studies published in English. Randomized control trials (RCTs) and non-randomized comparative observational studies were included. Systematic reviews were included for hand-searching of references by working group members. Single arm data was excluded. All records were uploaded to Covidence for screening.

Risk of Bias in individual studies

Risk of bias was determined by two investigators on Covidence. All differences were reconciled. Cochrane Risk of Bias and Newcastle–Ottawa tools were utilized for randomized and non-randomized studies, respectively.

Data extraction

All identified studies were screened at the abstract and full-text level by two separate investigators. Differences in inclusion or exclusion selection were adjudicated by the project leads. Data was collected using data extraction forms on Covidence by two separate investigators, with manual data adjudication in cases of conflicting data. PRISMA flowsheets are reported throughout the body of the text.

Statistical Analysis

Meta-analyses were conducted on Revman 5.4. Random effects meta-analyses were performed to build forest plots. Continuous outcomes using the same scale were compared using mean differences (MD), and continuous outcomes using different scales were compared using standardized mean differences (SMD). MD and SMD were compared using the inverse variance random-effects model. Binary outcomes were analyzed using risk ratios (RR) estimated by Mantel–Haenszel random effects model. X² and I² were used to estimate heterogeneity.

Results

A total of 7574 records were identified on initial database search. An additional 69 records were identified after hand-searching. After excluding 5349 duplicate studies, 1981 unique records remained across all key questions. Following screening at the title and abstract levels, 297 records were identified for full-text review (KQ1 n = 180, KQ2 n = 63, KQ3 n = 54). Studies were further screened for relevance in subject matter and reported outcomes (Total n = 46, KQ1 n = 19, KQ1b n = 7, KQ1p n = 5, KQ2 n = 6, KQ3 n = 9).

KQ1: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to standard surgical technique?

Out of 109 studies deemed appropriate for KQ1, a total of 19 studies were analyzed for KQ1, which consisted of 2 randomized clinical trials (RCTs) and 17 observational studies [20–39]. Of the RCTs, both studies compared routine (n = 249) against no IOC (n = 244). Of the observational studies, 6 studies compared routine IOC (n = 60,332) against no IOC (n = 48,984) [21, 23, 25, 28, 33, 37], while 11 studies compared selective IOC (n = 14,566) against no IOC (n = 78,114) [20, 22, 24, 27, 29–32, 34, 36, 38]. For KQ1, most studies were large and included patients with mixed case acuity (n = 15), while a minority were limited to elective (n = 2) or acute care cases (n = 1) (Table 1). Most studies included biliary colic (n = 14) or acute cholecystitis (n = 10), but some studies included patients with potentially more severe pathologies, such as gallstone pancreatitis (n = 2) [22, 36] and porcelain gallbladder (n = 1) (Table 1) [36].

Table 1. Characteristics of studies included in KQ1

Risk of Bias 

Of the 2 RCTs, all domains of bias were deemed to be low, with an overall rating of low risk of bias (Fig. 2). Most of the 17 observational studies were judged to have overall high risk of bias through the modified Newcastle Ottawa Scale for observational studies (Supplemental 2), though up to 25% of studies were thought to have low risk of bias. Concerns for risk of bias arose from comparability, as some studies did not control for additional variables in analyses and outcomes because some studies did not have long enough follow-up. Risk of bias in selecting patients was often deemed to be low.

Fig. 2 Risk of bias for 19 observational KQ1 studies as estimated by Newcastle Ottawa Scale for observational studies, which was previously modified for SAGES Guidelines. Colors indicate concern for risk of bias (Red = High, Yellow = Unclear, Green = Low) across three main domains (Selection, Comparability, Outcomes). Proportion of studies deemed to have high, unclear, or low risk of bias are represented as frequencies (out
of 100%)

Unsuccessful attempt: Two RCTs reported the number of technical failures specific to IOCs when attempting IOC (n = 249) or forgoing IOC (n = 244) [26, 35]. Meta-analysis favored the use of no IOC if avoiding technical failures is a highly desired outcome, with no heterogeneity in findings (OR [95%CI] 8.28 [1.02, 67.47], I² = 0%). Five observational studies also reported the number of technical failures in instances where IOC was and was not used [20, 29, 30, 33, 37]. Meta-analysis also favored the use of no IOC if wishing to avoid technical failures (OR 74.10 [10.40, 527.97], I² = 56%). This overall finding remained significant for studies with selective IOC (OR 71.51 [11.00, 464.64], I² = 16%), while a nonspecific trend was found for studies with routine IOC, which displayed high heterogeneity (OR 79.56 [0.71, 8960.49], I² = 83%).

