Impact of Fever Prevention in Brain Injured Patients
Phase: NA
Conditions: Fever, Ischemic Stroke, Intracerebral Hemorrhage, Subarachnoid Hemorrhage
Sponsor: C. R. Bard

 
 
 
 
 
Protocol Title 
Impact of Fever Prevention in Brain Injured Patients (INTREPID) 
 
 
Sponsor 
Bard Medical Division 
C. R. Bard, Inc. 
8195 Industrial Blvd. 
Covington, GA 30014 
 
 
Protocol Number/Version/Date 
BMD-1111 / Version 7.0 / March 9, 2020 
 
Clinical Trial Registration 
NCT02996266 
 

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
i 
CONFIDENTIAL 
 
 
BARD MEDICAL DIVISION 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Title:                            
Impact of Fever Prevention in Brain Injured Patients 
(INTREPID) 
 
Protocol Number:    
BMD-1111 
 
Version: 
 
 
7.0 
 
Study Type: 
Randomized, Controlled Trial; Investigational Device 
Exemption 
 
Date:  
 
 
March 9, 2020 
 
 
Study Device(s): 
 
Arctic Sun® 5000 Temperature Management System  
 
 
 
 
 
Sponsor: 
  
 
Bard Medical Division 
 
  
 
C. R. Bard, Inc. 
 
  
 
8195 Industrial Blvd. 
 
  
 
Covington, GA  30014 
 
Sponsor Contact: 
 
Peter Fayek 
 
 
 
 
Clinical Project Manager 
 
 
 
 
Global Clinical Development 
Becton Dickinson, Inc. 
 
 
 
 
75 N. Fairway Dr. 
 
 
 
 
Vernon Hills, IL  60067 
 
 
 
 
Peter.fayek@bd.com  
 
 
 
 
(847) 362-8796 
 
Protocol Author: 
 
Jaime Ritter 
Senior Manager, Clinical Sciences 
Global Clinical Development 
C. R. Bard, Inc./Becton Dickinson, Inc. 
8195 Industrial Blvd. 
Covington, GA  30014 
jaime.ritter@bd.com 
(770) 784-6437   
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
ii 
CONFIDENTIAL 
 
 
 
 
Protocol Signature Page 
 
The Investigator agrees to conduct the clinical study which is the subject of this protocol in 
accordance with the Clinical Study Agreement, this protocol, all applicable laws and regulations, 
and the conditions of approval imposed by the reviewing Ethics Committee or Institutional 
Review Board. 
 
 
Agreed to by (Investigator): 
 
_______________________________________________ 
 
Printed Name – Investigator 
 
_______________________________________________ 
 
Signature – Investigator 
 
 
_______________________________________________ 
 
Date 
 
  
Agreed to by (Sponsor): 
 
_______________________________________________ 
 
Printed Name – Sponsor 
 
_______________________________________________ 
 
Signature – Sponsor 
 
 
_______________________________________________ 
 
Date 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
iii 
CONFIDENTIAL 
 
Protocol Abbreviations/Acronyms 
Abbreviation/Acronym  
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AFC 
Aggressive Fever Control 
AGP 
ArcticGel™ Pads 
AS-5000 
Arctic Sun® 5000 Targeted Temperature Management System 
ASPECTS 
Alberta Stroke Program Early CT Score 
Bard 
C.R. Bard, Inc. 
BMD 
Bard Medical Division, C.R. Bard, Inc. 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CV 
Curriculum Vitae 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
EOS 
End of Study 
FDA 
United States Food and Drug Administration 
F/U 
Follow-Up 
ICDSC 
Intensive Care Delirium Screening Checklist 
ICF 
Informed Consent Form 
ICH 
Intracerebral Hemorrhage 
ICU 
Intensive Care Unit 
IFU 
Instruction for Use 
IRB 
Institutional Review Board 
IS 
Ischemic Stroke 
ITT 
Intent-to-treat 
LKN 
Last Known Normal 
LTF 
Lost to follow-up 
MAE 
Major Adverse Event 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
MoCA 
Montreal Cognitive Assessment 
PP 
Per protocol 
SADE 
Serious adverse device effect 
SAE 
Serious Adverse Event 
SAH 
Subarachnoid Hemorrhage 
SAP 
Statistical analysis plan  
SCA 
Sudden Cardiac Arrest 
SOC 
Standard of Care 
TBI 
Traumatic Brain Injury 
TH 
Therapeutic Hypothermia 
TTM 
Targeted Temperature Management 
WBC 
White Blood Cell 
WFNS 
World Federation of Neurological Societies Grading System for 
Subarachnoid Hemorrhage 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
iv 
CONFIDENTIAL 
TABLE OF CONTENTS 
  
1. 
INTRODUCTION ........................................................................................................... 1 
1.1. 
Study Rationale ............................................................................................... 3 
1.2. 
Device Description ........................................................................................... 3 
1.2.1. 
Test Device: Arctic Sun® 5000 Temperature Management System ... 3 
1.2.2. 
Control Device(s):  Standard Care / Cooling Method ......................... 4 
2. 
STUDY OBJECTIVES ................................................................................................... 4 
3. 
STUDY DESIGN ............................................................................................................. 4 
4. 
STUDY POPULATION ................................................................................................. 5 
4.1. 
Number of Subjects ......................................................................................... 5 
SEE SECTION 10.1 FOR SAMPLE SIZE CONSIDERATIONS. .................................... 5 
4.2. 
Study Population ............................................................................................. 5 
4.3. 
General Care of Enrolled Subjects ................................................................ 6 
4.4. 
Eligibility Criteria ........................................................................................... 6 
4.4.1. 
General Inclusion Criteria ................................................................... 6 
4.4.2. 
General Exclusion Criteria .................................................................. 6 
4.4.3. 
Disease Specific Inclusion / Exclusion Criteria .................................. 8 
5. 
STUDY SCHEDULE ...................................................................................................... 9 
6. 
STUDY PROCEDURES .............................................................................................. 11 
6.1. 
Evaluations ..................................................................................................... 11 
6.1.1. 
Informed Consent .............................................................................. 11 
6.1.2. 
Enrollment ......................................................................................... 11 
6.1.3. 
Eligibility ........................................................................................... 11 
6.1.4. 
Assignment of Subject Number ........................................................ 11 
6.1.5. 
Demographics and Medical History .................................................. 12 
6.1.6. 
Diagnostic Testing ............................................................................. 12 
6.1.7. 
Baseline Neurologic Assessments ..................................................... 12 
6.2. 
Randomization ............................................................................................... 13 
6.3. 
Physical Examination .................................................................................... 14 
6.4. 
Patient Temperature ..................................................................................... 14 
6.5. 
Medications .................................................................................................... 15 
6.6. 
Infection Surveillance ................................................................................... 15 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
v 
CONFIDENTIAL 
6.6.1. 
Urinalysis ........................................................................................... 15 
6.6.2. 
White Blood Cell Count .................................................................... 15 
6.7. 
Adverse Events .............................................................................................. 15 
6.8. 
Fever Prevention (FP) ................................................................................... 16 
6.8.1. 
Index Procedure ................................................................................. 16 
6.8.2. 
Monitoring for Heat Generation ........................................................ 17 
6.8.3. 
Arctic Sun Case Data ........................................................................ 18 
6.8.4. 
Skin Assessment ................................................................................ 19 
6.8.5. 
Counter-Warming .............................................................................. 19 
6.9. 
Standard Care ............................................................................................... 19 
6.9.1. 
Tier 1: Antipyretic Therapy ............................................................... 20 
6.9.2. 
Tier 2: Basic External Cooling .......................................................... 20 
6.9.3. 
Tier 3: Cooling Blankets ................................................................... 21 
6.9.4. 
Tier 4: Advanced Targeted Temperature Management .................... 21 
6.9.5. 
Monitoring for Shiver ........................................................................ 21 
6.9.6. 
Skin Assessment ................................................................................ 21 
6.10. Shiver Control Procedure ............................................................................. 22 
6.11. Fever Prevention Initiation / Standard Care Fever Treatment Initiation 25 
6.12. Acute Phase Routine Assessments ............................................................... 25 
6.13. Follow-Up Neurologic Assessments ............................................................. 25 
6.13.1. Modified Rankin Scale ...................................................................... 25 
6.13.2. National Institutes of Health Stroke Scale ........................................ 25 
6.13.3. Intensive Care Delirium Screening Checklist (ICDSC) .................... 26 
6.13.4. Barthel Index ..................................................................................... 26 
6.13.5. Glasgow Outcome Scale Extended ................................................... 26 
6.13.6. Montreal Cognitive Assessment ........................................................ 26 
6.14. Subject Discontinuation ................................................................................ 26 
6.15. Replacement of Subjects ............................................................................... 27 
7. 
ADVERSE EVENTS .................................................................................................... 27 
7.1. 
Definition of Adverse Events (AE) and Serious Adverse Event (SAE) .... 28 
7.2. 
Definition of Adverse Device Effect (ADE) and Serious Adverse Device Effect 
(SADE) ........................................................................................................... 28 
7.3. 
Definition of Major Adverse Events (MAE) ............................................... 28 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
vi 
CONFIDENTIAL 
7.4. 
Definition of Unanticipated Adverse Device Effect (UADE)  and 
Unanticipated Serious Adverse Device Effect (USADE) ........................... 29 
7.5. 
Relationship of Adverse Event To Device/Procedure ................................ 29 
7.6. 
Severity of Adverse Events ........................................................................... 30 
7.7. 
Reporting of Adverse Events ........................................................................ 30 
7.7.1. 
Reports of Adverse Events, Serious Adverse Events and Unanticipated 
Adverse Device Effects ........................................................................... 30 
7.8. 
Adjudication of Adverse Events .................................................................. 31 
8. 
MECHANICAL FAILURES, MALFUNCTIONS AND DEFECTS ....................... 31 
9. 
RISK/BENEFIT ANALYSIS ....................................................................................... 32 
10. STATISTICAL METHODS ........................................................................................ 33 
10.1. Sample Size Considerations ......................................................................... 33 
10.1.1. Sample Size Re-estimation ................................................................ 33 
10.2. Analysis Population(s) .................................................................................. 34 
10.3. Study Endpoints ............................................................................................ 34 
10.3.1. Primary Efficacy Endpoint ................................................................ 34 
10.3.2. Key Secondary Efficacy Endpoint .................................................... 35 
10.3.3. Other Secondary Efficacy Endpoints ................................................ 35 
10.3.4. Safety Endpoints ................................................................................ 35 
10.4. Statistical Analysis ........................................................................................ 36 
10.4.1. Primary Efficacy Endpoint Analysis ................................................. 36 
10.4.2. Key Secondary Efficacy Endpoint Analysis ..................................... 37 
10.4.3. Secondary Efficacy Endpoint Analysis ............................................. 39 
10.4.4. Safety Endpoint Analysis .................................................................. 39 
10.4.5. Multiplicity Control ........................................................................... 40 
10.5. Interim Analysis ............................................................................................ 40 
10.5.1. Administration of the Interim Analysis ............................................. 40 
10.5.2. Statistical Approach for Control of Alpha and other Consideration . 41 
11. CASE REPORT FORMS ............................................................................................. 43 
12. ADMINISTRATIVE REQUIREMENTS ................................................................... 43 
12.1. Publication Policy .......................................................................................... 43 
12.2. Investigator Selection .................................................................................... 43 
12.3. Investigator Training .................................................................................... 44 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
vii 
CONFIDENTIAL 
12.4. Regulatory and Ethical Considerations ...................................................... 44 
12.4.1. Institutional Review Board or Ethics Committee Approval ............. 44 
12.4.2. Informed Consent .............................................................................. 45 
12.5. Protocol Adherence and Amendment ......................................................... 45 
12.6. Data Collection .............................................................................................. 45 
12.7. Measures to Control Bias ............................................................................. 46 
12.8. Communications with the Sponsor .............................................................. 46 
12.9. Required Documentation .............................................................................. 46 
13. SITE MONITORING ................................................................................................... 47 
13.1. Study Initiation Visit ..................................................................................... 47 
13.2. Ongoing Monitoring Visits ........................................................................... 47 
13.3. Final Monitoring Visit .................................................................................. 48 
14. TERMINATION OF STUDY ...................................................................................... 48 
15. REPORTING REQUIREMENTS .............................................................................. 48 
16. RECORD RETENTION .............................................................................................. 48 
17. AUDIT/INSPECTIONS ............................................................................................... 49 
18. REFERENCES .............................................................................................................. 50 
19. APPENDICES ............................................................................................................... 52 
19.1. Modified Rankin Scale .................................................................................. 52 
19.2. Glasgow Coma Scale ..................................................................................... 53 
19.3. National Institutes of Health Stroke Scale .................................................. 55 
19.4. World Federation of Neurological Societies Grading Scale for Subarachnoid 
Hemorrhage ................................................................................................... 64 
19.5. Intracerebral Hemorrhage Score ................................................................ 65 
19.6. Intensive Care Delirium Screening Checklist ............................................. 66 
19.7. Barthel Index ................................................................................................. 67 
GUIDELINES ....................................................................................................................... 67 
19.8. Glasgow Outcome Scale Extended .............................................................. 69 
19.9. Montreal Cognitive Assessment ................................................................... 73 
19.10. Instructions for Use ....................................................................................... 74 
19.11. Guidelines for Treatment of Patients with Ischemic Stroke ..................... 90 
19.12. Guidelines for Treatment of Patients with the Intracerebral Hemorrhage101 
19.13. Guidelines for Treatment of Patients With Subarachnoid Hemorrhage105 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
viii 
CONFIDENTIAL 
 
19.14. Guide for Addressing Arctic Sun Water Temperature Below 25°C ...... 109 
19.15. Major Adverse Event Definition Guidance .............................................. 111 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
1 
 
1. INTRODUCTION  
 
There has been significant attention in recent studies exploring the use of therapeutic 
hypothermia (TH) to improve outcomes in brain-injured patients. In 2002, two studies 
served as the basis for using therapeutic hypothermia to 32-34°C in post-sudden cardiac 
arrest (SCA) patients, both showing a significant benefit not only in terms of survival 
but also functional outcome.1,2  These studies led to widespread adoption of TH in the 
post-cardiac arrest population. However, in 2013 the Targeted Temperature 
Management (TTM) trial showed that cooling patients to 36°C was as effective as 
cooling them to 33°C,3 leading to questions regarding the original 2002 studies.  Further 
review of the temperature data from the 2002 trials reveals that many patients in the 
control “normothermia” group were relatively hyperthermic (see Figure 1).   Indeed, it 
may have been this relative hyperthermia that led to worse outcomes in the control 
group, rather than a true beneficial effect from the hypothermia used in the treatment 
group. 
 
Figure 1. 
 
