Original article
Morbidity and mortality after minor bile duct injury following laparoscopic cholecystectomy
Authors
Klaske A. C. Booij1, Philip R. de Reuver1, Kenneth Yap1, Susan van Dieren2, Otto M. van Delden3, Erik A. Rauws4, Dirk J. Gouma1
Institutions
Institutions are listed at the end of article.
submitted 19. January 2014 accepted after revision 30. September 2014
Background and study aims: Cystic duct and Luschka duct leakage after laparoscopic cholecystectomy are often classified as minor injuries because the outcome of endoscopic stenting and percutaneous drainage is generally reported to be good. However, the potential associated early mortality and risk factors for mortality are scarcely reported. The aim of this study was to describe the outcome, mortality, and risk factors for poor survival of patients with type A bile duct injury (BDI) referred to a tertiary center. Patients and methods: Between January 1990 and January 2012, 800 patients were referred for BDI treatment and included in a prospective database. Results: Type A BDI, according to the Amsterdam and Strasberg classifications, was diagnosed in 216 patients. Treatment after referral was mainly endoscopic (n = 192 [88.9 %]) and radiologic
(n = 14 [6.5 %]). Complications related to endoscopic retrograde cholangiopancreatography (ERCP) occurred in 14 patients (6.5 %). Other complications were sepsis (n = 34 [15.7 %]), cardiopulmonary (n = 22 [10.2 %]), and abscess formation (n = 15 [6.9 %]). BDI-related mortality was 4.2 % (9/216). Multivariate analysis showed age (hazard ratio [HR] = 1.04, 95 % confidence interval [CI] 1.00 – 1.07) and American Society of Anesthesiologists class 3 or 4 (HR = 5.64, 95 % CI 2.31 – 13.77) to be independent factors significantly associated with mortality. Conclusions: Type A “minor” BDI after laparoscopic cholecystectomy is associated with considerable short-term mortality related to the patient’s condition at referral. Older patients and patients with ASA 3 or 4 have a significantly higher risk of mortality.
Introduction
In a population-based study, Flum et al. [2] demonstrated the detrimental effect of major BDI on survival in the United States. In a nationwide cohort of nearly 1.6 million Medicare beneficiaries, BDI patients were nearly three times more likely to die during the first few years after a cholecystectomy compared with patients without BDI. Although the poor outcome can partly be explained by selection of elderly patients, it was also due to selecting only patients who underwent surgical treatment for the major injury. More recently, improved outcome after multidisciplinary treatment has been reported by tertiary referral centers in Europe and the United States [11, 12]. Although mortality rates are low in these series, no specific data on the mortality after minor injury are reported. If cystic duct leakage is also associated with mortality, risk factors for poor survival should be identified to prevent future casualties. The aim of this study was to describe the outcome in patients referred to a tertiary center for the treatment of cystic duct leakage and, specifically,
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1390908 Endoscopy 2015; 47: 40–46 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Dirk J. Gouma, MD Department of Surgery Academic Medical Centre Meibergdreef 9 1105 AZ Amsterdam The Netherlands Fax: +31-20-5669243 [email protected]
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Bile duct injury (BDI) during laparoscopic cholecystectomy is a rare (0.1 % – 1.5 %) but severe complication and is associated with substantial morbidity, mortality, increased costs, hospitalization, and poor quality of life [1 – 4]. BDI will generally lead to bile leakage and abdominal sepsis, bile duct obstruction with obstructive jaundice, or both. Cystic duct leakage, often classified as a minor injury, is the most common site for leakage after laparoscopic cholecystectomy, and has a reported incidence of 1 % – 3 % [5 – 7]. Endoscopic treatment is safe, relatively simple, and effective for this type of injury, with reported success rates of 70 % – 95 % [8 – 11]. Although treatment of cystic duct leakage has been reported to be simple, late recognition and management of these “minor” BDIs can lead to severe deterioration in the patient’s condition, progressing to biliary peritonitis, sepsis, multiple organ failure, and death. Therefore, early recognition and optimal treatment is of utmost importance.
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Fig. 1 Cholangiogram following bile duct injury. a Cystic duct leakage visible after cannulation of the common bile duct. b Stent insertion. c After stent removal there is no leakage from the cystic duct.
to assess mortality after the injury and identify risk factors for poor survival.
Patients and methods !
Patients Between January 1990 and January 2012, 800 consecutive patients referred to the Academic Medical Centre in Amsterdam for management of a BDI were included in a prospective database. Clinical data obtained from the referring hospitals included indication for cholecystectomy, type of operation, and type of injury. Only patients diagnosed with a type A injury, cystic duct leakage, or leakage of Luschka duct, according to the Amsterdam classification [6] and Strasberg classification [7], were included in the present study. Patients’ medical charts were retrospectively reviewed to analyze operation reports and clinical data, including type of initial cholecystectomy, symptoms at referral, and diagnostic and therapeutic interventions. The final treatment modality was defined as the treatment by which the type A injury or complications of the injury were actually controlled and treated, and was subdivided into endoscopic, radiologic, and other treatments. Additional treatment was defined as all extra interventions necessary to stabilize the patient, such as percutaneous drainage or explorative re-laparotomy for drainage of collections.
Standard treatment The endoscopic management of BDI at the Academic Medical Centre in Amsterdam has been published previously [13]. In brief, after cannulation of the common bile duct (CBD), diagnostic cholangiography was performed, under prophylactic antibiotics, and the location and extent of the injury were determined. A hydrophilic guidewire and diagnostic catheter were advanced, bypassing the leak. Then, at the discretion of the endoscopist, either papillotomy alone was performed or a stent was inserted with or without a papillotomy. When a stent was inserted, an Amsterdam-type straight 10-Fr polyethylene stent was used to bridge
" Fig. 1), or only the papilla in case of leakage of the leakage (● Lushka duct. The stents were removed after 4 – 6 weeks [13]. If ERCP was not possible or was unsuccessful, percutaneous transhepatic cholangiography and drainage (PTCD) was performed. During this procedure, after administration of prophylactic antibiotics, ultrasound-guided puncture of the intrahepatic biliary system of either the left or right hepatic lobe using a 22G Chiba needle was used for diagnostic cholangiography. Injection of contrast material allowed fluoroscopic visualization of all bile ducts. When biliary leakage was identified, an external or internal – external biliary drainage catheter (8.5 – 12 Fr) was placed. Abdominal collections (bile or abscess) or liver abscesses were treated by percutaneous drainage. When adequate percutaneous drainage of collections was impossible or other intra-abdominal complications were present, explorative laparotomy was indicated.
Follow-up and evaluation of outcome Medical chart records were collected from the referring hospital with patients’ permission or when patients had deceased. In other cases, the information that was available at the tertiary center, including information from the referring hospital, was used. Follow-up data were obtained through regular outpatient visits, and long-term outcome was obtained by mail and telephone surveys to the general practitioner and the referring surgeons. Complications, success of stent therapy, and mortality were analyzed. Analyzed complications included ERCP-related complications such as cholangitis, stent dislocation, stent clogging, bleeding, and stent perforation. Other complications such as sepsis, intra-abdominal abscess, liver abscess, and cardiopulmonary complications, could not be analyzed separately because they were ongoing and therefore information on complications from the referring hospital and the tertiary center were combined for these cases. Endoscopic treatment was defined as successful if endoscopic stenting was the final therapy for the biliary leakage, the stents could be removed, and no further surgical or radiologic interven-
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Original article
Original article
tions were necessary. Unsuccessful stent therapy was defined as patients treated by means other than stent therapy (i. e. surgically or radiologically) or patients who died from BDI-related cause. Mortality was defined as BDI-related mortality and overall mortality. BDI-related mortality was defined as mortality caused by BDI and was further specified into early mortality (< 30 days after laparoscopic cholecystectomy) and total mortality (i. e. mortality at the date of last follow-up). Overall mortality was defined as all patients who had died at the date of last follow-up (i. e. both BDI related and unrelated). Potential risk factors for poor survival were evaluated and included age at laparoscopic cholecystectomy, sex, American Society of Anesthesiologists (ASA) classification, therapeutic interventions before and after referral, and complications.
