Perioperative Hypothermia and Myocardial Injury After Non-cardiac Surgery
Phase: NA
Conditions: Perioperative Care, Surgery--Complications, Hypothermia; Anesthesia, Myocardial Injury
Sponsor: The Cleveland Clinic

 
Very Mild PeRioperative HypOThErmia versus 
Aggressive Warming and myoCardial injury 
afTer non-cardiac surgery (PROTECT) 
February 01, 2021 
NCT03111875 
Daniel I. Sessler and Colleagues 
 
Department of OUTCOMES RESEARCH 
Cleveland Clinic  
 
 
 
 
Trial principle investigator: 
 
Daniel I. Sessler, M.D. 
 
Michael Cudahy Professor and Chair 
Department of OUTCOMES RESEARCH 
Cleveland Clinic 
9500 Euclid Ave — P77 
Cleveland, OH  44195 
United States 
 
Tel: 216-444-4900 
Fax: 216-444-6135 
Email: DS@OR.org 
Web: www.OR.org 
 
Chinese country leader: 
 
Yuguang Huang, M.D. 
 
Professor and Chair 
Department of Anesthesiology 
Peking Union Medical College 
Hospital (PUMCH) 
1 Shuaifuyuan 
Dongcheng District 
Beijing,  100730 
China 
 
Tel: +86-183-1092-5184 
email: garybeijing@163.com  
 

February 01, 2021 
 
2
Abstract 
Myocardial injury is the most common cause of death in the 30 days after non-cardiac 
surgery. Hypothermia increases sympathetic activation, promotes tachycardia, and 
causes hypertension — all of which may increase the risk of myocardial injury. Only one 
small study evaluated the relationship between moderate hypothermia and myocardial 
infarction, and was unable to make definitive conclusions. Moderate perioperative 
hypothermia is now uncommon, but mild hypothermia (≈35.5°C) remains common. 
Whether aggressive warming to a truly normothermic level (≈37°C) improves outcomes 
remains unknown. We therefore propose to test the primary hypothesis that aggressive 
warming reduces the incidence of major cardiovascular complications. Up to 5,058 
patients will be randomly assigned to routine care (core temperature ≈35.5°C) or 
aggressive warming (>37°C core temperature) in a multi-center trial. Patients will be 
randomly: 1) routine thermal management with rescue intraoperative forced-air 
warming to prevent core temperature from decreasing to less than 35.5°C; or, 
2) aggressive warming to a target final intraoperative core temperature between 37 and 
37.5°C. The primary outcome will be a composite of myocardial injury (troponin 
elevation, apparently of ischemic origin), non-fatal cardiac arrest, and all-cause mortality 
within 30 days of surgery. Secondary outcomes, also within 30 days, will include: 1) 30-
day deep or organ-space surgical site infection, as defined by Center for Disease Control 
criteria; 2) intraoperative transfusion requirement, defined as units of red blood cells 
transfused; 3) duration of hospitalization; and, 4) readmission within a month of surgery.  
  

February 01, 2021 
 
3
Trial Management 
Trial management will include an Executive Committee, a broader Steering 
Committee, and a Data and Safety Monitoring Board (DSMB) consisting of experienced 
trialists who have no other involvement in the study. The Steering Committee will advise 
the Executive Committee and Principle Investigator, as will the DSMB. Normally, the 
DSMB will evaluate blinded results (Group A vs. Group B) at each interim analysis, and 
at other intervals as they see necessary. The DSMB may request unblinded results if 
there is a safety concern.    
Executive Committee 
Daniel I. Sessler 
Andrea Kurz 
PJ Devereaux 
 
Steering Committee 
Member of the Executive Committee 
Yuguang Huang  
PUMCH, Beijing 
Lijian Pei  
PUMCH, Beijing 
Jingxiang Wu 
Shanghai Chest Hospital, Shanghai 
Chi Cheung 
Queen Mary Hospital, Hong Kong 
Sheng Wang 
Guangdong General Hospital 
Xiaoguang Zhang 
Shanghai Zhongshan Hospital 
Matthew Chan 
Chinese University of Hong Kong 
Wei Zhang 
Nanjing Drum Tower Hospital 
Hongfei Chen 
Xhanghai Oriental Hospital 
Xiaofeng Hu 
Zhejiang University Affiliated Hospital #2 
Rurong Wang 
West China Hospital, Sichuan University 
Xue Zhanggang 
Fudan University Shanghai Cancer Center 
Site directors from other participating hospitals 
 
Data and Safety Monitoring Board 
Jens-Ulrik Staehr Jensen, MD 
Assoc Prof & Head of Resp Med 
Herlev-Genntofte Hospital 
University of Copenhagen 
Copenhagen, Denmark 
Anupa Wadhwa, MD 
Professor of Anesthesiology 
University of California 
San Diego, California 
Ozan Akça, MD 
Professor of Anesthesiology 
University of Louisville 
Louisville, Kentucky 
Edward J. Mascha, PhD (non-voting statistician) 
Staff Biostatistician 
Department of Outcomes Research 
Cleveland Clinic 
 

