Perioperative Hypothermia and Myocardial Injury After Non-cardiac Surgery (PROTECT)

We propose to test the hypothesis that aggressive warming reduces the incidence of major cardiovascular complications, compared to routine care. Half of the participants will be randomly assigned to routine care (core temperature ≈35.5°C), while the other half will receive aggressive warming (>37°C core temperature) in a multi-center trial.

Study Overview

• Status: Completed
• Conditions: Myocardial Injury; Surgery--Complications; Perioperative Care; Hypothermia; Anesthesia
• Intervention / Treatment: Device: routine thermal management; Device: aggressive warming

Detailed Description

Hypothermia increases sympathetic activation, promotes tachycardia, and causes hypertension - all of which may increase the risk of myocardial injury. Moderate perioperative hypothermia is now uncommon, but mild hyperthermia (≈35.5°C) remains common. Whether aggressive warming to a truly normothermic level (≈37°C) improves outcomes remains unknown.

• Study Type: Interventional
• Enrollment (Actual): 5056
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • PUMCH
  • Chengdu, China
    • West China Hospital Sichuan Univeristy
  • Guangzhou, China
    • Guangdong General Hospital
  • Hong Kong, China
    • Chinese University of Hong Kong
  • Hong Kong, China
    • Queen Mary Hospital
  • Nanjing, China
    • NanJing Drum Tower Hospital
  • Shanghai, China
    • Shanghai Chest Hospital
  • Shanghai, China
    • Shanghai Oriental Hospital
  • Shanghai, China
    • Shanghai Zhongshan Hospital
  • Shanghai, China
    • FDSCC (Fudan University Shanghai
• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Scheduled for major noncardiac surgery expected to last 2-6 hours;
• Having general anesthesia;
• Expected to require at least overnight hospitalization;
• Expected to have >50% of the anterior skin surface available for warming;

• Have at least one of the following risk factors:

  a. Age over 65 years; b. History of peripheral vascular surgery; c. History of coronary artery disease; d. History of stroke or transient ischemic attack; e. Serum creatinine >175 µmal/L (>2.0 mg/dl); f. Diabetes requiring medication; e. Hypertension requiring medication; g. Current smoking.

Exclusion Criteria:

• Have a clinically important coagulopathy in the judgement of the attending anesthesiologist;
• Are septic (clinical diagnosis by the attending anesthesiologist);
• Body mass index exceeding 30 kg/m2;
• End-stage renal disease requiring dialysis;
• Surgeon believes patient to be at particular infection risk.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Routine thermal management; Patients assigned to routine thermal management will not be pre-warmed and ambient intraoperative temperature will be maintained near 20°C per routine. Only transfused blood will be warmed. An Multi-Position Upper Body Warming Blanket forced-air cover will be positioned over an appropriate non-operative site, but will not initially be activated. Should core temperature decrease to 35.5°C, the warmer will be activated as necessary to prevent core temperature from decreasing further.	Device: routine thermal management; A forced-air cover will be positioned but will not initially be activated. The warmer will be activated when core temperature decrease to 35.5°C.
Experimental: Aggressive thermal management; Patients assigned to aggressive warming will be pre-warmed with a full-body Bair Hugger or Bair Paws cover for ≈30 minutes before induction of anesthesia. The warmer will initially be set to "high" which corresponds to ≈43°C. It will be subsequently adjusted to make patients feel warm, but not uncomfortably so. Patients will be aggressively warmed during surgery to a target intraoperative core temperature between 37 and 37.5°C, using an Multi-Position Upper Body and Full Access Underbody Warming Blankets forced-air covers when clinically practical. All intravenous fluids will be warmed to body temperature.	Device: aggressive warming; Patients will be pre-warming 30 minutes before induction of anesthesia and aggressively warmed during surgery to a target intraoperative core temperature between 37 and 37.5°C.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Composite Outcome Consisted of Myocardial Injury After Non-cardiac Surgery (MINS), Non-fatal Cardiac Arrest, and All-cause Mortality	The primary outcome was a composite of myocardial injury after non-cardiac surgery, non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery. Myocardial injury was diagnosed when available troponin concentrations exceeded generation-specific and type-specific thresholds and were apparently of ischaemic origin (ie, no other obvious cause for artifactual elevation). We used the following thresholds based on available literature at time of adjudication: 1) non-high-sensitivity (fourth-generation) troponin T ≥0.03 ng/ml2; 2) high-sensitivity troponin T ≥65 ng/L; or high-sensitivity troponin T 20-64 ng/L and an increase ≥5 ng/L from baseline3; 3) high-sensitivity troponin I (Abbott assay) is ≥75 ng/L4; 4) high-sensitivity troponin I (Siemens assay) is ≥60 ng/L5; or, 5) troponin I (other assays) greater than local 99th percentiles. Myocardial infarction diagnosis required both troponin elevation and at least one diagnostic symptom or sign.	From the end of surgery to 30 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Readmission	Readmission to a hospital within a month of surgery	From the end of surgery to 30 days after surgery
Deep or Organ-space Surgical Site Infection	Surgical site infection is defined by US Centers for Disease Control and Prevention criteria. It is consisted of superficial infection, deep infection, and organ-space infection. Superficial infection: Infection involves only skin or subcutaneous tissue of the incision. Deep infection: Infection appears to be related to the operation and infection involves deep soft tissues (e.g., fascial and muscle layers) of the incision. Organ-space infection: Infection involves any part of the anatomy (e.g., organs or spaces), other than the incision, which was opened or manipulated during an operation.	From the end of surgery to 30 days after surgery
Number of Patients Requiring Intraoperative Transfusion	intraoperative transfusion will be yes if this patient received more than 0 unit of red blood cells.	From surgery start to surgery end
Duration of Hospitalization	The length of hospital stay in days, censored at 30 days	From the day of surgery to the day of discharge, or 30 days after surgery if the patients is still hospitalized

Collaborators and Investigators

• Sponsor: The Cleveland Clinic

Publications and helpful links

General Publications

• Sessler DI, Pei L, Li K, Cui S, Chan MTV, Huang Y, Wu J, He X, Bajracharya GR, Rivas E, Lam CKM; PROTECT Investigators. Aggressive intraoperative warming versus routine thermal management during non-cardiac surgery (PROTECT): a multicentre, parallel group, superiority trial. Lancet. 2022 May 7;399(10337):1799-1808. doi: 10.1016/S0140-6736(22)00560-8. Epub 2022 Apr 4.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2017
• Primary Completion (Actual): March 16, 2021
• Study Completion (Actual): May 17, 2022

Study Registration Dates

• First Submitted: April 7, 2017
• First Submitted That Met QC Criteria: April 7, 2017
• First Posted (Actual): April 13, 2017

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 11, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: myocardial injury; Hypothermia; non-cardiac surgery; Intraoperative warming
• Additional Relevant MeSH Terms: Body Temperature Changes; Wounds and Injuries; Hypothermia
• Other Study ID Numbers: 16-1017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigators are welcome to propose collaborative analyses.
• IPD Sharing Time Frame: Upon publication of the main paper.
• IPD Sharing Access Criteria: Via corresponding author,
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No