Dig Dis Sci DOI 10.1007/s10620-014-3255-7
ORIGINAL ARTICLE
Analysis of Risk Factors for Postoperative Complication of Repair of Bile Duct Injury After Laparoscopic Cholecystectomy Qiang Huang • Han Hui Yao • Feng Shao • Chen Wang • Yuan Guo Hu • Sanyuan Hu • Lu Jun Qiu
Received: 2 December 2013 / Accepted: 15 June 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Bile duct injury (BDI) after laparoscopic cholecystectomy (LC-BDI) is still a major problem. However, despite the many improvements in clinical management of patients undergoing repair, postoperative complications remain frequent and factors that increase the susceptibility to such adverse events remain unknown. Aim To report on a large experience with laparoscopic cholecystectomy-associated bile duct injuries (LC-BDIs) and define predictive factors associated with postoperative complication. Methods A retrospective medical record review of 94 patients referred for the surgical management of major BDIs to our center during a 12-year period between January 1, 1998, and December 31, 2010, was performed. Univariate statistical analysis and multivariate analysis were used to identify risk factors for postoperative complications. A nomogram was developed to predict postoperative complication, given associated risk factors, and bootstrap validation was performed. Results In univariate analysis, there is no factor significantly associated with short-term complication. There was a statistically significant relationship between type of repair and the risk of biliary strictures (p = 0.012). Other factors
Q. Huang S. Hu (&) Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Road, Jinan 250012, China e-mail: [email protected] H. H. Yao F. Shao C. Wang Y. G. Hu L. J. Qiu Department of General Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University, Hefei 230001, Anhui, China
significantly associated with late biliary strictures were sepsis (p = 0.007) and bile leak (p = 0.003). In multivariate analysis, bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication. The resulting nomogram demonstrated good accuracy in predicting long-term complication, with a bootstrap-corrected concordance index 0.7905. Conclusions Our results suggest that missed injuries that result in sepsis or bile leak as well as high injuries that require hepaticojejunostomy will result in a higher stricture rate after repair. Keywords Biliary injury Laparoscopic cholecystectomy Risk factors Complication
Introduction Bile duct injury (BDI) after laparoscopic cholecystectomy (LC-BDI) is still a major problem. BDI is associated with increased morbidity, reduced survival, and impaired quality of life [1–3]. Advances in operative technique and postoperative care have resulted in a decrease in the substantial rate of complication that was once associated with repair after LC-BDIs [4]. However, despite the many improvements in clinical management of patients undergoing repair, postoperative complications remain frequent. Reports from large-volume hepatobiliary surgery centers have focused mainly regarding the optimal timing of repair after LC-BDI to prevent postoperative complication [5–7]. Few studies have examined the risk factor of postoperative complication. The purpose of the present study was to review the results of surgical repair of LC-BDI and identify the predictors of postoperative complication.
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Patients and Methods A retrospective medical record review of all patients referred for the surgical management of major BDIs to our center during a 12-year period between January 1, 1998, and December 31, 2010, was performed. All patients who underwent repair surgery for LC-BDI were identified. Ninety-four patients formed the study cohort. All patients referred to our institution for a biliary injury had undergone elective laparoscopic cholecystectomy. Perioperative data including patient demographics, operative details, preoperative data, and postoperative outcomes were extracted. Research ethics board approval was obtained from An Hui provincial Hospital. All patients evaluated for LC-BDIs underwent preoperative investigations to evaluate biliary anatomy. The level of injury was assessed using either magnetic resonance cholangiography or percutaneous transhepatic cholangiography or endoscopic retrograde cholangiograms. The anatomic extent of LC-BDIs was classified using the Strasberg–Bismuth classification system [8]. Patients requiring surgical revision within the first 2 weeks of injury were also included in the early repair group. Repair between 2 and 24 weeks was considered as delayed repair. Short-term postoperative complications were defined as those occurring within 30 days of the repair surgery and were graded using the Dindo grade classification system [9] (Table 1). Bile leak was defined as intra-abdominal bile identified in the postoperative setting, excluding those
Table 1 Dindo classification of postoperative complications Grade
Description
Complications
I
Any deviation from the normal postoperative course and includes wound infections opened at the bedside
Delirium, leg numbness
II
Requiring pharmacological treatment with drugs other than that allowed for grade I complications
Cholangitis, Clostridium difficile infection, postoperative bleeding
IIIa
Requiring surgical, endoscopic, or radiological intervention not under general anesthesia
Bile duct stricture, bile leak, cholangitis, DVT/PE, intra-abdominal abscess, pleural effusion
IIIb
Requiring surgical, endoscopic, or radiological intervention under general anesthesia
Bile duct stricture, incisional hernia
IV
Life-threatening complication requiring intensive care unit management
V
Death of a patient
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identified intra-operatively during LC. Long-term postoperative complications were those occurring after 30 days post repair and included bile duct strictures. Clinically significant biliary stricture was defined as a stricture that resulted in signs and symptoms requiring either surgical or percutaneous intervention. The duration of follow-up was calculated from the date of the LC-BDI repair to last follow-up visit. The median patient follow-up was 65.5 months, with a range of 6–120 months. Statistical Analysis Chi-square tests were used for categorical variables, and logistic regression analysis was used for multivariate analysis. Variables examined include sex, age (B50 years or [50 years), presence or absence of bile leak, jaundice, sepsis, more complex LC-BDIs (classes E4 and E5), type of repair, and timing of the repair (early or delayed). Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used to determine the adequacy of the prediction models. The accepted level of significance was p \ 0.05. The internal validation of the models was assessed with the bootstrap re-sampling technique. Regression models were estimated in 200 bootstrap samples because 200 bootstraps are often sufficient to obtain stable estimates. Each resampling could be recognized as a replacement for the original samples. As a measure of discrimination, we calculated the concordance index (C-index) from a bootstrapped sample as an internal control. The nomogram was established by using selected risk factors for predicting an individual patient’s probability of developing complication after repair [10]. Statistical analyses were performed using R2.15.2 (http://www. R-project.org).
