Gastrointestinal Complications after Elective Pancreatoduodenectomy Do Not Differ between Perioperative Epidural Analgesia and Patient-Controlled Intravenous Analgesia: The Randomised Controlled PAKMAN Trial

Background: Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are frequently used for pain control after pancreatic surgery. However, there is substantial uncertainty regarding the postoperative morbidity associated with these two strategies. Evidence from a post-hoc analysis suggests that PCIA is associated with fewer gastrointestinal complications. Therefore, we designed the multicentre PAKMAN trial to compare the occurrence of gastrointestinal complications after pancreatic surgery with PCIA versus EDA. Methods: We conducted an adaptive, pragmatic, randomised, controlled, international, multicentre, superiority trial in nine European pancreatic surgery centres. Adult patients scheduled for elective pancreatic surgery were randomised to general anaesthesia with postoperative PCIA or general anaesthesia with intra- and postoperative EDA. The primary endpoint was a composite of pancreatic fistula, bile leakage, delayed gastric emptying, gastrointestinal bleeding, or postoperative ileus within 30 days after surgery. The trial was prospectively registered (DRK7784). Findings: Between 30 June 2015 and 1 October 2017, 371 patients were randomly assigned to PCIA (n=185) or EDA (n=186); 248 patients (124 in each group) were analysed. The primary composite endpoint did not differ between the two groups (OR 1⋅174, 95% CI 0⋅707-1⋅949; p=0⋅536). Neither individual components of the primary endpoint nor 30-day mortality, postoperative pain levels, or intra- and postoperative substitution of fluids differed significantly. Patients with EDA gained more weight by postoperative day 4 and received more vasopressors. The failure rate of EDA was 18⋅5%. Interpretation: The choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding gastrointestinal complications. The two procedures are comparable with regard to effectiveness and safety. However, EDA was associated with several shortcomings. Trial Registration: The PAKMAN trial was registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS; number DRK7784) on 23 March 2015. Funding Statement: Dietmar Hopp Stiftung gGmbH, Raiffeisenstr. 51, 68789 St. Leon-Rot, Germany (project number 23011217). Declaration of Interests: All authors declare that they have no conflicts of interest in relation to this trial. None of the authors has had any financial and personal relationships with funding bodies or any other people or organisations that could inappropriately influence their work within this project. Ethics Approval Statement: The PAKMAN trial protocol and other relevant documents were approved by the ethics committee of the Medical Faculty of Heidelberg University and the individual ethics committees of all other participating institutions before the first patient was enrolled. The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and the principles of Good Clinical Practice (ICH-GCP E6). Reporting of the trial complied with the recommendations of the CONSORT statement.