German Clinical Trials Register

Acronym/abbreviation of the study

PRBOT-II

URL of the study

No Entry

Brief summary in lay language

Postoperative bile leakage occurs in approximately 25% of patients after hepatic resection. Bearing the risk of severe complications such as intra-abdominal abscess, sepsis and postoperative liver failure, bile leakage is a relevant clinical problem. Even though most cases can be managed non-operatively, bile leakage often requires interventional management and prolongs patient‘s hospital stay. The prevention of postoperative bile leakage and its sequelae would decrease postoperative morbidity and mortality, leading to a substantial improvement in patient‘s postoperative outcome. The PREBOT II trial is a multicentre, randomised, controlled, phase II clinical trial with two parallel study arms investigating a PREoperative injection of BOTulinum toxin into the sphincter of Oddi to reduce postoperative bile leakage after hepatic resection.

Brief summary in scientific language

In Germany, more than 24,000 patients are scheduled annually for hepatic resection which is the treatment of choice for various hepatobiliary diseases. Despite improvements in surgical techniques and perioperative management, bile leakage with a rate of 20-30 % remains a major cause of postoperative morbidity and mortality. Even though most cases can be managed non-operatively, bile leakage often requires interventional management and prolongs the duration of recovery and the hospital stay. In patients with malignant disease, postoperative bile leakage frequently results in a delayed start of adjuvant treatment, which potentially impairs the patient’s oncological outcome. Thus, the prevention and treatment of postoperative bile leakage is of utmost importance. Endoscopic retrograde cholangiography (ERC) with sphincterotomy and bile duct stenting represents the preferred non-surgical treatment strategy for the management of bile leakage from the cut surface of the liver following hepatic resection. Biliary stenting aims to promote closure of the leakage by improving drainage of bile towards the duodenum, thereby reducing intra-ductal pressure at the leakage site. However, due to potential prosthesis associated complications biliary stenting is recommended only in the treatment of evident bile leakage, not for bile leakage prevention. So far, effective treatments to prevent bile leakage after hepatic resection do not exist. This early clinical trial is the first to evaluate a completely new approach to the prevention of postoperative bile leakage following hepatic resection. Besides several bile leakage testing methods were evaluated, also the kind of surgical transection has been evaluated, but none of them showed superior results. Endoscopic retrograde cholangiography (ERC) with sphincterotomy and bile duct stenting represents the preferred non-surgical treatment strategy for the management of bile leakage from the cut surface of the liver following hepatic resection. Biliary stenting aims to promote closure of the leakage by improving drainage of bile towards the duodenum, thereby reducing intra-ductal pressure at the leakage site. However, due to potential prosthesis associated complications biliary stenting is recommended only in the treatment of evident bile leakage, not for bile leakage prevention. Botulinum toxin is an inhibitor of acetylcholine release from nerve endings which has a temporary but potent effect on smooth muscle cells when injected locally. It has been widely used in the treatment of gastrointestinal diseases such as achalasia and sphincter of Oddi dysfunction, with convincing results in terms of safety and efficacy. In patients with sphincter of Oddi dysfunction, it has been shown that the injection of one single deposit of botulinum toxin into the papilla of Vater reduces sphincter of Oddi pressure effectively. Recently, preoperative injection of botulinum toxin into the sphincter of Oddi was shown to be safe and feasible in the prevention of pancreatic fistula after distal pancreatectomy. The rationale for preoperative injection of botulinum toxin into the sphincter of Oddi in patients undergoing distal pancreatectomy is to improve drainage of pancreatic juice towards the duodenum and thereby reduce backpressure on the resection margin of the pancreas. Analogous to the prevention of pancreatic fistula after distal pancreatectomy, the improvement of drainage of bile towards the duodenum by botulinum toxin mediated relaxation of the sphincter of Oddi seems promising in the prevention of bile leakage after hepatic resection, as it will decrease intraductal pressure and thus lower back-pressure of bile at the resection margin of the liver, resulting in a reduced risk of the development of bile leakage. The rationale of this procedure is derived from the principle of bile duct stenting for treatment of bile leakage. The main advantage of botulinum toxin is its completely reversible and self-limiting effect, which lasts for an average of five months after the intervention. This time frame is long enough to prevent postoperative bile leakage, as it occurs normal within the first days after hepatic resections. Thus, injecting botulinum toxin into the sphincter of Oddi before surgery seems reasonable and promising in patients undergoing hepatic resection to prevent postoperative bile leakage from the resected surface of the liver.