February 01, 2021 
 
4
Background 
In recent decades, intraoperative mortality has decreased by a factor-of-ten, even 
though we now care for much sicker and older patients.1 Preventable anesthetic-related 
intraoperative mortality is now so rare that it is hard to quantify.2 Postoperative mortality, 
in contrast, remains substantial. Overall 30-day postoperative mortality is about 1% in the 
United States, and about 2% amongst inpatients (outpatients die much less frequently).3,4 
To put this mortality in perspective, if the postoperative period were considered a disease, 
it would represent the third leading cause of death in the United States.5 Roughly a quarter 
of all 30-day postoperative deaths are cardiovascular, or consequent to cardiovascular 
events — with myocardial injury being by far the most common.6  
Worldwide, 8% of surgical inpatients >45 years of age have a postoperative 
myocardial injury as defined by a troponin elevation that is due to an ischemic etiology, 
with only 22% of these events fulfilling the diagnostic criteria of the universal definition of 
myocardial infarction.7 Only 7% of patients experiencing a perioperative myocardial 
infarction will have chest pain, and 65% are entirely clinically silent which means that they 
will go undetected without routine troponin screening.6-9 
It is tempting to dismiss asymptomatic biomarker elevation as “troponitis” and 
assume that it is inconsequential; however, this would be a mistake because 30-day 
mortality in patients with elevated postoperative troponin is significantly and substantially 
increased with and without symptoms.10 The term Myocardial Injury after Non-cardiac 
Surgery (MINS) recognizes that troponin elevations without a non-ischemic explanation 
(e.g., sepsis, pulmonary embolus) are clinically important — even in patients whose 
symptoms and signs do not meet the formal definition of a myocardial infarction.11  
Mortality at 30 days in patients with MINS is a concerning 10%, which represents 
a five-fold increase from background risk. Mortality increases exponentially as a function 
of peak postoperative troponin concentration, ranging from 9% for fourth-generation 
troponin T plasma concentrations of 0.03-0.29 ng/ml to 17% for concentrations ≥0.3 ng/ml. 
Moreover, it is not just mortality that is increased: a composite of nonfatal cardiac arrest, 
congestive heart failure, stroke, and death occurred at a rate of 2.4% in patients without 
MINS and 18.8% amongst those with MINS, a factor-of-eight increase.10 The 
corresponding thresholds for generation five, high-sensitivity troponin T are ≥20 ng/L with 
at least a 5 ng/L increase from baseline, or troponin ≥65 ng/L with or without an increase 
from baseline. When postoperative troponin concentrations are between 65 and 1,000 
ng/L, mortality is increased 70-fold.7  
It is thus reasonable to ask what perioperative factors might contribute to MINS. 
Among the likely candidates is hypothermia. Moderate perioperative hypothermia 
(e.g., 34.5°C) has been shown to cause surgical site infection,12 coagulopathy,13 reduced 
drug metabolism,14-16 prolonged postoperative recovery,17 and thermal discomfort.18 
Thermoregulatory vasoconstriction, a response to hypothermia, increases systemic 
vascular resistance and consequently causes hypertension.19 When combined with 
thermal discomfort and shivering, hypothermia also causes tachycardia. 

February 01, 2021 
 
5
Among the major complications of hypothermia, myocardial outcomes are least 
well established. A recent observational analysis suggests an association between SCIP-
10 compliance on temperature and cardiovascular outcomes.20 A single-center 
randomized trial of 300 patients evaluated cardiac outcomes, and the study was seriously 
under-powered.21 For example, only two hypothermic patients had a cardiac arrest and 
one had a myocardial infarction versus none in the normothermic group (36.7°C). Ten 
hypothermic patients experienced cardiovascular events versus two in normothermic 
patients. These fragile results, based on fewer than ten outcome events, are nearly as 
likely to be wrong as right,22 and a poor basis for health policy. The other relevant study 
had only 100 patients and was thus even more fragile.23   
An additional limitation of Frank et al21 is that diagnosis was primarily based on 
Holter ECG finding rather than troponin concentrations which are much more sensitive. 
Consequently, the overall myocardial infarction rate was <1% where the true rate is no 
less than 10% in vascular surgery patients. It is highly questionable whether any 
conclusion about hypothermia and myocardial outcomes can be derived from a study that 
missed 90% of the presumed myocardial events. The only other relevant trial was 
restricted to just 100 patients leaving it even less powered to detect clinically important 
outcomes.23 There thus remains considerable doubt as to the true effect of moderate 
hypothermia on cardiovascular outcomes.  
An additional issue is that perioperative normothermia is often defined as a core 
temperature ≥36°C. The difficulty is that 36°C is never a normal temperature in humans. 
Even at the circadian nadir, usually about 3:00 AM, core temperature is not normally 
below 36.5°C; and at about 3:00 PM, core temperature is typically about 37.5°C.24 On 
average, then, normal body temperature in humans is about 37°C, not the 36°C that is 
widely accepted as suitable for perioperative patients.20,25  
At any given time of day, core temperature is actively controlled by the 
thermoregulatory system.26 In other words, circadian temperature changes are not 
passive responses to environmental perturbations — which suggests that humans 
function best at temperature near 37°C. Consistent with this theory, randomized trials 
have shown that mild perioperative hypothermia causes coagulapathy,13,27 increased 
blood transfusion,13,27 surgical site infection,12 delayed drug metabolism,15,16,28 prolonged 
recovery,17 and prolongs the duration of hospitalization.12  
We therefore propose to test the hypothesis that aggressive warming to >37°C 
core temperature, versus typical thermal management (≈35.5°C) prevents major adverse 
cardiac events, defined as 30-day myocardial injury (troponin elevation), non-fatal cardiac 
arrest, and all-cause mortality. Secondary outcomes will include infection, transfusion, 
duration of hospitalization, and hospital re-admission within 30 days.  