Statistical analysis Data for patient characteristics, operation report characteristics, and type of injury are presented as numbers and percentages. Means with SD or median values with minimum and maximum values are presented, as appropriate. Patient survival was measured as time from initial operation until death, date of censoring, or end of follow-up on 1 January 2013. To detect whether factors influenced survival, univariate analysis by means of a log-rank test using the Kaplan – Meier procedure was performed. The factors tested were age, sex, ASA classification, therapeutic interventions before referral, complications, time of diagnosis or referral, and cystic duct vs. Luschka duct injury. Similarly, survival was compared between patients treated before and after 2001 to determine whether more modern treatment methods altered the outcome. The event rate per 1000 person years was calculated, and 95 % confidence intervals (CIs) were obtained using the exact Poisson distribution. The crude mortality rate for 20 years of follow-up was calculated as a percentage together with 95 %CI. A Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95 %CIs for both univariate and multivariate analyses. First, all variables of interest were analyzed univariately, followed by a multivariate analysis using a backward selection. The Cox proportional hazards assumption was examined by visually inspecting log– log plots with no deviations detected. A two-sided P value of < 0.05 was considered to be statistically significant. Data analyses were performed using SPSS software (version 22; IBM Corp., Armonk, New York USA).
Results !
Patient characteristics and referral pattern Of the 800 patients who were referred, 216 (27 %) were diagnosed with type A injury according to the Amsterdam and Strasberg classifications. Patient characteristics, indication for cholecystectomy, type of cholecystectomy, intraoperative cholangiog" Table 1. raphy, and ASA classification are summarized in ● The median time between operation and diagnosis of BDI was 8 days (range 0 – 70 days). In five patients (2.3 %), injury was diagnosed (n = 1) or suspected (n = 4) during laparoscopic cholecystectomy by cholangiography (n = 1) or by observing bile leakage (n = 4), and treatment was performed by placement of additional clips (n = 2) or placement of abdominal drainage catheters (n = 3) after consultation by telephone and subsequent referral.
Table 1 Characteristics of patients with type A bile duct injury after laparoscopic cholecystectomy who were referred for treatment at a tertiary center (n = 216). Age, mean ± SD, years
51.8 (15.7)
Sex, n (%) Female
135 (62.5)
Male
81 (37.5)
Indication for laparoscopic cholecystectomy, n (%) Symptomatic cholecystolithiasis
138 (63.9)
Acute cholecystitis
30 (13.9)
Delayed cholecystectomy
15 (6.9)
Other/not specified
33 (15.3)
Initial procedure, n (%) Open cholecystectomy Laparoscopic cholecystectomy
14 (6.5) 177 (81.9)
Conversion Intraoperative cholangiography, n (%)
25 (11.6) 7 (3.2)
ASA classification ASA 1
86 (39.8)
ASA 2
59 (27.3)
ASA 3
35 (16.2)
ASA 4 Unknown
– 36 (16.7)
ASA, The American Society of Anesthesiologists physical status classification.
Treatment at referring hospitals Treatment strategies at the referring hospitals are summarized in " Table 2. Patient referral to our center was performed after a ● median period of 10 days (range 0 – 539 days). Referral was generally due to unsuccessful treatment or missed diagnosis of persistent bile leakage. Six patients were referred more than 100 days after laparoscopic cholecystectomy because of cholangitis caused by persistent CBD stones (n = 2), cholangitis caused by CBD stenosis (n = 1), persistent cystic duct leakage despite stent therapy (n = 2), and a biliary fistula to the abdominal wall (n = 1).
Treatment and outcome at the tertiary center After referral, the actual treatment modality by which the type A injury was managed and the treatment outcome are summarized " Table 2, ● " Table 3, and ● " Fig. 2. in ● Nine patients (4.2 %) were referred for reasons other than endoscopic or radiologic management of injury: five second opinions, one surgical abscess drainage procedure, one patient needed to be stabilized in the intensive care unit without the need for additional treatment of the BDI, two patients needed an additional resection of part of the gallbladder that was left in situ. Of the 14 patients (6.5 %) in whom the injury was treated radiologically, the indications for PTCD (n = 9) were failed or complicated ERCP elsewhere (n = 5), patient condition precluded ERCP (n = 3; patients treated in the intensive care unit for extreme sepsis), and diagnostic PTCD for persistent complaints after leakage (n = 1). A rendezvous procedure was performed in one patient with papillary diverticulum. A re-laparotomy was performed in 11 patients (5.1 %) because of clinical deterioration or abdominal sepsis (n = 3), residual gallbladder with or without persistent leakage (n = 5), surgical drainage of multiloculated biloma or abscesses (n = 2), and biliary colic caused by a residual stone in the cystic duct remnant (n = 1). All patients with sepsis needed resuscitation in the intensive care unit and percutaneous drainage of abdominal collections to control sepsis.
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Original article
Table 2 Time of diagnosis and primary interventions of patients with type A bile duct injury after laparoscopic cholecystectomy (n = 216).
Table 3 Endoscopic treatment, and short- and long-term outcomes for type A bile duct injury treated at a tertiary center.
Moment of BDI diagnosis, n (%) During initial hospital stay
N = 192 5 (2.3) 105 (48.6)
After discharge
96 (44.4)
Unknown
10 (4.6)
Injury type, n (%) Cystic duct Luschka duct Both
164 (75.9) 47 (21.8) 5 (2.3)
Interventions at referring hospital, n (%) Percutaneous drainage
79 (36.6)
ERCP papillotomy
21 (9.7)
Stent
13 (6.0)
Papillotomy + stent
14 (6.5)
Explorative re-laparotomy
52 (24.1)
Interventions at tertiary center, n (%) 1 Endoscopy
192 (88.9)
ERCP papillotomy
60 (27.8)
ERCP stent
59 (27.3)
ERCP papillotomy + stent
67 (31.0)
Other
6 (2.8)
Radiology
14 (6.5)
PTCD
6 (2.8)
Percutaneous drainage
5 (2.3)
PTCD + percutaneous drainage Other Rendezvous procedure
3 (1.4) 9 (4.2) 1 (1.5)
Additional interventions, n (%) Explorative re-laparotomy
11 (5.1)
Percutaneous drainage
34 (15.7)
ERCP, endoscopic retrograde cholangiopancreatography; PTCD, percutaneous transhepatic cholangiographic drainage. 1 Final treatment modality for BDI.