Need for second intraoperative imaging technique: One observational study addressed the need for additional intraoperative imaging [25]. Comparison groups were of unequal size, with most instances representing cholecystectomy with IOC (n = 273) over cholecystectomy without IOC (n = 27). Heterogeneity index between studies could not be calculated in this instance where one study was investigated (Figs. 3, 4, 5, 6, 7, 8, 9, 10). Meta-analysis found that IOC and no IOC are at similar risk of requiring secondary intraoperative imaging (OR 2.63 [0.15, 45.63]).

OR time: Two observational studies reported duration of cholecystectomy associated with IOC (n = 129) and without IOC (n = 218) [22, 34]. Both studies investigated selective IOC use. Meta-analysis revealed that duration of surgery was significantly improved without IOC use (Mean difference [95%CI] 22.61 [16.87, 28.34], I² = 0%). There was no heterogeneity between studies in this finding (Figs. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).

Bleeding events: One RCT and two observational studies reported rates of bleeding events between IOC (RCT n = 63, observational study n = 11,393) and no IOC (RCT n = 59, observational study n = 41,933) [28, 29, 35]. A majority of the patients from observational studies were from studies investigating routine IOC use (IOC n = 11,227, no IOC n = 41,598) rather than selective IOC use (IOC n = 166, no IOC n = 335). Meta-analysis was not possible for RCT results, which were statistically equivocal (OR 3.93 [0.43, 36.24]). Meta-analysis of observational data revealed a similarly unclear trend (OR 1.13 [0.22, 5.93], I² = 39.1%) (Figs. 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).

Identification of aberrant anatomy: Four observational studies were found to report on identifying aberrant anatomy with (n = 5,331) and without IOC (n = 1,807) [20, 23, 25, 33]. Three observational studies investigated rates of identifying aberrant anatomy with IOC (n = 4,586) and without IOC (n = 901) in the setting of routine IOC and was found to trend towards supporting IOC (OR 2.24 [0.98, 5.08], I² = 15%) [23, 25, 33]. One observational study investigated aberrant anatomy with (n = 745) and without IOC (n = 906) in the setting of selective IOC (OR 15.94 [0.90, 283.34]) [20]. Overall, all observational studies together supported that IOC use was associated with increased odds of identifying aberrant anatomy with relatively low heterogeneity (OR 3.53 [1.09, 11.43], I² = 39.6%) (Figs. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40).

Intraoperative identification of bile duct injury: One RCT and seven observational studies reported on the incidence of identifying bile duct injuries [20, 23, 24, 26, 27, 30, 32, 33]. Two of the observational studies investigated routine IOC (4,313 IOC vs. 874 no IOC) [23, 33], while the remaining five observational studies investigated selective IOC use (13,606 IOC vs. 23,122 no IOC) [20, 24, 27, 30, 32]. The RCT was small with one event of bile duct injury in each comparison group (IOC vs. no IOC), and was therefore equivocal (OR 0.99 [0.06, 16.02]). Larger observational studies overall showed that IOC use was associated with increased detection of bile duct injury (OR 1.36 [1.04, 1.78], I² = 7%).

Intraoperative identification of stone: One RCT and thirteen observational studies reported the rates of identifying biliary stones with and without IOC (RCT 63 vs. 59, observational 51,194 vs. 11,755) [20–22, 24, 25, 29–37]. Both the RCT (OR 73.81 [4.36, 1,249.12]) and meta-analysis of the observational studies showed that intraoperative identification of stones was more often associated with IOC use (OR 140.96 [47.52, 418.09], I² = 48%). For observational studies, IOC in the setting of both routine (OR 135.42 [9.42, 1,946.79], I² = 73%) and selective use were strongly associated with intraoperative identification of stones (OR 143.67 [47.52, 431.90], I² = 27%) (Figs. 41, 42, 43, 44, 45, 46, 47, 48, 49, 50).

Need for postoperative imaging: One RCT reported on the need for postoperative imaging (186 IOC vs. 185 no IOC) [26] Due to small sample size and low incidence (1 IOC vs. 1 no IOC), analysis was equivocal (OR 0.99 [0.06, 16.02]).

Postoperative identification of BDI: Eight observational studies were included (58,902 IOC vs. 29,940 no IOC) [20, 23–25, 27, 30, 32, 37]. Three studies studied IOC use in the context of routine IOC (45,296 IOC vs. 6818 no IOC) [23, 25, 37], while five studies investigated IOC use in the context of selective IOC (13,606 IOC vs. 23,122 no IOC). Meta-analysis was equivocal (OR 0.47 [0.14, 1.63]).

Postoperative bile leak: Two RCTs (249 IOC vs. 244 no IOC) and four observational studies (1465 IOC vs. 1621 no IOC) were included [24–26, 29, 30, 35]. Observational studies overall were equivalent for IOC use in postoperative identification of bile leak (OR 0.97 [0.18, 5.40], I² = 60%). Of the three observational studies, one study found that avoiding IOC trended towards association with postoperative bile leak (273 IOC vs. 27 no IOC) (OR 0.09 [0.01, 0.68]) [25], while three studies found that using IOC trended towards association with postoperative bile leak (1192 IOC vs. 1592 no IOC) (OR 1.80 [0.61, 5.38], I² = 60%). Of note, the one study that favored the use of IOC in avoiding post-operative bile leak was a study on the routine use of IOC, while the three studies that found that IOC was associated with postoperative bile leak studied selective IOC.

Postoperative identification of common bile duct (CBD) stone: One RCT (186 IOC vs. 185 no IOC) and eleven observational studies (6547 IOC vs. 9116 no IOC) were identified to report rates of postoperative identification of stone in the common bile duct (CBD) [20–22, 24, 26, 29, 30, 32–34, 36, 38]. Based on 1 event of retained stone in the no IOC group, the RCT trended towards decreased incidence of retained stone with IOC (OR 0.33 [0.01, 8.15]). Observational studies were equivocal on this matter, with high study heterogeneity (OR 1.07 [0.34, 3.34], I² = 76%). Observational studies with both routine IOC (3809 IOC vs. 568 no IOC) (OR 1.05 [0.04, 26.81], I² = 86%) and selective IOC (2738 IOC 8548 no IOC) (OR 1.09 [0.28, 4.22], I2 74%) had high heterogeneity and equivocal results (Figs. 51, 52, 53, 54, 55, 56, 57).

Postoperative ERCP: One RCT (63 IOC vs. 59 no IOC) and twelve observational studies (3316 IOC vs. 9174 no IOC) were found to describe rates of postoperative ERCP [20, 22, 24, 25, 29–32, 34–36, 38, 39]. The RCT found that 30% (19/63) of patients who underwent IOC required postoperative ERCP, while 14% (8/59) of patients who did not undergo IOC required postoperative ERCP (OR 2.75 [1.10, 6.90]). Observational studies also found trends where patients who underwent IOC were more likely to undergo postoperative ERCP (OR 2.20 [0.99, 4.88], I2 86%). However, there was significant heterogeneity of 86% in the observational studies. Observational studies of routine IOC (392 IOC vs. 240 no IOC) trended towards less frequent ERCP following IOC with high heterogeneity (OR 0.53 [0.02, 12.43], I² = 89%) [25, 39]. Observational studies of selective IOC (2924 IOC vs. 8934 no IOC) included more patients and trended towards more frequent ERCP following IOC (OR 2.77 [1.12, 6.86], I² = 87%) [20, 22, 24, 29–32, 34, 36, 38], but high study heterogeneity again suggests that these results should be interpreted with caution.

Reoperation: Seven observational studies (14,059 IOC vs. 44,663 no IOC) included rates of reoperation [20, 23–25, 28–30]. Overall, there was a nonsignificant trend with high study heterogeneity for fewer reoperations with IOC (OR 0.67 [0.23, 2.01], I² = 82%). Studies investigating routine IOC (12,122 IOC vs. 42,163 no IOC) also trended towards fewer operations with IOC (OR 0.43 [0.11, 1.63], I² = 92%), but studies on selective IOC (1,937 IOC vs. 2,500 no IOC) trended towards the opposite (OR 2.34 [0.37, 14.90], I² = 0%).

KQ1b: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is routine intraoperative cholangiography superior to selective intraoperative cholangiography?

Out of 109 studies deemed appropriate for KQ1, a total of 2 RCTs (n=493) and 5 observational studies (n=116,943) were included, with data for 116,943 patients [40-46]. All studies in this KQ compared routine IOC (rIOC) (n=239 RCT, n=15,499 observational) to selective IOC (sIOC) (n=254 routine, n=101,444 observational). Studies included in this KQ often described a mix of acute and elective cases (n=3), while fewer studies described only elective (n=1) or only acute (n=1) cases (Table 2). One study included gallstone pancreatitis (Table 2) [46].

Table 2. Characteristics of included studies for KQ1b

Risk of bias 

Both RCTs were deemed to be low risk of bias in all domains listed by Cochrane Risk of Bias Tool 2.0, with an overall rating of low risk of bias. Of the 5 observational studies, 80% (n=4) were deemed to have overall low risk of bias, with only 1 study demonstrating unclear risk of bias.

Unsuccessful attempt: Two RCTs (239 rIOC vs 254 sIOC) and three observational studies (2,228 rIOC vs 2,380 sIOC) reported rates of unsuccessful attempts for IOC [40-44]. Meta-analysis of RCTs revealed that rIOCs are more associated with unsuccessful attempts than were sIOCs with minimal heterogeneity (Risk Ratio [95%CI] 5.06 [2.78, 9.19], I²=0%). Meta-analysis of observational studies also supports that rIOCs are more greatly associated with unsuccessful attempts (RR 8.05 [2.24, 28.95], I²=61%).