February 01, 2021 
 
6
 Methods 
This will be a multicenter, international, randomized clinical trial. The trial will be 
coordinated by the department of OUTCOMES RESEARCH in Cleveland Clinic, Ohio, USA. 
About 200 people will be enrolled at the Cleveland Clinic. About 5,058 patients will 
participate at about ten Chinese hospitals.  
Inclusion Criteria 
Consenting patients will be eligible if they are: 
1. Scheduled for major noncardiac surgery expected to last 2-6 hours; 
2. Having general anesthesia; 
3. Expected to require at least overnight hospitalization; 
4. Expected to have >50% of the anterior skin surface available for warming; 
5. Age over 45 years;  
6. Have at least one of the following risk factors: 
a. Age over 65 years; 
b. History of peripheral arterial 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; 
g. Hypertension requiring medication; 
h. Current smoking. 
 
Exclusion Criteria 
Patients will be ineligible if they: 
1. Have a clinically important coagulopathy in the judgement of the attending 
anesthesiologist; 
2. Are septic (clinical diagnosis by the attending anesthesiologist); 
3. Body mass index exceeding 30 kg/m2; 
4. End-stage renal disease requiring dialysis; 
5. Surgeon believes patient to be at particular infection risk.  
 
Protocol 
Patients will be randomized 1:1, stratified by site, with random-sized blocks. 
Investigators will access a web-based site about an hour before surgery is expected to 
start, after consent is obtained. Allocation will thus remain concealed until the last 
practical moment.  
The treatments will be: 1) routine thermal management with rescue 
intraoperative forced-air warming to prevent core temperature from decreasing to less 
than 35.5°C; or, 2) aggressive warming to a target intraoperative core temperature 
≥37°C. Patients will not be told to which group they are assigned. 

February 01, 2021 
 
7
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 upper- or lower-body 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.  
Patients assigned to aggressive warming will be pre-warmed with a full-body 
forced-air cover for ≈30 minutes before induction of anesthesia. The warmer will initially 
be set to “high” which corresponds to ≈43°C. It will 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 two 
forced-air covers when clinically practical. All intravenous fluids will be warmed to body 
temperature. There is no need to control ambient temperature since ambient temperature 
has little effect on core temperature in patients warmed with forced air (Pei, et al. 
unpublished).    
In nearly all countries except the United States, this approach can be considered 
a randomization to routine care versus extra warming.29 Numerous randomized trials 
demonstrate that pre-warming ameliorates redistribution hypothermia30-36 which is 
otherwise the major cause of hypothermia during the initial hour of general37 or neuraxial38 
anesthesia. About 30 minutes of pre-warming is needed for a clinically important benefit.39 
Fluid warming does not warm patients, but infusion of unwarmed fluids decreases body 
heat content and core temperature.40  
Measurements 
Baseline demographic and morphometric characteristics will be recorded, 
including height, weight, and sex. Cardiovascular risks will be recorded, including 
hypertension requiring treatment, diabetes requiring oral medications or insulin, end-
stage renal disease requiring dialysis, history of previous myocardial infarction, 
congestive heart failure, chronic obstructive pulmonary disease, and smoking status. 
Cardiovascular medications will be similarly recorded, including beta blockers, 
angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and statins.  
Type of surgery will be characterized as orthopedic, laparoscopic, open abdominal, 
neurosurgical (including spine), and other. Timing will be characterized as elective, urgent, 
or emergent. To characterize the risk of surgical site infection, we will record whether the 
operation involved colon resection, rectal resection, other abdominal surgery, and 
whether the wound was contaminated or dirty-infected.   
Intraoperative core temperature will be measured in the distal esophagus, 
nasopharynx (10-20 cm past the nares), or pulmonary artery. Temperature will be 
recorded at 15-minute intervals throughout surgery. Mean-arterial pressure and heart rate 
will also be recorded at 15-minute intervals throughout surgery. Mean arterial pressure 
and heart rate will also be recorded at 15-minute intervals for the initial postoperative hour.  

February 01, 2021 
 
8
It will be impossible to blind patients to prewarming and intraoperative clinicians 
and investigators to group assignment. However, all postoperative measurements will be 
made by investigators who are unaware of patients’ group assignment and intraoperative 
management. The study will thus be assessor blinded. 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.   
Blood for generation 4 or 5 troponin T, or troponin I(per clinical routine) will be 
recorded preoperatively up to 2 weeks prior to day of surgery, and on the first two 
postoperative days so long as patients remain hospitalized.7 Troponin samples will also 
be obtained if patients have shortness of breath or experience chest, neck, or arm pain. 
Blood troponin concentrations exceeding site thresholds (depending on individual types 
of troponin tests) should prompt cardiology consultation, an electrocardiogram, and if 
possible, and echocardiogram. Hemoglobin will also be obtained on the first postoperative 
morning. Other preoperative laboratory values and relevant testing will be recorded if 
available (but are not required per protocol), including hemoglobin, creatinine, and blood 
troponin concentrations after the mandated initial two postoperative days.   
Quality-of-recovery 15 will be assessed on the third postoperative day in person or 
by phone in patients already discharged.41 A Chinese version of the Quality-of-recovery 
instrument has been validated.42 If discharged patients cannot be reached on the third 
postoperative day, attempts will be made on the fourth postoperative day. Patients will 
also be evaluated for various outcomes on the day of hospital discharge and 30 days 
after surgery, with a +5-day window. That is, attempts to contact patients will begin about 
day 30 and continue through postoperative day 35. The study will be censored at day 30, 
even if patients remain hospitalized.  
The primary outcome will be a composite of myocardial injury after non-cardiac 
surgery (MINS), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery. 
Myocardial injury will be diagnosed by objective screening based on preoperative and 
first two postoperative day troponin values crossing site specific thresholds for MINS so 
long as patients remain hospitalized. Abnormal troponin concentrations will be evaluated 
as clinically indicated with ECG, echocardiography, and clinical symptoms; the resulting 
values will be recorded, as will other cardiovascular interventions such as angioplasty. 
MINS will be diagnosed by troponin exceeding individual sites thresholds apparently of 
ischemic origin (e.g., no other obvious cause for artifactual elevation). Myocardial 
infarction will also be centrally adjudicated and require both MINS and at least one 
symptom (e.g., chest pain or shortness of breath) or sign (e.g. ECG or echocardiogram 
abnormality).   
We will consider all patients who had an elevated serum troponin concentration 
anytime during the first 30 days after surgery and determine the presence of any ischemic 
features (i.e., whether patients fulfilled the universal definition of myocardial infarction),43 
whether there was a non-ischemic etiology that could explain the elevated troponin 

