Norepinephrine vs Phenylephrine During General Anesthesia (VEGA-1)

The Choice of Vasopressor for Treating Hypotension During General Anesthesia: a Pilot Pragmatic Cluster Cross-over Randomized Trial (the VEGA-1 Trial)

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.

Study Overview

• Status: Completed
• Conditions: Surgery; Hypotension; Anesthesia
• Intervention / Treatment: Drug: Norepinephrine; Drug: Phenylephrine

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

• Study Type: Interventional
• Enrollment (Actual): 2000
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General Hospital
    • San Francisco, California, United States, 94115
      • UCSF Medical Center at Mount Zion
    • San Francisco, California, United States, 94158
      • UCSF Medical Center at Mission Bay
    • San Francisco, California, United States, 94143
      • UCSF Medical Center at Parnassus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Norepinephrine; Norepinephrine continuous infusion as the first line vasopressor	Drug: Norepinephrine; Norepinephrine administered during anesthesia
ACTIVE_COMPARATOR: Phenylephrine; Phenylephrine continuous infusion as the first line vasopressor	Drug: Phenylephrine; Phenylephrine administered during anesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of total cases with assigned vasopressor given	First line vasopressor administration will be measured as a percent of total eligible cases with assigned vasopressor given during anesthesia time, up to 24 hours	Anesthesia time, up to 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Number of participants dying within 30 days after surgery	30 days
Acute kidney injury (AKI)	AKI using the Kidney Disease: Improving Global Outcomes (KDIGO) definition based on serum creatinine	7 days
Severe acute kidney injury	Stage 2 or 3 AKI using the KDIGO definition based on serum creatinine or need for Renal Replacement Therapy (RRT)	7 days
Hospital length of stay	Days between date of surgery and hospital discharge	In-hospital, up to 30 days
Myocardial Injury after non-cardiac surgery (MINS)	Number of patients with post-operative myocardial injury defined as a troponin elevation	7 days
Adverse Cardio-renal events	Number of patients meeting a combined endpoint of AKI and/or MINS	7 days
Rehospitalization within 30 days	Patients discharge and readmitted for more than 24 hours within 30 days after surgery	30 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Matthieu LEGRAND, MD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2021
• Primary Completion (ACTUAL): April 1, 2022
• Study Completion (ACTUAL): April 1, 2022

Study Registration Dates

• First Submitted: March 4, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (ACTUAL): March 9, 2021

Study Record Updates

• Last Update Posted (ACTUAL): May 5, 2022
• Last Update Submitted That Met QC Criteria: May 3, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: complications; outcome; cardiovascular; AKI; vasopressor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypotension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Norepinephrine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: A135759

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No