GUARDIAN (NCT04884802) Sub-study, Etomidate vs Propofol

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 etomidate vs propofol for anesthetic induction.

Detailed Description
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Patients participating in the underlying GUARDIAN trial (NCT04884802) will be randomized to: 1) routine intraoperative blood pressure management (routine pressure management); or 2) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg (tight pressure management). Patients participating in this sub-study will be additionally randomized to etomidate or propofol for induction of anesthesia.

Official Title
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GUARDIAN (NCT04884802) Sub-study Comparing Etomidate and Propofol

Conditions
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Major Surgery

Intervention / Treatment
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* Procedure: Routine blood pressure control
* Procedure: Tight blood pressure control
* Drug: Etomidate
* Drug: Propofol


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 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 end-stage renal disease requiring dialysis or estimated glomerular filtration rate (eGFR) <30 ml/min; 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 this 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: Routine Pressure Management with etomidate induction<br>Etomidate will be used as an induction agent. | Procedure: Routine blood pressure control<br>* Routine blood pressure control.<br>Drug: Etomidate<br>* Anesthetic induction with etomidate.<br>|
| Active Comparator: Routine Pressure Management with propofol induction<br>Propofol will be used as an induction agent. | Procedure: Routine blood pressure control<br>* Routine blood pressure control.<br>Drug: Propofol<br>* Anesthetic induction with propofol.<br>|
| Active Comparator: Tight Pressure Management with etomidate induction<br>Etomidate will be used as an induction agent. | Procedure: Tight blood pressure control<br>* Tight blood pressure control.<br>Drug: Etomidate<br>* Anesthetic induction with etomidate.<br>|
| Active Comparator: Tight Pressure Management with propofol induction<br>Propofol will be used as an induction agent. | Procedure: Tight blood pressure control<br>* Tight blood pressure control.<br>Drug: Propofol<br>* Anesthetic induction with propofol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of serious perfusion-related complications | Composite of serious perfusion-related complications. Specifically, we will consider a collapsed (one or more) composite of myocardial injury after non-cardiac surgery (MINS), non-fatal cardiac arrest, stroke, Stage 2-3 acute kidney injury, sepsis, and all-cause mortality within 30 days of surgery. | 30 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative Delirium | Delirium, defined by abnormal 3D CAM or CAM ICU (in ventilated patients) assessed twice daily during the initial four postoperative days. | Initial four postoperative days | 
| Major Adverse cardiac events | Myocardial infarction, non-fatal cardiac arrest, stroke, and all-cause mortality. | 1 year | 
| Cognition | T-MOCA | 1 Year |