February 01, 2021 
 
9
measurement, and whether the myocardial injury appears to have occurred during or after 
surgery (i.e., no evidence to support it was due to a preoperative event).  
Myocardial injury will be considered when a postoperative troponin concentration 
is elevated and believed to be consequent to myocardial ischemia. The thresholds differ 
depending on the assay generation and type. We will use the following thresholds based 
on available literature: 
1. non-high-sensitivity (fourth-generation) troponin T ≥0.03 ng/ml;  
2. high-sensitivity troponin T ≥65 ng/L; or high-sensitivity troponin T 20-64 ng/L and 
an increase ≥5 ng/L from baseline;  
3. high-sensitivity troponin I (Abbott assay) is ≥75 ng/L44; 
4. high-sensitivity troponin I (Siemens assay) is ≥60 ng/L (Borges, unpublished); 
5. troponin I (other assays) is at least twice local 99th percentiles; 
6. an increase of at least 20% in patients who have preoperative high-sensitivity 
troponin concentrations that exceed 80% of the relevant thresholds in items 2-5.  
For patients with a chronic elevation or an acute myocardial injury before surgery, 
a new myocardial injury after surgery requires identification of a new elevated troponin 
after surgery as per points 1-5 above, and the troponin elevation must be a 20% rise 
beyond the chronic troponin value or beyond the last measurement of the acute 
preoperative myocardial injury that was clearly demonstrated to have peaked and was 
coming down. Patients meeting diagnostic criteria for MINS will be evaluated for 
myocardial infarction with EKG and ECHO with cardiac consultation, which will help us 
detect all infarctions and increase the baseline incidence.  
Secondary outcomes will include:  
1) 30-day deep or organ-space surgical site infection, as defined by Center for 
Disease Control criteria*;  
2) Intraoperative transfusion requirement, defined as units of red blood cells 
transfused;  
3) Duration of hospitalization (censored at 30 days); 
4) Readmission within a month of surgery; 
 
Exploratory outcomes will be: 
1) Estimated intraoperative blood loss; 
2) The change in blood hemoglobin from preoperatively to the first 
postoperative morning; 
3) 30-day superficial surgical site infection; 
4) Quality-of-recovery 15 on the third postoperative day in person or by phone 
in patients already discharged;41 
5) 30-day myocardial infarction meeting requirements of the Third Universal 
Definition.43 
*Definitions of surgical site infections, modified from 1990 CDC criteria: 
http://www.cdc.gov/hicpac/SSI/table1-SSI.html. 
1. Superficial infection 

February 01, 2021 
 
10 
Infection involves only skin or subcutaneous tissue of the incision and at 
least one of the following: 
 Purulent drainage from the superficial incision. 
 Organisms isolated from culture of fluid or tissue from the superficial 
incision. 
 At least one of the following signs or symptoms of infection: pain or 
tenderness, localized swelling, redness, or heat and superficial incision is 
deliberately opened by surgeon, unless incision is culture-negative. 
 Diagnosis of superficial incisional SSI by the surgeon or attending physician. 
 
2. 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 and at least one 
of the following: 
 Purulent drainage from the deep incision but not from the organ/space 
component of the surgical site. 
 A deep incision spontaneously dehisces or is deliberately opened by a 
surgeon when the patient has at least one of the following signs or 
symptoms: fever (>38°C), localized pain, or tenderness, unless site is 
culture-negative. 
 An abscess or other evidence of infection involving the deep incision is 
found on direct examination, during reoperation, or by histopathologic or 
radiologic examination. 
 Diagnosis of a deep incisional SSI by a surgeon or attending physician. 
 
3. 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 and at least one of the following: 
 Purulent drainage from a drain that is placed through a stab wound‡ into the 
organ/space. 
 Organisms isolated from an aseptically obtained culture of fluid or tissue in 
the organ/space. 
 An abscess or other evidence of infection involving the organ/space that is 
found on direct examination, during reoperation, or by histopathologic or 
radiologic examination. 
 Diagnosis of an organ/space SSI by a surgeon or attending physician. 
Outcomes will be centrally adjudicated by investigators blinded to randomization 
and intraoperative core temperatures.  
Data will be recorded on case-report forms and directly entered via a web site into 
a secure REDCap database (i.e., with a tablet computer). All HIPAA rules will be followed; 
no identified data from remote sites will be entered into REDCap, and no Clinic data will 
be sent elsewhere. We will request a copy of the anesthesia record, redacted for 

