Preventing Postoperative Complications in Patients Undergoing High-risk Pancreatoduodenectomy With a Bundle Approach Including Hydrocortisone, Octreotide, and the Teres Ligament Patch (PANENCA): an International Randomized Controlled Multicenter Trial

The PANENCA trial is an international, multicenter, randomized controlled superiority trial designed to evaluate whether a standardized perioperative bundle approach reduces major postoperative complications in patients undergoing pancreatoduodenectomy who are at high risk for postoperative pancreatic fistula (POPF). High risk is defined preoperatively by a small main pancreatic duct diameter (≤3 mm) on cross-sectional imaging, which is associated with soft pancreatic parenchyma and an increased risk of anastomotic failure.

POPF remains the leading cause of morbidity and mortality following pancreatoduodenectomy. Several low-cost and widely available interventions have individually demonstrated effectiveness in reducing POPF or its sequelae; however, these measures have not been implemented consistently, systematically evaluated in a large international randomized trial, nor combined into a standardized perioperative strategy. The PANENCA trial therefore evaluates a bundled intervention (the HOP bundle) consisting of the following components:

1. Hydrocortisone, administered intravenously starting during induction of anesthesia to attenuate the postoperative inflammatory response, which is considered a key contributor to the development of POPF. Hydrocortisone is administered at a dose of 100 mg three times daily for three days, resulting in a total of 9 doses.
2. Octreotide, administered subcutaneously starting during induction of anesthesia, to reduce exocrine pancreatic secretion during the early postoperative period. Octreotide is administered at a dose of 0.1 mg three times daily for up to seven days or until earlier discharge, with a maximum of 21 doses.
3. A ligamentum teres hepatis patch, applied intraoperatively to mechanically protect the gastroduodenal artery stump from enzymatic erosion in the event of a POPF. The ligamentum teres is positioned between the gastroduodenal artery stump and the pancreatojejunostomy, functioning as an interpositional layer or wrap around one or both structures.

These interventions have potential complementary and non-overlapping mechanisms of action and are supported by prior randomized trials and meta-analyses. All investigational medicinal products are authorized and are used within approved or evidence-based indications.

Eligible patients are randomized in a 1:1 ratio prior to surgery to receive either the HOP bundle in addition to standard perioperative care or standard perioperative care alone. Randomization is stratified by participating center to account for potential inter-center variability. The trial is classified as a low-interventional clinical trial according to the European Union Clinical Trials Regulation (EU No 536/2014), as it uses authorized medicinal products, evidence-based dosing regimens, and does not require additional diagnostic or monitoring procedures beyond standard clinical practice.