PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): Legrand, Matthieu TITLE OF PROPOSED STUDY: The choice of vasopressors to prevent postoperative acute kidney injury after major non-cardiac surgery: a multicenter pragmatic cluster cross-over randomized trial (the VEGA-2 trial) Title ( max 81 characters ) Norepinephrine vs Phenylephrine for preventing postoperative acute kidney injury Abstract (30 lines) Around 50 million patients have surgery every year in the United States. Postoperative acute kidney injury (PO-AKI) is a major complication after surgery, occurring in 10 to 40% of cases after major surgery. PO-AKI is associated with higher risk of chronic kidney disease, cardiovascular events, prolonged hospitalization, higher costs, and mortality. Prevention of PO- AKI is considered a major outcome in perioperative medicine. Intraoperative hypotension has been repeatedly associated with an increased risk of PO-AKI and hypotension is a major contributing factor to PO-AKI. Prevention of hypotension is recommended to decrease the risk of PO-AKI. Vasopressors are the key pharmacologic intervention for the management of hypotension due to vasodilation induced by general anesthesia or the systemic inflammation triggered by the surgery. Phenylephrine and norepinephrine are the two most common intravenous vasopressors used for this purpose. However, the optimal choice of vasopressor to treat hypotension during surgery under general anesthesia is unknown. Phenylephrine is a pure alpha-1 agonist (vasoconstrictor), whereas norepinephrine has both alpha- and beta-adrenergic effects (vasoconstrictor/inotrope). Norepinephrine increases cardiac output and cardiovascular coupling and decreases inflammation- induced vascular permeability. Norepinephrine increases renal blood flow in vasodilatory shock. While several experts have recommended using norepinephrine as the first line vasopressor, randomized trials are missing, preventing to draw strong recommendations. Given the number of patients undergoing major non-cardiac surgery under anesthesia in the United States each year and the burden of PO-AKI, this is a major unaddressed question. We propose to perform a multicenter cluster-randomized, open-labeled, multiple-crossover trial of phenylephrine versus norepinephrine as the first-line infusion vasopressor in adult patients undergoing non-cardiac surgery with general anesthesia within the Multicenter Perioperative Outcomes Group (MPOG). This trial follows a pilot cluster-randomized trial (VEGA-1 trial, NCT04789330) that showed the feasibility of the trial in enrolling 3626 patients and provided key preliminary data. This study will provide the highest level of evidence regarding the best vasopressor to use and perfectly aligns with the mission of NIDDK to prevent kidney disease and improve health in the surgical population. This evidence generated by this trial will inform clinical guidelines and ultimately impact patient outcomes. VEGA-2 M.Legrand June 2023 1