February 01, 2021 
 
11 
protected health information, for auditing purposes. Similarly, we will request redacted 
copies of key lab tests and records related to defined outcomes.    
Statistical Plan 
Reported temperatures will include time-weighted average, minimum, and final 
intraoperative core temperatures.  
Analyses will be modified intent-to-treat, including all randomized patients who 
received treatment (i.e., patients randomized but not receiving treatment will not be 
included in any analyses). Randomized groups will be compared on baseline and 
demographic characteristics using absolute standardized difference, defined as the 
absolute difference in means, mean ranks, or proportions divided by the pooled standard 
deviation. All analyses will adjust for any imbalanced baseline characteristics between 
randomized groups, defined as the maximum of 0.10 and absolute standardized 
difference > 1.96 × √
1
𝑛1 +
1
𝑛2.  
Missing outcomes will be imputed using an appropriate method, after examining 
the missing mechanism and drop-out rates. If less than 5% of data are missing, we will 
assign worst outcome to the active treatment group and best outcome to the control group 
for patients missing all records of MINS, non-fatal cardiac arrest and mortality; we will 
apply the last observation carried forward (LOCF) method for patients missing 30-day 
follow-up data but having discharge assessment. If missing is 5~20%, we will use the 
multiple imputation method. 
Primary analysis 
 
      We will assess the effect of warming strategy on the binary-event composite of 
myocardial injury, non-fatal cardiac arrest, and all-cause mortality within 30 days of 
surgery, using a multivariate generalized estimating equations (GEE) method.44,45 A 
common effect GEE test with an unstructured working correlation matrix will be performed, 
assuming that each component is similarly affected by intervention. The treatment-by-
component interaction will be examined in a separate distinct effects GEE model to 
assess the heterogeneity of the treatment effect across outcomes.  
 
Secondly, we will estimate the average relative effect of aggressive warming 
across the three categories of complications, using a GEE ‘distinct effects’ model with an 
unstructured working correlation matrix. This method is not driven by component with the 
highest frequency but may have a lower power compared to common effects model 
because one complication has a lower expected incidence. Regardless of the existence 
of the interaction, we will report the treatment effect of aggressive warming for each 
complication. The significance criterion will be 0.017 for each association (i.e., 0.05/3, 
Bonferroni). 
Secondary analyses 

February 01, 2021 
 
12 
The effect of warming strategy on collapsed composite of 30-day deep or organ-
space surgical site infection and readmission within a month of surgery will be assessed 
using separate chi-square tests or multivariable logistic regression models, as appropriate.  
The effect of warming strategy on the intraoperative transfusion requirement, 
defined as units of red blood cells transfused, will be assessed using a multivariable 
Poisson or negative binomial regression model, as appropriate.  
Finally, the effect of warming strategy on time to discharge alive will be assessed 
using a Cox proportional hazards regression model. Patients who died before discharge 
will be assigned a censoring time equal to the longest observed duration of hospitalization.  
To assess the robustness of our primary analysis, we will conduct per-protocol 
analysis for primary outcome by analyzing the subset of patients who completed the 
treatment originally allocated and without missing outcome data. This analysis is 
expected to be biased in favor of the preferred treatment and therefore no inference will 
be made about results.  
Exploratory analyses 
 
Groups will be compared on estimated intraoperative blood loss; the change in 
blood hemoglobin from preoperatively until the first postoperative morning, adjusted for 
interim transfusions; and quality-of-recovery 15 on the third postoperative day. We will 
use multivariable linear regression models, adjusted for potential confounders. The effect 
of warming strategy on 30-day superficial surgical site infection and myocardial infarction 
will be assessed using a chi-square test or multivariable logistic regression model.  
          Moreover, the association between the time-weighted intraoperative core 
temperature and the primary outcome will be assessed using a multivariable logistics 
regression model, adjusted for all potential confounders. 
We will use an overall alpha of 0.05 for each of the primary, secondary, and tertiary 
analyses. Specifically, the significance criterion is 0.05 for primary analysis, 0.0125 for 
each secondary analysis (i.e., 0.05/4, Bonferroni). Holm-Bonferroni correction will be 
used for the exploratory analysis. 
Sample-size Estimate 
Amongst 10,000 patients enrolled in POISE-2, 8,449 met the inclusion criteria 
proposed for PROTECT. The incidence of MINS, nonfatal cardiac arrest, and total 
mortality within 30 days post-operatively were 10%, 0.1% and 1% respectively.46,47 
These studies were largely conducted outside the United States and we can thus assume 
that most patients were either unwarmed or inadequately warmed. We will thus assume 
that patients assigned to routine management will have a similar incidence of our 
composite outcome.  
A total of 4000 patients will give a power of 0.9 at the 0.05 significance level to 
detect a 30% or more relative reduction in the primary outcomes, comparing routine 

February 01, 2021 
 
13 
thermal management group to aggressive warming group. Sample size was calculated 
for common effect GEE model with unstructured covariance matrix, assuming a 
correlation of 0.1 between outcomes. We estimated sample size using the MULTBINPOW 
SAS macro [Mascha EJ Power Calculation for Tests on a Vector of Binary Outcomes], 
which can estimate the power for multivariate GEE model given varying correlation and 
sample size.  
After accounting for interim analysis at each 25% of the maximum enrollment 
(3 interim analyses and a final analysis, as needed), a maximum of 4802 patients would 
be needed (2401 per group) for the analysis.  
For the primary analysis, we will use a group sequential design with a nonbinding 
beta boundary, employing a gamma spending function with parameter gamma of -4 for 
efficacy and 0 for futility, thus spending beta (for futility monitoring) considerably faster 
than alpha (for efficacy monitoring). Boundaries for efficacy (futility in parentheses) at the 
each interim and final analyses are P ≤ 0.001 (P > 0.880), P ≤ 0.005 (P > 0.525), P ≤ 
0.014 (P > 0.169), and P ≤ 0.044 (P > 0.044), respectively, based on an anticipated 30% 
treatment effect. Figure 1 shows the z-statistic boundaries for efficacy and futility at each 
interim look.  