Bleeding events: One RCT (91 rIOC vs 99 sIOC) and one observational study (463 rIOC vs 1159 sIOC) reported rates of bleeding [40, 43]. Event rates were low with 2 total events in the RCT (1/91 rIOC vs 1/99 sIOC) and 1 event in the observational study (0/463 rIOC vs 1/1159 sIOC). Risk ratios were equivocal from both the RCT (RR 1.09 [0.07, 17.14]) and observational study (RR 0.83 [0.03, 20.42]).

Identification of aberrant anatomy: One RCT (91 rIOC vs 99 sIOC) and one observational study (1330 rIOC vs 800 sIOC) reported rates of identifying aberrant anatomy [43, 44]. Event rates were low with 2 events in the RCT (1/91 rIOC vs 1/99 sIOC) and 6 events in the observational study (5/1,330 rIOC vs 1/800 sIOC). Risk ratios were equivocal but seemed to trend toward favoring routine over selective IOC in the RCT (RR 1.09 [0.07, 17.14]) and observational study (RR 3.01 [0.35, 25.70]).

Intraoperative identification of BDI: Two RCTs (239 rIOC vs 254 sIOC) and three observational studies (2,228 rIOC vs 2,380 sIOC) described rates of identifying BDI intraoperatively [40-44]. Both RCTs (RR 0.66 [0.08, 5.36], I²=0%) and observational studies (RR 0.13 [0.02, 0.70], I²=0%) had nonsignificant trends towards less frequent incidence of intraoperative bile duct injuries with rIOC over sIOC.

Intraoperative identification of stone: Two RCTs (239 rIOC vs 254 sIOC) and four observational studies (2,474 rIOC vs 2,654 sIOC) described rates of intraoperative stone identification [40-45]. Both RCTs (RR 2.83 [1.08, 7.41], I²=0%) and observational studies (RR 6.37 [2.88, 14.11], I²=73%) were significantly in favor of more stones identified by rIOC vs sIOC.

Need for postoperative imaging: One RCT (91 rIOC vs 99 sIOC) described the need for postoperative imaging [43]. Event rates were low and were less likely to occur with rIOC than sIOC (RR 0.22 [0.01, 4.47]).

Postoperative identification of BDI: Two RCTs (239 rIOC vs 254 sIOC) and four observational studies (15,253 rIOC vs 101,170 sIOC) reported rates of postoperative identification of bile duct injuries [40-44, 46]. Analysis could not be performed for RCTs due to lack of any events. Meta-analysis of observational studies revealed a relatively equivocal picture between BDI in rIOC versus sIOC (OR 0.96 [0.67, 1.38], I²=0%).

Postoperative bile leak: One RCT (148 rIOC vs 155 sIOC) and one observational study (463 rIOC vs 1159 sIOC) reported rates of postoperative bile leak [4, 40]. Meta-analysis could not be performed on data from RCTs due to the absence of events. Meta-analysis of observational data suggests a slight trend toward more instances of postoperative bile leak with rIOC over sIOC (OR 2.51 [0.51, 12.50]).

Postoperative identification of CBD stone: Two RCTs and one observational study (1,330 rIOC vs 800 sIOC) were found to report postoperative identification of CBD stone [41, 43, 44]. Due to no events of interest in one RCT, only one RCT was analyzed (148 rIOC vs 155 sIOC). Both the RCT (RR 0.63 [0.15, 2.58]) and observational study (RR 0.13 [0.03, 0.62]) supported a trend to decreased postoperative detection of CBD stones with rIOC over sIOC.

Postoperative ERCP: Two RCTs (239 rIOC vs 254 sIOC) and four observational studies (14,169 rIOC vs 100,644 sIOC) reported rates of postoperative ERCP [40-43, 45, 46]. Risk ratios were estimated based on one RCT (148 rIOC vs 155 sIOC) due to absence of outcomes in one RCT. The RCT trended towards reduced rate of postoperative ERCP with rIOC (RR 0.67 [0.30, 1.51]), while observational studies trended towards increased rates of postoperative ERCPs with rIOC over sIOC (RR 1.60 [0.70, 3.64], I²=95%). Observational studies were highly heterogeneous for this outcome.

Reoperation: Two RCTs and one observational study (435 rIOC vs 421 sIOC) reported rates of reoperation [41-43]. RCT data were not eligible for meta-analysis due to absence of events. The observational study showed a potential trend towards decreased need for reoperation in rIOC over sIOC (OR 0.19 [0.01, 4.02]).

KQ1p: In pediatric patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to standard surgical technique?