 
 
The use of TH is quite likely beneficial in certain populations but is not without its 
potential adverse effects such as cardiac dysrhythmia and increased infection and 
bleeding risk.  Additionally, significant doses of sedatives and/or paralytics, which can 
confound neurologic assessment, are often required to control shivering in TH patients.  
Finally, TH delays drug metabolism and has shown detrimental effects on the ability to 
prognosticate neurologically, specifically after cardiac arrest.4,5  Considering the 
findings of the TTM trial3, review of the temperature curves from the 2002 SCA studies, 
and the known adverse effects of TH, controlled normothermia may prove to be an 
effective method of preventing secondary brain injury and improving neurological 
outcomes, may reduce potential complications, and alleviate concerns regarding neuro-
prognostication. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
2 
 
Approximately 700,000 patients have an ischemic stroke annually in the United States; 5 
– 10% of all strokes are subarachnoid hemorrhages and 15% of all strokes are 
intracerebral hemorrhages.6,7  Up to 90% of patients develop at least 1 fever within 7 
days in the ICU.8   Regardless of the etiology of the neurological injury, fever or 
elevated body temperature has been associated with worse outcomes. Clinical studies 
have explored the effects of fever within acute ischemic stroke, subarachnoid 
hemorrhage and intracerebral hemorrhage patients. 
 
In ischemic stroke, elevated body temperature on admission is associated with higher 
mortality (and lower body temperature associated with decreased mortality), and is 
independently related to stroke severity, infarct size and outcome.9  For each 1°C 
increase in temperature, the relative risk of poor outcome rises by 2.2.10  The odds of 
short term mortality double when an ischemic stroke patient develops a fever within 24 
hours of onset.11  In a study of 580 subarachnoid hemorrhage (SAH) patients, 
hyperthermia (>38.3°C) was found to contribute to worse outcomes (odds ratio 2.0), 
after controlling for higher clinical grade, re-hemorrhage, advanced age, and other 
comorbid diseases.12 Studies in intracerebral hemorrhage (ICH) patients have also found 
an association of fever with poor outcome, including within the first 72 hours of injury.13  
In a study of 266 ICH patients, early neurological deterioration was associated with a 
temperature >37.5°C.14   
 
In 2008, Greer et al performed a comprehensive meta-analysis of 14,431 patients with a 
variety of neurological injuries.  They found that fever/higher body temperature was 
associated with worse outcomes, regardless of the outcome measure used, compared to 
patients who were normothermic.15  The outcome measures examined included 
mortality, Glasgow Outcome Scale, Barthel Index, modified Rankin Scale, Canadian 
Stroke Scale, and both intensive care unit (ICU) and hospital length of stay. 15 
 
Overall, there is strong data that supports the association of poor outcomes with fever in 
brain injured patients. Despite several studies that have treated fever after its onset, from 
a physiological perspective, prevention of secondary injury may be a promising 
approach compared to strategies that are reactive. Fever has been known to increase 
excitatory neurotransmitters and oxygen free radicals which influence ischemic 
mechanisms within the penumbra.16 This can result in higher mortality rates and worse 
neurological outcomes.16  By preventing fever the cellular demand for oxygen should be 
decreased, the blood brain barrier should be stabilized and cell membranes should be 
stabilized. 16   
 
In 2009, Broessner et al, performed a randomized study to assess the safety and efficacy 
of prophylactic, catheter-based normothermia. 17  While the study demonstrated that 
prophylactic normothermia significantly reduced fever burden and was not associated 
with increased major adverse events, it was not powered to detect a difference in clinical 
outcomes.  Additional post-hoc analysis of the study data did however suggest that 
prophylactic normothermia might be beneficial in selected patients susceptible for 
fever.18  Mayer et al performed a study to compare the efficacy of the Arctic Sun 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
3 
 
Temperature Management System with conventional measures (cooling blankets) for 
treating fever in neuro-intensive care unit patients.19  They demonstrated that patients 
treated with the Arctic Sun System experienced a 75% reduction in fever burden and 
also spent less percent time febrile.  The authors note that there was a non-significant 
trend toward greater improvement in Glasgow Coma Scores in Arctic Sun-treated 
patients. 19  In a case-control study of SAH patients treated with advanced fever control, 
defined as controlled normothermia with an advanced temperature modulating device, 
40 cases and 80 controls were analyzed.20  All advanced fever control patients were 
treated with the Arctic Sun Temperature Management System; one patient was also 
treated with an intravascular system. There was a trend towards a lower rate of poor 
outcomes in the advanced fever control group at 3-months and a statistically significant 
lower rate of poor outcomes at 12-months. 20  In a recent review, Bohman and Levine 
conclude that “The value of therapeutic normothermia in the neurocritical care unit 
(NCCU) is increasingly accepted, yet prospective trials that demonstrate a functional 
benefit to patients are lacking.”21 
 
1.1. Study Rationale 
 
Multiple studies demonstrate that fever / elevated temperature is associated with 
poor outcomes in brain injured patients; however, there are no conclusive studies 
that demonstrate that fever prevention/controlled normothermia is associated with 
better outcomes.  This study will be conducted to assess the impact of advanced 
temperature control to prevent fever in brain injured patients.  The fever prevention 
group will use the Arctic Sun Temperature Management System and will be 
compared to standard care patients in whom fever may spontaneously develop.  If 
fever develops in a patient in the standard care group, they are treated with 
standard fever care measures according to a stepwise algorithm, consisting 
primarily of intermittent antipyretics (e.g., acetaminophen) and cooling blankets 
and, when necessary, advanced targeted temperature management devices.  
Outcomes will be measured across a number of assessments including, but not 
limited to 3- and 6-month follow-up modified Rankin Scale, Barthel Index Scale, 
Glasgow Outcomes Scale-Extended, Montreal Cognitive Assessment, mortality, 
delirium, and ICU and hospital length of stay.   
 
1.2. Device Description 
 
1.2.1. Test Device: Arctic Sun® 5000 Temperature Management System  
 
The Arctic Sun® Temperature Management System is intended for monitoring 
and controlling patient temperature.  The Arctic Sun® System is comprised of 
two main components, the Arctic Sun® 5000 (console) and ArcticGel™ Pads.  
The Arctic Sun® 5000 (AS-5000) consists of a touch screen used to program 
therapy, a port where a continuous patient temperature device is connected 
(e.g., esophageal probe, temperature-sensing Foley catheter, rectal probe), and 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
4 
 
a water reservoir.  The ArcticGel™ Pads feature a thin hydrogel coating that 
ensures they maintain contact with the patient’s skin throughout the treatment. 
The conductive property of the pad’s mimics water immersion.  When 
connected and in place, the Arctic Sun® System circulates water through the 
ArcticGel™ Pads at a specific temperature based on the prescribed, 
programmed therapy and the patient’s current temperature.  Patient 
temperature is continuously fed into the AS-5000 and water temperature 
adjustments are made as required to reach/maintain target temperatures.  See 
Appendix 19.10 for Instructions for Use (IFU). 
 
1.2.2. Control Device(s):  Standard Care / Cooling Method 
 
Per the Investigator’s discretion, patients randomized to the control arm may 
be treated with fans, ice packs, and/or any one of the many water or air 
circulating blankets available in the market (e.g., Soft-Temp® Conductive 
Warming Blanket, Adroit Medical Systems, Loudon, TN; Maxi-Therm® Lite 
Hyper-Hypothermia Blanket, Cincinnati Sub-Zero, Cincinnati, OH).  Standard 
cooling blankets usually consist of a control device that circulates cooled air 
or water through a blanket that is placed over and/or under the patient.  These 
cooling blanket systems do not always incorporate a method to continuously 
assess patient temperature so the clinician may be responsible for adjusting 
the air/water temperature up or down.   
 
Investigators will be responsible for obtaining IFU(s) for non-Bard devices 
used in the study.  
  
2. STUDY OBJECTIVES 
 
The objective of this study is to assess fever burden and the impact on outcomes of fever 
prevention using the Arctic Sun 5000 Temperature Management System as compared to 
standard fever care in brain-injured patients.    
 
Assessment of this objective will be performed by evaluating the: 
• 
Fever burden (°C-hour; defined as the area under the temperature curve above 
37.9°C); 
• 
3- , 6- , and 12-month follow-up neurologic assessment; 
• 
Mortality rates [7-day (or hospital discharge), 3-month, 6-month, 12-month]; 
and  
• 
Intensive care unit and hospital lengths of stay. 
 
See Section 10.3 for a detailed description of study endpoint measures. 
 
 
 
3. STUDY DESIGN 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
5 
 
 
This protocol describes a randomized, controlled multicenter clinical investigation 
designed to assess fever burden and early, short- and long-term clinical outcomes of 
fever prevention (FP) using the Arctic Sun 5000 Temperature Management System (test 
device) compared to standard fever care (control device(s)) in the treatment of moderate-
to-severe brain injured patients.  The target temperature in the FP group is 37.0⁰C 
through 336 hours (14 days) or until discharged/deemed medically ready for discharge 
from the ICU.  In this study, fever is clinically defined as ≥38°C.  
 
The primary outcome endpoint is the daily average fever burden (°C-hour) between 
randomization and through 336 hours (14 days) or ICU exit, whichever comes first.  The 
key secondary outcome endpoint is the level of functional independence at 90 days post-
injury (3-month) follow-up based on the modified Rankin Scale.  Other secondary 
endpoints will include additional neurologic outcomes measured at varying time points, 
mortality, delirium, and ICU and hospital length of stay (see Section 10.3).      
 
The primary safety endpoints will include adverse events, major adverse events, 
incidence of infection, and incidence of shivering.   
 
The study will follow brain-injured patients throughout their hospital stay and at 3-, 6-, 
and 12-months post injury for neurologic assessment.  After a pre-specified stabilization 
period, patients meeting inclusion/exclusion criteria will be consented and randomized 
to either the fever prevention (FP) or the standard care (SC) group.  Randomization will 
be stratified by study site, the type of brain injury (i.e., acute ischemic stroke, 
intracerebral hemorrhage, or subarachnoid hemorrhage), subject age and injury-specific 
severity score.   
 
4. STUDY POPULATION 
 
4.1. Number of Subjects 
 
This study is projected to enroll an estimated 1,176 subjects (588 subjects per study 
group) to yield 1,000 evaluable subjects, with a potential maximum of 2,000 
evaluable subjects at up to 50 study sites (U.S. and international) with no more than 
20% of the subjects enrolled at any one site.   
 
See Section 10.1 for sample size considerations. 
 
4.2. Study Population 
 
Adult subjects with a primary stroke diagnosis (i.e., acute ischemic stroke, 
intracerebral hemorrhage, or subarachnoid hemorrhage) will be screened for 
potential eligibility against the study protocol inclusion and exclusion criteria.  
Medical records documenting tests, examinations and evaluations may be used as 
the source documents for the initial screening criteria.  Specific screening tests 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
6 
 
and/or evaluations, typically performed as standard of care in neurocritical patients, 
will be recorded and used to verify inclusion/exclusion criteria.    Only those 
patients having gone through the prescribed disease-specific stabilization period 
will be considered for enrollment.   
   
During the screening and recruitment process, the Investigators or their designees 
will be responsible for describing the nature of the clinical study to the subject or 
healthcare proxy, verifying that the eligibility criteria have been met, and obtaining 
informed consent.   
 
4.3. General Care of Enrolled Subjects 
 
It is understood that care and treatment of the brain injured patient is individualized 
based on their specific needs and circumstances; however, there is a need to reduce 
the potential for treatment bias across sites/investigators participating in this study.  
To that end, when at all possible/reasonable, investigators should follow established 
society guidelines when caring for enrolled subjects.  Appendices 19.11, 19.12, and 
19.13 contain a summary of recommendations from the American Heart 
Association/ American Stoke Association guidelines for management of patients 
with acute ischemic stroke, spontaneous intracerebral hemorrhage, and 
subarachnoid hemorrhage, respectively.     
 
4.4. Eligibility Criteria  
 
4.4.1. General Inclusion Criteria  
 
A subject must meet all of the following criteria to be entered in the study: 
 
1. Adult patients ≥18 and ≤85* years of age; and  
 
2. Admitted with a primary neurological diagnosis of ischemic stroke, 
intracerebral hemorrhage, or subarachnoid hemorrhage; and 
 
3. Prior to onset of acute symptoms, was considered functionally 
independent (mRS 0-2)*; and  
 
4.  Meets disease-specific criteria. (See section 4.4.3) 
*NOTE: For subjects >80 and ≤85 years of age, the qualifying mRS 
must be = 0 
 
4.4.2. General Exclusion Criteria 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
7 
 
A subject must be excluded from study entry if any of the following criteria 
are met: 
 
1. Fever (≥38.0°C) for more than one hour or more than one instance 
prior to study enrollment; or 
 
2. Pre-existing neurological, psychiatric, or other condition that would 
confound neurological assessment or would make it difficult to 
accurately assess neurologic and/or functional outcome; or 
 
3. Has a pre-morbid condition that in the opinion of the investigator 
suggests poor likelihood of survival to 6 months; or 
 
4. Has a pre-morbid mRS ≥3 for subjects 18 – 80 years of age or ≥1 for 
subjects ≥81 years of age; or 
 
5. Diagnosed with brain death; or  
 
6. Is undergoing therapeutic hypothermia therapy; or 
 
7. Has sustained neurological injury felt to be catastrophic with little 
chance of recovery or is on comfort measures only; or 
 
8. Has a skin condition in which the use of the ArcticGel Pads is 
contraindicated (i.e., skin that has signs of ulceration, burns, hives, or 
rash); or 
 
9. Has poor skin integrity or poor tissue perfusion; or 
 
10. Participation in a concurrent investigational / interventional study 
(medical device or drug); or  
 
11. In the investigator’s opinion is likely to require a stay in the ICU ≤72 
hours; or 
 
12. Is known to be pregnant, or has a positive pregnancy test (for women 
of childbearing age); or 
 
13. Fever (≥38.0°C) at time of study enrollment. 
 
14. Fever at the time of randomization.* 
 
*A confirmatory temperature check must be performed no more than one 
hour prior to randomization to ensure that the subject has not become 
febrile between enrollment and randomization.  Subjects found to be 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
8 
 
febrile between enrollment and randomization will be considered screen 
failures. 
 
 
4.4.3. Disease Specific Inclusion / Exclusion Criteria 
 
DISEASE 
STATE* 
STABILIZATION 
PERIOD (Enrollment 
Timeframe) 
INCLUSION 
CRITERIA 
EXCLUSION CRITERIA 
Ischemic 
Stroke 
No less than 3 hours but 
no more than 24 hours 
from ictus 
• Imaging confirmed 
diagnosis  
• NIHSS ≥6 at the time 
of consideration of 
enrollment** 
• If performed, IV tPA 
or endovascular 
management meets 
institutional guidelines 
• Hemorrhagic conversion 
of an ischemic stroke is 
acceptable, provided it 
meets all ICH inclusion/ 
exclusion criteria below 
Intracerebral 
Hemorrhage 
• No less than 6 hours but 
no more than 36 hours 
from last known normal 
(LKN) time 
• No less than 4 hours 
after intracranial 
procedure to ensure 
stability post-operatively 
if surgery performed  
• Additionally, for patients 
on anticoagulation 
therapy, only after serial 
scans at least 4 hours 
apart show no further  
ICH expansion (>5cc) 
• Imaging confirmed 
diagnosis of primary 
ICH 
• NIHSS ≥6 at time of 
consideration of 
enrollment** 
• GCS ≥5 at time of 
consideration of 
enrollment*** 
• ICH volume of 1-60 cc 
• ICH known to be 
secondary to neoplasm or 
trauma 
 
 
Subarachnoid 
Hemorrhage 
• No less than 4 but no 
more than 48 hours after 
stabilization post 
intracranial 
endovascular/surgical 
procedure (if performed)  
• Within 72 hours of onset 
of symptoms 
• Aneurysmal/ 
aneurysmal pattern 
SAH confirmed within 
24 hours of symptom 
onset 
• Admission imaging 
shows Fisher Grade 2- 
4 OR Modified Fisher 
Scale 1 - 4 
 
• SAH due to trauma 
• Fisher Grade 1 OR 
Modified Fisher Scale 0 
• Non-securable aneurysm 
except angiogram 
negative SAH if all other 
I/E criteria met 
*Note: Randomization is based on the subject’s primary diagnosis.  
**Note: Guidance for performing NIHSS in comatose patients can be found in Appendix 19.3 
***Note: For intubated patients, the verbal portion of GCS may be imputed (see Appendix 19.2).  
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
9 
 
 
5. STUDY SCHEDULE 
 
All subjects who sign the informed consent and meet eligibility criteria will be 
randomized to either the FP or SC group and will be followed as per the protocol 
defined study procedures and follow-up visit schedule.  A confirmatory temperature 
check must be performed no more than one hour prior to randomization to ensure that 
the subject does not become febrile. If the subject becomes febrile between enrollment 
and randomization, they will be considered a screen failure.  Randomization and 
initiation of study procedures (e.g., index procedure, hourly temperature measurements) 
should take place as close to enrollment as possible.   
 