Successfull endoscopic treatment, n (%)
186 (86.1)
Endoscopic stent therapy, 1 n (%) Referring hospital only Tertiary center only Referring hospital and tertiary center No. of stent procedures, 2 median (range)
15 (6.9) 115 (53.2) 12 (5.6) 2.0 (0 – 6)
Duration of stent treatment,3 (n = 109), median (range), days
55 (13 – 557)
ERCP-related complications (< 30 days), n (%) 1
14 (6.5)
Cholangitis
3 (1.4)
Stent dislocation
2 (0.9)
Stent clogging
1 (0.5)
Bleeding
5 (2.3)
Stent perforation With intra-abdominal abscess Without intra-abdominal abscess Post-ERCP pancreatitis
2 (0.9) 1 (0.5) 1 (0.5) 2 (0.9)
Other complications, n (%) Sepsis
34 (15.7)
Cardiopulmonary
22 (10.2)
Abscess formation
15 (6.9)
Intra-abdominal abscess
9 (4.2)
Liver abscess
5 (2.3)
Both
1 (0.5)
BDI-related mortality, n (%) < 30 days
3 (1.4)
Total (at date of last follow-up)
9 (4.2)
ERCP, endoscopic retrograde cholangiopancreatography; BDI, bile duct injury. 1 Number of patients with complications. Patients could have more than one complication. 2 Endoscopic stent therapy was performed in 142 patients. 3 The number of stent procedures could only be retrieved for 127 patients. 4 The duration of stent treatment could only be retrieved for 109 patients.
Endoscopic treatment Details of the endoscopic management of BDI after referral are " Table 3. In total, 192 patients (88.9 %) were summarized in ● treated by endoscopic measures without further radiologic or surgical interventions. Six patients died from BDI-related causes (2.8 %) (see Mortality and survival, below). The long-term successful outcome of endoscopic treatment was 86.1 % (n = 186). Six patients were treated differently: diagnostic ERCP only (n = 3), dilation of the sphincter (n = 1), stone extraction (n = 1), and stent removal only (n = 1). Of the patients treated by endoscopic stenting, details of the number of stent procedures and ERCP-related complications were only available for patients treated in the referral center. Details of the duration of stent treatment could only be retrieved in 109 of the 142 patients treated by endoscopic stenting. In three additional patients, this duration could not be calculated because of early BDI-related mortality. In the other patients, data on duration of stenting was incomplete because stent removal usually occurred at the referring hospitals. In seven patients, the duration of stent treatment was more than 200 days because of the presence of CBD stones (n = 3), general poor patient condition precluding stent removal (n = 1), and post-inflammatory or stent-related CBD stenosis (n = 2). In one patient there was persistent bile leakage; thorough investigation eventually found the cause to be residual partial gallbladder, which was later removed.
Complications at the tertiary center Details of complications, both from the referring hospital and the " Table 3. The most frequently tertiary center are summarized in ● occurring ERCP-related complications were bleeding and cholangitis. Sepsis was caused by biliary peritonitis (n = 30 [13.9 %]), post-ERCP pancreatitis (n = 1 [0.5 %]), a combination of biliary peritonitis and bowel perforation (n = 2 [0.9 %]), and a combination of pneumonia and intra-abdominal abscess (n = 1 [0.5 %]).
Mortality and survival
" Table 3 and Details of mortality and survival are summarized in● " Table 4. A total of 24 patients (11.1 %) were lost to follow-up ● and could not be traced from the community-held personal data. The date of the last visit to the tertiary center or referring hospital was used for the date of last follow-up. The overall mortality rate, both BDI related and unrelated, for type A BDI was 20.3 per 1000 person years (95 %CI 14.2 – 28.1). After a median follow-up period of 7.16 years (IQR 3.24 – 13.17 years), the crude cumulative mortality, taking time into account was 14.2 % (95 %CI 12.5 % – 16.1 %). Unrelated death was due to various causes, such as cardiopulmonary disease and malignancy. BDI-related death was 9 /216 (4.2 %). Short-term mortality (n = 3) occurred in hospital within 30 days of laparoscopic cholecystectomy and was caused by abdominal sepsis in all cases. BDI-related death in the other six pa-
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During cholecystectomy
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Original article
Type A BDI n = 216
Endoscopy n = 192
ERCP n = 192
Re-laparotomy n=4
Radiology n = 14
PTCD n=6
Percutaneous drainage n=5
PTCD + Percutaneous drainage n=3
Re-laparotomy n=2
No other interventions performed
No other interventions performed
Other n=9
Rendezvous n=1
BDI-related mortality n=3
No other interventions performed
No related mortality
Re-laparotomy n=1
Percutaneous drainage n=0
Percutaneous drainage n = 30
Both n=2
Both n=2
No related mortality
BDI-related mortality n=6
Fig. 2 Management and outcome in patients with type A bile duct injury (BDI) treated at a tertiary referral center. ERCP, endoscopic retrograde cholangiopancreatography; PTCD, percutaneous transhepatic cholangiographic drainage.
Table 4
Univariate and multivariate analysis of risk factors for mortality in patients with type A bile duct injury after laparoscopic cholecystectomy.
n
P2
Univariate analysis1 HR (95 %CI)
Multivariate analysis
P2
HR (95 %CI)
216
1.08 [1.05 – 1.10]
Sex (male) 3
81
2.31 [1.20 – 4.46]
Re-laparotomy before referral 3
52
2.32 [1.19 – 4.54]
ASA 3 or 4 3
35
9.33 [4.49 – 19.38]
< 0.01
5.64 [2.31 – 13.77]
Sepsis 3
34
3.58 [1.71 – 7.48]
< 0.01
1.47 [0.52 – 4.14]
0.471
Cardiopulmonary 3
22
6.61 [2.65 – 16.52]
< 0.01
1.71 [0.53 – 5.54]
0.374
Re-laparotomy after referral 3
11
3.43 [1.33 – 8.83]
1.44 [0.42 – 4.95]
0.564
Age per yearly increase
1.04 [1.00 – 1.07]
0.047
0.012
2.14 [0.99 – 4.61]
0.051
0.014
1.45 [0.66 – 3.18]
< 0.01
0.011
0.350 < 0.01
HR, hazard ratio; CI, confidence interval; ASA, The American Society of Anesthesiologists physical status classification. 1 Univariate analysis: factors analyzed in univariate analysis that were not significant included indication for cholecystectomy, conversion, moment of diagnosis, delay in referral, or endoscopic or radiologic interventions at the tertiary center. 2 P value of log rank test. 3 The hazard ratio for this variable was compared with patients who were negative for this variable.
tients (2.8 %) was due to abdominal sepsis (n = 5), and a combination of bowel perforation and post-ERCP pancreatitis (n = 1). The mean age at time of BDI-related death in type A BDI patients was 66.9 ± 14.5 years. The mean period between type A injury and BDI-related mortality was 1.4 ± 0.8 months. " Table 4. The unadjusted Risk factors for mortality are shown in ● hazard ratio for death in patients suffering from type A BDI increased significantly with advancing age, male sex compared with female sex, and ASA class 3 or 4 compared with ASA class 1 or 2. Sepsis compared with no sepsis, and cardiopulmonary complications compared with no cardiopulmonary complications were significantly associated with worse survival. Both re-laparotomy before and after referral compared with no re-laparatomy before or after referral were associated with poor survival. Patients treated after 2001 had no statistically different survival compared with patients treated before 2001 (HR = 2.23, 95 %CI 0.94 – 5.29). Late recognition of injury compared with early recognition (HR = 1.02, 95 %CI 0.99 – 1.04), delay in referral (HR = 1.00, 95 %CI
0.999 – 1.007), and Luschka duct compared with cystic duct leakage (HR = 1.37, 95 %CI 0.662 – 2.85) had no effect on survival. " Table 4 shows the values for all parameters following univari● ate and multivariate analysis. After a backward selection, only age and ASA 3 or 4 were independent factors significantly associated with mortality on multivariate analysis. Male sex was nearly significantly associated with mortality.
Discussion !
