Human fibrin sealant reduces post-operative bile leakage of primary closure after laparoscopic common bile duct exploration in patients with choledocholithiasis.

CONTEXT: Primary closure of the common bile duct (CBD) without drainage is considered a suitable approach after laparoscopic CBD exploration (LCBDE); however, the risk of post-operative bile leakage is high. Up to now, it has not been clear whether human fibrin sealant can reduce post-operative bile leakage of the primary suture. AIMS: In this study, we evaluated the role of human fibrin sealant in primary closure of the CBD after LCBDE. SUBJECTS AND METHODS: Patients with choledocholithiasis who had undergone primary duct closure of the CBD after LCBDE were divided into two groups according to whether fibrin sealant was used. STATISTICAL ANALYSIS USED: Fisher's exact test or the Chi-square test was used for categorical variables to calculate frequencies and percentages between the groups. The Student's t-test was used to compare the means of the continuous variables between the groups.
RESULTS: The human fibrin sealant group had a lower rate of post-operative bile leakage compared to the other group (P < 0.05). There were no significant differences in additional parameters such as operative time, post-operative stay duration, time to drain removal, bile duct stenosis, acute allergic reaction and overall mortality.
CONCLUSIONS: Human fibrin sealant can reduce post-operative bile leakage in primary closure of CBD after LCBDE in patients with choledocholithiasis.

INTRODUCTION

Recent research has shown that primary closure of the common bile duct (CBD) without T-tube drainage is a safe alternative to T-tube placement after laparoscopic choledochotomy.[12] Nevertheless, only a few surgeons perform primary closure of the CBD laparoscopically due to concern for post-operative bile leakage.[34] Bile leakage after laparoscopic CBD exploration (LCBDE) remains one of the most important concerns for doctors, especially when T-tube drainage is not used. Researchers have demonstrated that human fibrin sealant can be successfully used to treat fistulous complications of digestive anastomoses,[5] but until now, it has not been clear whether human fibrin sealant can reduce post-operative bile leakage of the primary suture after LCBDE in patients with choledocholithiasis. This study aimed to evaluate whether using human fibrin sealant on the primary suture of the CBD in patients with choledocholithiasis could influence the incidence of bile leakage.

SUBJECTS AND METHODS

Patients

Between January 2013 and January 2018, 273 patients (142 men and 131 women, age range 25–74 years) at the Second Affiliated Hospital of Harbin Medical University who were treated with primary duct closure of the CBD after LCBDE were retrospectively analysed. All the patients had cholecystolithiasis with choledocholithiasis. According to whether fibrin sealant was used to seal the suture of CBD, the patients were divided into the fibrin sealant group (n = 108) and the control group (n = 165). The fibrin group consisted of 58 men (53.70%) and 50 women (46.30%), with a mean age of 49.1 years (range, 25–72 years). The control group had 84 men (50.91%) and 81 women (49.09%), with a mean age of 49.8 years (range: 27–74 years).

Cholecystolithiasis with choledocholithiasis were diagnosed by ultrasonic and magnetic resonance cholangiopancreatography and computed tomography combined with clinical features and blood biochemical data. The main symptoms of choledocholithiasis were abdominal pain and jaundice. The exclusion criteria included biliary pancreatitis, calculus of an intrahepatic duct, conversion to open surgery or the incomplete data of patients. The research team recorded the demographic characteristics and pre-operative clinical presentations of the patients for future use. The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University.

Operative approach

All patients underwent general anaesthesia. Surgery was carried out using a standard three-port or four-port approach for cholecystectomy, and trans-CBD exploration was performed routinely. A cholecystectomy was performed keeping the cystic duct intact, which facilitated the exposure of the CBD by pulling the gallbladder during bile duct exploration. The cystic duct was clipped early to avoid further displacement of stones from the gallbladder into the CBD. The CBD was opened through a supra-duodenal vertical incision. A 5-mm flexible choledochoscopy was used to examine the CBD. The stones were removed by saline flush or extracted using a stone basket. Biliary lithotripsy was used if necessary to break large stones or stones impacted at the ampulla. The choledochotomy was closed with continuous sutures using 4-0 absorbable vicryl (Ethicon, Inc., Somerville, NJ, USA) suture without T-tube drainage.