The study procedures and visit schedules for enrolled subjects is shown in Table 1.  
With the exception of the post-acute phase visit, all follow-up visits must be scheduled 
based on the date of symptom onset.  If a subject is unable to attend a scheduled study 
visit, this must be documented in the subject’s file and the site should request that the 
subject return as close to the scheduled visit date as possible. 
 
Note: For the purposes of this study, the definition of “deemed medically ready for 
discharge” is defined as follows: patient is medically stable and no longer requires 
critical/intensive level care or observation.  For example, a patient may be medically 
stable and no longer requires critical level care but cannot be discharged from the ICU 
due to a lack of beds in a standard care unit.  In this case, the acute phase of the study 
would be discontinued and the date the patient was deemed ready for discharge would 
be recorded in the appropriate case report form.  
 
Should a subject in the Fever Prevention arm prematurely discontinue the Arctic Sun 
5000 System OR a subject in the Standard Care arm have a targeted temperature 
management system initiated for fever control, the subject does not switch arms of the 
study.  All study procedures / assessments should continue as scheduled for their 
assigned arm.   
 
Should a subject’s medical care be changed to comfort-measures only, the acute phase 
of the study will be discontinued.  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
10 
 
Table 1:  Study Schedule  
 
Screening /  
Enrollment 
Acute Phase 
Post-Acute Phase Visit 
3 Month F/U 
Visit 
6 Month F/U 
Visit 
12 Month  
F/U Visit 
Procedure/Test/Follow-Up Windows 
Hospital / ICU 
Admission 
336 Hours (14 Days) i 5 Days Post-Acute Phase OR 
Hospital Dischargeii ±1 day 
3 mo ±30 days 
from 
LKN/Ictus 
6 mo±30 days 
from 
LKN/Ictus 
12 mo ±30 days 
from LKN/Ictus 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Describe study to potential subject 
X 
 
 
 
 
 
Informed Consent/Enrollment 
X 
 
 
 
 
 
Randomization* 
X 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
Modified Rankin Scale 
X (Pre-Morbid) 
 
X 
X 
X 
Xvi 
Glasgow Coma Scale 
X 
 
 
 
 
 
Intracerebral Hemorrhage Score (ICH Score) 
Xiv 
 
 
 
 
 
Barthel Index 
 
 
X 
X 
X 
 
Glasgow Outcome Scale - Extended 
 
 
X 
X 
X 
 
Montreal Cognitive Assessment 
 
 
X 
X 
X 
 
Diagnostic Imaging (CT Scan or MRI) 
Xiii 
 
 
 
 
 
NIH Stroke Scale 
Xv 
Xvii 
X 
X 
X 
 
Daily Intensive Care Delirium Screening Checklist 
 
X 
 
 
 
 
World Federation of Neurological Surgeons 
Grading System (SAH subjects only) 
Xiii 
 
 
 
 
 
Fever Prevention Index Procedure 
 
X 
 
 
 
 
Hourly Body Temperature* 
 
X 
 
 
 
 
Urinalysis (Subjects with Foley catheter) 
X 
Xviii 
 
 
 
 
Daily White Blood Cell Count  
 
X 
 
 
 
 
Shiver monitoring and control protocol  
 
X 
 
 
 
 
Antipyretic use / supplemental shiver control 
 
X 
 
 
 
 
End of full case data download from Arctic Sun 
 
X 
 
 
 
 
Adverse Events 
 
X 
Xix 
Xix 
Xix 
Xix 
* A confirmatory temperature check must be performed no more than one hour prior to randomization; should they be found to be febrile they will be considered a screen failure  
i – Acute Phase will continue through 336 Hours (14 days) for ALL subjects OR until the patient is discharged/deemed medically ready for discharge from the ICU or the subject goes on 
comfort-measures only, whichever occurs first; neurologic assessments performed during this phase are not blinded 
ii - Window will be 5 days after completion of Acute Phase OR at hospital discharge, whichever comes first   
iii - Testing performed at admission may be used for screening and as study baseline measures; if not previously performed, tests should be completed for eligibility screen and baseline 
iv – For ICH subjects only at screening 
v - Only for IS and ICH subjects at screening and enrollment 
vi – May be assessed by phone unless an actual visit is otherwise performed within the follow-up window 
vii – NIH Stoke Scale will be performed at day 2 and day 5 of the study for IS and ICH subjects when not fully sedated; not blinded assessments  
viii – Urinalysis performed at study enrollment, Day 7 (if still in the acute phase) and at the end of the acute phase/time of catheter removal for all catheterized subjects  
ix – Limited to MAEs only
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
11 
6. STUDY PROCEDURES 
 
The study visit schedule outlined in Table 1 summarizes the study procedures to be 
performed during each study interval or visit.  This section provides additional details of 
the individual study procedures.   
 
6.1. Evaluations 
 
6.1.1. Informed Consent 
 
The Investigator or designee will explain the study to the subject or proxy, 
answer all of the subject’s/proxy’s questions, and obtain written informed 
consent in a language which the subject/proxy is fluent before the collection 
of any study data or performance of any study procedures.   
 
The subject (or subject’s legally authorized representative) must be willing 
and able to sign and date the informed consent form.  The original will be 
retained with the subject records and a copy will be provided to the subject. 
 
6.1.2. Enrollment 
 
Subjects who sign an informed consent will be considered enrolled in this 
study.  Note: For subjects enrolled but not randomized, data collection will be 
limited to demographics and eligibility information. 
 
6.1.3. Eligibility 
 
The subject’s eligibility (inclusion/exclusion criteria) for study enrollment will 
be reviewed and documented on the appropriate case report form (CRF).  At 
the time of screening, it must be documented that study eligibility criteria 
were reviewed with the screening results noted.  Subjects who fail to meet 
eligibility criteria must not be enrolled in the study.   
 
A confirmatory temperature check must be performed no more than one hour 
prior to randomization to ensure that the subject does not become febrile. If 
the subject becomes febrile between enrollment and randomization, they will 
be considered a screen failure.  This will be documented on the appropriate 
CRF. 
 
6.1.4. Assignment of Subject Number 
A unique identification number will be given to study subjects.  Subject 
numbers will be assigned in sequential order.  The subject number will consist 
of six digits.  The first three digits will designate the study site.  The last three 
digits will designate the subject by number in sequential order (i.e., subject 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
12 
number 101 001 will be the first subject at site 101; 101 002 will be the 
second subject at site 101, etc.). 
 
6.1.5. Demographics and Medical History 
 
At enrollment, the subject's demographic information and medical history will 
be documented on the appropriate CRF.  Demographic data will include year 
of birth, gender, race, ethnicity, height and weight. 
 
Relevant medical history will be obtained by the physician including but not 
limited to the following:   
• 
Primary diagnosis 
• 
Hypertension 
• 
Heart failure 
• 
Ischemic heart disease 
• 
Acute myocardial infarction 
• 
Arrhythmia 
• 
Transient ischemic attack/stroke 
• 
Asthma/chronic obstructive pulmonary disease 
• 
Coagulopathy 
• 
Diabetes 
• 
Previous head trauma/injury 
• 
Neurological status 
 
6.1.6. Diagnostic Testing 
 
Because of the variety of disease states examined in this study, there are 
several types of diagnostic testing that might be performed as part of the 
institution’s/Investigator’s standard of care to confirm clinical diagnosis.  
Diagnostic tests may include, but are not limited to, computed tomography 
scan (CT scan), computed tomography angiography (CT angiography), or 
magnetic resonance imaging (MRI).  The type of testing used to confirm 
diagnosis and study eligibility will be documented. 
 
6.1.7. Baseline Neurologic Assessments 
 
6.1.7.1. 
Modified Rankin Scale 
 
All enrolled subjects will have a pre-morbid modified Rankin Scale22 
(mRS) documented.  See Appendix 19.1 for additional scoring 
information for Modified Rankin Scale.  
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
13 
6.1.7.2. 
Glasgow Coma Scale 
 
All enrolled subjects will have a Glasgow Coma Scale23 documented at 
baseline.  See Appendix 19.2 for additional scoring information for the 
Glasgow Coma Scale. 
 
6.1.7.3. 
National Institutes of Health Stroke Scale 
 
Ischemic Stroke and Intracerebral Hemorrhage subjects will have a 
National Institutes of Health Stroke Scale (NIHSS) 24 documented at 
baseline.  See Appendix 19.3 for additional information on the process 
for scoring the NIHSS. 
 
6.1.7.4. 
World Federation of Neurological Societies Grading Scale for 
Subarachnoid Hemorrhage (WFNS) 
 
Non-traumatic, subarachnoid hemorrhage patients will have a WFNS 
Scale25 documented at baseline.  This will also be used during 
randomization as a measure of injury severity.  See Appendix 19.4 for 
additional information on scoring the WFNS Scale. 
 
6.1.7.5. 
Intracerebral Hemorrhage Score 
 
Intracerebral hemorrhage patients will have an intracerebral 
hemorrhage score26 calculated and documented at baseline to be used 
during randomization as a measure of injury severity.  See Appendix 
19.5 for additional information on calculating the ICH score. 
 
6.2. Randomization 
 
Randomization will occur after informed consent is obtained, after study 
personnel ensure the subject meets all general and disease-specific inclusion 
and none of the exclusion criteria.  A confirmatory temperature check must be 
performed no more than one hour prior to randomization to ensure that the 
subject does not become febrile. If the subject becomes febrile between 
enrollment and randomization, they will be considered a screen failure.  
Randomization and initiation of study procedures (e.g., index procedure, 
hourly temperature measurements) should take place as close to enrollment as 
possible.   
 
Using a minimization algorithm, enrolled subjects will be stratified by four 
factors: neurological diagnosis, investigational site, age (<70 years vs. ≥70 
years), and baseline severity and randomized into either the fever prevention 
group or the standard care group at a 1:1 ratio.  Baseline severity for IS 
subjects will be according to the NIHSS score (<17 vs. ≥17, on a scale of 0-
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
14 
42, with higher scores indicating greater severity).  For ICH subjects, baseline 
severity will be based on the ICH score (≤2 vs. ≥3, with higher scores 
indicating greater severity).  For SAH subjects, baseline severity will be 
according to the World Federation of Neurological Societies Grading System 
for Subarachnoid Hemorrhage (≤III vs. ≥IV, on a scale of I-V, with higher 
scores indicating greater severity).    
 
The randomization process will be handled via use of an interactive web-
based system.   
   
6.3. Physical Examination 
 
For the purposes of the study, a limited physical exam will be performed 
including height and weight measurements.  The limited physical exam must 
assess, at minimum, all of the systems listed in the case report form. 
 
6.4. Patient Temperature 
 
There are two purposes for measuring/monitoring patient temperature within 
the study: 1) primary endpoint of fever burden; and 2) control of patient 
temperature using the Arctic Sun System.  For the fever burden endpoint, all 
subjects must have hourly temperature measured using one standardized 
thermometry method.  Ideally, a continuous core temperature measurement 
method will be used (e.g., temp-sensing Foley catheter, esophageal probe, or 
3M™ BairHugger™ Temperature Monitoring System).  So as to more closely 
mimic standard of care for temperature measurement, each investigative site 
will be allowed to select the thermometry method they feel is most appropriate 
to standardize to. This method must be used for all hourly measurement, for 
all subjects, regardless of the study arm that they are randomized to, and 
regardless of the continuous thermometer that may be used for controlling the 
Arctic Sun System.  For example, if a subject in the fever prevention group 
has a temp-sensing Foley catheter in place for control of the Arctic Sun 
System, but the site has standardized to temporal artery thermometry, the 
subject must still have hourly temperatures taken using the temporal method.  
Standardized hourly temperature measurements are required throughout the 
acute phase of the study (336 hours/14 days), or until the subject is 
discharged/deemed ready for discharge from the ICU/placed on comfort 
measures only, whichever comes first).   
 
The second purpose for measuring temperature is for the control of the Arctic 
Sun System.  Subjects randomized to the fever prevention group must have a 
continuous core temperature probe (i.e., Foley catheter or esophageal probe) 
(see section 6.8.1 for more detail).   
   
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
15 
6.5. Medications  
 
Antipyretics and other medications (e.g., antimicrobials) given to treat fever 
during the acute phase of the study will be recorded.  Additionally, 
medications given to control shivering will be recorded.  Because 
acetaminophen and similar medications/antipyretics may be used either to 
treat fever or to treat shivering, the specific indication for use will be collected 
in the appropriate case report form.   
 
6.6. Infection Surveillance 
 
To assist the Investigator in identifying potential infection in enrolled 
subjects, regular active screening will be performed by the following methods.  
Investigators should refer to Guidelines for evaluation of new fever in 
critically ill adult patients: 2008 update from the American College of Critical 
Care Medicine and the Infectious Diseases Society of America for additional 
recommendations. 
 
6.6.1. Urinalysis 
 
Urinalysis will be performed for all subjects with a Foley catheter at study 
enrollment (baseline) or day of catheter insertion, day 7 of the acute phase (if 
the subject is still in the ICU), and at the end of the acute phase or when the 
catheter is removed, whichever comes first. 
 
6.6.2. White Blood Cell Count 
 
A white blood cell (WBC) count will be performed daily for all subjects 
during the acute phase.  WBC counts performed as part of complete blood 
counts collected for other purposes are acceptable if collected within the 
appropriate timeframe.  
 
6.7. Adverse Events  
 
Each subject will be monitored for the occurrence of both adverse events 
(AEs) and major adverse events (MAEs) according to definitions in Section 7.  
All AEs will be monitored from study randomization through the acute phase 
of the study (discharge from the ICU) and MAEs will be monitored from 
randomization through the end of study participation.   
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
16 
6.8. Fever Prevention (FP) 
 
Subjects randomized to the fever prevention group will have the following 
procedures.  See Figure 2. 
 
Figure 2. 
 