February 01, 2021 
 
14 
 
Stage 
Boundary Values 
Lower 
Upper 
Alpha 
Beta 
Beta 
Alpha 
1 
-3.16 
-0.15 
0.15 
3.16 
2 
-2.82 
-0.64 
0.64 
2.82 
3 
-2.44 
-1.37 
1.37 
2.44 
4 
-2.01 
-2.01 
2.01 
2.01 
 
Figure 1. Group sequential boundaries for efficacy (bottom, dark blue), harm (top, dark 
blue) and futility (light blue) assuming 4 possible looks (3 interim and final).  Y-axis is the 
standardized treatment effect (difference in proportions / standard error of difference). X-
axis depicts cumulative proportion of total sample size over time. The standardized Z 
values corresponding to the boundaries is presenting in the table below. A sample size of 
4802 in total is needed, assuming 4000 in fixed sample design, 90% power and alpha=0.05. 
SAS version 9.4 or higher (SAS Institute, Cary, NC, USA) and R software version 3.2.1 or 
higher (R Project for Statistical Computing, Vienna, Austria) will be used for the analyses.  
Table 1 provides the probabilities of stopping the trial for the underlying true 
treatment effect. Alternative (30% risk reduction), half-way between Null and Alternative 
and 1.5 times the alternative effect. For example, if the alternative hypothesis were true, 
the cumulative probability of crossing either efficacy or futility boundary at the 1st, 2nd, 3rd 
and 4th looks would be 0.109, 0.437, 0.812 and 1 respectively.  

February 01, 2021 
 
15 
 
Table 1. Expected Cumulative Stopping Probabilities. 
 
In addition to the planned 4,802 patients, we will enroll an additional 250 patients 
to accounting for an expected maximum 5% dropout rate (lost to follow-up and failure to 
receive any treatment). Therefore, we anticipate to enroll a maximum of 5,052 patients 
in total. We also plan six pilot patients at each study site to confirm feasibility before 
beginning to randomize subjects.  
 
 
Adaptive Design Option  
 
     Since assumptions of primary outcome incidence and effect size our only estimates, 
we consider an adaptive design with the possibility of increasing the sample size in case 
the risk reduction is small. Our adaptive method for modifying the sequential design is 
based on the principle that we can protect the overall type I error rate by preserving 
conditional rejection probability of the remaining portion of the trial.48 The new sample 
size of adaptive extension design will be calculated by formulae shown in Gao et al,49 to 
raise the estimate of conditional power from its current value to a new target. Hypothesis 
testing will be done by comparing the final Z statistics to a new critical value satisfies 
conditional rejection probability principle.  
 
     Specifically, we will consider an adaptive extension at the third interim analysis 
(n=3,601) with no early stopping either for efficacy or futility. The conditional power will 
be calculated from accruing data and pre-planned sample size. If the conditional power 
is within a promising zone from 0.4 to 0.8, we will plan for increasing the sample size to 
repower the trial. The smallest treatment effect we would consider in the adaptive design 
is 15% reduction in the composite outcome. The effect size from the accrued unblinding 
data will be used for planning adaptive design. The magnitude of the sample size increase 
will be determined by requiring the target conditional power to be 0.9, subject to a cap of 
10,000 randomized patients.  
 
    For statistical inference on adaptive group sequential design, we will implement the 
method described in Gao and colleagues.50 By transforming the event obtained in the 
adaptive trial into an equivalent event that might have been obtained in the original trial 
without adaptation, we can compute the overall p-value, the confidence interval and the 
median-unbiased point estimate for the treatment effect, combining the results from all 
stages (pre and post adaptation). If the adaptation is followed by a single stage analysis, 
Effect  
Expected 
Stopping Stage 
Stopping Probabilities 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Null 
2.48 
0.121 
0.526 
0.872 
1.000 
½ Null, Alt 
2.89 
0.093 
0.345 
0.675 
1.000 
Alternative 
2.64 
0.109 
0.437 
0.812 
1.000 
Alt X 1.5 
1.86 
0.315 
0.836 
0.988 
1.000 

February 01, 2021 
 
16 
the confidence interval and the median unbiased point estimate are available in closed 
form. Otherwise, the R package AGSDest [Niklas Hack and Werner Brannath, 2015] will 
be used for the analysis.  
 
     Decisions on an adaptive extension of the trial will be done in conjunction with the 
statistician(s) and the study executive committee, and without unblinding site 
investigators as to the actual treatment effect observed on the intervention for which the 
extension is planned. If, for product or budgetary reasons, sponsor participation is 
required in the adaptive decision-making, then a sponsor member may participate in the 
study executive committee discussion of the adaptive design under the condition that 
specifics of interim results would not be shared with the rest of the sponsoring 
institution(s) or anyone outside of the deliberating group. Trial results for an intervention 
for which there is an adaptive extension will not be made public or published in any 
fashion until the adaptive portion of the study is also complete. 
 
