50 million patients undergo surgery each year in the United States. Postoperative mortality is considered the third leading cause of death worldwide. Hypotension during surgery have been linked to increased postoperative morbidity and mortality. Episodes of hypotension during surgery are associated with an increased risk of acute kidney injury, stroke, cardiac events and death. Treating or preventing hypotension during general anesthesia and major surgery was found to improve outcomes. At this time, it is unclear what is the best vasopressor to maintain blood pressure during surgery under general anesthesia. With this pilot pragmatic trial, the investigators will explore the impact of norepinephrine (NE) or phenylephrine (PE) on post-operative events in patients undergoing major surgery with general anesthesia and needing vasopressors infusion to maintain their systemic arterial pressure.

Postoperative mortality is considered the third leading cause of death worldwide. Hemodynamic instability and specifically hypotension during surgery have been linked to increased postoperative morbidity and mortality. Episodes of hypotension during surgery are associated with an increased risk of acute kidney injury, stroke, cardiac events and death. Treating or preventing hypotension during general anesthesia and major surgery was found to improve outcomes. At this time, it is unclear what is the best vasopressor to maintain blood pressure during surgery.

Hypotension during anesthesia and surgery is commonly treated with vasopressors such as phenylephrine (PE), a synthetic pure vasoconstrictor, or norepinephrine (NE), which has both inotropic and vasoconstrictor activity. NE increases cardiac output and increases cardio-vascular coupling due to alpha-agonist effects compared to PE, a purely vasoconstrictive agent.

The investigators hypothesize that norepinephrine will be superior to phenylephrine. The effect size is expected to be modest, therefore requiring a large sample size, and will vary between subgroups determined by patients' individual characteristics.

This pilot trial (VEGA-1) will allow to 1) test the feasibility of the study using a cross-over cluster randomized controlled trial and 2) estimate the effect size of the use of NE or PE on post-operative outcome in the overall population but also investigate the Heterogeneity in Treatment Effect (HTE) of the drugs among subgroups or clusters of patients for designing a larger trial.

Design: pragmatic, cluster-randomized, open-labeled, multiple-crossover trial across hospital from University of California, San Francisco (UCSF) and University of California, Los Angeles (UCLA). Centers will be assigned to use either PE or NE for the first-line intravenous infusion of vasopressor in the OR. Data will be collected in routine clinical care and automatically extracted from the electronic health record (EHR).

Primary endpoint:

- Separation between study groups in the first line vasopressor administration (% of cases with appropriate vasopressor with respect to group attribution).

Secondary endpoints:

• Death within 30 days
• Acute kidney injury defined by the KDIGO definition
• Severe acute kidney injury (stage 2 or 3 of the KDIGO definition)
• Myocardial Injury following non-cardiac surgery (MINS)
• Adverse cardio-renal events
• Hospital length of stay
• Rehospitalization within 30 days

Inclusion Criteria:

• age 18 Years and older
• Surgery under general anesthesia and requiring infusion of vasopressors to maintain the mean arterial pressure.
• Surgery duration>2 hours

Exclusion Criteria:

• Cardiac surgery
• Patients on ECMO
• Organ transplantation
• Outpatient (come-and-go surgery)
• Obstetric procedures
• Patient already receiving NE or PE before induction of anesthesia
• Patients transferred immediately (i.e. within 24 hours) after surgery to another hospital.
• Patients with severe trauma

Mortality was collected until 30 days post-surgery, and other adverse events were collected until 7 days post-surgery.

Pragmatic trial with events recorded throughout the eHR