Mortality is the most devastating complication of BDI. The present series demonstrated that “minor” BDI can lead to severe deterioration of the general condition as a result of biliary peritonitis, secondary infection causing sepsis, and eventually death. After a median follow-up of 7.16 years, the cumulative crude incidence for 7 years of total BDI-related mortality in patients referred for the treatment of a type A BDI was 14.2 % (95 %CI 12.5 % – 16.1 %), most often caused by abdominal sepsis.
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In previous series, which mainly focussed on major BDI, the reported mortality was 1.3 % – 3.9 % [11, 14, 15]. It should be emphasized that patients with ongoing biliary sepsis are generally not candidates for surgical repair. Mortality caused by type A BDI leakage is scarcely reported. Pitt et al. [11] described no mortality in patients with type A injury treated at their hospital. A multivariate analysis by de Reuver et al. [12] found no significant difference in 10-year survival between patients with minor and major injury. Furthermore, they found the survival in BDI patients treated in a tertiary center to be similar to that in the general Dutch population. The difference in survival might also be explained by selection bias. Because ERCP with stent insertion is available in most hospitals in The Netherlands, more complex patients, with ongoing biliary peritonitis, are referred for tertiary treatment. A re-laparotomy before referral was performed in a quarter of patients in the present study, which might elucidate the severity of ongoing sepsis in these patients. Although this has not been confirmed by other studies, this might represent a negative selection bias for outcome [11]. In a recently published series of 239 patients with cystic duct leakage, no BDI-related mortality was reported, and the reported success rate, defined as no need for further interventions after initial course of treatment, was higher than in the present series (96 % vs. 86 %). This is probably also explained by the selection bias of patients already experiencing complicated or failed endoscopic treatment elsewhere. Age, male sex, co-morbidity, re-laparotomy either before or after referral, sepsis, and cardiopulmonary complications were associated with risk for mortality following univariate analysis in the present study. The present series did not investigate whether the same surgeon performed the cholecystectomy and the explorative surgery with the intention of reconstruction. However, previous reports have described worse survival in cases where the same surgeon performed both the initial and the repair procedures [2]. The present series again shows the associated detrimental sequela of early re-laparotomy, and the worse survival of re-laparotomy compared with no re-laparotomy, even without the reconstruction. An analysis of all cholecystectomies in Denmark showed that older age, ASA class of more than 1, and open cholecystectomy were risk factors for poor outcome [16]. We have previously shown in a multivariate analysis of 500 patients, that male sex and a reconstructive procedure during the initial cholecystectomy had a significant negative effect on survival [12]. Late recognition of BDI, time to referral, and subtype of type A injury (cystic duct vs. Luschka duct injury) were not risk factors for survival (P = 0.220, P = 0.139, and P = 0.25, respectively). The use of intraoperative cholangiography (n = 7 [3.2 %]) was too limited to draw any conclusions. Another study showed no difference in the rate of minor BDI between selective and routine use of intraoperative cholangiography [17]. The median duration of stent treatment was 55 days, which is relatively long compared with other studies [11]. This is probably because the duration of stent treatment was more than 200 days in a few patients as a result of the presence of CBD stones, poor general patient condition not permitting stent removal, and postinflammatory or stent-induced CBD stenosis. Referral in the present series was performed after a median period of 10 days, which is a relative long time because patients with bile leakage generally start to become symptomatic within 1 – 6 days after surgery. These early symptoms are generally nonspecific and consist of general malaise, nausea, vomiting, anorexia, ab-
dominal pain, and low-grade fever. These vague symptoms might probably be responsible for the delay in diagnosis. As early sterile intraperitoneal bile collections are tolerated relatively well (in young fit patients) for a reasonable time, a large number of patients are discharged from hospital before becoming symptomatic. However, any patient who does not improve clinically within the first 24 – 48 hours after laparoscopic cholecystectomy should be suspected of having a biloma and bile leakage, and should be analyzed by imaging. Patients with infected bile as a result of previous interventions will suffer from early biliary peritonitis and are at risk for biliary sepsis. Diagnostic imaging should be followed by percutaneous drainage, and ERCP and/or magnetic resonance cholangiopancreatography are recommended without delay [12]. Inadequately treated bile collections may cause sepsis, respiratory distress, or even multi-organ failure. The need for admission to the intensive care unit in 16 % of the patients after referral and explorative re-laparotomy in 11 patients underscore the risk of inadequately treated abdominal bile collections leading to uncontrolled sepsis. The combination of biliary sepsis (infected abdominal collections) and cardiopulmonary co-morbidity was the main reason for early death. The delayed referral of many of the patients in this series may have contributed to the observed morbidity and mortality. Although the Dutch Guidelines on Gallstone Disease do include the option of placing a subhepatic drain during laparoscopic cholecystectomy if there is any risk of future leakage or infection, this procedure does not seem to be common practice, as a drain is left behind in only 16.8 % of suspected BDI [18]. The type of clips used during laparoscopic cholecystectomy is of interest in case of postoperative complications. If postoperative imaging is necessary, metal clips might be helpful to locate the cystic stump and classify the injury. Clip migration and resulting leakage after laparoscopic cholecystectomy is a rare but well recognized complication [19, 20]. Another important risk factor for leakage is an increased CBD pressure as a result of persistent bile duct stones; this can be prevented by routine cholangiography [17]. As this study has several limitations, conclusions should be interpreted with caution. Although it is the first study to show considerable mortality after cystic duct leakage, this might be due to the selection of BDI patients who were referred to a tertiary center. However, multivariate analysis showed that ASA 3 or 4 patients are at the highest risk of mortality. In some circumstances, percutaneous biliary drainage of the gallbladder or subtotal cholecystectomy may be a favorable alternative to conventional cholecystectomy [21, 22]. In conclusion, minor bile duct injury after laparoscopic cholecystectomy is associated with substantial morbidity and even mortality. This is mainly due to the presence of biliary peritonitis in these patients. Recognition of the early nonspecific symptoms will help to identify potential BDI and indicate imaging assessment or endoscopic treatment. A “diagnostic” re-laparotomy is contraindicated, as this procedure is associated with worse outcome. Especially in older patients with co-morbidity, early and adequate intervention for cystic duct leakage and biliary peritonitis might prevent unnecessary casualties. Competing interests: None
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Original article
Institutions 1 Department of surgery, Academic Medical Centre, Amsterdam, The Netherlands 2 Clinical Research Unit, Academic Medical Centre, Amsterdam, The Netherlands 3 Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands 4 Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands
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11 Pitt HA, Sherman S, Johnson MS et al. Improved outcomes of bile duct injuries in the 21st century. Ann Surg 2013; 258: 490 – 499 12 de Reuver PR, Rauws EA, Bruno MJ et al. Survival in bile duct injury patients after laparoscopic cholecystectomy: a multidisciplinary approach of gastroenterologists, radiologists, and surgeons. Surgery 2007; 142: 1 – 9 13 de Reuver PR, Rauws EA, Vermeulen M et al. Endoscopic treatment of post-surgical bile duct injuries: long term outcome and predictors of success. Gut 2007; 56: 1599 – 1605 14 Tornqvist B, Stromberg C, Persson G et al. Effect of intended intraoperative cholangiography and early detection of bile duct injury on survival after cholecystectomy: population based cohort study. BMJ 2012; 345: e6457 15 Sicklick JK, Camp MS, Lillemoe KD et al. Surgical management of bile duct injuries sustained during laparoscopic cholecystectomy in 200 patients. Ann Surg 2005; 241: 786 – 792 16 Harboe KM, Bardram L. The quality of cholecystectomy in Denmark: outcome and risk factors for 20,307 patients from the national database. Surg Endosc 2011; 25: 1630 – 1641 17 Buddingh KT, Weersma RK, Savenije RA et al. Lower rate of major bile duct injury and increased intraoperative management of common bile duct stones after implementation of routine intraoperative cholangiography. J Am Coll Surg 2011; 213: 267 – 274 18 Booij KA, de Reuver PR, Nijsse B et al. Insufficient safety measures reported in operation notes of complicated laparoscopic cholecystectomies. Surgery 2014; 155: 384 – 389 19 Goshi T, Okamura S, Takeuchi H et al. Migrated endoclip and stone formation after cholecystectomy: a case treated by endoscopic sphincterotomy. Intern Med 2009; 48: 2015 – 2017 20 Ray S, Bhattacharya SP. Endoclip migration into the common bile duct with stone formation: a rare complication after laparoscopic cholecystectomy. JSLS 2013; 17: 330 – 332 21 Kortram K, de Vries ReilinghTS, Wiezer MJ et al. Percutaneous drainage for acute calculous cholecystitis. Surg Endosc 2011; 25: 3642 – 3646 22 Davis B, Castaneda G, Lopez J. Subtotal cholecystectomy versus total cholecystectomy in complicated cholecystitis. Am Surg 2012; 78: 814 – 817
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Morbidity and mortality after minor bile duct injury following laparoscopic cholecystectomy
Authors
Klaske A. C. Booij1, Philip R. de Reuver1, Kenneth Yap1, Susan van Dieren2, Otto M. van Delden3, Erik A. Rauws4, Dirk J. Gouma1
Institutions
Institutions are listed at the end of article.