 
Significance 
Hypothermia has been proposed as a cause of morbid myocardial outcomes. But 
whether very mild hypothermia (i.e., 0.5°C) provokes myocardial complications has yet to 
be convincingly demonstrated because both existing studies are seriously under-powered, 
with fragile results based on fewer than ten outcome events. The proposed large trial will 
determine whether the results of the single existing under-powered trial are valid.  
Mild hypothermia remains common in nearly every country except the United 
States. Unwarmed patients having major surgery typically have final core intraoperative 
temperatures near 34.5°C. Inadequately warmed surgical patients are typically near 
35.5°C at the end of surgery. Even in the United States, many surgical patients have final 
intraoperative core temperatures near 35.5°C. More serious core hypothermia 
(i.e., 34.5°C) has been shown to provoke major complications, especially bleeding and 
surgical wound infections. Whether aggressive warming to a truly normothermic 
temperature (e.g., 37°C) is preferable to routine management remains unknown.  
Limitations 
Validity of the trial depends critically on achieving the target temperatures. There 
is little doubt that most unwarmed patients having major surgery will decrease to a core 
temperature near 35.5°C in a cool ambient environment. More challenging will be 
reaching a core temperature between 37 and 37.5°C by the end of surgery. Even with 
pre-warming, a high ambient temperature, and aggressive forced-air warming, core 
temperatures in some patients may not exceed 37°C by the end of surgery. Realistically, 
we hope to have at least 1°C difference in final intraoperative core temperature across 
the study population. Smaller differences are unlikely to cause outcome differences and 
would cause the study to fail on technical grounds.  

February 01, 2021 
 
17 
It will be impossible to blind the preoperative and intra-operative teams to thermal 
management. Similarly, patients will know that they were pre-warmed, although they will 
not be told to which group they were assigned or what they might expect as a 
consequence. The primary outcome (a composite of myocardial injury, non-fatal cardiac 
arrest, and all-cause mortality) is objective and unlikely to be influenced by patient 
perception of warming. Most of the secondary outcomes are also objective or unlikely to 
be influenced by lack of blinding.  
 
Human Subjects 
Based on an early recommendation,51 a final core temperature of ≥36°C is widely 
considered “normothermic” and has been incorporated into various guidelines. For 
example, the Surgical Care Improvement Project (recommendation #10) suggested a 
final intraoperative temperature or 36°C and/or use of active over-body warming whether 
or not core temperature reached 36°C.20 Curiously, the American Society of 
Anesthesiologist does not have a standard for maintenance of core temperature. Perhaps 
as a consequence, many — but hardly all52 — surgical patients are actively warmed in 
the United States. Warming is relatively uncommon even in other western countries.29 In 
developing countries, few patients are actively warmed. For example, a 2015 cross-
sectional survey of Beijing hospitals found that only 11% of surgical patients were actively 
warmed, and that more than a third of all patients having operations lasting at least 2 
hours were hypothermic at the end of surgery.53  
Recommendations to warm surgical patients are based on many randomized trials 
have shown that moderate hypothermia (≈34.5°C) causes complications relative to 
≈36.5°C. For example, mild perioperative hypothermia causes surgical site infection,12 
promotes coagulopathy,13 and prolongs postoperative recovery.17 Among these 
complications, coagulopathy is by far the best documented in many individual studies and 
a meta-analysis.13 As little as 1°C hypothermia detectably increases surgical blood loss. 
But whether smaller temperature differences matter is less obvious. The only study to 
ever demonstrate an outcome difference from just 0.5°C of hypothermia showed a slight 
increase in blood loss, with no significant difference in transfusion requirements.54 
Consequently, 0.5°C is widely used as the non-inferiority “delta” in trials of warming 
systems55 and validations for clinical thermometers.56 Not a single outcome study has 
evaluated perioperative temperatures of 37°C or greater.   
There is thus little evidence to support 36°C as the optimal perioperative target 
temperature. A slightly lower temperature such as 35.5°C may be equally safe, or a higher 
temperature might be better. It would be well worth knowing if 35.5°C is safe because 
that temperature can often be maintained without the cost and effort of active warming 
— at least in patients having small operations in a warm operating room. In contrast, 
reliably warming patients to ≥37°C usually requires 30 minutes of pre-warming, two 
intraoperative forced-air warming covers, and a fluid warmer. (Intraoperative core 
temperature using a single intraoperative forced-air cover, the conventional approach, 
averages only 36°C.57) Thus while it is possible to warm most patients to ≥37°C, doing so 

February 01, 2021 
 
18 
requires investing the time and cost of pre-warming, along with the cost of two 
intraoperative forced-air warming covers and a fluid warmer.  
The added time, cost, and difficulty of maintaining intraoperative core temperature 
≥37°C would be well worth investing if it reduced major complications, especially 
myocardial injury. But whether it does currently remains unknown. We propose to 
compare an inexpensive (or cost-free) approach that might be equally safe with a more 
expensive approach that potentially disrupts clinical routine but might reduce 
complications. Because the outcome of the trial is impossible to predict, there is thus full 
equipoise between the two temperature management strategies that we will evaluate.           
Patients who meet inclusion criteria will be approached about participating by site-
specific study personnel. In recognition of cultural differences between China and the 
United States with respect to medical decision-making58 investigators will be encouraged 
to allow the patient to participate in the informed consent process to the extent that he/she 
wishes, and will utilize a legally authorized representative should the patient prefer family-
based consent.1 
 
Time Line 
 
Study Procedure 
Screening 
Day of 
Surgery 
POD 1 
POD 2e 
POD 3e 
Dischargec 
POD 
30d 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Labs 
Hemoglobin 
Xa 
Xa 
X 
Xa 
Xa 
 
 
Creatinine 
Xa 
 
 
 
