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The GUARDIAN Trial

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ClinicalTrials.gov Identifier: NCT04884802
Recruitment Status : Recruiting
First Posted : May 13, 2021
Last Update Posted : August 18, 2021
Sponsor:
Information provided by (Responsible Party):
The Cleveland Clinic

Tracking Information
First Submitted Date  ICMJE April 5, 2021
First Posted Date  ICMJE May 13, 2021
Last Update Posted Date August 18, 2021
Actual Study Start Date  ICMJE July 25, 2021
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2021)
Composite of major perfusion-related complications [ Time Frame: 30 days after major non-cardiac surgery ]
a composite of major perfusion-related complications (myocardial injury, stroke, non-fatal cardiac arrest, Stage 2-3 acute kidney injury, sepsis, and death)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2021)
  • Postoperative delirium [ Time Frame: 4 Postoperative hospital days ]
    Three-dimensional Confusion Assessment Method (3D CAM)
  • Major adverse cardiac events [ Time Frame: 1 year ]
    Myocardial infarction, non-fatal cardiac arrest, stroke, and all-cause mortality.
  • Cognition [ Time Frame: 1 year ]
    T-MOCA
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2021)
Postoperative delirium [ Time Frame: 4 Postoperative hospital days ]
Three-dimensional Confusion Assessment Method (3D CAM)
Current Other Pre-specified Outcome Measures
 (submitted: June 15, 2021)
  • ICU admission [ Time Frame: 30 days. ]
    Admission.
  • Hospital readmission [ Time Frame: 30 days. ]
    Readmission.
  • Atrial fibrillation [ Time Frame: 30 days. ]
    Atrial fibrillation
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The GUARDIAN Trial
Official Title  ICMJE Tight Perioperative Blood Pressure Management to Reduce Serious Cardiovascular, Renal, and Cognitive Complications.
Brief Summary The treatments will be: 1) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg, delayed resumption of chronic antihypertensive medications, and a target ward systolic pressure ≥110 mmHg (tight pressure management); or, 2) routine intraoperative blood pressure management and prompt resumption of chronic antihypertensive medications (routine pressure management).
Detailed Description

Consenting patients who take either angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or calcium channel blockers will be asked not to take the medications on the morning of surgery, and instead bring them with them to the hospital. Qualifying patients will be randomized 1:1, with random-sized blocks.

The treatments will be: 1) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg, delayed resumption of chronic antihypertensive medications, and a target ward systolic pressure >110 mmHg (tight pressure management); or, 2) routine intraoperative blood pressure management and prompt resumption of chronic antihypertensive medications (routine pressure management).

Tight pressure management: In patients assigned to tight pressure management, angiotensin converting enzyme inhibitors and angiotensin receptor blockers will not be given the morning of surgery. Other chronic antihypertensives will only be given as necessary to treat hypertension.

A norepinephrine or phenylephrine infusion (in the preferred local concentration) will be prepared, connected to an intravenous catheter, and activated at a low rate. Norepinephrine can be safely given through a central catheter or peripherally.

General anesthesia will be induced with propofol or etomidate which will be given in repeated small boluses or target-controlled infusion in an effort to keep mean arterial pressure ≥85 mmHg. Clinicians will be encouraged to use etomidate when rapid-sequence inductions are required. Simultaneously, the vasopressor infusion will be adjusted with the same goal. Anesthetic dose, fluid administration, and vasopressor administration will be adjusted with the goal of maintaining the individual designated baseline mean arterial pressure. Invasive or non-invasive advanced hemodynamic monitoring is not required, but should be used when practical. Clinicians should use available information to optimize vascular volume, afterload, and inotropy.

Resumption of chronic anti-hypertensive medications will be delayed until the third postoperative day unless deemed necessary to treat hypertension or for some other clear indication because >90% of MINS occurs within 48 hours after surgery. When necessary to treat hypertension, chronic antihypertensive or new medications can be used per clinician preference. Clinicians will make what efforts they can to maintain postoperative systolic arterial pressures ≥110 mmHg during the initial three postoperative days by maintaining adequate hydration, using inotropic and chronotropic drugs, and vasopressor as necessary. This protocol specifies the blood pressure target but leaves implementation to clinical judgement.

Routine pressure management: In patients assigned to routine pressure management, ACEIs, ARBs, and/or calcium channel blockers can be given the morning of surgery if deemed appropriate by the attending anesthesiologist. The arterial catheter will be inserted before or after induction of anesthesia per clinician preference. General anesthesia will be induced and maintained per routine. Blood pressure will not be deliberately reduced, but per routine clinicians will presumably not intervene until MAP is <65 mmHg. As usual, chronic anti-hypertensive medications will be restarted shortly after surgery unless contraindicated by hypotension.

In both groups, other aspects of anesthetic management will be at the discretion of the responsible anesthesiologist, including the types and volumes of various fluids. Volatile or intravenous anesthesia is permitted.

There will be no limitation on ancillary vasoactive, chronotropic, and inotropic drugs. Clinicians will be free to use advanced hemodynamic monitoring (e.g., pulse-wave analysis, esophageal Doppler, etc.). Blood products will be given per routine. Similarly, postoperative analgesic management will be per routine and clinician preference. Neuraxial and peripheral nerve blocks are permitted, but epidural catheters should not be activated until surgery is nearly finished.