Results Patient Characteristics Ninety-four patients were reviewed. There were 27 men and 67 women with a mean age of 46.4 years (range 20–74 years). The annual distribution of these patients is depicted in Fig. 1. Eighty patients (85 %) were referred from community hospitals and 14 patients (15 %) from academic hospitals. When BDIs presented after the LC was performed, patients presented with bile leak [n = 16 (17 %)], jaundice [defined as having a total bilirubin serum level more than twice the upper limit of normal; n = 55 (59 %)], and/or intra-abdominal sepsis [defined as having a fever 38 °C, elevated white blood cell count, and abdominal pain; n = 25 (27 %)]. Preoperative investigations included endoscopic retrograde cholangiopancreatography
Dig Dis Sci Table 3 Univariate complications
analysis Total
for
Short-term complications
Sex Male
27
5
Female Age
67
15
B50
60
13
[50
34
7
Academic
14
3
Community
80
17
Present
16
4
Absent
78
16
Present
55
11
Absent
39
9
69
14
25
6
Hospital of origin
Bile leak
Jaundice Fig. 1 Year of presentation of patients with bile duct injury after laparoscopic cholecystectomy referred to our center
Sepsis Present Table 2 Patient characteristics of 94 patients undergoing repair Characteristic
N (%)
Sex Male Female Age
27 (29 %) 67 (71 %) 46.4 (20–74)
Site of laparoscopic cholecystectomy Community hospital Academic hospital
80 (85 %) 14 (15 %)
Patient presentation Bile leak Jaundice
16 (17 %) 55 (59 %)
Sepsis
25 (27 %)
Preoperative investigations ERCP
32 (34 %)
Computed tomography
78 (83 %)
Magnetic resonance imaging
65 (69 %)
Percutaneous transhepatic cholangiography
15 (16 %)
Injury classification A
0
B
0
C
0
D
0
E1
20 (21 %)
E2
18 (19 %)
E3 E4
26 (28 %) 17 (18 %)
E5
13 (14 %)
Absent Strasberg LC-BDI classification
predictors
E1–E3
64
16
E4–E5, complex
30
4
Type of repair Choledochojejunostomy
63
13
Hepaticojejunostomy
31
7
Early
52
8
Delayed
42
12
Timing
of
short-term
v2
p
3.5235
0.061
0.0151
0.902
0.0002
0.988
0.1596
0.690
0.1290
0.719
0.3407
0.559
1.6598
0.198
0.0470
0.828
2.4121
0.120
in 32 patients (34 %), computed tomography in 78 patients (83 %), magnetic resonance imaging in 65 patients (69 %), and percutaneous transhepatic cholangiogram in 15 patients (16 %). The LC-BDIs occurring in our cohort of patients were Strasberg type E1 in 20 patients (21 %), E2 in 18 patients (19 %), E3 in 26 patients (28 %), E4 in 17 patients (18 %), and E5 in 13 patients (14 %) (Table 2). It was our institutional policy to perform LC-BDIs at the time of presentation during this study. Patients with suspected LC-BDIs were admitted and underwent preoperative assessment of their biliary anatomy. The patients with biliary peritonitis, sepsis or organ failure were managed initially by biliary drainage, percutaneous or surgical drainage of abdominal collections and treatment of sepsis. The repair of these patients was delayed. When sepsis and intra-abdominal contamination had been controlled and fitness for surgery optimized, definitive surgical repair was performed.
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Dig Dis Sci Table 4 Univariate complications
analysis Total
for
Long-term complications
Sex 27
4
Female Age
67
13
long-term
v2
p
B50
60
12
34
5
Hospital of origin Academic
14
3
Community
80
14
Present
16
7
Absent
78
10
Present
55
10
Absent
39
7
69
8
25
9
Bile leak
Jaundice
Sepsis
E1–E3
64
11
E4–E5, complex
30
6
Type of repair Choledochojejunostomy
63
7
Hepaticojejunostomy
31
10
Early
52
10
Delayed
42
7
Timing
Table 5 Multivariate analysis predictors of long-term complications Odd ratio
95 % CI
p
Present
7.06
1.81–27.55
0.005
Absent
1 1.14–13.07
0.03
1.16–13.74
0.028
Bile leak 0.601
Sepsis 0.4106
[50
Present Strasberg LC-BDI classification
of
0.2735
Male
Absent
predictors
0.522
Present
3.86
Absent
1
Type of repair 0.1241
0.725
8.5733
0.003
0.0008
0.977
7.3784
0.007
0.1091
0.741
6.2717
0.012
0.1396
0.709
Hepaticojejunostomy
3.99
Choledochojejunostomy
1
Fig. 2 ROC curve for prediction of long-term complication estimated using multiple logistic regression
Sixty-three Roux en-Y choledochojejunostomies (67 %) and 31 hepaticojejunostomies (33 %) were performed. The mean amount of time for patients to undergo surgical repair after experiencing sepsis was 30.9 days (median 30 days). The total short-term complication rate was 21.2 % (20 patients) in the cohort. Complications were classified according to the Dindo classification system. The most common was cholangitis, which occurred in 13 patients (10 %). Other short-term complications included intraabdominal abscess (3 patients), wound infection (1 patients), urinary tract infection (1 patient), postoperative bleeding (1 patients), and gastrointestinal bleeding (1 patient). There was no case of death. Long-term complications developed in 17 patients (18 %). The major long-term complication was bile duct stricture, which developed in 16 patients (17 %). All postoperative biliary strictures were evaluated by interventional
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radiology with percutaneous transhepatic cholangiography (PTC) and managed with the placement of a biliary catheter (PBD) across the stricture. There were no cases of secondary biliary cirrhosis.
