Clinical trial NCT04884802: The GUARDIAN Trial
Official title: Tight Perioperative Blood Pressure Management to Reduce Serious Cardiovascular, Renal, and Cognitive Complications.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Blood Pressure
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2021-05-13
Enrollment: 6254
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group randomized trial.
Primary purpose: PREVENTION

Brief summary: The treatments will be: 1) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg (tight pressure management); or, 2) routine intraoperative blood pressure management (routine pressure management).

Detailed description: Qualifying patients will be randomized 1:1, with random-sized blocks, stratified by site.

The treatments will be: 1) norepinephrine or phenylephrine infusion to maintain intraoperative MAP ≥85 mmHg (tight pressure management); or, 2) routine intraoperative blood pressure management (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.

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. 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 \<60 mmHg - although they are free to.

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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Composite of major perfusion-related complications
timeFrame: 30 days after major non-cardiac surgery
Secondary outcomes:
measure: Postoperative delirium
timeFrame: 4 Postoperative hospital days
measure: Major adverse cardiac events
timeFrame: 1 year
measure: Cognition
timeFrame: 1 year
Other outcomes:
measure: ICU admission
timeFrame: 30 days.
measure: Hospital readmission
timeFrame: 30 days.
measure: Atrial fibrillation
timeFrame: 30 days.
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Wake Forest
country: United States
facility: Wake Forest University
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Fairview Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Beijing
country: China
facility: Beijing Shijitan Hospital, Capital Medical University
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Beijing
country: China
facility: Peking University First Hospital
city: Chang Chun
country: China
facility: China-Japan Union Hospital of Jilin University
city: Chengdu
country: China
facility: West China University Hospital
city: Hong Kong
country: China
facility: Prince of Wales Hospital, Chinese University of Hong Kong, Shatin
city: Shanghai
country: China
facility: Shanghai Chest Hospital
city: Shanghai
country: China
facility: Shanghai Ninth People's Hospital
city: Larisa
country: Greece
facility: University of Thessaly
city: Rome
country: Italy
facility: IRCCS Regina Elena National Cancer Institute
city: Tokyo
country: Japan
facility: National Defense Medical College
Study officials:
affiliation: The Cleveland Clinic
name: Daniel I Sessler, MD
role: STUDY_CHAIR
References: