Clinical trial NCT06802224: The Choice of Vasopressor to Prevent Postoperative Acute Kidney Injury After Major Non-Cardiac Surgery
Official title: Norepinephrine vs Phenylephrine as the First-line Vasopressor to Prevent Postoperative Acute Kidney Injury After Major Non-cardiac Surgery
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Anesthesia
Surgery With General Anesthesia
Noncardiac Surgery
Hypotension During Surgery
Acute Kidney Injury (AKI)
Myocardial Injury After Noncardiac Surgery (MINS)
Vasopressor
Keywords: Norepinephrine
Phenylephrine
Major adverse kidney events
Pragmatic
Cluster randomized
Crossover
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Michigan
name: Henry Ford Health System
name: University of Washington
name: University of Texas Southwestern Medical Center
name: Wake Forest University Health Sciences
name: University of Virginia
name: University of Maryland
name: Duke University
First posted: 2025-01-31
Enrollment: 18000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a multicenter, multiple periods, cluster-randomized, crossover trial design in 10 to 12 sites of the Multicenter Perioperative Outcomes Group (MPOG). The randomization at each site will alternate on a monthly basis between the norepinephrine arm and phenylephrine arm. Each cluster will be a different medical center in a different health system in North America. There will be a 2 month run-in at each site, followed by 12 crossover periods with data collection (6 months randomized to PE, 6 months randomized to NE).

This cluster randomization aligns with current clinical practice and is therefore more feasible than an individualized randomization. It also enrolls a diverse population representative of the population being treated in the participating centers. This cluster-randomized crossover design increases the power and the ability to show a realistic difference between the two groups through enrollment of a very large number of patients.
Primary purpose: TREATMENT

Brief summary: Low blood pressure, also known as hypotension, is very common during major surgery under general anesthesia. Prolonged or severe hypotension can lead to complications such as kidney injury after surgery that slow down patient recovery. Anesthesiologists commonly administer medications called vasopressors to treat low blood pressure during surgery. These medications help raise the blood pressure back up to a safe range. Two vasopressor medications are commonly used for this purpose: norepinephrine and phenylephrine. Each of these medications has slightly different effects on the heart and blood vessels (cardiovascular system). It remains unknown which of these standard medications is better for treating low blood pressure during surgery. The goal of this clinical trial is to determine which of these two medications is better at preventing injury to the kidneys after major noncardiac surgery as well as other complications such as heart problems. Major surgeries are defined as those lasting at least two hours under general anesthesia. This trial will randomize about ten centers in North America to use either norepinephrine or phenylephrine as the primary medication to treat low blood pressure in adults undergoing major noncardiac surgery. Each hospital will prioritize one of the drugs each month, and the assigned drug will rotate each month at each hospital. No further participant involvement will be required as de-identified data are collected as part of standard medical care.

Detailed description: VEGA-2 is an open-label, pragmatic, multiple periods, cluster-randomized, crossover trial across hospitals from MPOG. Hospital centers will be assigned to use either phenylephrine (PE) or norepinephrine (NE) for the first-line intravenous vasopressor in the operating room for the treatment of intraoperative hypotension. Centers will be randomly assigned to use PE during even-numbered months and NE during odd-numbered months, or vice versa. Data will be collected from routine clinical care and automatically extracted from the electronic health record. No additional lab tests or procedures will be required for the study. Only the randomization (of each hospital to the sequence of interventions) will be different from usual care.

The intervention is the first line vasopressor used for both infusion and bolus dosing, either PE or NE . Anesthesia providers will use the concentration that their respective center already uses in line with local anesthesia and pharmacy standard operating procedures. Anesthesiologists will provide standard of care during the intraoperative period. They will evaluate the need for vasopressors based on hemodynamic assessment and the arterial pressure goals during the procedure. Anesthesia providers will be encouraged to maintain mean arterial pressure above 65 mmHg or within 20% from baseline, but the arterial pressure targets can be adjusted on an individual basis, for instance during pre-surgical time-out, or based on individual assessment. Doses of bolus or continuous infusion of vasopressors will be adjusted to reach these goals on an individual basis. Of note, the anesthesia provider could use the alternative vasopressor if they consider the benefit of one drug being higher. A second line vasopressor will be allowed. The choice of the first line vasopressors will be determined by the randomization block.