Univariate Analysis of Factors Associated Short-Term Complication There were no associations between short-term postoperative complications and any of the perioperative variables: sex (p = 0.061), age (p = 0.902), jaundice (p = 0.719), sepsis (p = 0.559), type of repair (p = 0.828), timing of the repair (p = 0.120), hospital of origin (p = 0.988), and complex LC-BDIs (p = 0.198) (Table 3).
Dig Dis Sci
Fig. 3 Nomogram was established for predicting an individual patient’s probability of developing long-term complication after repair. To obtain nomogram predicted probability of complication, locate patient values at each axis. Draw a vertical line to the ‘‘Point’’ axis to determine how many points are attributed for each variable value. Sum the points for all variables. Locate the sum on the ‘‘Total
Points’’ line to be able to assess the individual probability of complication. The nomogram incorporates three variables. Points for each prognostic variable were allocated according to the scale shown here. A total score was determined by adding individual parameter points and used to calculate the predicted probability of developing long-term complication after repair
Univariate Analysis of Factors Associated Long-Term Complication
Internal Validation of the Model and Nomogram
Univariate analysis showed that certain types of operation were significantly associated or not associated with longterm complication. There was a statistically significant relationship between type of repair and the risk of biliary strictures (p = 0.012). Other factors significantly associated with late biliary strictures were sepsis (p = 0.007) and bile leak (p = 0.003). The factors including sex (p = 0.601), age (p = 0.522), timing of the repair (p = 0.709), hospital of origin (p = 0.725), and complex LC-BDIs (p = 0.741) were not significantly associated long-term complication (Table 4). Multivariate Analysis of Factors Associated LongTerm Complication Multivariate analysis revealed that bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication (Table 5). Figure 2 shows the ROC curve for the resulting equation, which is based on bile leak, jaundice, sepsis, and type of repair. The predictive model had an AUC of 0.8193, indicating good accuracy.
The resulting model was internally validated using the bootstrap validation method. The model demonstrated good accuracy for predicting long-term complication, with an unadjusted C-index of 0.8193 and a bootstrap-corrected C-index of 0.7905. Figure 3 shows the regression coefficient-based nomogram. Bile leak, jaundice, type of repair, and sepsis are risk factors for long-term complication.
Discussion Despite improvements in technology, biliary injury continues to be a serious complication of laparoscopic cholecystectomy [11, 12]. These injuries occur in patients who have acute or chronic inflammation that obscures normal anatomic planes in the hepato-cystic triangle [13]. When an injury is recognized at original surgery, a primary repair by an experienced surgeon is associated with reduced morbidity and shorter illness and lower cost. In our department, it has been our policy to repair LC-BDI at the time of presentation without delay. There is consensus that LCBDI are best handled in specialized hepatobiliary units [4,
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12]. Successful repair has been reported in 80–92 % of patients in a unit experienced in the management [14–16]. A similar success rate was achieved in our study. Moreover, the control of sepsis and the ongoing bile leak is the primary goal of the initial management of a BDI. If this can be accomplished, proceeding with surgical reconstruction is not urgent. In fact, reconstruction in the face of peritonitis portends a worse outcome in patients. However, advance in diagnosis and in treatment of BDI is paramount in preventing life-threatening complications of cholangitis, biliary cirrhosis, portal hypertension, end-stage liver disease, and death, which also resulted in a decrease in the substantial rate of complication that was once associated with repair after LC-BDIs. In our study, we found that there were no specific risk factors identified for short-term complications. However, it was found that bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication. The ROC curve is a graphical technique for assessing the ability of a test to discriminate between those with and those without outcome. The curve is obtained by calculating the sensitivity and specificity of the test at every possible cutoff point, and plotting sensitivity against 1-specificity. The area under the curve (AUC) between 0.5 and 1.0 indicates sensible models; the higher the better. By integrating these variables, the predictive model demonstrated an AUC of 0.8193, also indicating good discrimination. Clinically evident bile leak following LC-BDI may be the increased rate of bile contamination of the peritoneal cavity in these patients. Even in the absence of intraabdominal sepsis, bile leak may result in increased acute inflammatory changes in the surgical bed [17]. Moreover, patients with clinically evident bile leak following LC-BDI underwent repair compared earlier with patients without clinical bile leak. Early postoperative inflammation and tissue friability result in increased technical difficulties at time of repair. These inflammatory changes may be absent early in LC-BDI and be minimal in immediately identified. But these inflammatory changes may predispose patients to fibrosis, resulting in a late biliary stricture [16]. This study also found that the presence of intra-abdominal sepsis is an independently risk factor for long-term complication. Intraabdominal sepsis may result in increased rate of perianastomotic infection, even drained effectively. Under these circumstances, ductal tissue is often ischemic and is replaced by fibrotic scar tissue, which causes the delayed stricture. Preoperative jaundice, which was assumed to be a surrogate for biliary dilatation, was presented in 59 % of patients who later developed a biliary stricture. One might assume that a large bile duct would make a subsequent biliary stricture after choledochojejunostomy or hepaticojejunostomy; however,