After primary duct closure, according to whether fibrin sealant was used, the patients were divided into the fibrin sealant group or the control group. In the fibrin sealant group, the suture of the CBD was sealed with human fibrin sealant (Shanghai RAAS Blood Products Co., Ltd., Shanghai, China) in a thin layer, mixing the two components of fibrin sealant before application. The operating field was kept untouched for at least 90 s to allow the fibrin sealant to firmly polymerise. If no fibrin sealant was used, the patients were enrolled into the control group. Drainage was placed in the sub-hepatic space in all patients. If there was no evidence of bile leakage, the peritoneal drain was removed on the post-operative day 3 or 4. Post-operative parameters including operative time, time to removal of drain, post-operative serum bilirubin concentration, rate of bile leakage, rate of bile duct stenosis, length of post-operative stay, acute allergic reactions and mortality were calculated in both the groups. Bile leakage was defined as the discharge of fluid via the intra-abdominal drains with a bilirubin concentration at least three times greater than the serum bilirubin concentration. All patients received regular follow-up every 3 months until 24 months post-operatively.

Statistical analysis

Continuous variables were presented as the mean with standard deviation. The data were analysed using Statistical Product and Service Solutions (SPSS, Version 19.0, IBM Corporation, Armonk, New York, USA) software. Fisher's exact test or the Chi-square test was used for categorical variables to calculate frequencies and percentages among the groups. The Student's t-test was used to compare the means of the continuous variables between the groups. A P < 0.05 was considered statistically significant.

RESULTS

There were no statistically significant differences in pre-operative clinical presentation between the two groups [Table 1]. All patients were followed up for at least 6 months. One patient from each group was lost to follow-up 9 months post-operatively, and another patient in the control group was lost to follow-up 12 months post-operatively. These patients were lost to follow-up due to changes in contact information. The total follow-up rate was 98.90%, and the mean follow-up period was 22.57 ± 3.14 months (ranged from 3 to 24 months).

Table 1

Clinical characteristics of patients in the two groups

	Fibrin sealant	Control	P
Sex (male/female)	58/50	84/81	0.65
Age (years)	49.1±13.1	49.8±15.6	0.69
BMI (kg/m2)	21.2±2.6	21.6±2.3	0.47
Previous upper abdominal surgery, n (%)	3 (2.78)	5 (3.03)	1.00
Cholangitis, n (%)	5 (4.63)	7 (4.24)	1.00
Acute cholecystitis, n (%)	8 (7.41)	10 (7.27)	0.66
Jaundice, n (%)	58 (53.70)	85 (51.52)	0.72
CBD diameter (cm)	1.47±0.42	1.41±0.43	0.07
Stones (n)	3.05±1.39	2.94±1.25	0.33

BMI: Body mass index, CBD: Common bile duct

The post-operative outcomes of the two groups are provided in Table 2. Operative time, post-operative stay and time to drain removal were not significantly different between the two groups. There was no difference in post-operative serum bilirubin concentration between two groups. Bile duct stenosis was not found in either group. One patient in the fibrin sealant group and two patients in the control group had recurrence of CBD stones. Moreover, they were treated by endoscopic retrograde cholangiopancreatography (ERCP). The rate of post-operative bile leakage in the fibrin sealant group was lower than that of the control group (P < 0.05). No patients in the fibrin sealant group had bile leakage, while nine patients experienced post-operative bile leakage in the control group. Six of these were minor bile leakages, which stopped spontaneously with sufficient peritoneal drainage. The other three patients were treated with endoscopic nasobiliary drainage and abdominal cavity drainage. No patient underwent reoperation. No acute allergic reaction was observed in either group. The overall mortality was 0% in both the groups. Other complications included one patient who developed pneumonia in the fibrin sealant group. In addition, one case in the fibrin sealant group and two cases in the control group had infection at the trocar site for gallbladder extraction. No cardiovascular complications including myocardial infarction, deep vein thrombosis or renal injury occurred during the period of hospitalisation. Acute pancreatitis, post-operative cholangitis and bile duct stricture did not occur in either group during the follow-up period.

Table 2

Comparison of clinical outcomes between the two groups

	Fibrin sealant	Control	P
Operative time (min)	112±14	109±13	0.09
Post-operative stay (day)	5.4±0.9	5.4±1.4	0.66
Serum bilirubin concentration (µmol/L)	40±15	41±16	0.27
Time to removal of drain (day)	3.4±0.8	3.6±1.5	0.12
Bile leakage, n (%)	0	9 (5.45)	0.01
Bile duct stenosis, n (%)	0	0	-
Recurrence of stone, n (%)	1 (0.92)	2 (1.21)	1.00
Allergic reaction, n (%)	0	0	-
Other complications, n (%)	2 (1.85)	2 (1.21)	1.00
Mortality, n (%)	0	0	-