 
 
6.8.1.  Index Procedure 
 
Subjects randomized to the FP group must have a continuous core 
temperature probe (i.e., Foley catheter; Note: an esophageal probe may be 
used in intubated patients but will need to be replaced with a Foley catheter 
when the subject is extubated; rectal probes may not be used) placed prior to 
initiation of the Arctic Sun System.  The appropriately sized ArcticGel Pads 
will be placed on the subject based on their weight; the pads will be 
connected to the AS-5000. The target temperature will be set to 37⁰C and the 
system initiated and operated according to the Instructions for Use.  (*Note: 
To avoid pressure points, if appropriately sized pads are not immediately 
available, use the next smaller sized pads; replace pads with appropriately 
sized pads as soon as possible.)   
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
17 
 
For patient comfort and to reduce the potential for early onset shivering, 
counter-warming should be applied concurrently; see section 6.8.4.  
Additionally, the initial target temperature may be set to match the actual 
patient temperature up to 37.5°C.  If this is done, the patient temperature 
should be read from the Arctic Sun console.  The target temperature should 
be decreased by approximately 0.1°C after each hour of therapy until the 
target temperature of 37.0°C is reached (no more than 10 hours).  See section 
6.10 more information on shiver control procedures. 
 
Short suspensions in therapy for purposes of conducting diagnostic 
procedures, subject mobilization, etc., are to be expected; however, the 
duration of these suspensions must be as short as possible.  Suspension in 
therapy ≥1 hour must be documented in the appropriate CRF.  
 
6.8.1.1. 
ArcticGel Pad Changes 
 
ArcticGel Pads should be changed every 5 days for duration of the 
subject’s participation in the study.  During the pad change process, the 
skin under the pads should be fully assessed for signs of injury.  If skin 
injury is noted, this should be reported as an adverse event.    (Note: If 
cool water is circulating through the pads, it is not uncommon for the 
skin to appear pink or mottled when the pads are initially removed.  If 
skin injury is suspected, allow the skin to warm and reassess the area 
prior to reapplication of the pads.)    
 
To avoid subject injury, ArcticGel Pads should not be replaced on skin 
that has signs of ulceration, burns, hives, or rash or on areas with poor 
skin integrity or poor tissue perfusion.  Additionally, if the subject is 
suffering from edema, pads should be repositioned frequently to avoid 
undue tension/stress on the skin or therapy suspended until the edema is 
controlled. 
 
Note that the use of ArcticGel Pads does not prevent patient turning, 
physical therapy, and/or mobilization.  Pads can be drained and 
temporarily disconnected from the Arctic Sun console for purposes of 
mobilization or physical therapy when required.     
 
6.8.2. Monitoring for Heat Generation 
 
Subjects should be assessed hourly for signs of heat generation (fever or 
shivering) via the Bedside Shivering Assessment and/or assessment of the AS-
5000 water temperature.  If fever is suspected, the Investigator should perform 
an appropriate investigation (e.g., cultures) and treat the patient accordingly.  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
18 
If shivering is detected/suspected, the Shiver Control Procedure should be 
immediately implemented (See section 6.10). 
 
6.8.2.1. 
Bedside Shivering Assessment (BSAS) 
 
Score 
Definition 
0 
None: No shivering noted on palpation of the masseter, 
neck, or chest wall 
1 
Mild: Shivering localized to the neck and/or thorax only 
2 
Moderate: Shivering involves gross movements of the 
upper extremities (in addition to neck and/or thorax) 
3 
Severe: Shivering involves gross movements of the trunk 
and upper and lower extremities 
 
 
6.8.2.2. 
Arctic Sun 5000 (AS-5000) Water Temperature 
 
The Arctic Sun water temperature should be assessed hourly by the 
bedside nurse to determine if the system is working to cool the patient 
(water temperature for a normothermic patient is typically 28⁰-30⁰C).  
If the water temperature is below 25⁰C this could indicate that the 
subject is generating heat (fever or shivering).  Perform a BSAS to 
determine if shivering is present and at what level.   See Appendix 
19.14: Guide for Addressing Arctic Sun Water Temperature Below 
25°C.   
 
At the end of the fever prevention period, case data for each subject 
will be downloaded from the Arctic Sun 5000.  This data, which 
contains various performance metrics including, but not limited to 
water temperature and water flow rate, will be analyzed to determine if 
the subject had indicators of fever. 
 
6.8.3. Arctic Sun Case Data 
 
At the end of the acute phase, case data for each subject will be downloaded 
from the Arctic Sun 5000 console and uploaded to a site-specific email 
address. Data files should be uploaded as soon as possible after the subject 
completes the acute phase.  This data, which contains various performance 
metrics including, but not limited to water temperature and water flow rate, 
will be analyzed to determine if the subject had indicators of fever. 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
19 
6.8.4. Skin Assessment 
 
The skin under ArcticGel Pads should be assessed at least 4 times per day (no 
less than every 6 hours).  Assessment can be performed by gently pulling up 
a corner of the ArcticGel Pad and visualizing the skin underneath.  If skin 
injury is detected, the pad should be removed, and the injury documented as 
an adverse event.   (Note: If cool water is circulating through the pads, it is 
not uncommon for the skin to appear pink or mottled when the pads are 
initially removed.  If skin injury is suspected, allow the skin to warm and 
reassess the area prior to reapplication of the pads.)   
 
To avoid subject injury, ArcticGel Pads should not be placed on skin that has 
signs of ulceration, burns, hives, or rash or on areas with poor skin integrity 
or poor tissue perfusion.  Additionally, if the subject is suffering from edema, 
pads should be repositioned frequently do avoid undue tension/stress on the 
skin or therapy suspended until the edema is controlled. 
 
6.8.5. Counter-Warming 
 
In order to reduce the potential for shivering, a Bair-Hugger should be 
initiated concurrently with the AS-5000.  If the Bair-Hugger is not tolerated 
by the subject or may interfere with other devices and/or procedures, the 
subject’s hands and feet should be covered with mittens, socks, or extra 
blankets at the time the AS-5000 is initiated.  Additional counter-warming 
measures should be implemented according the Shiver Control Procedure if 
shivering is detected/suspected (See section 6.10).   
 
6.9. Standard Care 
 
Subjects randomized to the standard care group may be medically managed 
according to the institution’s/Investigator’s standard approach unless/until they 
develop fever.  Should the subject develop fever, defined as ≥38°C, the subject will 
have their fever managed in a standardized, escalating fashion as described below.  
The decision to initiate treatment or advance to the next tier in the treatment plan is 
at the investigator’s discretion; however, it is recommended that at least one hour 
should elapse between tiers to allow each individual intervention to take effect.  
Tiers are intended to be implemented consecutively.  See Figure 3.  Alterations to 
tiers should be pre-specified and reviewed and approved by the study Coordinating 
Investigators. 
 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
20 
Figure 3. 
  
 
 
6.9.1. Tier 1: Antipyretic Therapy 
 
To treat active fever, subjects in the SC group will have PRN 
acetaminophen 650 - 1000 mg PO or NG administered.  If the 
subject’s temperature drops below 38.0⁰C they can be maintained on 
PRN acetaminophen therapy.  Other antipyretics (e.g., ibuprofen, 
diclofenac, or paracetamol), routes, and/or doses may be 
substituted/added at the physician’s discretion. 
 
6.9.2. Tier 2: Basic External Cooling 
 
At the investigator’s discretion, if the subject’s temperature remains 
≥38.0⁰C after administration of Tier 1, ice packs applied to the neck, 
axilla and/or groin, fans, and/or tepid baths may be added.  If the 
subject’s temperature drops below 38.0⁰C the ice packs, fans, and/or 
tepid baths will be discontinued.  Basic external cooling can be used 
PRN to supplement antipyretic therapy. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
21 
6.9.3. Tier 3: Cooling Blankets 
 
At the investigator’s discretion, if the subject’s temperature remains 
≥38.0⁰C after application of Tier 2, a standard cooling blanket (e.g., 
Soft-Temp® Conductive Warming Blanket, Adroit Medical Systems, 
Loudon, TN; Maxi-Therm® Lite Hyper-Hypothermia Blanket, 
Cincinnati Sub-Zero, Cincinnati, OH) may be placed under the subject 
and set to the lowest temperature allowed according to hospital 
protocol.  A bath blanket or sheet may be placed between the cooling 
blanket and the subject for comfort if desired.  To reduce the potential 
for shivering, the subject’s hands and feet may be covered with 
mittens, socks, or extra blankets at the time the cooling blanket is 
applied.   If the subject’s temperature drops below 37.5⁰C the water 
temperature should be adjusted up to maintain them at normothermia 
(to avoid overshoot). 
 
Should the subject’s temperature remain ≥38.0⁰C after the cooling 
blanket is placed under them, a second blanket may be placed on top 
of them.   
 
6.9.4. Tier 4: Advanced Targeted Temperature Management   
 
At the investigator’s discretion, if the subject’s temperature remains 
≥38.0⁰C after application of Tier 3, an available advanced targeted 
temperature management device with feedback loop and continuous 
patient temperature monitoring (e.g., Arctic Sun 5000, Blanketrol 
System, MediTherm System) may be applied. 
 
6.9.5. Monitoring for Shiver 
 
Subjects undergoing fever treatment should be assessed hourly for signs 
of shivering via the Bedside Shivering Assessment.  If shivering is 
detected/suspected, the Shiver Control Procedure should be 
immediately implemented (See section 6.10). 
 
6.9.6. Skin Assessment 
 
The skin under external cooling devices (e.g., cooling blankets) should 
be assessed at least 4 times per day (no less than every 6 hours).  
Assessment can be performed by lifting the devices and visualizing the 
skin underneath.  If skin injury is detected, the device should be 
removed, and the injury documented as an adverse event. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
22 
6.10. 
Shiver Control Procedure 
 
Subjects in the FP group and those undergoing fever treatment in the SC 
group shall be monitored at least hourly for shivering.  If detected/ suspected, 
subjects will have their shivering managed in a standardized, escalating 
fashion as described below. *See Figure 4.  Addressing and/or controlling 
shiver in its earliest stages may potentially reduce the need to escalate to 
additional control tiers, may reduce subject discomfort, and may reduce the 
incidence of shiver-related adverse events. 
 
*Note: Based on hospital-specific formularies and/or protocols, alternative 
drugs and/or dosing may be substituted for those listed in tiered shiver control 
(e.g., Buspirone mg PO or NG q 8 hours vs PRN).  Substitutions should be 
pre-specified and reviewed and approved by the study Coordinating 
Investigators. 
 
Additionally, according to existing hospital protocols, tier 1 shiver control 
procedures may be considered and implemented in patients randomized to the 
fever prevention arm prior to the onset of shiver. The timing between tiers is 
offered as guidance and clinical judgement should be used to determine how 
quickly to escalate to a higher tier when shivering continues or is considered 
to be severe.  Because they act synergistically, when moving from one tier to 
another, interventions from prior tiers should be continued.   
 
Also note that, consistent with hospital protocols, patients sedated or 
paralyzed for ventilation, shiver control, or other reasons should periodically 
undergo a “sedation holiday” where sedation is weaned or turned off to allow 
for neurologic assessment as well as assessment of readiness for extubation.  
This applies to patients who, in the investigator’s opinion, are hemo-
dynamically stable enough to tolerate being off sedation.  For intubated 
patients, if sedation for shiver control is precluding extubation, devices such 
as cooling blankets or Arctic Sun should be temporarily suspended.  These 
devices and necessary shiver control measures (up to, but not including Tier 
4) may and should be restarted once the patient is extubated and deemed 
stable and appropriate by the treating team but optimally no greater than 6 
hours post-extubation.   
 
 
 
 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
23 
Figure 4. 
 
 
 
6.10.1.1. Tier 1 Shiver Control 
 
If shivering is detected/suspected, institute the following: 
• Ensure appropriate counter-warming measures are applied.  For FP 
subjects only (those with AS-5000), if not already in place, apply a 
Bair Hugger and set it on the maximum temperature (temperature 
can be lowered if not tolerated by the patient) 
• Acetaminophen 650 mg PO or NG q 4 hours 
• Buspirone 30 mg PO or NG q 8 hours 
 
6.10.1.2. Tier 2 Shiver Control 
 
If shivering continues 1 hour after Tier 1 measures are implemented, 
add the following: 
• If serum magnesium level is <2.5mg/dL, magnesium sulfate 1g 
IV q 4 hours PRN to reach goal of serum Mg level of 3-4 mg/dL 
• Meperidine 12.5 mg IV q 2 - 4 hours  
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
24 
6.10.1.3. Tier 3 Shiver Control 
 
If shivering continues after Tier 2 measures are implemented, add the 
following: 
• Dexmedetomidine infusion 0.2 – 1.2 mcg/kg/hour 
 
6.10.1.4. Tier 4 Shiver Control (Intubated Subjects Only) 
 
If the subject is already intubated and if shiver continues after Tier 1, 2, 
and 3 measures are implemented, one of the following may be added: 
• Propofol continuous infusion, max dose 50 mcg/kg/min 
• Fentanyl continuous infusion 10-250 mcg/hr 
  
6.10.1.5. Arctic Sun Target Temperature Adjustment 
 
There are several instances in which the Arctic Sun target temperature 
may be adjusted.  For patients being initiated on Arctic Sun, if the 
patient’s starting temperature is above the target of 37.0°C, Arctic Sun 
will work to “cool” them to target temperature.  In this case, for patient 
comfort and to reduce the potential for early onset shivering, the initial 
Arctic Sun target temperature may be set to match the actual patient 
temperature up to 37.5°C.  If this is done, the patient temperature 
should be read from the Arctic Sun console.  The target temperature 
should be decreased by approximately 0.1°C after each hour of therapy 
until the target temperature of 37.0°C is reached (no more than 10 
hours). 
 
Additionally, for patients already on Arctic Sun, when the water 
temperature drops below 25°C, it indicates that the machine is working 
to actively decrease the patient’s temperature or to control temperature 
in a patient generating heat (shiver or fever).  If shivering is 
detected/suspected, the tiered shiver control approach outlined above 
should be implemented.  If shivering is BSAS ≥2, the Arctic Sun target 
temperature can be temporarily increased up to 37.5°C until shivering is 
controlled.  If shivering is not detected and Tier 1 shiver control 
procedures do not affect the Arctic Sun water temperature, fever is the 
most likely source of heat generation and should be addressed 
accordingly.  For patient comfort and to reduce the potential for new 
onset of shivering, the Arctic Sun target temperature can be temporarily 
increased up to 37.5°C until treatment of the fever is initiated.  After 
shiver is controlled or fever treatment initiated, the target temperature 
in Arctic Sun should be decreased by 0.1°C after each hour of therapy 
until 37.0°C is reached (no more than 10 hours).  Suspension in Arctic 
Sun therapy ≥1 hour must be documented in the appropriate CRF. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
25 
6.11. 
Fever Prevention Initiation / Standard Care Fever Treatment Initiation 
 
Procedural details to be recorded for FP subjects and SC subjects may include 
but not be limited to: 
• 
Date and time of initiation; 
• 
Patient core temperature at initiation; 
• 
Antipyretic medications; and  
• 
Supplemental external fever control methods (e.g., fan, ice pack; 
cooling blanket). 
 
6.12. 
Acute Phase Routine Assessments 
 
Assessments including, but not limited to hourly core body temperature, anti-
pyretic medications, and shivering control medications will be documented for 
all subjects through the acute phase of the study. 
  