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ductal dilatation was not protective against stricture formation. In our study, preoperative jaundice did not protect against biliary stricture formation. With univariate analysis and multivariate analysis, patients repaired by Roux en-Y hepaticojejunostomies had higher rate of stricture formation. However, it was not type of operation but the location of biliary injury which resulted in a higher stricture rate after repair. When Roux en-Y hepaticojejunostomies were performed, the LC-BDIs occur high in the biliary tree, involving the proximal extrahepatic biliary system. Concomitant vasculobiliary injuries are often present in these patients, which lead to ischemia of bile duct. The policy is to wait for collateral circulation within the hilar plate to provide an adequate arterial blood supply to the biliary confluence and the extrahepatic portion of the bile duct before performing the biliary repair. However, the outcome following bile duct injury repair was worse in these patients [18]. Previous authors tested univariate models to analyze risk factors of postoperative complication [19]. However, we performed multivariate analysis to estimate adjusted odd ratio. Furthermore, nomograms provide a simple way to adjudicate the appropriate weight to each variable included in the model. A major strength of the nomograms described is that they were developed making use of all available clinical information and all the variables modeled are readily available and reproducible, which allows for application in different settings. For example, a patient with intra-abdominal sepsis (69 points) who was performed hepaticojejunostomies (71 points) has a total of 140 points, yielding an estimated probability of long-term complication of 42 %. The bootstrap-corrected C-index of 0.7905 suggests a sufficient level of accuracy. Although the nomogram model demonstrated good accuracy for predicting complication, there are several limitations to the data that must be considered. First, we did perform computed tomography with vascular reconstruction to identify vasculobiliary injuries. However, outcome following bile duct injury repair was worse in patients with concomitant vasculobiliary injury. Second, with any predictive model, the point estimates have an inherent range of uncertainty, and the size of this range increases for patients who do not have adverse effect. Given the small number of adverse effects following LC-BDI, it is unlikely that any single study will be able to fully assess the risk factors for adverse events following LC-BDI with adequate power. Third, the use of retrospective data introduces the possibility of treatment selection bias. Patients with Strasberg– Bismuth A–D were not included in this study, so odd ratio estimates may be less precise for these patients. Third, we used ERCP or PTC to evaluate biliary anatomy, not for treatment, which were not associated with short-term and long-term outcome [19]. However, there may be
Dig Dis Sci
correlation between these preoperative intervention and outcome. Finally, intra-abdominal sepsis was defined as having a fever 38 °C, elevated white blood cell count and abdominal pain [19]. However, leukocytosis, pain, and fever could be seen with significant biloma without abdominal infection. These patients were included in intraabdominal sepsis group in current study. Thus, odd ratio estimated by logistic regression model may be less precise. In summary, our results suggest that missed injuries that result in sepsis or bile leak as well as high injuries that require hepaticojejunostomy will result in a higher stricture rate after repair. Conflict of interest
None.
References 1. Mirza DF, Narsimhan KL, Ferras Neto BH, Mayer AD, McMaster P, Buckels JA. Bile duct injury following laparoscopic cholecystectomy: referral pattern and management. Br J Surg. 1997;84:786–790. 2. Flum DR, Cheadle A, Prela C, Dellinger EP, Chan L. Bile duct injury during cholecystectomy and survival in medicare beneficiaries. JAMA. 2003;290:2168–2173. 3. Boerma D, Rauws EA, Keulemans YC, et al. Impaired quality of life 5 years after bile duct injury during laparoscopic cholecystectomy: a prospective analysis. Ann Surg. 2001;234:750–757. 4. Sicklick JK, Camp MS, Lillemoe KD, et al. Surgical management of bile duct injuries sustained during laparoscopic cholecystectomy: perioperative results in 200 patients. Ann Surg. 2005;241:786–792. 5. Carroll BJ, Birth M, Phillips EH. Common bile duct injuries during laparoscopic cholecystectomy that result in litigation. Surg Endosc. 1998;12:310–314. 6. Olsen D. Bile duct injuries during laparoscopic cholecystectomy. Surg Endosc. 1997;11:133–138.