Eligibility criteria: Inclusion Criteria:

* Age 18 years or older
* Surgery under general anesthesia with a surgery duration of 2 hours or more
* Received intravenous vasopressors during surgery

Exclusion Criteria:

* Cardiac surgery
* Extra-corporeal membrane oxygenation
* Organ transplantation
* Obstetric procedures
* Procedures on the kidney
* Outpatient procedures
* Already receiving NE or PE or inotropes before induction of anesthesia (at the time of anesthesia start)
* American Society of Anesthesiologists physical status classification 5 or 6
* Patient for whom a local protocol recommends a specific first line vasopressor
* Most recent documented estimated glomerular filtration rate (eGFR) \< 15 mL/min/1.73m\^2 or preoperative renal replacement therapy within 60 days before surgery
* Patients who do not have a preoperative creatinine value within 60 days before surgery
* Alive patients who do not have a postoperative creatinine value

Primary outcomes:
measure: Acute Kidney Injury (AKI)
timeFrame: 7 days
Secondary outcomes:
measure: Major Adverse Kidney Events (MAKE)
timeFrame: 28 days
Other outcomes:
measure: Myocardial Injury after Noncardiac Surgery (MINS)
timeFrame: 28 days
measure: Hospital length of stay
timeFrame: 28 days
measure: Hypotension
timeFrame: During anesthesia care
measure: Duration of hypotension
timeFrame: During anesthesia care
measure: Severe hypotension
timeFrame: During anesthesia care
measure: Duration of severe hypotension
timeFrame: During anesthesia care
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Sachin Kheterpal, MD MBA
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Matthieu Legrand, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Allison Janda, MD
role: STUDY_DIRECTOR
affiliation: University of California, San Francisco
name: Michael P Bokoch, MD PhD
role: STUDY_DIRECTOR
References:
citation: Chiu C, Fong N, Lazzareschi D, Mavrothalassitis O, Kothari R, Chen LL, Pirracchio R, Kheterpal S, Domino KB, Mathis M, Legrand M. Fluids, vasopressors, and acute kidney injury after major abdominal surgery between 2015 and 2019: a multicentre retrospective analysis. Br J Anaesth. 2022 Sep;129(3):317-326. doi: 10.1016/j.bja.2022.05.002. Epub 2022 Jun 8.
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citation: Pancaro C, Shah N, Pasma W, Saager L, Cassidy R, van Klei W, Kooij F, Vittali D, Hollmann MW, Kheterpal S, Lirk P. Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study. Anesth Analg. 2020 Oct;131(4):1060-1065. doi: 10.1213/ANE.0000000000004445.
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citation: Mets B. Should Norepinephrine, Rather than Phenylephrine, Be Considered the Primary Vasopressor in Anesthetic Practice? Anesth Analg. 2016 May;122(5):1707-14. doi: 10.1213/ANE.0000000000001239. No abstract available.
citation: Legrand M, Zarbock A. Ten tips to optimize vasopressors use in the critically ill patient with hypotension. Intensive Care Med. 2022 Jun;48(6):736-739. doi: 10.1007/s00134-022-06708-y. Epub 2022 May 3. No abstract available.
citation: Mathis MR, Naik BI, Freundlich RE, Shanks AM, Heung M, Kim M, Burns ML, Colquhoun DA, Rangrass G, Janda A, Engoren MC, Saager L, Tremper KK, Kheterpal S, Aziz MF, Coffman T, Durieux ME, Levy WJ, Schonberger RB, Soto R, Wilczak J, Berman MF, Berris J, Biggs DA, Coles P, Craft RM, Cummings KC, Ellis TA 2nd, Fleishut PM, Helsten DL, Jameson LC, van Klei WA, Kooij F, LaGorio J, Lins S, Miller SA, Molina S, Nair B, Paganelli WC, Peterson W, Tom S, Wanderer JP, Wedeven C; Multicenter Perioperative Outcomes Group Investigators. Preoperative Risk and the Association between Hypotension and Postoperative Acute Kidney Injury. Anesthesiology. 2020 Mar;132(3):461-475. doi: 10.1097/ALN.0000000000003063.
citation: Salmasi V, Maheshwari K, Yang D, Mascha EJ, Singh A, Sessler DI, Kurz A. Relationship between Intraoperative Hypotension, Defined by Either Reduction from Baseline or Absolute Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery: A Retrospective Cohort Analysis. Anesthesiology. 2017 Jan;126(1):47-65. doi: 10.1097/ALN.0000000000001432.
citation: 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.