 
 
 
Troponin 
X 
Xa 
X 
X 
Xa 
 
 
Procedures 
ECG 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
ECHO 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Cardiac 
Catheterization 
 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Intraoperative Data 
 
X 
 
 
 
 
 
Cardiovascular 
morbidity/mortality survey 
 
 
X 
X 
X 
X 
X 
QOR15 
 
 
 
 
Xb 
 
 
Surgical Site Infection survey 
 
 
 
 
 
X 
X 
 
                                            
1 Council for International Organizations of Medical Sciences (CIOMS) (2002). Commentary on Guideline 4 
(Individual Informed Consent), Cultural considerations.  International Ethical Guidelines for Biomedical 
Research Involving Human Subjects. http://www.cioms.ch/frame_guidelines_nov_2002.htm.  

a: If available 
b: If patient is not reachable on day 3, survey can be completed on day 4 
c: If patient is discharged on postoperative days 1-3, complete forms for postoperative day and discharge 
d: If patient is not reachable on day 30, attempt to contact for consecutive 5 days 
e: Complete if patient is still in hospital 
 
 

February 01, 2021 
 
20 
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February 01, 2021 
 
24 
PROTOCOL AMMENDMENT LOG: 
5/1/2017 - Based on new findings from second VISION cohort, we needed to change the 
PROTECT protocol. Specifically, we needed to get a preoperative troponin, but 
then only for two days afterwards. The preoperative troponin could be obtained 
any time before surgery, including in a preoperative assessment clinic or on the 
morning of surgery. As before, we'd like to know about any troponin measurements 
after the first two postoperative days, but measurements are not required after the 
first two days.  
9/26/2017 – Generation–four Troponin T, generation–five Troponin T or Troponin I will be 
used to screen for MINS depending upon site preference. Threshold values for 
generation-five Troponin T listed as absolute change ≥5ng/L or postoperative 
values ≥ 65ng/L will be used to diagnose MINS. 
10/12/2017 – “up to 2 weeks prior to day of surgery” added to page 9 paragraph 2. 
Troponin tests up to 2 weeks prior to day of surgery will be considered as pre-
operative troponin. 
11/02/2017 – Definition of MINS using generation five Troponin T was updated based on 
VISION 2 cohort study. An increase of ≥5 to a value of at least 20 ng/L would be 
considered as MINS and required evaluation with EKG, ECHO or Cardiac Consult. 
12/03/2017 – Page 10 paragraph 2 line 1-4: Diagnostic criteria for MINS based upon 
generation four Troponin T, generation five Troponin T and Troponin I was 
rephrased for clarity. Page 10 paragraph 2 line 5-6: either EKG, ECHO or Cardiac 
Consultation changed to EKG and ECHO with cardiac consultation. 
10/26/18 — Edward Mascha removed from the Executive Committee. 
11/4/18 — Inclusion criterion changed from “peripheral vascular surgery” to “peripheral 
arterial surgery.” Chi Cheung from Queen Mary hospital removed from the Steering 
Committee.  
12/10/18 — Jens-Urlik Jensen substituted for Brian Ilfeld as Chair of the DSMB. Dr. Ilfeld 
declined after better understanding the requirements. 
1/17/19 — Changed management from “aggressive warming to a target final 
intraoperative core temperature ≥37°C” to “aggressive warming to a target 
intraoperative core temperature ≥37°C.” 
5/27/2020 — “Bair Hugger and Bair Paws” changed to “forced-air” because 3M withdrew 
funding for the trial.  
10/29/2020 — Because the trial is enrolling quickly and well, the Executive Committee 
decided to skip the third interim and analysis. That is, we plan to complete the trial 
without an interval assessment with the goal of shrinking the confidence intervals 
around whatever the findings might be. This decision was made without any 
access to by-group results.  

February 01, 2021 
 
25 
02/01/2021 --- The following was deleted Page 9, second Paragraph 
 
Myocardial injury after non-cardiac surgery will be defined as having a generation-four 
troponin T of ≥ 0.03 ng/ml, peak post-operative generation-five troponin T of ≥ 65ng/L, 
peak post-operative generation-five troponin T ≥ 20ng/L with change of ≥ 5ng/L from 
baseline and values exceeding local 99th percentile for troponin I. 
 
The following was added P9 
 
 
Myocardial injury will be considered when a postoperative troponin concentration is 
elevated and believed to be consequent to myocardial ischemia. The thresholds differ 
depending on the assay generation and type. We will use the following thresholds based 
on available literature: 
1. non-high-sensitivity (fourth-generation) troponin T ≥0.03 ng/ml;  
2. high-sensitivity troponin T ≥65 ng/L; or high-sensitivity troponin T 
20-64 ng/L and an increase ≥5 ng/L from baseline;  
3. high-sensitivity troponin I (Abbott assay) is ≥75 ng/L44; 
4. high-sensitivity troponin I (Siemens assay) is ≥60 ng/L (Borges, 
unpublished); 
5. troponin I (other assays) is at least twice local 99th percentiles; 
6. an increase of at least 20% in patients who have preoperative high-
sensitivity troponin concentrations that exceed 80% of the relevant 
thresholds in items 2-5.  
For patients with a chronic elevation or an acute myocardial injury before surgery, a new 
myocardial injury after surgery requires identification of a new elevated troponin after 
surgery as per points 1-5 above, and the troponin elevation must be a 20% rise beyond 
the chronic troponin value or beyond the last measurement of the acute preoperative 
myocardial injury that was clearly demonstrated to have peaked and was coming down.