7. Goykhman Y, Kory I, Small R, et al. Long-term outcome and risk factors of failure after bile duct injury repair. J Gastrointest Surg. 2008;12:1412–1417. 8. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy [see comment]. J Am Coll Surg. 1995;180:101–125. 9. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240: 205–213. 10. Harrell FE Jr, Califf RM, Pryor DB, et al. Evaluating the yield of medical tests. JAMA. 1982;247:2543–2546. 11. Melton GB, Lillemoe KD, Cameron JL, et al. Major bile duct injuries associated with laparoscopic cholecystectomy: effect of surgical repair on quality of life. Ann Surg. 2002;235:888–895. 12. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct strictures: management and outcome in the 1990s. Ann Surg. 2000;232:430–441. 13. Bergman JJ, van den Brink GR, Rauws EA, et al. Treatment of bile duct lesions after laparoscopic cholecystectomy. Gut. 1996;38:141–147. 14. Huang Q, Shao F, Qiu LJ, Wang C. Early vs. delayed repair of isolated segmental, sectoral and right hepatic bile duct injuries. Hepatogastroenterology. 2011;58:725–728. 15. Al-Ghnaniem R, Benjamin IS. Long-term outcome of hepaticojejunostomy with routine access loop formation following iatrogenic bile duct injury. Br J Surg. 2002;89:1118–1124. 16. Murr MM, Gigot JF, Nagorney DM, Harmsen WS, Ilstrup DM, Farnell MB. Long-term results of biliary reconstruction after laparoscopic bile duct injuries. Arch Surg. 1999;134:604–609. 17. Schmidt SC, Langrehr JM, Hintze RE, Neuhaus P. Long-term results and risk factors influencing outcome of major bile duct injuries following cholecystectomy [retraction in Br J Surg. 2006;93(12):1562]. Br J Surg. 2005;92:76–82. 18. Sarno G, Al-Sarira AA, Ghaneh P, Fenwick SW, Malik HZ, Poston GJ. Cholecystectomy-related bile duct and vasculobiliary injuries. Br J Surg. 2012;99:1129–1136. 19. Sahajpal AK, Chow SC, Dixon E, Greig PD, Gallinger S, Wei AC. Bile duct injuries associated with laparoscopic cholecystectomy: timing of repair and long-term outcomes. Arch Surg. 2010;145:757–763.
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ORIGINAL ARTICLE
Analysis of Risk Factors for Postoperative Complication of Repair of Bile Duct Injury After Laparoscopic Cholecystectomy Qiang Huang • Han Hui Yao • Feng Shao • Chen Wang • Yuan Guo Hu • Sanyuan Hu • Lu Jun Qiu
Received: 2 December 2013 / Accepted: 15 June 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Bile duct injury (BDI) after laparoscopic cholecystectomy (LC-BDI) is still a major problem. However, despite the many improvements in clinical management of patients undergoing repair, postoperative complications remain frequent and factors that increase the susceptibility to such adverse events remain unknown. Aim To report on a large experience with laparoscopic cholecystectomy-associated bile duct injuries (LC-BDIs) and define predictive factors associated with postoperative complication. Methods A retrospective medical record review of 94 patients referred for the surgical management of major BDIs to our center during a 12-year period between January 1, 1998, and December 31, 2010, was performed. Univariate statistical analysis and multivariate analysis were used to identify risk factors for postoperative complications. A nomogram was developed to predict postoperative complication, given associated risk factors, and bootstrap validation was performed. Results In univariate analysis, there is no factor significantly associated with short-term complication. There was a statistically significant relationship between type of repair and the risk of biliary strictures (p = 0.012). Other factors
Q. Huang S. Hu (&) Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Road, Jinan 250012, China e-mail: [email protected] H. H. Yao F. Shao C. Wang Y. G. Hu L. J. Qiu Department of General Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University, Hefei 230001, Anhui, China
significantly associated with late biliary strictures were sepsis (p = 0.007) and bile leak (p = 0.003). In multivariate analysis, bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication. The resulting nomogram demonstrated good accuracy in predicting long-term complication, with a bootstrap-corrected concordance index 0.7905. Conclusions Our results suggest that missed injuries that result in sepsis or bile leak as well as high injuries that require hepaticojejunostomy will result in a higher stricture rate after repair. Keywords Biliary injury Laparoscopic cholecystectomy Risk factors Complication
Introduction Bile duct injury (BDI) after laparoscopic cholecystectomy (LC-BDI) is still a major problem. BDI is associated with increased morbidity, reduced survival, and impaired quality of life [1–3]. Advances in operative technique and postoperative care have resulted in a decrease in the substantial rate of complication that was once associated with repair after LC-BDIs [4]. However, despite the many improvements in clinical management of patients undergoing repair, postoperative complications remain frequent. Reports from large-volume hepatobiliary surgery centers have focused mainly regarding the optimal timing of repair after LC-BDI to prevent postoperative complication [5–7]. Few studies have examined the risk factor of postoperative complication. The purpose of the present study was to review the results of surgical repair of LC-BDI and identify the predictors of postoperative complication.
