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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Routine thermal management | Active Comparator | 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. |
|
| Aggressive thermal management | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| aggressive warming | Device | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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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:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic Foundation | Cleveland | Ohio | 44195 | United States | ||
| PUMCH |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38026375 | Derived | Song S, Pei L, Chen H, Zhang Y, Sun C, Yi J, Huang Y. Analysis of hospital and payer costs of care: aggressive warming versus routine warming in abdominal major surgery. Front Public Health. 2023 Nov 2;11:1256254. doi: 10.3389/fpubh.2023.1256254. eCollection 2023. | |
| 35390321 | Derived | 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. |
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Investigators are welcome to propose collaborative analyses.
Upon publication of the main paper.
Via corresponding author,
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4 more patients than protocol were enrolled due to potential withdrawal. Thus we have a total of 5056 patients enrolled in the actual trial rather than 5052 specified in the protocol.
4 more patients were enrolled due to potential withdrawal.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 1, 2021 |
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To maintain blinding, the anesthesia record will be sealed in an opaque envelope before patients leave the post-anesthesia care unit. The envelope will be marked "Do not open until [date 35 days after surgery]." Some hospitals will have electronic records; in those cases, we will ask investigators evaluating postoperative outcomes not to access the anesthesia record.
| routine thermal management | Device | 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. |
|
| 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 |
| Readmission | Readmission to a hospital within a month of surgery | From the end of surgery to 30 days after surgery |
| Beijing |
| China |
| West China Hospital Sichuan Univeristy | Chengdu | China |
| Guangdong General Hospital | Guangzhou | China |
| Chinese University of Hong Kong | Hong Kong | China |
| Queen Mary Hospital | Hong Kong | China |
| Nanjing Drum Tower Hospital | Nanjing | China |
| FDSCC (Fudan University Shanghai | Shanghai | China |
| Shanghai Chest Hospital | Shanghai | China |
| Shanghai Oriental Hospital | Shanghai | China |
| Shanghai Zhongshan Hospital | Shanghai | China |
| FG001 | 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. 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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. |
| BG001 | 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. 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Baseline data were missing in three patients in the aggressive warming group and four patients in the routine thermal management group. | Count of Participants | Participants |
| |||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
| |||||||||||||||
| Body mass index, kg/m^2 | Mean | Standard Deviation | kg/m^2 |
| |||||||||||||||
| Type of surgery | Count of Participants | Participants |
| ||||||||||||||||
| Type of troponin | Count of Participants | Participants |
| ||||||||||||||||
| Timing of surgery | Count of Participants | Participants |
| ||||||||||||||||
| Risk of surgical site infection | Count of Participants | Participants |
| ||||||||||||||||
| Cardiac risk | Count of Participants | Participants |
| ||||||||||||||||
| Medication use | The use of beta blockers, angiotension converting, and etc., is not exclusive for each patient. For example, a patient could use multiple medications thus any use of the following medication is not the sum of all the medication use number below. | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 16 patients were missing in Routine thermal management and 10 patients were missing in aggressive thermal management group. | Posted | Count of Participants | Participants | From the end of surgery to 30 days after surgery |
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| Secondary | 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. | 20 patients were missing on this outcome in aggressive thermal management group and 27 patients were missing in routine thermal management group | Posted | Count of Participants | Participants | From the end of surgery to 30 days after surgery |
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| Secondary | Number of Patients Requiring Intraoperative Transfusion | intraoperative transfusion will be yes if this patient received more than 0 unit of red blood cells. | 13 patients missing on this outcome from treatment group and 20 patients missing on this outcome from control group | Posted | Count of Participants | Participants | From surgery start to surgery end |
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| Secondary | Duration of Hospitalization | The length of hospital stay in days, censored at 30 days | 35 patients were missing on this outcome from treatment group and 41 patients were missing on this outcome from control group | Posted | Median | Inter-Quartile Range | days | From the day of surgery to the day of discharge, or 30 days after surgery if the patients is still hospitalized |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Readmission | Readmission to a hospital within a month of surgery | 59 patients were missing on this outcome from control group and 45 patients were missing on this outcome from treatment group | Posted | Count of Participants | Participants | From the end of surgery to 30 days after surgery |
|
from end of surgery to postoperative 30 days
Adverse events were tabulated as a measure of safety. We considered unexpected safety events that were not predefined outcomes to be adverse events. Events were designated serious when they prolonged hospitalisation or were life threatening. Events were reported by site investigators to the central coordination site at the Cleveland Clinic. Each was independently designated as serious or not by two investigators (EYA, MCC, FA-C, and SML) who were blinded to treatment allocation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. | 24 | 2,506 | 30 | 2,506 | 24 | 2,506 |
| EG001 | 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. 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. | 18 | 2,507 | 17 | 2,507 | 22 | 2,507 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| blood transfusion issue | Blood and lymphatic system disorders | Non-systematic Assessment | AMET was called during blood transfusion. Temp was noted to be 1 degree high and pt complained of abdominal and back pain and chills, tachy to the 130s. Transfusion was stopped, analgesia provided, and cardiac enzymes were negative. |
| |
| hypotension | Cardiac disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| diarrhea or ilues | Gastrointestinal disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Intraoperative liver rupture, abdominal bleeding | Hepatobiliary disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| infection | Infections and infestations | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Injury | Injury, poisoning and procedural complications | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| respiratory disorder | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| vascular disorder | Vascular disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac disorders | Cardiac disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| Gastrointestinal disorders | Gastrointestinal disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| General disorders | General disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Infections and infestations | Infections and infestations | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Nervous system disorders | Nervous system disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Renal and urinary disorders | Renal and urinary disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
| |
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Vascular disorders | Vascular disorders | Non-systematic Assessment | Adverse Events were monitored/assessed without regard to the specific Adverse Event Term |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel I. Sessler, MD | Cleveland Clinic | 216-444-4900 | sessled@ccf.org |
| Jan 23, 2023 |
| Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007035 | Hypothermia |
| ID | Term |
|---|---|
| D001832 | Body Temperature Changes |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Colon resection |
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| Rectal resection |
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| Other abdominal surgeries |
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| Contaminated or dirty-infected wound |
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| Hypertension requiring treatment |
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| Diabetes requiring medication (oral or insulin) |
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| End-stage renal failure requiring dialysis |
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| Peripheral vascular disease |
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| Previous myocardial infarction |
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| Smoker |
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| Congestive heart failure |
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| Chronic obstructive pulmonary disease |
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| Beta blockers |
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| Angiotension converting enzyme inhibitors |
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| Angiotension receptor blockers |
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| Statin |
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| 0.10 |
| Risk Ratio (RR) |
| 0.68 |
| 2-Sided |
| 95.6 |
| 0.43 |
| 1.08 |
| Superiority |
average relative effect |
| 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. 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. |
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