Hypothermia; Anesthesia, Myocardial Injury, Perioperative Care, Surgery--Complications
Conditions
Keywords
Hypothermia, Intraoperative warming, non-cardiac surgery, myocardial injury
Brief summary
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.
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.
Interventions
DEVICEaggressive 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.
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.
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
SINGLE (Outcomes Assessor)
Masking description
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.
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Composite Outcome Consisted of Myocardial Injury After Non-cardiac Surgery (MINS), Non-fatal Cardiac Arrest, and All-cause Mortality | From the end of surgery to 30 days after surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Deep or Organ-space Surgical Site Infection | From the end of surgery to 30 days after surgery | 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. |
| Number of Patients Requiring Intraoperative Transfusion | From surgery start to surgery end | intraoperative transfusion will be yes if this patient received more than 0 unit of red blood cells. |
| Duration of Hospitalization | From the day of surgery to the day of discharge, or 30 days after surgery if the patients is still hospitalized | The length of hospital stay in days, censored at 30 days |
| Readmission | From the end of surgery to 30 days after surgery | Readmission to a hospital within a month of surgery |
Countries
China, United States
Participant flow
Recruitment details
4 more patients were enrolled due to potential withdrawal.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 2,506 |
| 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. | 2,507 |
| Total | 5,013 |
Baseline characteristics
| Characteristic | Routine Thermal Management | Aggressive Thermal Management | Total |
|---|---|---|---|
| Age, Continuous | 67.2 years STANDARD_DEVIATION 8 | 67.4 years STANDARD_DEVIATION 8 | 67.3 years STANDARD_DEVIATION 8 |
| Body mass index, kg/m^2 | 23.2 kg/m^2 STANDARD_DEVIATION 3 | 23.4 kg/m^2 STANDARD_DEVIATION 3 | 23.3 kg/m^2 STANDARD_DEVIATION 3 |
| Cardiac risk Any cardiac risk | 1791 Participants | 1755 Participants | 3546 Participants |
| Cardiac risk Chronic obstructive pulmonary disease | 48 Participants | 52 Participants | 100 Participants |
| Cardiac risk Congestive heart failure | 18 Participants | 14 Participants | 32 Participants |
| Cardiac risk Diabetes requiring medication (oral or insulin) | 466 Participants | 534 Participants | 1000 Participants |
| Cardiac risk End-stage renal failure requiring dialysis | 2 Participants | 2 Participants | 4 Participants |
| Cardiac risk Hypertension requiring treatment | 1201 Participants | 1234 Participants | 2435 Participants |
| Cardiac risk Peripheral vascular disease | 23 Participants | 28 Participants | 51 Participants |
| Cardiac risk Previous myocardial infarction | 46 Participants | 39 Participants | 85 Participants |
| Cardiac risk Smoker | 610 Participants | 558 Participants | 1168 Participants |
| Medication use Angiotension converting enzyme inhibitors | 128 Participants | 143 Participants | 271 Participants |
| Medication use Angiotension receptor blockers | 197 Participants | 211 Participants | 408 Participants |
| Medication use Any use of the following (beta blockers, Angiotension converting, Angiotension receptor, or Statin) | 599 Participants | 606 Participants | 1205 Participants |
| Medication use Beta blockers | 199 Participants | 204 Participants | 403 Participants |
| Medication use Statin | 313 Participants | 294 Participants | 607 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Risk of surgical site infection Any infection risk | 1414 Participants | 1421 Participants | 2835 Participants |
| Risk of surgical site infection Colon resection | 392 Participants | 376 Participants | 768 Participants |
| Risk of surgical site infection Contaminated or dirty-infected wound | 438 Participants | 429 Participants | 867 Participants |
| Risk of surgical site infection Other abdominal surgeries | 407 Participants | 397 Participants | 804 Participants |
| Risk of surgical site infection Rectal resection | 344 Participants | 378 Participants | 722 Participants |
| Sex: Female, Male Female | 801 Participants | 836 Participants | 1637 Participants |
| Sex: Female, Male Male | 1701 Participants | 1668 Participants | 3369 Participants |