123
Dig Dis Sci
Patients and Methods A retrospective medical record review of all patients referred for the surgical management of major BDIs to our center during a 12-year period between January 1, 1998, and December 31, 2010, was performed. All patients who underwent repair surgery for LC-BDI were identified. Ninety-four patients formed the study cohort. All patients referred to our institution for a biliary injury had undergone elective laparoscopic cholecystectomy. Perioperative data including patient demographics, operative details, preoperative data, and postoperative outcomes were extracted. Research ethics board approval was obtained from An Hui provincial Hospital. All patients evaluated for LC-BDIs underwent preoperative investigations to evaluate biliary anatomy. The level of injury was assessed using either magnetic resonance cholangiography or percutaneous transhepatic cholangiography or endoscopic retrograde cholangiograms. The anatomic extent of LC-BDIs was classified using the Strasberg–Bismuth classification system [8]. Patients requiring surgical revision within the first 2 weeks of injury were also included in the early repair group. Repair between 2 and 24 weeks was considered as delayed repair. Short-term postoperative complications were defined as those occurring within 30 days of the repair surgery and were graded using the Dindo grade classification system [9] (Table 1). Bile leak was defined as intra-abdominal bile identified in the postoperative setting, excluding those
Table 1 Dindo classification of postoperative complications Grade
Description
Complications
I
Any deviation from the normal postoperative course and includes wound infections opened at the bedside
Delirium, leg numbness
II
Requiring pharmacological treatment with drugs other than that allowed for grade I complications
Cholangitis, Clostridium difficile infection, postoperative bleeding
IIIa
Requiring surgical, endoscopic, or radiological intervention not under general anesthesia
Bile duct stricture, bile leak, cholangitis, DVT/PE, intra-abdominal abscess, pleural effusion
IIIb
Requiring surgical, endoscopic, or radiological intervention under general anesthesia
Bile duct stricture, incisional hernia
IV
Life-threatening complication requiring intensive care unit management
V
Death of a patient
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identified intra-operatively during LC. Long-term postoperative complications were those occurring after 30 days post repair and included bile duct strictures. Clinically significant biliary stricture was defined as a stricture that resulted in signs and symptoms requiring either surgical or percutaneous intervention. The duration of follow-up was calculated from the date of the LC-BDI repair to last follow-up visit. The median patient follow-up was 65.5 months, with a range of 6–120 months. Statistical Analysis Chi-square tests were used for categorical variables, and logistic regression analysis was used for multivariate analysis. Variables examined include sex, age (B50 years or [50 years), presence or absence of bile leak, jaundice, sepsis, more complex LC-BDIs (classes E4 and E5), type of repair, and timing of the repair (early or delayed). Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used to determine the adequacy of the prediction models. The accepted level of significance was p \ 0.05. The internal validation of the models was assessed with the bootstrap re-sampling technique. Regression models were estimated in 200 bootstrap samples because 200 bootstraps are often sufficient to obtain stable estimates. Each resampling could be recognized as a replacement for the original samples. As a measure of discrimination, we calculated the concordance index (C-index) from a bootstrapped sample as an internal control. The nomogram was established by using selected risk factors for predicting an individual patient’s probability of developing complication after repair [10]. Statistical analyses were performed using R2.15.2 (http://www. R-project.org).
Results Patient Characteristics Ninety-four patients were reviewed. There were 27 men and 67 women with a mean age of 46.4 years (range 20–74 years). The annual distribution of these patients is depicted in Fig. 1. Eighty patients (85 %) were referred from community hospitals and 14 patients (15 %) from academic hospitals. When BDIs presented after the LC was performed, patients presented with bile leak [n = 16 (17 %)], jaundice [defined as having a total bilirubin serum level more than twice the upper limit of normal; n = 55 (59 %)], and/or intra-abdominal sepsis [defined as having a fever 38 °C, elevated white blood cell count, and abdominal pain; n = 25 (27 %)]. Preoperative investigations included endoscopic retrograde cholangiopancreatography
Dig Dis Sci Table 3 Univariate complications
analysis Total
for
Short-term complications
Sex Male
27
5
Female Age
67
15
B50
60
13
[50
34
7
Academic
14
3
Community
80
17
Present
16
4
Absent
78
16
Present
55
11
Absent
39
9
69
14
25
6
Hospital of origin
Bile leak
Jaundice Fig. 1 Year of presentation of patients with bile duct injury after laparoscopic cholecystectomy referred to our center
Sepsis Present Table 2 Patient characteristics of 94 patients undergoing repair Characteristic
N (%)
Sex Male Female Age
27 (29 %) 67 (71 %) 46.4 (20–74)
Site of laparoscopic cholecystectomy Community hospital Academic hospital
80 (85 %) 14 (15 %)
Patient presentation Bile leak Jaundice
16 (17 %) 55 (59 %)
Sepsis
25 (27 %)
Preoperative investigations ERCP
32 (34 %)
Computed tomography
78 (83 %)
Magnetic resonance imaging
65 (69 %)
Percutaneous transhepatic cholangiography
15 (16 %)
Injury classification A
0
B
0
C
0
D
0
E1
20 (21 %)
E2
18 (19 %)
E3 E4
26 (28 %) 17 (18 %)
E5
13 (14 %)
Absent Strasberg LC-BDI classification
predictors
E1–E3
64
16
E4–E5, complex
30
4
Type of repair Choledochojejunostomy
63
13
Hepaticojejunostomy
31
7
Early
52
8
Delayed
42
12
Timing
of
short-term
v2
p
3.5235
0.061
0.0151
0.902
0.0002
0.988
0.1596
0.690
0.1290
0.719
0.3407
0.559
1.6598
0.198
0.0470
0.828
2.4121
0.120
in 32 patients (34 %), computed tomography in 78 patients (83 %), magnetic resonance imaging in 65 patients (69 %), and percutaneous transhepatic cholangiogram in 15 patients (16 %). The LC-BDIs occurring in our cohort of patients were Strasberg type E1 in 20 patients (21 %), E2 in 18 patients (19 %), E3 in 26 patients (28 %), E4 in 17 patients (18 %), and E5 in 13 patients (14 %) (Table 2). It was our institutional policy to perform LC-BDIs at the time of presentation during this study. Patients with suspected LC-BDIs were admitted and underwent preoperative assessment of their biliary anatomy. The patients with biliary peritonitis, sepsis or organ failure were managed initially by biliary drainage, percutaneous or surgical drainage of abdominal collections and treatment of sepsis. The repair of these patients was delayed. When sepsis and intra-abdominal contamination had been controlled and fitness for surgery optimized, definitive surgical repair was performed.