submitted 19. January 2014 accepted after revision 30. September 2014
Background and study aims: Cystic duct and Luschka duct leakage after laparoscopic cholecystectomy are often classified as minor injuries because the outcome of endoscopic stenting and percutaneous drainage is generally reported to be good. However, the potential associated early mortality and risk factors for mortality are scarcely reported. The aim of this study was to describe the outcome, mortality, and risk factors for poor survival of patients with type A bile duct injury (BDI) referred to a tertiary center. Patients and methods: Between January 1990 and January 2012, 800 patients were referred for BDI treatment and included in a prospective database. Results: Type A BDI, according to the Amsterdam and Strasberg classifications, was diagnosed in 216 patients. Treatment after referral was mainly endoscopic (n = 192 [88.9 %]) and radiologic
(n = 14 [6.5 %]). Complications related to endoscopic retrograde cholangiopancreatography (ERCP) occurred in 14 patients (6.5 %). Other complications were sepsis (n = 34 [15.7 %]), cardiopulmonary (n = 22 [10.2 %]), and abscess formation (n = 15 [6.9 %]). BDI-related mortality was 4.2 % (9/216). Multivariate analysis showed age (hazard ratio [HR] = 1.04, 95 % confidence interval [CI] 1.00 – 1.07) and American Society of Anesthesiologists class 3 or 4 (HR = 5.64, 95 % CI 2.31 – 13.77) to be independent factors significantly associated with mortality. Conclusions: Type A “minor” BDI after laparoscopic cholecystectomy is associated with considerable short-term mortality related to the patient’s condition at referral. Older patients and patients with ASA 3 or 4 have a significantly higher risk of mortality.
Introduction
In a population-based study, Flum et al. [2] demonstrated the detrimental effect of major BDI on survival in the United States. In a nationwide cohort of nearly 1.6 million Medicare beneficiaries, BDI patients were nearly three times more likely to die during the first few years after a cholecystectomy compared with patients without BDI. Although the poor outcome can partly be explained by selection of elderly patients, it was also due to selecting only patients who underwent surgical treatment for the major injury. More recently, improved outcome after multidisciplinary treatment has been reported by tertiary referral centers in Europe and the United States [11, 12]. Although mortality rates are low in these series, no specific data on the mortality after minor injury are reported. If cystic duct leakage is also associated with mortality, risk factors for poor survival should be identified to prevent future casualties. The aim of this study was to describe the outcome in patients referred to a tertiary center for the treatment of cystic duct leakage and, specifically,
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1390908 Endoscopy 2015; 47: 40–46 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Dirk J. Gouma, MD Department of Surgery Academic Medical Centre Meibergdreef 9 1105 AZ Amsterdam The Netherlands Fax: +31-20-5669243 [email protected]
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Bile duct injury (BDI) during laparoscopic cholecystectomy is a rare (0.1 % – 1.5 %) but severe complication and is associated with substantial morbidity, mortality, increased costs, hospitalization, and poor quality of life [1 – 4]. BDI will generally lead to bile leakage and abdominal sepsis, bile duct obstruction with obstructive jaundice, or both. Cystic duct leakage, often classified as a minor injury, is the most common site for leakage after laparoscopic cholecystectomy, and has a reported incidence of 1 % – 3 % [5 – 7]. Endoscopic treatment is safe, relatively simple, and effective for this type of injury, with reported success rates of 70 % – 95 % [8 – 11]. Although treatment of cystic duct leakage has been reported to be simple, late recognition and management of these “minor” BDIs can lead to severe deterioration in the patient’s condition, progressing to biliary peritonitis, sepsis, multiple organ failure, and death. Therefore, early recognition and optimal treatment is of utmost importance.
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Fig. 1 Cholangiogram following bile duct injury. a Cystic duct leakage visible after cannulation of the common bile duct. b Stent insertion. c After stent removal there is no leakage from the cystic duct.
to assess mortality after the injury and identify risk factors for poor survival.
Patients and methods !
Patients Between January 1990 and January 2012, 800 consecutive patients referred to the Academic Medical Centre in Amsterdam for management of a BDI were included in a prospective database. Clinical data obtained from the referring hospitals included indication for cholecystectomy, type of operation, and type of injury. Only patients diagnosed with a type A injury, cystic duct leakage, or leakage of Luschka duct, according to the Amsterdam classification [6] and Strasberg classification [7], were included in the present study. Patients’ medical charts were retrospectively reviewed to analyze operation reports and clinical data, including type of initial cholecystectomy, symptoms at referral, and diagnostic and therapeutic interventions. The final treatment modality was defined as the treatment by which the type A injury or complications of the injury were actually controlled and treated, and was subdivided into endoscopic, radiologic, and other treatments. Additional treatment was defined as all extra interventions necessary to stabilize the patient, such as percutaneous drainage or explorative re-laparotomy for drainage of collections.
Standard treatment The endoscopic management of BDI at the Academic Medical Centre in Amsterdam has been published previously [13]. In brief, after cannulation of the common bile duct (CBD), diagnostic cholangiography was performed, under prophylactic antibiotics, and the location and extent of the injury were determined. A hydrophilic guidewire and diagnostic catheter were advanced, bypassing the leak. Then, at the discretion of the endoscopist, either papillotomy alone was performed or a stent was inserted with or without a papillotomy. When a stent was inserted, an Amsterdam-type straight 10-Fr polyethylene stent was used to bridge
" Fig. 1), or only the papilla in case of leakage of the leakage (● Lushka duct. The stents were removed after 4 – 6 weeks [13]. If ERCP was not possible or was unsuccessful, percutaneous transhepatic cholangiography and drainage (PTCD) was performed. During this procedure, after administration of prophylactic antibiotics, ultrasound-guided puncture of the intrahepatic biliary system of either the left or right hepatic lobe using a 22G Chiba needle was used for diagnostic cholangiography. Injection of contrast material allowed fluoroscopic visualization of all bile ducts. When biliary leakage was identified, an external or internal – external biliary drainage catheter (8.5 – 12 Fr) was placed. Abdominal collections (bile or abscess) or liver abscesses were treated by percutaneous drainage. When adequate percutaneous drainage of collections was impossible or other intra-abdominal complications were present, explorative laparotomy was indicated.
Follow-up and evaluation of outcome Medical chart records were collected from the referring hospital with patients’ permission or when patients had deceased. In other cases, the information that was available at the tertiary center, including information from the referring hospital, was used. Follow-up data were obtained through regular outpatient visits, and long-term outcome was obtained by mail and telephone surveys to the general practitioner and the referring surgeons. Complications, success of stent therapy, and mortality were analyzed. Analyzed complications included ERCP-related complications such as cholangitis, stent dislocation, stent clogging, bleeding, and stent perforation. Other complications such as sepsis, intra-abdominal abscess, liver abscess, and cardiopulmonary complications, could not be analyzed separately because they were ongoing and therefore information on complications from the referring hospital and the tertiary center were combined for these cases. Endoscopic treatment was defined as successful if endoscopic stenting was the final therapy for the biliary leakage, the stents could be removed, and no further surgical or radiologic interven-
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Original article
Original article
tions were necessary. Unsuccessful stent therapy was defined as patients treated by means other than stent therapy (i. e. surgically or radiologically) or patients who died from BDI-related cause. Mortality was defined as BDI-related mortality and overall mortality. BDI-related mortality was defined as mortality caused by BDI and was further specified into early mortality (< 30 days after laparoscopic cholecystectomy) and total mortality (i. e. mortality at the date of last follow-up). Overall mortality was defined as all patients who had died at the date of last follow-up (i. e. both BDI related and unrelated). Potential risk factors for poor survival were evaluated and included age at laparoscopic cholecystectomy, sex, American Society of Anesthesiologists (ASA) classification, therapeutic interventions before and after referral, and complications.
Statistical analysis Data for patient characteristics, operation report characteristics, and type of injury are presented as numbers and percentages. Means with SD or median values with minimum and maximum values are presented, as appropriate. Patient survival was measured as time from initial operation until death, date of censoring, or end of follow-up on 1 January 2013. To detect whether factors influenced survival, univariate analysis by means of a log-rank test using the Kaplan – Meier procedure was performed. The factors tested were age, sex, ASA classification, therapeutic interventions before referral, complications, time of diagnosis or referral, and cystic duct vs. Luschka duct injury. Similarly, survival was compared between patients treated before and after 2001 to determine whether more modern treatment methods altered the outcome. The event rate per 1000 person years was calculated, and 95 % confidence intervals (CIs) were obtained using the exact Poisson distribution. The crude mortality rate for 20 years of follow-up was calculated as a percentage together with 95 %CI. A Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95 %CIs for both univariate and multivariate analyses. First, all variables of interest were analyzed univariately, followed by a multivariate analysis using a backward selection. The Cox proportional hazards assumption was examined by visually inspecting log– log plots with no deviations detected. A two-sided P value of < 0.05 was considered to be statistically significant. Data analyses were performed using SPSS software (version 22; IBM Corp., Armonk, New York USA).
Results !
Patient characteristics and referral pattern Of the 800 patients who were referred, 216 (27 %) were diagnosed with type A injury according to the Amsterdam and Strasberg classifications. Patient characteristics, indication for cholecystectomy, type of cholecystectomy, intraoperative cholangiog" Table 1. raphy, and ASA classification are summarized in ● The median time between operation and diagnosis of BDI was 8 days (range 0 – 70 days). In five patients (2.3 %), injury was diagnosed (n = 1) or suspected (n = 4) during laparoscopic cholecystectomy by cholangiography (n = 1) or by observing bile leakage (n = 4), and treatment was performed by placement of additional clips (n = 2) or placement of abdominal drainage catheters (n = 3) after consultation by telephone and subsequent referral.
Table 1 Characteristics of patients with type A bile duct injury after laparoscopic cholecystectomy who were referred for treatment at a tertiary center (n = 216). Age, mean ± SD, years
51.8 (15.7)
Sex, n (%) Female
135 (62.5)
Male
81 (37.5)
Indication for laparoscopic cholecystectomy, n (%) Symptomatic cholecystolithiasis
138 (63.9)
Acute cholecystitis
30 (13.9)
Delayed cholecystectomy
15 (6.9)
Other/not specified
33 (15.3)
Initial procedure, n (%) Open cholecystectomy Laparoscopic cholecystectomy
14 (6.5) 177 (81.9)
Conversion Intraoperative cholangiography, n (%)
25 (11.6) 7 (3.2)
ASA classification ASA 1
86 (39.8)
ASA 2
59 (27.3)
ASA 3
35 (16.2)
ASA 4 Unknown
– 36 (16.7)
ASA, The American Society of Anesthesiologists physical status classification.
Treatment at referring hospitals Treatment strategies at the referring hospitals are summarized in " Table 2. Patient referral to our center was performed after a ● median period of 10 days (range 0 – 539 days). Referral was generally due to unsuccessful treatment or missed diagnosis of persistent bile leakage. Six patients were referred more than 100 days after laparoscopic cholecystectomy because of cholangitis caused by persistent CBD stones (n = 2), cholangitis caused by CBD stenosis (n = 1), persistent cystic duct leakage despite stent therapy (n = 2), and a biliary fistula to the abdominal wall (n = 1).
Treatment and outcome at the tertiary center After referral, the actual treatment modality by which the type A injury was managed and the treatment outcome are summarized " Table 2, ● " Table 3, and ● " Fig. 2. in ● Nine patients (4.2 %) were referred for reasons other than endoscopic or radiologic management of injury: five second opinions, one surgical abscess drainage procedure, one patient needed to be stabilized in the intensive care unit without the need for additional treatment of the BDI, two patients needed an additional resection of part of the gallbladder that was left in situ. Of the 14 patients (6.5 %) in whom the injury was treated radiologically, the indications for PTCD (n = 9) were failed or complicated ERCP elsewhere (n = 5), patient condition precluded ERCP (n = 3; patients treated in the intensive care unit for extreme sepsis), and diagnostic PTCD for persistent complaints after leakage (n = 1). A rendezvous procedure was performed in one patient with papillary diverticulum. A re-laparotomy was performed in 11 patients (5.1 %) because of clinical deterioration or abdominal sepsis (n = 3), residual gallbladder with or without persistent leakage (n = 5), surgical drainage of multiloculated biloma or abscesses (n = 2), and biliary colic caused by a residual stone in the cystic duct remnant (n = 1). All patients with sepsis needed resuscitation in the intensive care unit and percutaneous drainage of abdominal collections to control sepsis.
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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42
Original article
Table 2 Time of diagnosis and primary interventions of patients with type A bile duct injury after laparoscopic cholecystectomy (n = 216).
Table 3 Endoscopic treatment, and short- and long-term outcomes for type A bile duct injury treated at a tertiary center.
Moment of BDI diagnosis, n (%) During initial hospital stay
N = 192 5 (2.3) 105 (48.6)
After discharge
96 (44.4)
Unknown
10 (4.6)
Injury type, n (%) Cystic duct Luschka duct Both
164 (75.9) 47 (21.8) 5 (2.3)
Interventions at referring hospital, n (%) Percutaneous drainage
79 (36.6)
ERCP papillotomy
21 (9.7)
Stent
13 (6.0)
Papillotomy + stent
14 (6.5)
Explorative re-laparotomy
52 (24.1)
Interventions at tertiary center, n (%) 1 Endoscopy
192 (88.9)
ERCP papillotomy
60 (27.8)
ERCP stent
59 (27.3)
ERCP papillotomy + stent
67 (31.0)
Other
6 (2.8)
Radiology
14 (6.5)
PTCD
6 (2.8)
Percutaneous drainage
5 (2.3)
PTCD + percutaneous drainage Other Rendezvous procedure
3 (1.4) 9 (4.2) 1 (1.5)
Additional interventions, n (%) Explorative re-laparotomy
11 (5.1)
Percutaneous drainage
34 (15.7)
ERCP, endoscopic retrograde cholangiopancreatography; PTCD, percutaneous transhepatic cholangiographic drainage. 1 Final treatment modality for BDI.
