GUARDIAN (NCT04884802) Sub-study, Phenylephrine v. Norepinephrine

Study Overview
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Brief Summary
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Some patients participating in the underlying GUARDIAN trial (NCT04884802) will be additionally randomized to norepinephrine or phenylephrine infusion to maintain the designated target intraoperative mean arterial pressure.

Detailed Description
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Patients participating 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). Patients participating in this sub-study will be additionally randomized to norepinephrine or phenylephrine infusion to maintain the designated target intraoperative mean arterial pressure.

Official Title
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GUARDIAN (NCT04884802) Sub-study Comparing Phenylephrine and Norepinephrine

Conditions
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Blood Pressure

Intervention / Treatment
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* Drug: Phenylephrine
* Drug: Norepinephrine
* Drug: Phenylephrine
* Drug: Norepinephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 45 years old; Scheduled for major noncardiac surgery expected to last at least 2 hours; Having general anesthesia, neuraxial anesthesia, or the combination; Expected to require at least overnight hospitalization (planned ICU admission is acceptable); 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 intraoperative 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: Age >65 years; History of peripheral arterial surgery; 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),77 19 ng/L (Siemens assay, [Borges, unpublished]), or 25% 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.78,79 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.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tight Pressure Management with phenylephrine<br>Pressure maintenance with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial. | Drug: Phenylephrine<br>* Phenylephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.<br>|
| Active Comparator: Tight Pressure Management with norepinephrine<br>Pressure maintenance with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial. | Drug: Norepinephrine<br>* Norepinephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.<br>|
| Active Comparator: Routine Pressure Management with phenylephrine<br>Pressure maintenance with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial | Drug: Phenylephrine<br>* Phenylephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.<br>|
| Active Comparator: Routine Pressure Management with norepinephrine<br>Pressure maintenance with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial. | Drug: Norepinephrine<br>* Norepinephrine will be infused at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of major perfusion-related complications | Composite of major perfusion-related complications (Myocardial injury, stroke, non-fatal cardiac arrest, stage 2-3 acute kidney injury, sepsis, and death | 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 |