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Dig Dis Sci Table 4 Univariate complications
analysis Total
for
Long-term complications
Sex 27
4
Female Age
67
13
long-term
v2
p
B50
60
12
34
5
Hospital of origin Academic
14
3
Community
80
14
Present
16
7
Absent
78
10
Present
55
10
Absent
39
7
69
8
25
9
Bile leak
Jaundice
Sepsis
E1–E3
64
11
E4–E5, complex
30
6
Type of repair Choledochojejunostomy
63
7
Hepaticojejunostomy
31
10
Early
52
10
Delayed
42
7
Timing
Table 5 Multivariate analysis predictors of long-term complications Odd ratio
95 % CI
p
Present
7.06
1.81–27.55
0.005
Absent
1 1.14–13.07
0.03
1.16–13.74
0.028
Bile leak 0.601
Sepsis 0.4106
[50
Present Strasberg LC-BDI classification
of
0.2735
Male
Absent
predictors
0.522
Present
3.86
Absent
1
Type of repair 0.1241
0.725
8.5733
0.003
0.0008
0.977
7.3784
0.007
0.1091
0.741
6.2717
0.012
0.1396
0.709
Hepaticojejunostomy
3.99
Choledochojejunostomy
1
Fig. 2 ROC curve for prediction of long-term complication estimated using multiple logistic regression
Sixty-three Roux en-Y choledochojejunostomies (67 %) and 31 hepaticojejunostomies (33 %) were performed. The mean amount of time for patients to undergo surgical repair after experiencing sepsis was 30.9 days (median 30 days). The total short-term complication rate was 21.2 % (20 patients) in the cohort. Complications were classified according to the Dindo classification system. The most common was cholangitis, which occurred in 13 patients (10 %). Other short-term complications included intraabdominal abscess (3 patients), wound infection (1 patients), urinary tract infection (1 patient), postoperative bleeding (1 patients), and gastrointestinal bleeding (1 patient). There was no case of death. Long-term complications developed in 17 patients (18 %). The major long-term complication was bile duct stricture, which developed in 16 patients (17 %). All postoperative biliary strictures were evaluated by interventional
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radiology with percutaneous transhepatic cholangiography (PTC) and managed with the placement of a biliary catheter (PBD) across the stricture. There were no cases of secondary biliary cirrhosis.
Univariate Analysis of Factors Associated Short-Term Complication There were no associations between short-term postoperative complications and any of the perioperative variables: sex (p = 0.061), age (p = 0.902), jaundice (p = 0.719), sepsis (p = 0.559), type of repair (p = 0.828), timing of the repair (p = 0.120), hospital of origin (p = 0.988), and complex LC-BDIs (p = 0.198) (Table 3).
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Fig. 3 Nomogram was established for predicting an individual patient’s probability of developing long-term complication after repair. To obtain nomogram predicted probability of complication, locate patient values at each axis. Draw a vertical line to the ‘‘Point’’ axis to determine how many points are attributed for each variable value. Sum the points for all variables. Locate the sum on the ‘‘Total
Points’’ line to be able to assess the individual probability of complication. The nomogram incorporates three variables. Points for each prognostic variable were allocated according to the scale shown here. A total score was determined by adding individual parameter points and used to calculate the predicted probability of developing long-term complication after repair
Univariate Analysis of Factors Associated Long-Term Complication
Internal Validation of the Model and Nomogram
Univariate analysis showed that certain types of operation were significantly associated or not associated with longterm complication. There was a statistically significant relationship between type of repair and the risk of biliary strictures (p = 0.012). Other factors significantly associated with late biliary strictures were sepsis (p = 0.007) and bile leak (p = 0.003). The factors including sex (p = 0.601), age (p = 0.522), timing of the repair (p = 0.709), hospital of origin (p = 0.725), and complex LC-BDIs (p = 0.741) were not significantly associated long-term complication (Table 4). Multivariate Analysis of Factors Associated LongTerm Complication Multivariate analysis revealed that bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication (Table 5). Figure 2 shows the ROC curve for the resulting equation, which is based on bile leak, jaundice, sepsis, and type of repair. The predictive model had an AUC of 0.8193, indicating good accuracy.
The resulting model was internally validated using the bootstrap validation method. The model demonstrated good accuracy for predicting long-term complication, with an unadjusted C-index of 0.8193 and a bootstrap-corrected C-index of 0.7905. Figure 3 shows the regression coefficient-based nomogram. Bile leak, jaundice, type of repair, and sepsis are risk factors for long-term complication.