DISCUSSION

Choledocholithiasis is the most common cause of obstructive jaundice and cholangitis, occurring in approximately 10%–18% of patients with cholecystolithiasis.[6789] Concomitant cholecystolithiasis and choledocholithiasis can be managed with laparoscopic cholecystectomy (LC) as well as pre- or post-operative ERCP. However, performing LC followed by ERCP is more complicated, and patients must undergo an extra-invasive procedure.[10] Although previous research has demonstrated that a single-stage combined tri-endoscopic approach or intra-operative ERCP for concomitant cholecystolithiasis and choledocholithiasis is safe,[111213] this method is not suitable for most hospitals. In addition, there are complications associated with endoscopic sphincterotomy. LCBDE allows the treatment of cholecystolithiasis and choledocholithiasis to be performed simultaneously. LCBDE has gradually become one of the most popular surgical treatments for patients with cholecystolithiasis and choledocholithiasis. Previous studies also showed that LCBDE is safe and effective for patients with concomitant cholecystolithiasis and choledocholithiasis.[1415] In addition, anatomical damage to the sphincter of Oddi is avoided in LCBDE, which can be very important especially in young individuals.[16] For these reasons, LCBDE may become the major approach to treat patients with cholecystolithiasis and choledocholithiasis in the future.

The CBD is conventionally closed with T-tube drainage after choledochotomy and removal of CBD stones. However, this method carries a T-tube-related morbidity of 10%–20%, including fluid and electrolyte disturbances, local discomfort, prolonged biliary fistulas, late biliary stricture and prolonged hospital stay.[1718] Moreover, the rates of bile leakage are not reduced even with the T-tube drainage of the CBD.[819] Studies in the literature report a rate of bile leakage up to 6% after T-tube removal.[817] Many surgeons think that the transcystic approach to LCBDE is the ideal method because choledochotomy and suturing of the CBD can be avoided. In addition, it has lower complication rate than the trans-CBD method. However, the success rate of bile duct stone removal by transcystic route is lower than that of the trans-CBD method.[1718192021] Therefore, many surgeons found that the application of this method was limited and converted to the trans-CBD approach.[1422] In recent years, accumulating research has shown that primary closure of the CBD without drainage is a safe alternative to T-tube placement after laparoscopic choledochotomy.[17] It has been reported that primary closure of the CBD significantly reduces the hospital stay without increasing the morbidity or mortality. Some retrospective studies have shown that primary closure of the CBD after laparoscopic choledochotomy is feasible.[3] Nevertheless, spasm of the sphincter of Oddi after LCBDE or migration of intrahepatic bile duct stones to the CBD may induce increased pressure in the biliary tract. Under such circumstances, bile leakage may still occur after primary closure of the CBD without decompression of the T-tube. In addition without dilation, the bile duct is more likely to leak because lack of dilation is one of the main causes of bile leakage after primary closure following LCBDE.[2324]

Human fibrin sealant is a biodegradable and biocompatible combination of highly concentrated human-derived fibrinogen and thrombin. It is activated by calcium chloride to polymerise into a fibrin fibre matrix. Human fibrin sealant has been shown to reduce post-operative bleeding and anastomosis leakage as well as promote post-operative wound healing.[2526272829] Moreover, the use of fibrin sealant has been suggested in bariatric surgery, and it has been shown that the use of fibrin sealant in laparoscopic sleeve gastrectomy significantly reduces post-operative bleeding.[30] Moreover, fibrin sealant has shown some efficacy in healing leaks in a non-operative setting in both laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy.[2627] Although human fibrin sealant has been shown to reduce post-operative bleeding and anastomosis leakage and to promote wound healing after operations, it is not yet clear whether it can reduce post-operative bile leakage of the primary suture and whether it causes adverse reactions after LCBDE in patients with choledocholithiasis. In this study, the rate of post-operative bile leakage in the fibrin sealant group was lower than that of the control group. The reason may be that human fibrin sealant had sealed the gap between two stitches. In addition, homologous human fibrin sealants are extracted from human blood, so it may reduce allergic reactions. In this study, no allergic reactions or other adverse effects related to human fibrin sealant were observed. This research has some limitations; a major one is that this study is a retrospective research. In addition, all of the cases came from one hospital. Therefore, a prospective random clinical study in several centres with a larger sample is needed.

CONCLUSIONS

To the best of our knowledge, this study was the first to evaluate the effectivity and safety of human fibrin sealant on the primary duct closure after laparoscopic choledochotomy. The results confirm that human fibrin sealant reduces post-operative bile leakage of the primary closure after LCBDE in patients with choledocholithiasis. The encouraging results of this study by this simple and easy technique may lead to a more widespread application of human fibrin sealant in primary bile duct closure after LCBDE.

Financial support and sponsorship

This study was supported by a grant from the Natural Science Foundation of Heilongjiang province (No. H2016028).

Conflicts of interest

There are no conflicts of interest.