The GUARDIAN Trial - Vasopressor Sub-Study

Tight Perioperative Blood Pressure Management to Reduce Serious Cardiovascular, Renal, and Cognitive Complications: The GUARDIAN Trial (Vasopressor Sub-study Comparing Phenylephrine and Norepinephrine)

This is a sub-study of the overall GUARDIAN trial (NCT04884802) in which some GUARDIAN trial participants will be additionally randomized to norepinephrine or phenylephrine infusion to maintain the designated target intraoperative mean arterial pressure.

Study Overview

• Status: Enrolling by invitation
• Conditions: Blood Pressure
• Intervention / Treatment: Drug: Phenylephrine; Drug: Norepinephrine; Procedure: Routine Blood Pressure Management; Procedure: Tight Blood Pressure Management

Detailed Description

Participants in the underlying GUARDIAN trial (NCT04884802) will be randomized to: 1) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg (tight pressure management); or, 2) routine intraoperative blood pressure management (routine pressure management). Participants in this sub-study will be additionally randomized to norepinephrine or phenylephrine infusion to maintain the designated target intraoperative mean arterial pressure.

• Study Type: Interventional
• Enrollment (Estimated): 6254
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Peking Union Medical College Hospital
  • Beijing, China
    • Beijing Shijitan Hospital, Capital Medical University
  • Shanghai, China
    • Shanghai Chest Hospital
  • Shanghai, China, 200025
    • Shanghai Ninth People's Hospital
  • Sichuan, China
    • West China Hospital
• Greece
  • Larissa, Greece
    • University of Thessaly
• Japan
  • Tokyo, Japan
    • National Defense College
• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Main Campus
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Fairview Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. At least 45 years old;
2. Scheduled for major noncardiac surgery expected to last at least 2 hours;
3. Having general anesthesia, neuraxial anesthesia, or the combination;
4. Expected to require at least overnight hospitalization (planned ICU admission is acceptable);
5. Are designated ASA physical status 2-4 (ranging from mild systemic disease through severe systemic disease that is a constant threat to life);
6. Expected to have direct intraoperative blood pressure monitoring with an arterial catheter;
7. Cared for by clinicians willing to follow the GUARDIAN protocol;

8. Subject to at least one of the following risk factors:

   1. Age >65 years;
   2. History of peripheral arterial disease;
   3. History of coronary artery disease;
   4. History of stroke or transient ischemic attack;
   5. Serum creatinine >175 μmol/L (>2.0 mg/dl) within 6 months;
   6. Diabetes requiring medication;
   7. Current smoking or 15 pack-year history of smoking tobacco;
   8. Scheduled for major vascular surgery;
   9. Body mass index ≥35 kg/m2;
   10. Preoperative high-sensitivity troponin T >14 ng/L or troponin I equivalent, defined as ≥15 ng/L (Abbott assay), 19 ng/L (Siemens assay, [Borges, unpublished]), or 25% of the 99% percentile for other assays - all within 6 months;
   11. B-type natriuretic protein (BNP) >80 ng/L or N-terminal B-type natriuretic protein (NTProBNP) >200 ng/L within six months.

Exclusion Criteria:

1. Are scheduled for carotid artery surgery;
2. Are scheduled for intracranial surgery;
3. Are scheduled for partial or complete nephrectomy;
4. Are scheduled for pheochromocytoma surgery;
5. Are scheduled for liver or kidney transplantation;
6. Require preoperative intravenous vasoactive medications;
7. Have a condition that precludes routine or tight blood pressure management such as surgeon request for relative hypotension;
8. Require beach-chair positioning;
9. Have a documented history of dementia;
10. Have language, vision, or hearing impairments that may compromise cognitive assessments;
11. Have contraindications to norepinephrine or phenylephrine per clinician judgement;
12. Have previously participated in the GUARDIAN trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Routine Blood Pressure Management with Phenylephrine; Routine blood pressure control with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.	Drug: Phenylephrine; Phenylephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.; Procedure: Routine Blood Pressure Management; Routine blood pressure control.
Active Comparator: Routine Blood Pressure Management with Norepinephrine; Routine blood pressure control with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.	Drug: Norepinephrine; Norepinephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.; Procedure: Routine Blood Pressure Management; Routine blood pressure control.
Active Comparator: Tight Blood Pressure Management with Phenylephrine; TIiht blood pressure control with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial	Drug: Phenylephrine; Phenylephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.; Procedure: Tight Blood Pressure Management; Tight blood pressure control.
Active Comparator: Tight Blood Pressure Management with Norepinephrine; Tight blood pressure control with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.	Drug: Norepinephrine; Norepinephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.; Procedure: Tight Blood Pressure Management; Tight blood pressure control.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with a Composite of Major Perfusion-Related Complications	The primary outcome is a composite of major perfusion-related complications (myocardial injury, stroke, non-fatal cardiac arrest, Stage 2-3 acute kidney injury, deep or organ-space infection, sepsis, and death) in the 30 days after major non-cardiac surgery.	During the initial 30 days after major non-cardiac surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative delirium	Three dimensional Confusion Assessment Method (3D CAM)	4 Postoperative hospital days

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center, Houston
• Investigators: Principal Investigator: Daniel I Sessler, MD, The University of Texas Health Science Center, Houston

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): April 25, 2027

Study Registration Dates

• First Submitted: June 14, 2021
• First Submitted That Met QC Criteria: June 15, 2021
• First Posted (Actual): June 22, 2021

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 23, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Amino Alcohols; Ethanolamines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Norepinephrine; Phenylephrine
• Other Study ID Numbers: HSC-MS-24-1026 (vasopressor)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Each center will retain ownership of its own data. Publication of center-specific data will not be allowed until after the Main Trial Report is published, or two years have elapsed since enrollment of the last patient. The Executive Committee welcomes suggestions for sub-studies based on a partial or the full trial dataset. Sub-studies will be allocated based on importance and novelty of the proposals, and priority will be given to high-enrolling centers. However, all multi-center publications will be on a collaborative basis and include appropriate co-authors. The Executive Committee will do its best to be fair and equitable in assigning sub-studies.

Data will be shared with external parties on a collaborative basis with approval of the Executive Committee and appropriate data-use agreements.

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