Discussion Despite improvements in technology, biliary injury continues to be a serious complication of laparoscopic cholecystectomy [11, 12]. These injuries occur in patients who have acute or chronic inflammation that obscures normal anatomic planes in the hepato-cystic triangle [13]. When an injury is recognized at original surgery, a primary repair by an experienced surgeon is associated with reduced morbidity and shorter illness and lower cost. In our department, it has been our policy to repair LC-BDI at the time of presentation without delay. There is consensus that LCBDI are best handled in specialized hepatobiliary units [4,
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12]. Successful repair has been reported in 80–92 % of patients in a unit experienced in the management [14–16]. A similar success rate was achieved in our study. Moreover, the control of sepsis and the ongoing bile leak is the primary goal of the initial management of a BDI. If this can be accomplished, proceeding with surgical reconstruction is not urgent. In fact, reconstruction in the face of peritonitis portends a worse outcome in patients. However, advance in diagnosis and in treatment of BDI is paramount in preventing life-threatening complications of cholangitis, biliary cirrhosis, portal hypertension, end-stage liver disease, and death, which also resulted in a decrease in the substantial rate of complication that was once associated with repair after LC-BDIs. In our study, we found that there were no specific risk factors identified for short-term complications. However, it was found that bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication. The ROC curve is a graphical technique for assessing the ability of a test to discriminate between those with and those without outcome. The curve is obtained by calculating the sensitivity and specificity of the test at every possible cutoff point, and plotting sensitivity against 1-specificity. The area under the curve (AUC) between 0.5 and 1.0 indicates sensible models; the higher the better. By integrating these variables, the predictive model demonstrated an AUC of 0.8193, also indicating good discrimination. Clinically evident bile leak following LC-BDI may be the increased rate of bile contamination of the peritoneal cavity in these patients. Even in the absence of intraabdominal sepsis, bile leak may result in increased acute inflammatory changes in the surgical bed [17]. Moreover, patients with clinically evident bile leak following LC-BDI underwent repair compared earlier with patients without clinical bile leak. Early postoperative inflammation and tissue friability result in increased technical difficulties at time of repair. These inflammatory changes may be absent early in LC-BDI and be minimal in immediately identified. But these inflammatory changes may predispose patients to fibrosis, resulting in a late biliary stricture [16]. This study also found that the presence of intra-abdominal sepsis is an independently risk factor for long-term complication. Intraabdominal sepsis may result in increased rate of perianastomotic infection, even drained effectively. Under these circumstances, ductal tissue is often ischemic and is replaced by fibrotic scar tissue, which causes the delayed stricture. Preoperative jaundice, which was assumed to be a surrogate for biliary dilatation, was presented in 59 % of patients who later developed a biliary stricture. One might assume that a large bile duct would make a subsequent biliary stricture after choledochojejunostomy or hepaticojejunostomy; however,
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ductal dilatation was not protective against stricture formation. In our study, preoperative jaundice did not protect against biliary stricture formation. With univariate analysis and multivariate analysis, patients repaired by Roux en-Y hepaticojejunostomies had higher rate of stricture formation. However, it was not type of operation but the location of biliary injury which resulted in a higher stricture rate after repair. When Roux en-Y hepaticojejunostomies were performed, the LC-BDIs occur high in the biliary tree, involving the proximal extrahepatic biliary system. Concomitant vasculobiliary injuries are often present in these patients, which lead to ischemia of bile duct. The policy is to wait for collateral circulation within the hilar plate to provide an adequate arterial blood supply to the biliary confluence and the extrahepatic portion of the bile duct before performing the biliary repair. However, the outcome following bile duct injury repair was worse in these patients [18]. Previous authors tested univariate models to analyze risk factors of postoperative complication [19]. However, we performed multivariate analysis to estimate adjusted odd ratio. Furthermore, nomograms provide a simple way to adjudicate the appropriate weight to each variable included in the model. A major strength of the nomograms described is that they were developed making use of all available clinical information and all the variables modeled are readily available and reproducible, which allows for application in different settings. For example, a patient with intra-abdominal sepsis (69 points) who was performed hepaticojejunostomies (71 points) has a total of 140 points, yielding an estimated probability of long-term complication of 42 %. The bootstrap-corrected C-index of 0.7905 suggests a sufficient level of accuracy. Although the nomogram model demonstrated good accuracy for predicting complication, there are several limitations to the data that must be considered. First, we did perform computed tomography with vascular reconstruction to identify vasculobiliary injuries. However, outcome following bile duct injury repair was worse in patients with concomitant vasculobiliary injury. Second, with any predictive model, the point estimates have an inherent range of uncertainty, and the size of this range increases for patients who do not have adverse effect. Given the small number of adverse effects following LC-BDI, it is unlikely that any single study will be able to fully assess the risk factors for adverse events following LC-BDI with adequate power. Third, the use of retrospective data introduces the possibility of treatment selection bias. Patients with Strasberg– Bismuth A–D were not included in this study, so odd ratio estimates may be less precise for these patients. Third, we used ERCP or PTC to evaluate biliary anatomy, not for treatment, which were not associated with short-term and long-term outcome [19]. However, there may be
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correlation between these preoperative intervention and outcome. Finally, intra-abdominal sepsis was defined as having a fever 38 °C, elevated white blood cell count and abdominal pain [19]. However, leukocytosis, pain, and fever could be seen with significant biloma without abdominal infection. These patients were included in intraabdominal sepsis group in current study. Thus, odd ratio estimated by logistic regression model may be less precise. In summary, our results suggest that missed injuries that result in sepsis or bile leak as well as high injuries that require hepaticojejunostomy will result in a higher stricture rate after repair. Conflict of interest
None.
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