6.13. 
Follow-Up Neurologic Assessments 
 
Follow-up neurological assessments will be performed by study personnel 
certified in the procedures and/or scoring of the assessments.  Assessments 
performed during the acute phase of the study will not be blinded.  Personnel 
performing assessments during the Post-Acute Phase visit and/or 3-, 6-, and 
12-month visits will be blinded to treatment assignment.   
 
Note: Should subjects be physically unable to return for 3- and 6-month 
follow-up visits, alternate arrangements may be made per the Sponsor’s 
determination.  Sites shall contact the Sponsor for guidance. 
 
6.13.1. Modified Rankin Scale   
 
Subjects will have a modified Rankin Scale documented in the Post-Acute 
Phase and at the 3-, 6-, and 12-months follow-up visits. For the 12-month 
visit, this assessment may be performed remotely (e.g., telephone call). 
Scoring of Modified Rankin Scale is provided in Appendix 19.1. 
 
6.13.2. National Institutes of Health Stroke Scale  
 
Ischemic stroke and intracerebral hemorrhage subjects will have a NIHSS 
documented at days 2 and 5 during the acute phase of the study.  If the subject 
is sedated at a level that precludes day 2 and/or day 5 NIHSS, the assessment 
may be skipped and documented in the appropriate CRF.   
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
26 
Additionally, all subjects will have a NIHSS documented in the Post-Acute 
Phase and at the 3- and 6-months follow-up visits.  NIHSS scoring is provided 
in Appendix 19.3. 
 
6.13.3. Intensive Care Delirium Screening Checklist (ICDSC) 
 
Subjects will have an ICDSC27 documented daily during the acute phase of 
the study.  Additional information on calculating the ICDSC score can be 
found in Appendix 19.6. 
 
6.13.4. Barthel Index  
 
Subjects will have a Barthel Index28 assessment documented in Post-Acute 
Phase and at the 3- and 6-months follow-up visits.  Additional information on 
how the Barthel Index score is calculated can be found in Appendix 19.7. 
 
6.13.5. Glasgow Outcome Scale Extended 
 
Subjects will have a Glasgow Outcome Scale Extended29 documented in the 
Post-Acute Phase and at the 3- and 6-months follow-up visits.  Additional 
information on scoring the Glasgow Outcome Scale Extended can be found in 
Appendix 19.8   
 
6.13.6. Montreal Cognitive Assessment 
 
Subjects will have a Montreal Cognitive Assessment (MoCA)30 documented 
in Post-Acute Phase and at the 3- and 6-months follow-up visits.  Additional 
information on calculating the MoCA score can be found in Appendix 19.9. 
 
6.14. 
Subject Discontinuation  
 
Subjects may be discontinued for the following reasons: 
 
• 
Subject is Lost to Follow-Up (LTF): A subject may be considered LTF if 
the investigational site personnel are unable to locate the subject despite 
two documented attempts to notify the subject via all means (telephone, e-
mail, and/or text) and a third attempt by certified mail.  Where the subject 
has given prior permission, a designated representative (e.g., spouse, 
relative) will also be contacted.  Additionally, where prior permission has 
been granted, the subject’s primary care physician may be contacted for 
outcome information. 
 
• 
Subject consent is withdrawn: The subject requests to terminate his/her 
participation in the study (the Investigator must attempt to identify and 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
27 
document the reasons for termination). Subjects will be informed that they 
have the right to withdraw from the study at any time, for any reason, 
without affecting their future care.   
 
• 
Investigator decision: Participation may be immediately terminated by the 
Investigator if, in the opinion of the Investigator, the subject would be 
exposed to inappropriate risk by continuing in the study. 
 
• 
Death:  The subject becomes deceased.  If available, the date and cause of 
death should be documented.  
 
• 
Study termination: The study is terminated by Sponsor. 
 
Once a subject discontinues from the study, the Investigator must complete a Study 
Completion CRF and the reason for subject discontinuation must be fully 
documented. 
 
6.15. 
Replacement of Subjects 
 
A subject that discontinues from the trial will not be replaced. 
 
7. ADVERSE EVENTS 
 
The Principal Investigator is responsible for the detection and documentation of all 
adverse events meeting the criteria and definition of an adverse event or serious adverse 
event.  When possible, the Investigator should report a diagnosis as the event term(s).  If 
a definitive diagnosis cannot be made, signs, symptoms, and abnormal laboratory values 
should be reported as the event term(s).  Skin injuries that are suspected to be associated 
with the use of ArcticGel Pads (including bruising, tearing, skin ulcerations, blistering, 
and necrosis) should be reported as adverse events related to the study device.   
 
While instances of shiver are being captured and reported as a study endpoint, there may 
be instances that potentially meet the definition of serious injury (i.e., necessitates 
medical or surgical intervention to preclude permanent impairment of a body function).  
As such, any instance of shiver requiring Tier 4 treatment must be reported as an adverse 
event. 
 
All AEs will be monitored from study randomization through the Acute Phase of the 
study (336 hours/discharge from the ICU/deemed ready for discharge from ICU/placed 
on comfort measures only, whichever comes first) and MAEs will be monitored from 
randomization through the end of study participation.   Adverse events will be 
documented in the medical record or source documentation and on the study appropriate 
CRF(s).  All events will be followed through resolution.  Events with an onset prior to 
randomization should be reported in the subject’s medical history.    
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
28 
7.1.     Definition of Adverse Events (AE) and Serious Adverse Event (SAE) 
 
In this study, an adverse event is defined as any untoward medical occurrence, 
unintended disease or injury, or unanticipated complication per the Investigator’s 
assessment regardless of relationship to the investigational device. A serious 
adverse event is defined by ISO 14155 and/or 21 CFR 803.3 as an adverse event 
that: a) led to death; b) led to serious deterioration in health that resulted in life-
threatening illness or injury, resulted in permanent impairment, required inpatient 
hospitalization/prolonged hospitalization, or resulted in medical/surgical 
intervention to prevent life-threatening illness/injury or permanent impairment; or 
c) led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
 
A pre-existing condition should not be reported as an AE unless there has been a 
substantial increase in severity or frequency of the condition, which has not been 
attributed to natural history.  Pre-existing conditions should be considered as part of 
the subject’s medical history.  Exacerbation of an existing condition should be 
reported as an AE, if the event meets the protocol definition of an AE.   
 
 
7.2. 
Definition of Adverse Device Effect (ADE) and Serious Adverse Device Effect 
(SADE) 
 
An adverse device effect is defined as any adverse event that is considered to be 
related to the use of an investigational medical device. This definition includes any 
event resulting from insufficiencies or inadequacies in the instructions for use, 
deployment, implantation, or operation or any malfunction of the investigational 
device (study device) and includes any event that is a result of a user error.  A 
serious adverse device effect is defined as any adverse device effect that has 
resulted in any of the consequences characteristic of a serious adverse event or that 
might have led to any of these consequences if suitable action had not been taken or 
intervention had not been made or if circumstances had been less than opportune.   
 
7.3. Definition of Major Adverse Events (MAE) 
 
In this study, an MAE will be defined as one of the following: 
• Pneumonia; 
• Sepsis; 
• Malignant cerebral edema; or 
• Death 
 
See Appendix 19.15 for guidance regarding MAE definitions. 
  
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
29 
7.4. 
Definition of Unanticipated Adverse Device Effect (UADE)  and Unanticipated 
Serious Adverse Device Effect (USADE)  
 
An unanticipated adverse device effect is defined by 21 CFR 812.3 as any serious 
adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence, or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare 
of subjects.  An unanticipated serious adverse device effect is defined by ISO 14155 
as a serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report. 
 
Refer to the product IFUs for a list of AEs that are expected or associated with the 
use of the study device(s). 
 
7.5. Relationship of Adverse Event To Device/Procedure 
 
The determination of the relationship of an AE to the device or procedure must be 
made by the physician Investigator and the following guidelines should be used: 
 
• 
Device: This category should be restricted to AEs directly attributable to 
devices used for study conduct during the Acute Phase of the study, 
including but not limited the Arctic Sun System, temperature probes used 
to operate Arctic Sun, thermometers for hourly temperature assessments, 
or standard cooling blankets. (E.g., skin injury under ArcticGel Pad) 
 
• 
Procedure:  A procedure includes any study-related activity performed 
during the Acute-Phase of the study (e.g., hourly temperature 
measurement; urethral trauma associated with temp-sensing Foley catheter 
insertion; maintaining normothermia (e.g., severe shivering requiring Tier 
4 treatment)). 
 
The following categories should be used by the physician Investigator for 
assigning the certainty of relatedness: 
 
• 
Definitely Related:  An AE is definitely related if it is obvious, certain or 
there is little doubt regarding the relationship. 
 
• 
Possibly Related:  An AE is possibly related if it is capable of being 
related but relatively unlikely. 
 
• 
Not Related:  An AE is not related if it is determined that there is no 
plausible association. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
30 
7.6. Severity of Adverse Events 
 
Each AE should be assessed for its severity, or the intensity of an event, 
experienced by the subject. 
 
• 
Mild:  Awareness of a sign or symptom that does not interfere with the 
subject’s activity or is transient and is resolved without treatment or 
sequelae. 
 
• 
Moderate:  May interfere with the subject’s activity and require additional 
intervention and/or treatment and may have additional sequelae. 
 
• 
Severe:  Significant discomfort to the subject and/or interferes with the 
subject’s activity.  Additional intervention and or treatment are necessary.  
Additional sequelae occur.  Severe is used to describe the intensity of an 
event experienced by the subject. 
 
 
7.7. Reporting of Adverse Events 
      
7.7.1. Reports of Adverse Events, Serious Adverse Events and Unanticipated 
Adverse Device Effects 
 
The procedure for reporting AEs, SAEs, SADEs or USADEs is as follows: 
 
• 
If an AE or SAE occurs during the Acute-Phase of the study, all 
sections of the appropriate CRF(s) must be completed.  
• 
All SAEs occurring during the Acute-Phase of the study, including 
SADEs, and UADEs (including initial reports and follow-up reports 
with additional event details) must be reported to the Sponsor within 
24 hours of the investigational site becoming aware of the event(s).  
The Intrepid Event Notification Form may be emailed to  
BMD-INTREPID@crbard.com 
• 
De-identified copies of all requested relevant documentation should 
be submitted to the Sponsor within 72 hours of knowledge, as 
appropriate.   
 
Reporting of adverse events to individual Institutional Review Boards 
(IRBs)/Ethics Committees (ECs) and/or regulatory authorities will follow the 
local regulations in each participating country. 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
31 
7.8. Adjudication of Adverse Events 
 
To ensure consistency in determination of relatedness of adverse events, a Clinical 
Events Committee (CEC) will adjudicate all AEs determined by the site investigator 
to be related or possibly related to a study device or procedure.  Additionally, the 
CEC will adjudicate all SAEs and MAEs.   
 
The CEC will be comprised of at least three (3) members (neurointensivists, 
neurologists, or neurosurgeons) who are not directly involved in the conduct of the 
study. The CEC will be responsible for the development of specific criteria used for 
the categorization of clinical events and clinical endpoints in the study as 
determined by the CEC charter. 
  
8. MECHANICAL FAILURES, MALFUNCTIONS AND DEFECTS  
 
The Investigator will record if a Bard device (Arctic Sun 5000 System, ArcticGel Pads) 
used in the study procedure failed to meet its performance specifications whether due to 
mechanical failure, malfunction or defects.  This applies to: devices used to treat the 
subject, or devices in which the package was opened, but the device was not used for 
treatment, or devices with which treatment was attempted, but the device did not 
remain through the entire study period. 
 
All mechanical failures, malfunctions, missing components, foreign matter inclusion or 
any other defects of the study device or any components of the device kit that do not 
perform to specifications will be recorded on the “Device Failure” Case Report Form.   
 
Devices meeting any of the above criteria will be labeled “Biohazard.”  BMD will 
contact the site and provide specific shipping instructions and packaging materials, 
including a pre-paid Federal Express return label, to permit the return of device to 
BMD.   
 
Reported malfunctions will be investigated and reported under 21 CFR part 803 by 
BMD if necessary, and in a manner consistent with the policies and procedures BMD 
uses for its commercially available devices.  The site may be contacted to provide 
additional information to allow BMD to conduct a thorough investigation. 
 
The Investigator will record any device deficiencies, defined as an inadequacy of a 
medical device with respect to its identity, quality, durability, reliability, safety or 
performance; includes device malfunctions, use errors and inadequate labeling, in the 
CRF.  A device deficiency has occurred if an investigational device used in the study 
procedure failed to meet its performance specifications whether due to mechanical 
failure, malfunction or defects.  Device deficiencies also include use errors and 
inadequate labeling.  This applies to:  
 
• 
devices used on the subject; or 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
32 
• 
devices in which the package was opened, but the device was not used on the 
subject; or  
• 
devices with which fever control was attempted, but the device did not remain 
on the subject. 
 
If the device deficiency was associated with an AE, the reporting provisions for AEs, 
ADEs, SAEs, SADEs and USADEs as outlined in Section 7 above apply. All device 
deficiencies will be recorded on the “Device Deficiency” CRF.   
 
The Investigator is responsible for reporting device failures occurring with devices used 
in the standard care fever control group to the appropriate manufacturer. 
 
9. RISK/BENEFIT ANALYSIS 
 
There are well established standard care methods to control fever in neurocritical 
patients including anti-pyretic medications and external cooling methods such as fans, 
ice packs, and cooling blankets.  Patients with fever, those treated with external cooling 
methods, and those treated with the Arctic Sun 5000 System may be at risk for shivering 
and associated adverse events.  As such, prevention and/or control of shivering has been 
considered and incorporated into study procedures.   
 
The Arctic Sun 5000 Temperature management System and the ArcticGel Pads utilized 
in this study have 510(k) clearance from the U.S. FDA, are CE marked and will be used 
in accordance with the indications of the labeling in effect during the study.   
 
Subjects randomized to the fever prevention group may have a higher risk of skin 
irritation/injury compared to those in the standard care group due to direct skin contact 
with the cooling surface of the ArcticGel Pads.  
 
Regardless of which group the subject is randomized to, they will receive treatment to 
control fever.  Devices used for this purpose will be used in a manner consistent with 
their Instructions for Use/Operator’s Manual.  Study procedures do not pose any 
additional potential risk to the health, safety or welfare of the subject over and above 
treatment for their primary diagnosis and fever. 
 
Evidence from limited investigations suggests that fever control may be associated with 
better outcomes.  It is impossible to determine what, if any benefit enrolled subjects may 
gain by participating in this study.   While patients enrolled in this study may not 
directly benefit from study procedures, the information gained may benefit future 
patients.    
 
The risks and potential benefits associated with the study procedures will be described in 
full to the subject or their proxy by the Investigator during the informed consent process.   
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
33 
10. STATISTICAL METHODS 
 
This section describes the planned statistical analyses for this study.  A detailed 
Statistical Analysis Plan (SAP) will be completed and placed on file prior to the 
database lock.  The SAP will contain a comprehensive explanation of the methodology 
used in the statistical analyses described below. 
 
 
10.1. Sample Size Considerations 
 
The study sample size is primarily driven by the key secondary endpoint, and the 
study is powered for both the primary endpoint and the key secondary endpoint. 
The test of the key secondary endpoint is conditional on the success of the test of 
the primary endpoint.  
 