Because patients must be fairly sick to qualify for GUARDIAN, some will go to directly from surgery to critical care units, or much less often, become unstable and require transfer from a routine ward to an ICU. In either case, every effort will be to maintain randomized treatments and blood pressure targets.

In all cases, good judgement will predominate. Clinicians should always act in their patients' best interests, irrespective of the GUARDIAN protocol

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Parallel group randomized trial.
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Blood Pressure
Intervention  ICMJE
  • Procedure: Tight pressure management
    Norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg, delayed resumption of chronic antihypertensive medications, and a target ward MAP ≥80 mmHg (tight pressure management)
  • Procedure: Routine pressure management
    ACEIs, ARBs, and/or calcium channel blockers can be given the morning of surgery if deemed appropriate by the attending anesthesiologist. Intraoperative blood pressure will be managed per clinical routine. As usual, chronic anti-hypertensive medications will be restarted shortly after surgery unless contraindicated by hypotension.
  • Drug: Induction agent
    etomidate and propofol - randomly assigned
    Other Name: etomidate and propofol
  • Drug: Vasopressor
    pressure maintenance with phenylephrine and norepinephrine - randomly assigned
    Other Name: phenylephrine and norepinephrine
Study Arms  ICMJE
  • Experimental: Tight pressure management

    In patients assigned to tight blood pressure control, angiotensin converting enzyme inhibitors and angiotensin receptor blockers will not be given the morning of surgery. Other chronic antihypertensives will only be given as necessary to treat hypertension. Norepinephrine or phenylephrine infusion will be infused at a rate sufficient to maintain intraoperative MAP ≥ 85 mmHg.

    Resumption of chronic anti-hypertensive medications will be delayed until the third postoperative day unless deemed necessary to treat hypertension or for some other clear indication.

    The target for postoperative systolic arterial pressures ≥110 mmHg during the initial three postoperative days.

    Interventions:
    • Procedure: Tight pressure management
    • Drug: Induction agent
    • Drug: Vasopressor
  • Routine pressure management
    ACEIs, ARBs, and/or calcium channel blockers can be given the morning of surgery if deemed appropriate by the attending anesthesiologist. Intraoperative blood pressure will be managed per clinical routine. As usual, chronic anti-hypertensive medications will be restarted shortly after surgery unless contraindicated by hypotension.
    Interventions:
    • Procedure: Routine pressure management
    • Drug: Induction agent
    • Drug: Vasopressor
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 26, 2021)
6254
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2021)
80
Estimated Study Completion Date  ICMJE April 25, 2025
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • ≥45 years old
  • Scheduled for major noncardiac surgery expected to last at least 2 hours;
  • Having general endotracheal, neuraxial anesthesia, or the combination;
  • Expected to require at least overnight hospitalization;
  • Are designated ASA physical status 2-4 (ranging from mild systemic disease through severe systemic disease that is a constant threat to life);
  • Chronically taking at least one anti-hypertensive medication;
  • Expected to have direct blood pressure monitoring with an arterial catheter;
  • Cared for by clinicians willing to follow the GUARDIAN protocol;
  • Subject to at least one of the following risk factors:
  • History of peripheral arterial disease;
  • History of coronary artery disease;
  • History of stroke or transient ischemic attack;
  • Serum creatinine >175 µmol/L (>2.0 mg/dl);
  • Diabetes requiring medication;
  • Current smoking or 15 pack-year history of smoking tobacco;
  • Scheduled for major vascular surgery;
  • Body mass index ≥35 kg/m2;
  • Preoperative high-sensitivity troponin T >14 ng/L or troponin I equivalent; defined as ≥15 ng/L (Abbott assay),73 19 ng/L (Siemens assay, [Borges, unpublished]), or 50% of the 99% percentile for other assays; B-type natriuretic protein (BNP) >80 ng/L or N-terminal B-type natriuretic protein (NT-ProBNP) >200 ng/L

Exclusion Criteria:

  • Are scheduled for carotid artery surgery;
  • Are scheduled for intracranial surgery;
  • Are scheduled for partial or complete nephrectomy;
  • Are scheduled for pheochromocytoma surgery;
  • Are scheduled for liver or kidney transplantation;
  • Require preoperative intravenous vasoactive medications;
  • Have a condition that precludes routine or tight blood pressure management such as surgeon request for relative hypotension;
  • Require beach-chair positioning;
  • Have a documented history of dementia;
  • Have language, vision, or hearing impairments that may compromise cognitive assessments;
  • Have contraindications to norepinephrine or phenylephrine per clinician judgement;
  • Have previously participated in the GUARDIAN trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Roberta Johnson 216-444-9950 johnsor13@ccf.org
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04884802
Other Study ID Numbers  ICMJE 21-175
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be shared on a collaborative basis.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Within two years after publication of the main trial report, and for at least 5 years thereafter.
Access Criteria: Daniel Sessler at DS@OR.org.
Responsible Party The Cleveland Clinic
Study Sponsor  ICMJE The Cleveland Clinic
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Daniel I Sessler, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP