The GUARDIAN Pilot Trial
The GUARDIAN Pilot Trial
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 MAP ≥80 mmHg (tight pressure management); or, 2) routine intraoperative blood
 pressure management and prompt resumption of chronic antihypertensive medications (routine
 pressure management).
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.

 Randomization will be implemented by clinicians in collaboration with research personnel.
 Arterial catheter transducers will be positioned at the level of the right atrium, and
 adjusted as necessary if patient position is changed.

 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 MAP ≥80 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. Clinicians will be encouraged to insert the required arterial catheter before
 anesthetic induction because much hypotension occurs shortly after anesthetic induction.

 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 (e.g., preventing atrial fibrillation in a chronic beta-blocker user) 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 mean arterial pressures ≥80 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
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 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;

 -  B-type natriuretic protein (BNP) >80 ng/L or N-terminal B-type natriuretic protein
 (NT-ProBNP) >100 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 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.