Out of 109 studies deemed appropriate for KQ1, there were 5 observational studies with data for 9,588 patients [47-50]. Literature review yielded no RCTs. The observational studies compared IOC (n=3,716) against no IOC (n=5,872). Four of these studies described outcomes for selective IOC (n=6,723) [47-49, 51], while one study described outcomes for routine IOC (n=2,865) [50]. No comparative data existed to evaluate several topics (need for second intraoperative imaging technique, bleeding events, identification of aberrant anatomy, intraoperative aberrant anatomy, need for postoperative imaging, postoperative bile leak, reoperation), thus not allowing for statistical analysis. The studies included in this KQ all described mixed case acuity (n=5), however, included diagnoses were somewhat different from the pathologies described for adult patients in KQ1 and KQ1b, as pediatric papers included biliary dyskinesia or hemoglobinopathy [49], and hemolytic disease (Table 3) [51]. Furthermore, gallstone pancreatitis was included in all papers (n=5).

Table 3. Characteristics of included studies for KQ1p

Risk of bias

Overall risk of bias was high (n=4) or unclear (n=1). All 5 studies were judged to have high or uncertain risk of bias in the outcomes domain. Four of 5 studies were judged to have high or uncertain risk of bias for comparability, and 2 of 5 studies had high or uncertain risk of bias for selection.

Unsuccessful attempt: One selective observational study (31 IOC vs 17 no IOC) reported rates of unsuccessful attempts [48]. With one event, data from this observational study were equivocal for IOC versus no IOC in pediatric patients (OR 1.72 [0.07, 44.58]).

OR time: Two selective observational studies (85 IOC vs 75 no IOC) reported on the duration of surgery [49, 51]. The observational studies showed longer operating times for IOC versus no IOC (Mean difference[95%CI] 29.99 minutes [15.37, 44.60], I²=0%).

Intraoperative identification of BDI: One observational study using routine IOC (1,453 IOC vs 1,412 no IOC) reported intraoperative rates of bile duct injury identification [50]. In this study, IOC use was associated with fewer incidences of bile duct injury compared to no IOC (OR 0.03 [0.00, 0.22]).

Intraoperative identification of stone: Two observational studies on selective IOCs (53 IOC vs 57 no IOC) reported rates of intraoperative identification of stone [48, 49]. Meta-analysis of both studies showed a trend towards increased rates of identifying stones with IOC over no IOC (OR 6.71 [0.78, 58.05], I²=0%).

 Postoperative identification of BDI: Three observational studies, all investigating selective use of IOC, (116 IOC vs 92 no IOC) were found to report rates of postoperative BDI identification [48, 49, 51]. There was a nonsignificant trend towards decreased incidence of postoperatively identified BDI with IOC use (OR 0.18 [0.02, 1.76], I²=0%).

 Postoperative identification of CBD stone: One observational study investigating routine use of IOC (1,453 IOC vs 1,412 no IOC) reported rates of retained stones [50]. Meta-analysis showed a nonsignificant trend toward decreased odds of retained stone with IOC (OR 0.51 [0.23, 1.15]).

Postoperative ERCP: Three observational studies with selective IOC (2,200 IOC vs 4,425 no IOC) reported rates of postoperative ERCP [47-49]. On meta-analysis, there was a nonsignificant trend towards increased rates of postoperative ERCP with IOC over no IOC use (OR 1.81 [0.60, 5.47], I²=44%).

KQ2: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to fluorescent imaging with indocyanine green?

Out of 33 studies that were found on literature search for KQ2, 6 studies were included in analysis. Of these studies, there was 1 RCT with data for 120 patients [26, 52-56]. This RCT study compared IOC (n=60) against FI (n=60) [54]. There were 5 observational studies with data for 510 patients [26, 52, 53, 55, 56]. These observational studies compared IOC (n=246) against FI (n=264). No comparative data for several topics (bleeding events, need for postoperative imaging, postoperative bile leak, postoperative identification of CBD stone, and reoperation) was found, prohibiting analysis. Most studies included only patients of elective case acuity (n=4), which supports improved comparability (Table 4). Included diagnoses also seemed relatively homogenous compared to those of prior KQ studies with the exception of one study that included gallstone pancreatitis (Table 4) [54].

Table 4. Characteristics of included studies for KQ2.

Risk of bias

The single RCT was rated to be at low risk of bias in all five domains provided by Cochrane Risk of Bias Tool 2.0, and was rated to have an overall low risk of bias. Observational studies were uniquely all deemed to have low risk of bias, suggesting high quality studies.

Unsuccessful attempt: One RCT (60 IOC vs 60 FI) and four observational studies (201 IOC vs 219 FI) reported rates of technical failure [52-56]. The RCT showed a significant and large effect toward greater rates of failure with IOC (RR 19.00 [1.13, 319.27]). Observational studies also showed significant association between IOC and technical failure over FI with ICG (RR 2.86 [1.33, 6.14], I²=17%).

Need for second intraoperative imaging technique: One RCT (51 IOC vs 60 FI) and three observational studies (130 IOC vs 159 FI) reported rates of second intraoperative imaging techniques [52, 54-56]. RCT showed decreased need for second intraoperative imaging with IOC (RR 0.05 [0.00, 0.84]). This trend was mirrored in observational studies, but was not significant (RR 0.76 [0.18, 3.27], I²=31%).

OR time: One RCT (60 IOC vs 60 FI) and three observational studies (159 IOC vs 181 FI) reported duration of surgery [52-55]. The RCT data did not report SD, therefore mean difference could not be estimated. Observational studies showed a trend towards longer operative time with IOC over FI with ICG (Mean difference[95%CI] 10.77 minutes [6.64, 14.91]).

Identification of aberrant anatomy: One observational study reported frequency for the rates of aberrant anatomy, but meta-analysis could not be estimated due to absence of events.

Intraoperative identification of BDI: One RCT (60 IOC vs 60 FI) and two observational studies reported rates of intraoperative identification of BDI [54-56]. Based on one instance of intraoperative BDI in the FI group, the RCT data supported decreased rates of intraoperative BDI with IOC over FI (RR 0.33 [0.01, 8.02]). Observational studies could not be analyzed due to absence of events.

Intraoperative identification of stones: One RCT (60 IOC vs 60 FI) and one observational study reported rates of intraoperative identification of stone [53, 54]. Based on 2 instances of intraoperative identification of stones in the IOC group, RCT data supports a nonsignificant trend where IOC is superior to FI with ICG in identifying stones (RR 5.00 [0.25, 102.00]).

Postoperative identification of BDI: One RCT and one observational study reported rates of postoperative BDI identification [54,56], however analysis could not be performed due to lack of events.

Postoperative ERCP: Postoperative ERCP use was reported by one RCT (60 IOC vs 60 FI) [54]. There was a nonsignificant trend for increased postoperative ERCP with IOC use (RR 2.00 [0.19, 21.47]).

KQ3: In patients undergoing laparoscopic cholecystectomy for benign biliary disease, is intraoperative cholangiography superior to laparoscopic ultrasound?

Of 27 studies identified for KQ3, 9 studies were included in meta-analysis. Literature review yielded no RCTs. There were 9 observational studies with data for 5,204 patients [16, 57-64]. These observational studies compared IOC (n=2,723) against LUS (n=2,481). No comparative data could be obtained to evaluate several outcomes: bleeding events, need for postoperative imaging, reoperation. Many studies in this KQ did not report the case acuity (n=6) (Table 5), and multiple studies did not have a clear description of included diagnoses, which is a challenge in ensuring comparability.

 Table 5. Characteristics of included studies for KQ3

Risk of bias

Most of the 9 observational studies were deemed to have low (n=5) or unclear (n=1) overall risk of bias. High risk of bias seemed to be primarily driven by risk of bias in patient selection (n=2) or comparability (n=2). Only 1 study was believed to have high risk of bias in outcomes (n=1), suggesting that most studies reported a sufficiently long follow-up period with low enough attrition.

Unsuccessful attempt: Seven observational studies (2,516 IOC vs 2,081 LUS) reported rates of unsuccessful attempts [16, 57-59, 61, 62, 64]. Meta-analysis revealed that IOCs were more associated with technical failure than LUS (OR 9.78 [2.46, 38.98], I²=74%). Though heterogeneity was high, the confidence interval of most included studies did not cross 1.0.

Need for second intraoperative imaging technique: Five observational studies (622 IOC vs 824 LUS) reported rates of utilizing a second intraoperative imaging technique [16, 58, 60, 63, 64]. Meta-analysis showed a nonsignificant trend towards decreased second imaging techniques for IOC over LUS (OR 0.19 [0.02, 1.74], I²=84%).

OR time: Five observational studies (1,406 IOC vs 1,633 LUS) reported duration of surgery [57-59, 62, 63]. Meta-analysis revealed slightly increased operative time for IOC (Mean difference[95%CI] 5.47 minutes [0.74, 10.20], I²=100%).

Identification of aberrant anatomy: One observational study (50 IOC vs 53 LUS) reported rates of aberrant anatomy [58]. Observational data trended towards increased rates of identifying aberrant anatomy with IOC over LUS (OR 10.35 [0.54, 197.45]).

Intraoperative identification of BDI: Three observational studies reported any rates of intraoperative BDI identification, but only one had enough events for analysis (685 IOC vs 269 LUS) [58, 60, 61]. There was a nonsignificant trend towards increased intraoperative BDI identification with IOC vs LUS (OR 3.56 [0.19, 66.33]).

Intraoperative identification of stone: Seven observational studies (2,214 IOC vs 2,037 LUS) reported rates of intraoperative identification of stone [57-59, 61-64]. Meta-analysis summarizing data was relatively equivocal in intraoperative stone identification of IOC versus LUS (OR 0.89 [0.71, 1.12], I²=0%).

Postoperative identification of BDI: One observational study (685 IOC vs 269 LUS) reported postoperative rates of identifying BDI [61]. Event rates were low (1/685 IOC vs 0/269), and data was equivocal (OR 1.18 [0.05, 29.08]).

Postoperative bile leak: One observational study (7 IOC vs. 200 LUS) reported rates of postoperative bile leak [63]. Sample size (7 IOC) and event rates (1/7 IOC vs. 1/200 LUS) were low. Data was significant for increased rates of postoperative bile leak with IOC over LUS (33.17 [1.85, 595.78]).

Postoperative identification of CBD stone: Seven observational studies (2,214 IOC vs 2,037 LUS) reported rates of retained stones [57-59, 61-64]. IOC and LUS groups had similar rates of retained stones (27/2,214 vs 2,037, respectively). Effect size was small, and meta-analysis was equivocal for postoperative identification of CBD stones by IOC versus LUS (OR 1.53 [0.84, 2.78], I²=0%).

Postoperative ERCP: Two observational studies (465 IOC vs 480 LUS) reported rates of postoperative ERCP [59, 62]. IOC and LUS had rare but similar rates of requiring postoperative ERCP (3/465 vs 3/480, respectively). Meta-analysis revealed equivocal odds for postoperative ERCP in IOC versus LUS (OR 1.01 [0.20, 5.08], I²=0%).

DISCUSSION

Bile duct injuries and retained stones are rare but serious complications for patients as well as costly sequelae of the surgical treatment of benign biliary disease. While IOC is well-studied, it is not universally utilized, and newer options have emerged. This systematic review compares IOC with alternative methods of intraoperative biliary imaging in terms of key outcomes that include but are not limited to bile duct injuries and retained stones.

Summary of evidence

Although many studies have evaluated IOC in comparison to no IOC, as well as routine versus selective IOC, there are limited comparative studies comparing IOC with other methods, such as FI with ICG and LUS. Studies evaluating the use of IOC in specific settings such as the pediatric population and pregnant patients were often excluded from high-quality, comparative studies. Another limitation is that the two main outcomes of interest, BDI (whether detected intra- or postoperatively) and retained stones, are relatively rare. Even in the broadest comparisons performed in this systematic review (IOC versus no IOC), differences in outcomes of interest were often not statistically significant. Risk of bias (RoB) was notably high for pediatric studies, especially in terms of follow-up and adjusting for confounding factors, suggesting a greater need for longitudinal studies. RoB was overall low for all RCT studies included, as well as for observational studies included in KQ1b and KQ2, suggesting that at least some high-quality studies support these findings.

Using IOC routinely was associated with the advantages of identifying aberrant anatomy and identifying stones intraoperatively. The data was equivocal for intraoperative identification of BDI and retained stones, while IOC was associated with increased OR time and postoperative ERCP use. The increased OR time associated with intraoperative cholangiogram may be justified by the time saved in the postoperative setting in avoiding additional imaging, laboratory tests, and interventions. It is unclear if higher rates of postoperative ERCP following IOC represent detection of stones that would have remained asymptomatic, or if the stones would have presented later. It is also unclear if these data were affected by selection bias, as preoperative ERCP may have precluded IOC in some patients.

Performing routine IOC maintained the benefits of selective IOC with better identification of stones and potential improvements in identifying anatomy. Routine IOC additionally had nonsignificant associations with fewer ERCPs, bile duct injuries, and postoperative stone retention.

More BDIs were identified with IOC compared to FI with ICG and LUS, which may be indicative of its use in cases with higher suspicion for BDI. However, both FI and LUS were more likely to require secondary intraoperative imaging, as only IOC is both diagnostic and therapeutic. Furthermore, FI with ICG and LUS were more likely to have indeterminate imaging findings. As a result, these findings should be considered alongside clinician experience and other relevant factors.

Relationship to literature

Similar systematic reviews on this topic differ in conclusions, but in general, seem to have found trends that agree with this report’s findings. Notably, the systematic review performed by the multi-society Prevention of Bile Duct Injury Consensus Work Group supported a liberal use of cholangiograms compared to no IOC [65]. Other systematic reviews and meta analyses on IOC versus no IOC also supported the use of IOC, but at varying levels due to the scarcity of data [66-68], as was mentioned in this study.

Few systematic reviews investigated outcomes of IOC versus other intraoperative bile duct imaging techniques. Two studies reviewed the literature to investigate diagnostic capability of IOC versus LUS and concluded that the two methods were comparable, with additional benefit attributed to LUS for its non-invasive and non-radiation-dependent features [69, 70].