Successfull endoscopic treatment, n (%)
186 (86.1)
Endoscopic stent therapy, 1 n (%) Referring hospital only Tertiary center only Referring hospital and tertiary center No. of stent procedures, 2 median (range)
15 (6.9) 115 (53.2) 12 (5.6) 2.0 (0 – 6)
Duration of stent treatment,3 (n = 109), median (range), days
55 (13 – 557)
ERCP-related complications (< 30 days), n (%) 1
14 (6.5)
Cholangitis
3 (1.4)
Stent dislocation
2 (0.9)
Stent clogging
1 (0.5)
Bleeding
5 (2.3)
Stent perforation With intra-abdominal abscess Without intra-abdominal abscess Post-ERCP pancreatitis
2 (0.9) 1 (0.5) 1 (0.5) 2 (0.9)
Other complications, n (%) Sepsis
34 (15.7)
Cardiopulmonary
22 (10.2)
Abscess formation
15 (6.9)
Intra-abdominal abscess
9 (4.2)
Liver abscess
5 (2.3)
Both
1 (0.5)
BDI-related mortality, n (%) < 30 days
3 (1.4)
Total (at date of last follow-up)
9 (4.2)
ERCP, endoscopic retrograde cholangiopancreatography; BDI, bile duct injury. 1 Number of patients with complications. Patients could have more than one complication. 2 Endoscopic stent therapy was performed in 142 patients. 3 The number of stent procedures could only be retrieved for 127 patients. 4 The duration of stent treatment could only be retrieved for 109 patients.
Endoscopic treatment Details of the endoscopic management of BDI after referral are " Table 3. In total, 192 patients (88.9 %) were summarized in ● treated by endoscopic measures without further radiologic or surgical interventions. Six patients died from BDI-related causes (2.8 %) (see Mortality and survival, below). The long-term successful outcome of endoscopic treatment was 86.1 % (n = 186). Six patients were treated differently: diagnostic ERCP only (n = 3), dilation of the sphincter (n = 1), stone extraction (n = 1), and stent removal only (n = 1). Of the patients treated by endoscopic stenting, details of the number of stent procedures and ERCP-related complications were only available for patients treated in the referral center. Details of the duration of stent treatment could only be retrieved in 109 of the 142 patients treated by endoscopic stenting. In three additional patients, this duration could not be calculated because of early BDI-related mortality. In the other patients, data on duration of stenting was incomplete because stent removal usually occurred at the referring hospitals. In seven patients, the duration of stent treatment was more than 200 days because of the presence of CBD stones (n = 3), general poor patient condition precluding stent removal (n = 1), and post-inflammatory or stent-related CBD stenosis (n = 2). In one patient there was persistent bile leakage; thorough investigation eventually found the cause to be residual partial gallbladder, which was later removed.
Complications at the tertiary center Details of complications, both from the referring hospital and the " Table 3. The most frequently tertiary center are summarized in ● occurring ERCP-related complications were bleeding and cholangitis. Sepsis was caused by biliary peritonitis (n = 30 [13.9 %]), post-ERCP pancreatitis (n = 1 [0.5 %]), a combination of biliary peritonitis and bowel perforation (n = 2 [0.9 %]), and a combination of pneumonia and intra-abdominal abscess (n = 1 [0.5 %]).
Mortality and survival
" Table 3 and Details of mortality and survival are summarized in● " Table 4. A total of 24 patients (11.1 %) were lost to follow-up ● and could not be traced from the community-held personal data. The date of the last visit to the tertiary center or referring hospital was used for the date of last follow-up. The overall mortality rate, both BDI related and unrelated, for type A BDI was 20.3 per 1000 person years (95 %CI 14.2 – 28.1). After a median follow-up period of 7.16 years (IQR 3.24 – 13.17 years), the crude cumulative mortality, taking time into account was 14.2 % (95 %CI 12.5 % – 16.1 %). Unrelated death was due to various causes, such as cardiopulmonary disease and malignancy. BDI-related death was 9 /216 (4.2 %). Short-term mortality (n = 3) occurred in hospital within 30 days of laparoscopic cholecystectomy and was caused by abdominal sepsis in all cases. BDI-related death in the other six pa-
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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During cholecystectomy
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Original article
Type A BDI n = 216
Endoscopy n = 192
ERCP n = 192
Re-laparotomy n=4
Radiology n = 14
PTCD n=6
Percutaneous drainage n=5
PTCD + Percutaneous drainage n=3
Re-laparotomy n=2
No other interventions performed
No other interventions performed
Other n=9
Rendezvous n=1
BDI-related mortality n=3
No other interventions performed
No related mortality
Re-laparotomy n=1
Percutaneous drainage n=0
Percutaneous drainage n = 30
Both n=2
Both n=2
No related mortality
BDI-related mortality n=6
Fig. 2 Management and outcome in patients with type A bile duct injury (BDI) treated at a tertiary referral center. ERCP, endoscopic retrograde cholangiopancreatography; PTCD, percutaneous transhepatic cholangiographic drainage.
Table 4
Univariate and multivariate analysis of risk factors for mortality in patients with type A bile duct injury after laparoscopic cholecystectomy.
n
P2
Univariate analysis1 HR (95 %CI)
Multivariate analysis
P2
HR (95 %CI)
216
1.08 [1.05 – 1.10]
Sex (male) 3
81
2.31 [1.20 – 4.46]
Re-laparotomy before referral 3
52
2.32 [1.19 – 4.54]
ASA 3 or 4 3
35
9.33 [4.49 – 19.38]
< 0.01
5.64 [2.31 – 13.77]
Sepsis 3
34
3.58 [1.71 – 7.48]
< 0.01
1.47 [0.52 – 4.14]
0.471
Cardiopulmonary 3
22
6.61 [2.65 – 16.52]
< 0.01
1.71 [0.53 – 5.54]
0.374
Re-laparotomy after referral 3
11
3.43 [1.33 – 8.83]
1.44 [0.42 – 4.95]
0.564
Age per yearly increase
1.04 [1.00 – 1.07]
0.047
0.012
2.14 [0.99 – 4.61]
0.051
0.014
1.45 [0.66 – 3.18]
< 0.01
0.011
0.350 < 0.01
HR, hazard ratio; CI, confidence interval; ASA, The American Society of Anesthesiologists physical status classification. 1 Univariate analysis: factors analyzed in univariate analysis that were not significant included indication for cholecystectomy, conversion, moment of diagnosis, delay in referral, or endoscopic or radiologic interventions at the tertiary center. 2 P value of log rank test. 3 The hazard ratio for this variable was compared with patients who were negative for this variable.
tients (2.8 %) was due to abdominal sepsis (n = 5), and a combination of bowel perforation and post-ERCP pancreatitis (n = 1). The mean age at time of BDI-related death in type A BDI patients was 66.9 ± 14.5 years. The mean period between type A injury and BDI-related mortality was 1.4 ± 0.8 months. " Table 4. The unadjusted Risk factors for mortality are shown in ● hazard ratio for death in patients suffering from type A BDI increased significantly with advancing age, male sex compared with female sex, and ASA class 3 or 4 compared with ASA class 1 or 2. Sepsis compared with no sepsis, and cardiopulmonary complications compared with no cardiopulmonary complications were significantly associated with worse survival. Both re-laparotomy before and after referral compared with no re-laparatomy before or after referral were associated with poor survival. Patients treated after 2001 had no statistically different survival compared with patients treated before 2001 (HR = 2.23, 95 %CI 0.94 – 5.29). Late recognition of injury compared with early recognition (HR = 1.02, 95 %CI 0.99 – 1.04), delay in referral (HR = 1.00, 95 %CI
0.999 – 1.007), and Luschka duct compared with cystic duct leakage (HR = 1.37, 95 %CI 0.662 – 2.85) had no effect on survival. " Table 4 shows the values for all parameters following univari● ate and multivariate analysis. After a backward selection, only age and ASA 3 or 4 were independent factors significantly associated with mortality on multivariate analysis. Male sex was nearly significantly associated with mortality.
