Norepinephrine vs Phenylephrine During General Anesthesia

NCT ID: NCT04789330

Last Updated: 2025-12-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 3626 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-01
• Study Completion Date: 2022-04-01

Brief Summary

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.

Detailed Description

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

Conditions

Anesthesia; Surgery; Hypotension

Keywords

vasopressor; outcome; AKI; cardiovascular; complications

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: SINGLE

Study Groups

Norepinephrine

Norepinephrine continuous infusion as the first line vasopressor

Group Type: ACTIVE_COMPARATOR

Norepinephrine

Intervention Type: DRUG

Norepinephrine administered during anesthesia

Phenylephrine

Phenylephrine continuous infusion as the first line vasopressor

Group Type: ACTIVE_COMPARATOR

Phenylephrine

Intervention Type: DRUG

Phenylephrine administered during anesthesia

Interventions

Norepinephrine

Norepinephrine administered during anesthesia

Intervention Type: DRUG

Phenylephrine

Phenylephrine administered during anesthesia

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Matthieu LEGRAND, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States

Zuckerberg San Francisco General Hospital

San Francisco, California, United States

UCSF Medical Center at Mount Zion

San Francisco, California, United States

UCSF Medical Center at Parnassus

San Francisco, California, United States

UCSF Medical Center at Mission Bay

San Francisco, California, United States

Countries

United States

References

Legrand M, Kothari R, Fong N, Palaniappa N, Boldt D, Chen LL, Kurien P, Gabel E, Sturgess-DaPrato J, Harhay MO, Pirracchio R, Bokoch MP; VEGA-1 trial investigators. Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial. Br J Anaesth. 2023 May;130(5):519-527. doi: 10.1016/j.bja.2023.02.004. Epub 2023 Mar 14.

Reference Type: RESULT

PMID: 36925330 (View on PubMed)

Krone S, Bokoch MP, Kothari R, Fong N, Tallarico RT, Sturgess-DaPrato J, Pirracchio R, Zarbock A, Legrand M. Association between peripheral perfusion index and postoperative acute kidney injury in major noncardiac surgery patients receiving continuous vasopressors: a post hoc exploratory analysis of the VEGA-1 trial. Br J Anaesth. 2024 Apr;132(4):685-694. doi: 10.1016/j.bja.2023.11.054. Epub 2024 Jan 19.

Reference Type: DERIVED

PMID: 38242802 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

A135759

Identifier Type: -

Identifier Source: org_study_id