Few systematic reviews investigated outcomes of selective IOC compared to those of routine IOC. One systematic review concluded that routine IOC was recommended over selective IOC due to increased detection rate of bile duct stones [71], however a second review reported no differences in outcomes between selective and routine IOC [68]0

To our knowledge, there have been no systematic reviews that have investigated the same comparisons between methods of bile duct imaging. As the same group of investigators reviewed, analyzed, and interpreted the data, we believe that this study will be a helpful, comprehensive addition to the existing literature.

Limitations

Limitations of this study include the small event rates of BDIs and retained stones in addition to relatively small sample sizes of studies published on intraoperative bile duct imaging. Although the broadest key questions on intraoperative bile duct imaging with the most relevant literature were selected for investigation, some outcomes were analyzed with data from one or two small RCTs or observational studies. Panelist discussions to be published in the guideline manuscript will provide conditional recommendations in the setting of data limitations.

Future research recommendations

In general, large, randomized studies are needed for evaluating intraoperative imaging. Notably absent from adult and pediatric studies were studies that included pregnant patients. While short spurts of low-dose radiation to the upper abdomen with the use of abdominal and pelvic shields can improve the safety of IOC, some risk with ionizing radiation remains. ICG and LUS may be safe and effective alternatives for pregnant women [72], but outcomes of intraoperative imaging in pregnant women has not yet been tested.

Another understudied subgroup are pediatric patients. The risk of benign biliary disease in children has been rising in the past few decades [73-75], possibly related to rising childhood obesity [76], but data on intraoperative imaging for children remains sparse.

Conclusion

Use of routine versus selective IOC, and IOC versus ICG appear to minimize the potential for undesirable outcomes after cholecystectomy for benign biliary disease. IOC appears comparable to LUS in avoiding these outcomes, but LUS is more likely to require confirmatory imaging in some instances, which may limit its reliability. Although IOC does have some downsides like increased OR time, it appears to offer advantages with regards identifying CBD stones and aberrant anatomy. Application in the pediatric population requires further research.

Supplementary Information

Acknowledgement :The authors would like to acknowledge Holly Ann Burt for her contribution in performing the literature search for all included studies. We would also like to acknowledge Sarah Colón for her help in organizing the guidelines committee meetings and communication.

Funding: This study received no external funding. The SAGES Education and Research Foundation (SERF) grant supported the guideline fellow, methodologist, statistician and librarian.

Declarations

Disclosures: Julie Hong, Sunjay Kumar, Intekhab Akram, Sharif Rauf
Khan, Lawrence N. Cetrulo, Jefrey Chiu, Brian Davis, Marian McDonald, Subhashini Ayloo, Ali Kchaou, David Overby, Dena G. Shehata,
Eduardo Moreno-Paquentin, and Emily Mirafor have no conficts
of interest to disclose. Romeo Ignacio is a stockholder of publicly
available stock in Abbott Laboratories and AbbVie. Bethany J. Slater
reports consulting fees from Hologic and holds positions as Chair of
the SAGES Guideline Committee, Member of the Board for SAGES,
and Member of the Executive Board for IPEG.

Ethical approval: Not applicable.
Informed consent: Not applicable

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Author Affiliations

Julie Hong¹, Sunjay Kumar², Intekhab Akram³, Sharif Rauf Khan³, Lawrence N. Cetrulo⁴, Romeo Ignacio⁵, Jeffrey Chiu⁶, Brian Davis⁷, Marian McDonald⁸, Subhashini Ayloo⁹, Ali Kchaou¹⁰, David Overby¹¹, Dena G. Shehata¹², Eduardo Moreno‑Paquentin¹³, Bethany J. Slater¹⁴, Emily Miraflor¹⁵

1. Department of Surgery, New York Presbyterian-Queens, New York, NY, USA
2. Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
3. Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
4. Department of Surgery, University of Washington School of Medicine, Seattle, USA
5. Division of Pediatric Surgery, Department of Surgery, University of California San Diego School of Medicine, San Diego, CA, USA
6. Department of Surgery, AdventHealth, Orlando, FL, USA
7. Christus Trinity Clinic, Corpus Christi, TX, USA
8. University of Pennsylvania, Philadelphia, PA, USA
9. Department of Surgery, Aleda E. Lutz VA Medical Center, Sagina, MI, USA
10. Department of General and Digestive Surgery, Faculty of Medicine, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
11. Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
12. Department of Surgery, Lahey Hospital and Medical Center, Burlington, MA, USA
13. Department of Surgery, ABC Medical Center, Mexico City, Mexico
14. Department of Surgery, University of Chicago, Chicago, IL, USA
15. Department of Surgery, University of California-East Bay, Oakland, CA, USA

Corresponding author: Dena G. Shehata