Discussion !
Mortality is the most devastating complication of BDI. The present series demonstrated that “minor” BDI can lead to severe deterioration of the general condition as a result of biliary peritonitis, secondary infection causing sepsis, and eventually death. After a median follow-up of 7.16 years, the cumulative crude incidence for 7 years of total BDI-related mortality in patients referred for the treatment of a type A BDI was 14.2 % (95 %CI 12.5 % – 16.1 %), most often caused by abdominal sepsis.
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In previous series, which mainly focussed on major BDI, the reported mortality was 1.3 % – 3.9 % [11, 14, 15]. It should be emphasized that patients with ongoing biliary sepsis are generally not candidates for surgical repair. Mortality caused by type A BDI leakage is scarcely reported. Pitt et al. [11] described no mortality in patients with type A injury treated at their hospital. A multivariate analysis by de Reuver et al. [12] found no significant difference in 10-year survival between patients with minor and major injury. Furthermore, they found the survival in BDI patients treated in a tertiary center to be similar to that in the general Dutch population. The difference in survival might also be explained by selection bias. Because ERCP with stent insertion is available in most hospitals in The Netherlands, more complex patients, with ongoing biliary peritonitis, are referred for tertiary treatment. A re-laparotomy before referral was performed in a quarter of patients in the present study, which might elucidate the severity of ongoing sepsis in these patients. Although this has not been confirmed by other studies, this might represent a negative selection bias for outcome [11]. In a recently published series of 239 patients with cystic duct leakage, no BDI-related mortality was reported, and the reported success rate, defined as no need for further interventions after initial course of treatment, was higher than in the present series (96 % vs. 86 %). This is probably also explained by the selection bias of patients already experiencing complicated or failed endoscopic treatment elsewhere. Age, male sex, co-morbidity, re-laparotomy either before or after referral, sepsis, and cardiopulmonary complications were associated with risk for mortality following univariate analysis in the present study. The present series did not investigate whether the same surgeon performed the cholecystectomy and the explorative surgery with the intention of reconstruction. However, previous reports have described worse survival in cases where the same surgeon performed both the initial and the repair procedures [2]. The present series again shows the associated detrimental sequela of early re-laparotomy, and the worse survival of re-laparotomy compared with no re-laparotomy, even without the reconstruction. An analysis of all cholecystectomies in Denmark showed that older age, ASA class of more than 1, and open cholecystectomy were risk factors for poor outcome [16]. We have previously shown in a multivariate analysis of 500 patients, that male sex and a reconstructive procedure during the initial cholecystectomy had a significant negative effect on survival [12]. Late recognition of BDI, time to referral, and subtype of type A injury (cystic duct vs. Luschka duct injury) were not risk factors for survival (P = 0.220, P = 0.139, and P = 0.25, respectively). The use of intraoperative cholangiography (n = 7 [3.2 %]) was too limited to draw any conclusions. Another study showed no difference in the rate of minor BDI between selective and routine use of intraoperative cholangiography [17]. The median duration of stent treatment was 55 days, which is relatively long compared with other studies [11]. This is probably because the duration of stent treatment was more than 200 days in a few patients as a result of the presence of CBD stones, poor general patient condition not permitting stent removal, and postinflammatory or stent-induced CBD stenosis. Referral in the present series was performed after a median period of 10 days, which is a relative long time because patients with bile leakage generally start to become symptomatic within 1 – 6 days after surgery. These early symptoms are generally nonspecific and consist of general malaise, nausea, vomiting, anorexia, ab-
dominal pain, and low-grade fever. These vague symptoms might probably be responsible for the delay in diagnosis. As early sterile intraperitoneal bile collections are tolerated relatively well (in young fit patients) for a reasonable time, a large number of patients are discharged from hospital before becoming symptomatic. However, any patient who does not improve clinically within the first 24 – 48 hours after laparoscopic cholecystectomy should be suspected of having a biloma and bile leakage, and should be analyzed by imaging. Patients with infected bile as a result of previous interventions will suffer from early biliary peritonitis and are at risk for biliary sepsis. Diagnostic imaging should be followed by percutaneous drainage, and ERCP and/or magnetic resonance cholangiopancreatography are recommended without delay [12]. Inadequately treated bile collections may cause sepsis, respiratory distress, or even multi-organ failure. The need for admission to the intensive care unit in 16 % of the patients after referral and explorative re-laparotomy in 11 patients underscore the risk of inadequately treated abdominal bile collections leading to uncontrolled sepsis. The combination of biliary sepsis (infected abdominal collections) and cardiopulmonary co-morbidity was the main reason for early death. The delayed referral of many of the patients in this series may have contributed to the observed morbidity and mortality. Although the Dutch Guidelines on Gallstone Disease do include the option of placing a subhepatic drain during laparoscopic cholecystectomy if there is any risk of future leakage or infection, this procedure does not seem to be common practice, as a drain is left behind in only 16.8 % of suspected BDI [18]. The type of clips used during laparoscopic cholecystectomy is of interest in case of postoperative complications. If postoperative imaging is necessary, metal clips might be helpful to locate the cystic stump and classify the injury. Clip migration and resulting leakage after laparoscopic cholecystectomy is a rare but well recognized complication [19, 20]. Another important risk factor for leakage is an increased CBD pressure as a result of persistent bile duct stones; this can be prevented by routine cholangiography [17]. As this study has several limitations, conclusions should be interpreted with caution. Although it is the first study to show considerable mortality after cystic duct leakage, this might be due to the selection of BDI patients who were referred to a tertiary center. However, multivariate analysis showed that ASA 3 or 4 patients are at the highest risk of mortality. In some circumstances, percutaneous biliary drainage of the gallbladder or subtotal cholecystectomy may be a favorable alternative to conventional cholecystectomy [21, 22]. In conclusion, minor bile duct injury after laparoscopic cholecystectomy is associated with substantial morbidity and even mortality. This is mainly due to the presence of biliary peritonitis in these patients. Recognition of the early nonspecific symptoms will help to identify potential BDI and indicate imaging assessment or endoscopic treatment. A “diagnostic” re-laparotomy is contraindicated, as this procedure is associated with worse outcome. Especially in older patients with co-morbidity, early and adequate intervention for cystic duct leakage and biliary peritonitis might prevent unnecessary casualties. Competing interests: None
Booij Klaske AC et al. Morbidity and mortality after bile duct injury … Endoscopy 2015; 47: 40–46
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Original article
Original article
Institutions 1 Department of surgery, Academic Medical Centre, Amsterdam, The Netherlands 2 Clinical Research Unit, Academic Medical Centre, Amsterdam, The Netherlands 3 Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands 4 Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands
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