The key secondary endpoint is neurologic outcomes assessed by the modified 
Rankin Scale (mRS).  In additional to its standard scale, the 6-category mRS 
outcome score will also be dichotomized as a binary outcome (scores of 0 to 3 for 
success and scores of 4 to 6 for failure). Sample size is estimated based on the 
dichotomized binary outcome with the assumed FP success rate of 50% and the SC 
success rate of 40%. A sample size of 1000 subjects (500 in each group) will 
provide an 88% power by a two-group chi-square test at two-sided α=0.05 (nQuery 
7.0). Given such a sample size, the analysis based on the standard scale may be 
slightly more powerful. Both analyses, either using the original standard scale or 
dichotomized scale, will be performed for mRS in this study. 
 
Assuming a 15% attrition rate, the total sample size of randomized subjects is 
1,176, with a 1:1 ratio to the FP and SC group (588 subjects in each of the group). 
 
The primary endpoint of fever burden will be analyzed at the interim when 588 
subjects (half of the planned sample size of 1,176 subjects) have completed the 3-
month visit. Since fever burden does not follow normal distribution, Wilcoxon 
rank-sum tests will be used to analyze the data and the sample size estimation will 
be based on such test as well. In the SC group, the proportion of patients who 
develop fever and therefore show positive fever burden is estimated at 40%.  In the 
FP group, it is expected that few will have positive fever burden; using a 
conservative assumption, we estimate 10% of subjects will show a positive fever 
burden. Under such assumptions, the probability that fever burden in the SC group 
is higher than in the FP group is 65% (nQuery 7.0 Assistant). Consequently, the test 
of the primary endpoint will have more than 99% power to show a statistically 
significant difference between the two groups with 500 subjects (nQuery 7.0).   
 
10.1.1. Sample Size Re-estimation 
 
An interim analysis will be conducted when the first 588 subjects (half of the 
planned sample size) have completed the 3-month visit (including subjects who 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
34 
were discontinued early from the study), at which time the primary analysis will 
be performed to evaluate the treatment effect in fever burden. The key 
secondary endpoint of modified Rankin Scale will be evaluated as well for 
futility and sample size re-estimation. If recommended by the Data Monitoring 
Committee (DMC) and deemed appropriate, the sample size may increase up to 
double the planned sample size (up to 2,000 evaluable subjects).  The overall 
study characteristics will be displayed by simulation as further described in 
section 10.5. 
 
10.2. Analysis Population(s) 
 
Enrolled: The enrolled subjects consist of all subjects who sign the informed 
consent.  
 
Intent-to-Treat (ITT): This is the population of all subjects who have been 
consented and randomized.    
 
As Treated (AT): This is the ITT population but based on the actual treatment 
received, not based on randomized, if there are patients who received the 
wrong treatment. 
 
Per Protocol (PP): This population is defined as all subjects in the ITT who do 
not have any major protocol deviation. Major protocol deviations include 
major inclusion/exclusion deviations or other major protocol deviations, as 
will be defined in the statistical analysis plan.   
 
All efficacy analyses including the primary and key secondary endpoints will 
be primarily based on the ITT population. Analysis of the AT and PP 
populations will also be performed on the primary and key secondary 
endpoints as sensitivity analyses.  The safety analyses will be performed on 
the AT population using the as-treated principle, i.e., subjects will be analyzed 
based on the actual treatment they receive instead of the randomized 
treatment. 
 
10.3. 
Study Endpoints 
 
10.3.1. 
Primary Efficacy Endpoint 
 
The primary endpoint is the daily average fever burden (°C-hour). Each 
patient’s daily average fever burden will be calculated as the patient’s total 
fever burden divided by the total number of hours the patient was in the 
acute phase and then multiplied by 24 hours (Total fever burden/(total 
hour) ×24 hour).    Total fever burden is defined as the area under the 
temperature curve (AUC) during the acute observation period that is above 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
35 
37.9°C.  The acute phase is 336 hours or total hours from randomization to 
discharge/deemed medically ready for discharge from the intensive care 
unit, whichever comes first.   Although the Arctic Sun System records the 
patient’s temperature every minute, to compare the treatment groups 
consistently, calculation of fever burden will be based on as based on 
hourly temperature data. 
 
10.3.2. Key Secondary Efficacy Endpoint 
 
A key objective of this study is to determine whether fever prevention with 
the Arctic Sun 5000 Temperature Management System improves outcomes 
in moderate/severe brain-injured patients compared with standard care.  
Improved outcomes will be assessed using the endpoint of modified Rankin 
Scale (mRS) assessed at month 3 (6-category mRS outcome scores; mRS 
score 5 and 6 combined together). Note that mRS score 0-5 are directly 
collected at month 3; mRS will be scored 6 if subject died before the 3-
month visit. 
 
10.3.3.     Other Secondary Efficacy Endpoints 
 
Other secondary endpoints will include; but not be limited to: 
• 
Neurologic outcome measures 
o Modified Rankin Scale measured at 6- and 12-months 
o National Institutes of Health Stroke Scale measured at 3- and 
6-months 
o Barthel Index measured at 3- and 6-months 
o Glasgow Outcome Scale Extended measured at 3- and 6-
months 
o Montreal Cognitive Assessment measured at 3- and 6-months 
• 
Intensive Care Unit length of stay 
• 
ICU Delirium 
• 
Use of mechanical ventilation 
• 
Hospital length of stay 
• 
Mortality [7-day (or hospital discharge), 3-, 6-, and 12-month] 
 
 
10.3.4.    Safety Endpoints 
 
The safety endpoints will include major adverse events (MAEs), the overall 
incidence of adverse events (AEs), the incidence of infection, and the 
incidence of shivering.   
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
36 
10.4. Statistical Analysis  
 
10.4.1.  Primary Efficacy Endpoint Analysis 
 
The primary endpoint is daily average fever burden and will be evaluated by 
the following hypothesis: 
 
H0: The median of the daily average fever burden of FP treatment group is 
the same as that of SC treatment group. 
H1: The median of the daily average fever burden of FP treatment group is 
lower than that of SC treatment group. 
 
10.4.1.1. Primary Analysis 
 
The primary analysis will be conducted at the study interim.  Only 
when statistical significance is achieved at 0.05 level (i.e. p-value 
≤0.05), will the study continue to its full sample size to evaluate other 
study endpoints. Otherwise, the study will stop for futility. 
 
Since fever burden is not normally distributed, the daily average fever 
burden in the two treatment groups will be compared using a van 
Elteren test, which is a direct extension of the Wilcoxon rank-sum tests, 
with stratification on patient diagnosis (ICH, AIS or SAH).  Superiority 
of FP will be demonstrated if the p-value from the two-sided test is less 
than 0.05, and the median value of the FP group is less than SC group. 
 
10.4.1.2. Supportive Analysis 
 
A dichotomized variable (positive fever burden versus no fever burden) 
will be analyzed by Cochran-Mental-Haenszel (CMH) with patient 
diagnosis (IS, ICH, or SAH) as stratification factor.  
 
The daily average fever burden will also be analyzed using a two-
sample t-test (un-adjusted analysis). Exploratory analysis using an 
ANOVA model may also be conducted with other potential 
confounding factors included in the model. 
 
The total fever burden may also be analyzed similarly as the daily 
average fever burden. 
 
10.4.1.3. Poolability Analysis by Investigational Sites 
 
The sites with less than 10 randomized subjects will be sorted by site 
number and pooled by order to form one or more combined site(s) with 
at least 10 randomized subjects. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
37 
 
The poolability of the investigational sites on the primary endpoint will 
be tested using a ranked ANOVA model. The daily average fever 
burden will be ranked first and the ranks will be fitted with an ANOVA 
model with treatment, sites, and treatment and site interaction as 
factors. If the p-value for the interaction test is <0.15, it will be 
considered evidence of a statistically significant interaction effect, and 
additional analyses will be performed to explore the differences among 
the investigation sites to assess potential causes and whether or not they 
are clinically meaningful. 
 
10.4.1.4. Subgroup Analysis 
 
The primary endpoint will be explored in the following subgroups: 
  
• Gender 
  
• Age (<70, ≥70) 
  
• Patient diagnosis (ICH, AIS or SAH) 
• Injury severity (high or low, where high score includes 
NIHSS ≥ 17, ICH Score  ≥3, or WFNS ≥ 4 for IS, ICH, and 
SAH patients respectively, and low score includes NIHSS < 
17, ICH Score ≤2 , or WFNS ≤ 3 for IS, ICH, and SAH 
patients respectively) 
• Acetaminophen use (antipyretic) 
 
10.4.1.5. Handling of Missing Data 
 
Minimal missing data are expected for this endpoint. The analysis will 
be based on evaluable subjects. A multiple imputation method will be 
used to evaluate the missing data. 
 
10.4.2. Key Secondary Efficacy Endpoint Analysis 
 
The key secondary endpoint is the 6-category mRS outcome score and will be 
evaluated by the following hypothesis: 
 
H0: The median of mRS at month 3 in the FP treatment group is the same as 
that in the SC treatment group. 
H1: The median of mRS at month 3 in the FP treatment group is lower than 
that in the SC treatment group. 
 
10.4.2.1. Primary Analysis 
 
The analysis will be performed at the full planned sample size, or the 
re-estimated sample size, when all subjects finish the 3-month follow-
up visit. A “shift analysis” will be employed to analyze the 6-category 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
38 
mRS outcome scales. This is essentially a van Elteren test (a particular 
form of Cochran-Mantel-Haenszel (CMH) test), with stratification on 
patient diagnosis (ICH, IS or SAH).31  Superiority of  FP will be 
demonstrated if the p-value from the two-sided test is less than 0.05, 
and the median value of the FP group is less than SC group. 
 
10.4.2.2. Supportive Analysis 
 
Additionally, the 6-category mRS outcome scores will be analyzed 
using a proportional odds model that includes treatment and patient 
diagnosis (ICH, AIS or SAH) as factors in the model.  Odds ratio and 
its 95% confidence interval will be estimated and reported. 
 
The mRS will also be dichotomized as a binary outcome and analyzed 
using two definitions of success.  In the first analysis, scores of 0 to 3 
for success and scores of 4 to 6 for failure will be used; in the second, 
scores of 0 to 2 for success and 3 to 6 for failure will be used. The mRS 
success rate at month 3will be analyzed by the Cochran-Mantel-
Haenszel (CMH) test with stratification on patient diagnosis (ICH, IS or 
SAH). 
 
The mRS scores at 6-month will be analyzed similarly for the 6-
category scores and the dichotomized binary outcome. 
 
10.4.2.3. Poolability Analysis by Investigational Sites 
 
The sites with less than 10 randomized subjects will be sorted by site 
number and pooled by order to form one or more combined site(s) with 
at least 10 randomized subjects. 
 
The poolability of the investigational sites on the key secondary 
endpoints will be tested using a logistic regression model using the full 
6-category range of the mRS as response with treatment, sites, and 
treatment and site interaction as factors. If the p-value for the 
interaction test is <0.15, it will be considered evidence of a statistically 
significant interaction effect, and additional analyses will be performed 
to explore the differences among the investigation sites to assess 
potential causes and whether or not they are clinically meaningful. 
 
10.4.2.4. Subgroup Analysis 
 
The key secondary endpoint will be explored in the following 
subgroups: 
• Gender 
• Age (<70, ≥70) 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
39 
• Patient diagnosis (ICH, AIS or SAH) 
• Injury severity (high or low, where high score includes NIHSS 
≥ 17, ICH Score ≥3, or WFNS ≥ 4 for IS, ICH, and SAH 
patients respectively, and low score includes NIHSS < 17, ICH 
Score ≤2, or WFNS ≤ 3 for IS, ICH, and SAH patients 
respectively) 
• Acetaminophen use (antipyretic) 
 
10.4.2.5. Handling of Missing Data 
 
Study endpoints may be missing due to withdrawal of consent, 
investigator’s decision, or lost to follow-up. As long as the missing data 
is unrelated to the study intervention and the observed and unobserved 
data, limiting the analysis to those subjects who contribute endpoints 
produces unbiased estimates of the event rates. 
 
The reason for missing data for all subjects will be reported. In 
addition, the worst-case analysis (if in FP then score of 6; if in SC then 
score of 0 will be assigned to the missing mRS) and tipping point 
analysis will be performed to assess the sensitivity of the main analysis. 
A multiple imputation method will be used to evaluate the missing data. 
 
10.4.3. Secondary Efficacy Endpoint Analysis 
 
For analysis of binary variables in secondary endpoints, the two-group chi-
square test will be used.  For analysis of continuous variables in secondary 
endpoints, the two-sample t-test will be used.  For time to event variables, 
Kaplan-Meier survival analysis will be used. 
 
10.4.4. Safety Endpoint Analysis 
 
Summaries of all AEs by treatment arm will include: 
• The number (n) and percentage (%) of patients with at least 1 event by  
  System Organ Class (SOC) and Preferred Terms (PT) 
• Event by intensity (severe, moderate, mild), presented by SOC and PT 
• Event by relationship to treatment or procedure (related, not related),  
  presented by SOC and PT 
• Serious adverse event presented by SOC and PT 
 
MAE and incidence of shivering will be listed and summarized by treatment 
arm. 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
40 
10.4.5. Multiplicity Control 
 
The primary endpoint and the key secondary endpoint will be tested in 
hierarchical fashion according to the following sequence. 
 
1. The primary endpoint, the daily average fever burden, will be tested at 
two-sided alpha=0.05 when half of the planned sample size complete the 
3-month assessment. 
 
2.  Conditional on success of the primary endpoint, the key secondary 
endpoint, the mRS scores, will be tested at two-sided alpha=0.05 at the 
full planned sample size or the re-estimated sample size. 
 
All other secondary endpoints will be for exploratory purposes and not 
adjusted for multiplicity and reported with unadjusted nominal p-values. 
 
10.5. Interim Analysis 
 
10.5.1. Administration of the Interim Analysis 
 
An independent data monitoring committee (DMC) will be assembled which 
will be composed of medical experts with experience in treating subjects with 
stroke and a statistician, all of whom are not otherwise involved in any other 
aspects of the conduct of the study. The DMC will review safety data on an 
ongoing basis including adverse events. During the course of the study, the 
DMC will review the efficacy data in accordance with the guidelines for the 
pre-planned interim analyses. An independent statistician will provide data 
analyses support to DMC.  
 
The interim analysis will be performed when half of the planned sample size 
subjects have completed the 3-month visit. A two-step decision will be made 
at the interim based on the following decision criteria: 
  
1)  futility decision based on the primary endpoint; and, 
2)  futility or sample size increase decision on the key secondary endpoint.  
 
The study can only stop because of futility; there will be no stopping of the 
study due to strong result in effectiveness. If the result of the primary endpoint 
is a success, an interim study report will be produced for regulatory 
submission. The study will continue unless futility is shown for the key 
secondary endpoint.  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
41 
 
For the analysis of the primary endpoint of fever burden, the primary analysis 
is at the interim, which will be performed by the independent statistician. The 
statistician will also work with a regulatory affairs specialist (independent of 
clinical study team) to produce an interim study report for regulatory 
submission. The interim study report will not include analysis of the 
secondary endpoints. All of the interim results will be blinded to any 
personnel at the investigational sites and any Bard personnel who are involved 
with the conduct of the study. 
 