| Timing of surgery Elective | 2432 Participants | 2440 Participants | 4872 Participants |
| Timing of surgery Unknown | 4 Participants | 3 Participants | 7 Participants |
| Timing of surgery Urgent or emergent | 70 Participants | 64 Participants | 134 Participants |
| Type of surgery Laparoscopic | 1301 Participants | 1313 Participants | 2614 Participants |
| Type of surgery Neurosurgical | 89 Participants | 126 Participants | 215 Participants |
| Type of surgery Open abdominal | 613 Participants | 610 Participants | 1223 Participants |
| Type of surgery Orthopaedic | 49 Participants | 56 Participants | 105 Participants |
| Type of surgery Other | 312 Participants | 261 Participants | 573 Participants |
| Type of surgery Unknown | 4 Participants | 3 Participants | 7 Participants |
| Type of surgery Urological | 138 Participants | 138 Participants | 276 Participants |
| Type of troponin High-sensitivity T | 825 Participants | 823 Participants | 1648 Participants |
| Type of troponin Low-sensitivity I | 1482 Participants | 1484 Participants | 2966 Participants |
| Type of troponin Low-sensitivity T | 199 Participants | 200 Participants | 399 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 2,506 | 18 / 2,507 |
| other Total, other adverse events | 24 / 2,506 | 22 / 2,507 |
| serious Total, serious adverse events | 30 / 2,506 | 17 / 2,507 |
Outcome results
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.
Time frame: From the end of surgery to 30 days after surgery
Population: 16 patients were missing in Routine thermal management and 10 patients were missing in aggressive thermal management group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Routine Thermal Management | Number of Participants With a Composite Outcome Consisted of Myocardial Injury After Non-cardiac Surgery (MINS), Non-fatal Cardiac Arrest, and All-cause Mortality | 239 Participants |
| Aggressive Thermal Management | Number of Participants With a Composite Outcome Consisted of Myocardial Injury After Non-cardiac Surgery (MINS), Non-fatal Cardiac Arrest, and All-cause Mortality | 246 Participants |
p-value: 0.6995.6% CI: [0.87, 1.24]Mixed Models Analysis
p-value: 0.195.6% CI: [0.43, 1.08]Mixed Models Analysis
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.
Time frame: From the end of surgery to 30 days after surgery
Population: 20 patients were missing on this outcome in aggressive thermal management group and 27 patients were missing in routine thermal management group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Routine Thermal Management | Deep or Organ-space Surgical Site Infection | 157 Participants |
| Aggressive Thermal Management | Deep or Organ-space Surgical Site Infection | 178 Participants |
p-value: 0.2598.75% CI: [0.87, 1.47]log-binomial models
Secondary
Duration of Hospitalization
The length of hospital stay in days, censored at 30 days
Time frame: From the day of surgery to the day of discharge, or 30 days after surgery if the patients is still hospitalized
Population: 35 patients were missing on this outcome from treatment group and 41 patients were missing on this outcome from control group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Routine Thermal Management | Duration of Hospitalization | 8 days |
| Aggressive Thermal Management | Duration of Hospitalization | 8 days |
Secondary
Number of Patients Requiring Intraoperative Transfusion
intraoperative transfusion will be yes if this patient received more than 0 unit of red blood cells.
Time frame: From surgery start to surgery end
Population: 13 patients missing on this outcome from treatment group and 20 patients missing on this outcome from control group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Routine Thermal Management | Number of Patients Requiring Intraoperative Transfusion | 236 Participants |
| Aggressive Thermal Management | Number of Patients Requiring Intraoperative Transfusion | 254 Participants |
p-value: 0.4198.75% CI: [0.87, 1.33]log-binomial models
Secondary
Readmission
Readmission to a hospital within a month of surgery
Time frame: From the end of surgery to 30 days after surgery
Population: 59 patients were missing on this outcome from control group and 45 patients were missing on this outcome from treatment group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Routine Thermal Management | Readmission | 135 Participants |
| Aggressive Thermal Management | Readmission | 161 Participants |