 
10.5.2. Statistical Approach for Control of Alpha and other Consideration 
 
It is well known that adaptive design with sample size re-estimation can 
increase the power of the study but may cause inflation of type 1 error rate. 
On the other hand, futility analysis may decrease the power of the study and 
reduce the type 1 error rate. The proposed study design includes both features 
in the interim analysis for the key secondary endpoint of mRS. It is important 
to evaluate the impact on study power and type 1 error rate.  
 
The rules of the two-step decision to be made at the interim are described 
below (See Figure 5 for illustration): 
 
1. If the primary analysis of fever burden is not successful (p-value > 
0.05), then the study will stop for futility; otherwise, an interim study 
report will be produced without any data for the key secondary 
endpoint of mRS , and the study will continue or stop based on the 
step 2 decision.   
 
2. If the primary analysis of fever burden is successful, the futility and 
sample size re-estimation decision will be evaluated based on the 
dichotomized binary mRS outcome (scores of 0 to 3 for success and 
scores of 4 to 6 for failure) using  the conditional power (CP) 
calculated under the current trend: If CP is less than 5%, the study will 
stop for futility; if the CP is between 5% and 30% or greater than 85%, 
the study will be finished at planned sample size (1000 subjects); if the 
CP is between 30% and 85%, the sample size will be re-estimated 
based on the observed effect at IA (current trend). If the re-estimated 
sample size is greater than 2000 evaluable subjects, the final sample 
size will be capped at 2000 evaluable subjects. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
42 
Figure 5.  Proposed Interim Analysis Procedure 
                         
 
Note: CP is the conditional power under current trend on the key secondary 
binary endpoint (mRS scores of 0 to 3 for success and scores of 4 to 6 for 
failure). 
 
 
𝐶𝑃θ̂ = 1 −Φ (
𝑧𝛼/2−𝐸𝜃̂{𝐵(1)|𝐵(𝑡)=𝑏}
√1−𝑡
) = 1 −Φ (
𝑧𝛼/2−𝜃̂
√1−𝑡) 
 
Where the B-value and 𝜃̂ are defined following Proschan, et al:32 assume the 
success rate for the FP is 𝑝𝑇, and for the SC is 𝑝𝐶. At the interim, treatment 
difference  𝛿̂1 = 𝑝̂𝑇−𝑝̂𝐶, with the standard error 𝑆𝐸𝑝̂𝑇−𝑝̂𝐶= {𝑝̂𝑇(1 −
𝑝̂𝑇)/𝑁𝑇+𝑝̂𝐶(1−𝑝̂𝐶)/𝑁𝐶}1/2. Then test statistics (𝑡) =
𝑝̂𝑇−𝑝̂𝐶
𝑆𝐸𝑝̂𝑇−𝑝̂𝐶 , and the empirical 
estimate 𝜃̂ =
𝐵(𝑡)
𝑡
=
𝑍(𝑡)
√𝑡 (t=1/2). 
 
Interim Analysis after the 
first 588 treated subjects 
completed 3-month 
assessment/discontinued 
CP<5% 
Stop for 
futility 
30%≤CP<85% 
Sample size re-
estimation and 
increased up to 
2000 subjects 
5%≤CP<30% 
or CP≥85% 
Continue the 
study to 
planned 1176 
subjects 
Fever burden 
success 
(p-value ≤ 0.05) 
Fever burden not 
successful 
 (p-value > 0.05) 
Stop for 
futility 
IA study 
report 
without mRS 
Step I 
Step II 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
43 
A simulation study was performed to evaluate the operating characteristics. 
The study was simulated under null hypothesis (𝑝𝐶= 40%, and 𝑝𝑇= 40%) and 
under alternative hypothesis (𝑝𝐶= 40%, and 𝑝𝑇= 50%), respectively, with 
1000 subjects (500 in treatment arm and 500 in control arm). At the interim, 
the CP was calculated, and the decision was made based on Figure 5. For each 
simulation, at the end of the study, the two treatment arms were compared by 
a chi-square test at two-sided α=0.05. Based on 10000 simulations, the overall 
type 1 error for this study is 2.1%, which is well under control (<5%), and the 
overall study power is 90.8%. 
 
Trial operating characteristics 
 
Futility at IA 
Probability of Sample 
Size increased 
Reject Null 
Under Null Hypothesis  
(𝑝𝐶= 40%, and 𝑝𝑇= 40%) 
73.3% 
9.6% 
2.1% 
Under Alternative Hypothesis  
(𝑝𝐶= 40%, and 𝑝𝑇= 50%) 
4.8% 
24.4% 
90.8% 
 
 
11. CASE REPORT FORMS  
 
The Investigator is responsible for ensuring the accuracy and completeness of all study 
documentation.  All clinical study data will be recorded in the CRFs provided to the 
investigational site.  
 
12. ADMINISTRATIVE REQUIREMENTS 
 
This study will be conducted in accordance with Good Clinical Practice (GCP); the 
principles of the Declaration of Helsinki; applicable requirements of the USA Code of 
Federal Regulations (CFR); applicable requirements of the European Union (EU) 
Clinical Trial Directive (CTD) and local regulations if the study is conducted in the EU; 
and any specific national, regional and local regulations if the study is conducted 
elsewhere.  
 
12.1. 
Publication Policy 
 
A Publications Committee will be established to define and manage publications 
emanating from this study. 
 
12.2. 
Investigator Selection 
 
The Investigator must be of good standing as an Investigator and knowledgeable in 
relevant areas of clinical research to ensure adherence to the requirements of the 
protocol, including the protection of human subjects.  Other site personnel must 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
44 
have appropriate research experience and infrastructure to ensure adherence to the 
protocol and enrollment of sufficient numbers of evaluable subjects.   
 
The curriculum vitae (CV) of the Investigator will be maintained in the Sponsor 
files as documentation of previous medical training.  Federal databases will be 
searched to ensure that the Investigator and/or the site are not prohibited from 
engaging in federally Sponsored clinical research. 
 
The Principal Investigator will sign the signature page of this protocol, agreeing to 
comply with all applicable government regulations and the requirements of this 
study. 
 
12.3. 
Investigator Training 
 
Prior to the start of the study, up to two (2) investigators from each participating 
site will undergo a mandatory study training that will be designed to cover aspects 
of the use of the study devices and the requirements of this protocol.  The training 
is designed to ensure safe and effective use of the study devices and enhance 
protocol adherence. 
12.4. 
Regulatory and Ethical Considerations 
 
The Sponsor will obtain favorable opinion/approval to conduct the study from the 
appropriate regulatory agency in accordance with any applicable country-specific 
regulatory requirements prior to a site initiating the study in that country.   
 
12.4.1. Institutional Review Board or Ethics Committee Approval  
 
Before commencement of the study, the Investigator must provide Sponsor 
with written documentation of IRB/EC approval.  (The sponsor may obtain 
approval from a leading or central IRB/EC in certain countries, depending on 
local requirements.)  This approval must refer to the Informed Consent Form 
and the study by both the title and the protocol number assigned by Sponsor.  
The Investigator, if a member of the IRB/EC, is not to participate in the 
approval decision for this study.  This non-participation should be noted in the 
approval letter, if possible.  Any additional requirements of the IRB/EC or 
national, regional or local regulations will be followed. 
 
No device supplies, if applicable, will be shipped to the Investigator until the 
IRB/EC approval has been supplied to Sponsor and all relevant agreements 
have been executed. 
 
If required by national, regional or local regulations, the IRB/EC must give 
written renewal of the original approval at least annually to continue the 
study.  A copy of the written renewal must be provided to Sponsor. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
45 
 
12.4.2. Informed Consent 
 
Prior to screening or the procedure, the Investigator must explain to each 
subject (or the subject’s legally authorized representative) the nature of the 
study, its purpose, expected duration, and the benefits and risks of study 
participation.  After this explanation and before entering screening or the 
study, the subject (or legally authorized representative) must voluntarily sign 
and date the appropriate IRB/EC-approved Informed Consent form.  
 
12.5. 
Protocol Adherence and Amendment  
 
The study will be conducted as described in this protocol.  Investigators are not 
permitted to deviate from this protocol except to protect the patient’s rights, safety 
or well-being.  Any deviations from this protocol must be documented by the 
Investigator.  If an emergency situation arises in which the rights, safety or well-
being of a subject may require immediate alternative intervention, the Investigator 
should act in the best interests of the subject.  Sponsor and the site’s IRB/EC must 
be notified immediately if this occurs.  This should be followed with written 
confirmation that describes the emergency action and outcomes to Sponsor and the 
IRB/EC within 10 working days.  Protocol deviations will be reviewed during 
monitoring visits; as appropriate, investigators will be required to identify 
corrective and preventive actions to prevent further deviations.  An investigator 
may be disqualified from the study for repeated and/or egregious protocol 
deviations. 
 
This protocol may be amended as necessary by the Sponsor.  Any protocol 
amendments will be documented via an incremented version of this protocol (with 
the relevant revision history) and a “was/is” comparison table to highlight the 
protocol changes.  Amendments to the protocol must undergo the same approval 
process by the Sponsor, investigators, ethics committees and regulatory authorities 
as the original protocol. 
 
 
12.6. 
Data Collection 
 
The Investigator is responsible for completely and accurately recording study data 
in the appropriate sections of the CRFs provided by Sponsor.  The CRFs must be 
signed by the Investigator or by his/her authorized person as designated in a note to 
file. 
 
The monitor will ensure the quality of data recording at each investigational site by 
comparison to supporting source documents during periodic site visits.  Adherence 
to proper recording of information as well as assuring that corrections are being 
made will also be addressed during these periodic visits. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
46 
 
The site is responsible for downloading data from the Arctic Sun 5000 console and 
uploading to a site-specific email address. Data files should be uploaded as soon as 
possible after the case is completed. 
 
12.7. 
Measures to Control Bias 
 
For this study, several measures are being used to control or reduce potential bias.  
Those measures include, but are not limited to the following: 
 
o Subject randomization; 
o Personnel performing follow-up neurologic assessments at 3-, 6-, and 12-
month visits blinded to treatment assignment; 
o Statistical analysis plan; 
o Use of an independent statistician to conduct the planned interim analysis; 
and, 
o Use of a Data Monitoring Committee for the planned interim analysis. 
 
12.8. 
Communications with the Sponsor 
 
Although the Investigator and his/her staff may have contact with other key 
individuals at Sponsor throughout the course of the study, all communications 
regarding conduct of the study must be channeled through the assigned clinical 
research associate or the project manager designated on the cover page of this 
protocol. 
 
12.9. 
Required Documentation  
 
At a minimum, the following documentation must be received by the Sponsor prior 
to study commencement:  
• 
CVs for the principal Investigator and sub-Investigators;  
• 
Signed Financial Disclosure Statement; 
• 
Signed Clinical Study Agreement;  
• 
Fully executed Confidentiality/Nondisclosure Agreement for Investigator 
and Sub-Investigators; 
• 
Signed “Agreement to Participate” (page ii of this protocol);  
• 
Written approval from the IRB/EC of both the protocol and informed 
consent form;   
• 
IRB/EC Assurance of Compliance Form or equivalent. 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
47 
13. SITE MONITORING 
 
The study monitors are designated as agents of the Sponsor and are assigned to oversee 
the conduct and progress of the study and to be the principal communication link 
between Sponsor and Investigator.   
 
The study monitors will be involved in Investigator selection and training, assurance of 
IRB/EC approvals, and periodic on-site inspection and monitoring of sites and records, 
to ensure continued compliance with the protocol and adequacy of the Investigator and 
the facility to carry out the study.  In addition, the monitor will verify that the device is 
being used in accordance with the protocol.   
 
The monitor will perform several types of site visits during the course of the study.  In 
all cases, the study monitor will provide a written summary of the visit, including 
necessary follow-up items, to the Investigator and Sponsor. 
 
13.1. 
Study Initiation Visit 
 
Before the study begins, the study monitor will visit the site.  The purpose of this 
visit is to review with the Investigator and staff the provisions and proper conduct 
of the clinical evaluation.  This includes a detailed review of the protocol and CRFs 
with instructions as to their completion, as well as reviewing regulations pertaining 
to the conduct of the clinical study.  Arrangements for timely and accurate reporting 
of clinical data and relevant medical events will be established as well as ensuring 
safe and secure storage for the study devices.  Additionally, device training will be 
provided to the research staff as well as bedside nurses caring for study subjects.   
 
The study monitor will: 
 
• 
confirm that the ICF to be used is the one approved by the IRB/EC  
• 
verify that all necessary documents are on file at the site; and 
• 
confirm that there are provisions to continue and maintain all documents and 
records throughout the study as required by good clinical practice regulations. 
 
13.2. 
Ongoing Monitoring Visits  
 
The study monitor will maintain personal contact with the Investigator and staff 
throughout the study by telephone, e-mail, fax, mail, and on-site visits.  Monitoring 
will begin after the first subjects are enrolled and continue until the study is 
completed.  This monitoring will assure continued protocol compliance, adequate 
subject enrollment, accurate data reporting (including the comparison of CRFs with 
subject records), device accountability, and continued IRB/EC acceptance of the 
study.  The study monitor will evaluate and summarize the results of each visit in 
written reports, identifying any ongoing data problems with any study site and 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
48 
specifying recommendations for resolution of noted deficiencies.  A formal 
monitoring plan will describe the planned extent of source data verification. 
 
13.3. 
Final Monitoring Visit 
 
At the completion of the study, the study monitor will conduct a final on-site visit.  
The purpose of this visit is to collect all outstanding study data documents, confirm 
that the Investigator’s files are accurate and complete, review the record retention 
requirements with the Investigator, and assure that all applicable requirements for 
closure of the study are met.  The actions and observations made at this visit will 
be recorded and filed. 
 
 
14. TERMINATION OF STUDY  
 
Sponsor reserves the right to suspend enrollment or terminate the study at any time as 
set forth in the Clinical Study Agreement.  Written notice will be submitted to the 
Investigator in advance of such termination. 
 
Sponsor may suspend enrollment or terminate the study at a specific site for reasons 
including, but not limited to, inadequate data collection, low subject enrollment rate, 
achievement of the total enrollment, or non-compliance with the protocol or other 
clinical research requirements. 
 
Sponsor may request that site personnel undergo training on the protocol and clinical 
research requirements during the study. 
 
15. REPORTING REQUIREMENTS  
 
The Investigator must promptly report to Sponsor any withdrawal of Institutional 
Review Board (IRB) or Ethics Committee (EC) approval at the site.  Additional 
reporting requirements of the Investigator include: 
 
• Reporting to the IRB/EC of all Informed Consent violations. 
• Reporting to Sponsor of any SAEs, SADEs USADEs or device deficiencies that 
could have led to a SADE, as outlined in this protocol. 
 
16. RECORD RETENTION  
 
The Investigator shall retain all study records for a period of at least 2 years after the 
date on which the investigation is terminated or completed or as required by local 
laws/regulations, whichever is longer.  All Investigators will be notified by the Sponsor 
when the record retention period has ended.  The Investigator may withdraw from the 
responsibility to maintain records for the period required and transfer custody of the 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
49 
records to any other person who will accept responsibility for retaining them.  Notice of 
a transfer shall be given to Sponsor no later than 10 working days after transfer occurs. 
 
17. AUDIT/INSPECTIONS 
 
The investigational sites may also be subject to quality assurance audit by personnel of 
the Sponsor (and its affiliates) and the Sponsor’s study contractor personnel, as well as 
by IRB/ECs and regulatory authorities.  It is important that the Principal Investigator and 
the relevant investigational site personnel are available during the audits and that 
sufficient time is devoted to the process.   
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
50 
18. REFERENCES 
 
1. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic 
hypothermia to improve the neurologic outcome after cardiac arrest. NEJM. 
2002;346(8):549-556. 
2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-
of-hospital cardiac arrest with induced hypothermia. NEJM. 2002;346(8):557-
563. 
3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 
33 degrees C versus 36 degrees C after cardiac arrest. NEJM. 
2013;369(23):2197-2206. 
4. Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic 
hypothermia after cardiac arrest. Pharmacotherapy. 2008;28(1):102-111. 
5. Greer DM, Rosenthal ES, Wu O. Neuroprognostication of hypoxic-ischaemic coma 
in the therapeutic hypothermia era. Nature reviews; Neurology. 2014;10(4):190-203. 
6. Rincon F, Rossenwasser RH, Dumont A. The epidemiology of admissions of 
nontraumatic subarachnoid hemorrhage in the United States. Neurosurgery. 
2013;73(2):217-22. 
7. Rincon F, Mayer SA. The epidemiology of intracerebral hemorrhage in the United 
States from 1979 to 2008. Neurocrit Care. 2013;19(1):95-102. 
8. Marion DW. Controlled normothermia in neurologic intensive care. Crit Care Med. 
2004;32(2 Suppl):S43-5 
9. Kammersgaard LP, Jorgensen HS, Rungby JA, et al. Admission body temperature 
predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. 
Stroke. 2002;33(7):1759-1762. 
10. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: 
relation to stroke severity, infarct size, mortality, and outcome. Lancet. 
1996;347(8999):422-425. 
11. Prasad K, Krishnan PR. Fever is associated with doubling of odds of short-term 
mortality in ischemic stroke: an updated meta-analysis. Acta Neurologica 
Scandinavica. 2010;122(6):404-8. 
12. Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical complications 
on outcome after subarachnoid hemorrhage. Crit Care Med. 2006;34(3):617-623. 
13. Schwarz S, Hafner K, Aschoff A, Schwab S. Incidence and prognostic 
significance of fever following intracerebral hemorrhage. Neurology. 
2000;54(2):354-361. 
14. Leira R, Davalos A, Silva Y, et al. Early neurologic deterioration in intracerebral 
hemorrhage: predictors and associated factors. Neurology. 2004;63(3):461-467. 
15. Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman GC. Impact of fever on 
outcome in patients with stroke and neurologic injury: a comprehensive meta-
analysis. Stroke. 2008;39(11):3029-3035. 
16. Arboix A. Fever after intracerebral hemorrhage. Neurology India. 
2005;53(2):206. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
51 
17. Broessner G, Beer R, Lackner P, et al.. Prophylactic, Endovascularly Based, 
Long-Term Normothermia in ICU Patients With Severe Cerebrovascular 
Disease: Bicenter Prospective, Randomized Trial. Stroke. 2009;40:e657-e665. 
18. Fischer M, Lackner P, Beer R, Helbok R, et al.. Cooling Activity is Associated 
with Neurological Outcome in Patients with Severe Cerebrovascular Disease 
Undergoing Endovascular Temperature Control. Neurocrit Care. 
2015;23(2):205-9. 
19. Mayer SA, Kowalski RG, Presciutti M, Ostapkovich ND, et al.. Clinical trial of a 
novel surface cooling system for fever control in neurocritical care patients. Crit 
Care Med. 2004;32(12):2508-15. 
20. Badjatia N, Fernandez L, Schmidt JM, Lee K, et al.. Impact of Induced 
Normothermia on Outcome After Subarachnoid Hemorrhage: A Case-Control 
Study. Neurosurgery. 2010;66(4):696-700. 
21. Bohman LE, Levine JM. Fever and therapeutic normothermia in severe brain 
injury: an update. Curr Opin Crit Care. 2014;20(2):182-8. 
22. Wilson JTL, Hareendran A, Grant M, et al. Improving the Assessment of 
Outcomes in Stroke; Use of a Structured Interview to Assign Grades on the 
Modified Rankin Scale. Stroke. 2002;33:2243-2246. 
23. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A 
practical scale. Lancet. 1974;132(7872):81-84. 
24. The Internet Stroke Center.  http://www.strokecenter.org/professionals/stroke-
diagnosis/stroke-assessment-scales/  Accessed March 20, 2015. 
25. Drake CG, Hunt WE, Sano K, Kassell N, Teasdale G, Pertuiset B, et al. Report 
of World Federation of Neurological Surgeons Committee on a Universal 
Subarachnoid Hemorrhage Grading Scale. J Neurosurg. 1988 Jun. 68(6):985-  
26. Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The 
ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 
2001 Apr;32(4):891-7 
27. Brummel NE, Vasilevskis EE, Han JH, et al. Implementing Delirium Screening 
in the ICU. Crit Care Med. 2013;41(9):2196-2208. 
28. Mahoney FI, Barthel D. Functional evaluation: the Barthel Index. Maryland 
State Med J. 1965;14:56-61. 
29. Wilson JTL, Pettigrew LEL, Teasdale GM. Structured Interviews for the 
Glasgow Outcome Scale and the Extended Glasgow Outcome Scale: Guidelines 
for Their Use. J Neurotrauma. 1998;15(8):573-585. 
30. The Montreal Cognitive Assessment. http://www.mocatest.org/wp-
content/uploads/2015/tests-instructions/MoCA-Test-English_7_1.pdf  Accessed 
November 20, 2015. 
31. Savitz SI, Lew R, Bluhmki E, Hacke W, Fisher M. Shift analysis versus 
dichotomization of the modified Rankin Scale outcome scores in the NINDS and 
ECASS-II trials. Stroke. 2007 Dec;38(12):3205-12. 
32. Proschan MA, Lan KKG, & Wittes JT. Statistical Monitoring of Clinical Trials: 
A Unified Approach. Springer, New York, 2006 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
52 
19. APPENDICES 
 
19.1. 
Modified Rankin Scale 
 
Modified Rankin Scale 
Structured Interview 
5=Severe disability: bedridden, 
incontinent, and requiring 
constant nursing care and attention
 
 
5=Severe disability; someone needs to be 
available at all times; care may be 
provided by either a trained or an 
untrained caregiver. Question: Does the 
person require constant care? 
4=Moderately severe disability: 
unable to walk without assistance, 
and unable to attend to own bodily 
needs without assistance. 
4=Moderately severe disability; need for 
assistance with some basic ADL, but not 
requiring constant care. Question: Is 
assistance essential for eating, using the 
toilet, daily hygiene, or walking? 
3=Moderate disability; requiring 
some help, but able to walk without 
assistance. 
3=Moderate disability; need for assistance 
with some instrumental ADL but not 
basic ADL. Question: Is assistance 
essential for preparing a simple meal, 
doing household chores, looking after 
money, shopping, or traveling locally? 
2=Slight disability; unable to carry 
out all previous activities but able 
to look after own affairs without 
assistance. 
2=Slight disability; limitations in 
participation in usual social roles, but 
independent for ADL. Questions: Has 
there been a change in the person’s ability 
to work or look after others if these were 
roles before stroke? Has there been a 
change in the person’s ability to 
participate in previous social and leisure 
activities? Has the person had problems 
with relationships or become isolated? 
1=No significant disability despite 
symptoms; able to carry out all 
usual duties and activities. 
1=No significant disability; symptoms 
present but not other limitations. 
Question: Does the person have difficulty 
reading or writing, difficulty speaking or 
finding the right word, problems with 
balance or coordination, visual problems, 
numbness (face, arms, legs, hands, feet), 
loss of movement (face, arms, legs, hands, 
feet), difficulty with swallowing, or other 
symptom resulting from stroke? 
0=No symptoms at all. 
0=No symptoms at all; no limitations and 
no symptoms. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
53 
19.2. 
Glasgow Coma Scale 
 
ACTIVITY 
SCALE 
SCORE 
Eye Opening 
 Non 
 To pain 
 To speech 
 Spontaneous 
 
1 = Even to supra-orbital pressure 
2 = Pain from sternum/limb/supra-orbital 
pressure 
3 = Non-specific response, not necessarily to 
command 
4 = Eyes open, not necessarily aware 
 
Motor Response 
 None 
 Extension 
 
 Flexor Response 
 
 Withdrawal 
 Localizes pain 
 
 Obeys commands 
 
1 = To any pain; limbs remain flaccid 
2 = Shoulder adducted and shoulder and 
forearm internally rotated 
3 = Withdrawal response or assumption of 
hemiplegic posture 
4 = Arm withdraws to pain, shoulder abducts 
5 = Arm attempts to remove supra-orbital/chest 
pressure 
6 = Follows simple commands 
 
Verbal Response 
 None 
 Incomprehensible 
 Inappropriate 
 Confused 
 Oriented 
 
1 = No verbalization of any type 
2 = Moans/groans, no speech 
3 = Intelligible, no sustained sentences 
4 = Converses but confused, disoriented 
5 = Converses and oriented 
 
TOTAL (3-15) 
 
 
 
 
Predicted Verbal Glasgow Coma Scale for Intubated Patients 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
54 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
55 
19.3. 
National Institutes of Health Stroke Scale 
 
Instructions 
Scale Definition 
Score 
1a. Level of Consciousness: The investigator 
must choose a response if a full evaluation is 
prevented by such obstacles as an 
endotracheal tube, language barrier, 
orotracheal trauma/bandages. A 3 is scored 
only if the patient makes no movement (other 
than reflexive posturing) in response to 
noxious stimulation. 
0 = Alert; keenly responsive. 
1 = Not alert; but arousable by minor 
stimulation to obey, answer, or respond. 
2 = Not alert; requires repeated stimulation 
to attend, or is obtunded and requires 
strong or painful stimulation to make 
movements (not stereotyped). 
3 = Responds only with reflex motor or 
autonomic effects or totally unresponsive, 
flaccid, and areflexic. 
 
1b. LOC Questions: The patient is asked the 
month and his/her age. The answer must be 
correct - there is no partial credit for being 
close. Aphasic and stuporous patients who do 
not comprehend the questions will score 2. 
Patients unable to speak because of 
endotracheal intubation, orotracheal trauma, 
severe dysarthria from any cause, language 
barrier, or any other problem not secondary to 
aphasia are given a 1. It is important that only 
the initial answer be graded and that the 
examiner not "help" the patient with verbal or 
non-verbal cues. 
0 = Answers both questions correctly. 
1 = Answers one question correctly. 
2 = Answers neither question correctly. 
 
1c. LOC Commands: The patient is asked to 
open and close the eyes and then to grip and 
release the non-paretic hand. Substitute 
another one step command if the hands cannot 
be used. Credit is given if an unequivocal 
attempt is made but not completed due to 
weakness. If the patient does not respond to 
command, the task should be demonstrated to 
him or her (pantomime), and the result scored 
(i.e., follows none, one or two commands). 
Patients with trauma, amputation, or other 
physical impediments should be given 
suitable one-step commands. Only the first 
attempt is scored. 
0 = Performs both tasks correctly. 
1 = Performs one task correctly. 
2 = Performs neither task correctly. 
 
2. Best Gaze: Only horizontal eye movements 
will be tested. Voluntary or reflexive 
(oculocephalic) eye movements will be 
scored, but caloric testing is not done. If the 
patient has a conjugate deviation of the eyes 
that can be overcome by voluntary or 
reflexive activity, the score will be 1. If a 
patient has an isolated peripheral nerve 
paresis (CN III, IV or VI), score a 1. Gaze is 
0 = Normal. 
1 = Partial gaze palsy; gaze is abnormal in 
one or both eyes, but forced deviation or 
total gaze paresis is not present. 
2 = Forced deviation, or total gaze paresis 
not overcome by the oculocephalic 
maneuver. 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
56 
testable in all aphasic patients. Patients with 
ocular trauma, bandages, pre-existing 
blindness, or other disorder of visual acuity or 
fields should be tested with reflexive 
movements, and a choice made by the 
investigator. Establishing eye contact and then 
moving about the patient from side to side 
will occasionally clarify the presence of a 
partial gaze palsy. 
3. Visual: Visual fields (upper and lower 
quadrants) are tested by confrontation, using 
finger counting or visual threat, as 
appropriate. Patients may be encouraged, but 
if they look at the side of the moving fingers 
appropriately, this can be scored as normal. If 
there is unilateral blindness or enucleation, 
visual fields in the remaining eye are scored. 
Score 1 only if a clear-cut asymmetry, 
including quadrantanopia, is found. If patient 
is blind from any cause, score 3. Double 
simultaneous stimulation is performed at this 
point. If there is extinction, patient receives a 
1, and the results are used to respond to item 
11. 
0 = No visual loss.  
1 = Partial hemianopia.  
2 = Complete hemianopia.  
3 = Bilateral hemianopia (blind including 
cortical blindness). 
 
4. Facial Palsy: Ask – or use pantomime to 
encourage – the patient to show teeth or raise 
eyebrows and close eyes. Score symmetry of 
grimace in response to noxious stimuli in the 
poorly responsive or non-comprehending 
patient. If facial trauma/bandages, orotracheal 
tube, tape or other physical barriers obscure 
the face, these should be removed to the 
extent possible. 
0 = Normal symmetrical movements.  
1 = Minor paralysis (flattened nasolabial 
fold, asymmetry on smiling).  
2 = Partial paralysis (total or near-total 
paralysis of lower face).  
3 = Complete paralysis of one or both 
sides (absence of facial movement in the 
upper and lower face). 
 
5. Motor Arm: The limb is placed in the 
appropriate position: extend the arms (palms 
down) 90 degrees (if sitting) or 45 degrees (if 
supine). Drift is scored if the arm falls before 
10 seconds. The aphasic patient is encouraged 
using urgency in the voice and pantomime, 
but not noxious stimulation. Each limb is 
tested in turn, beginning with the non-paretic 
arm. Only in the case of amputation or joint 
fusion at the shoulder, the examiner should 
record the score as untestable (UN), and 
clearly write the explanation for this choice. 
0 = No drift; limb holds 90 (or 45) degrees 
for full 10 seconds.  
1 = Drift; limb holds 90 (or 45) degrees, 
but drifts down before full 10 seconds; 
does not hit bed or other support.  
2 = Some effort against gravity; limb 
cannot get to or maintain (if cued) 90 (or 
45) degrees, drifts down to bed, but has 
some effort against gravity.  
3 = No effort against gravity; limb falls.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
_____________________  
5a. Left Arm  
5b. Right Arm 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
57 
6. Motor Leg: The limb is placed in the 
appropriate position: hold the leg at 30 
degrees (always tested supine). Drift is scored 
if the leg falls before 5 seconds. The aphasic 
patient is encouraged using urgency in the 
voice and pantomime, but not noxious 
stimulation. Each limb is tested in turn, 
beginning with the non-paretic leg. Only in 
the case of amputation or joint fusion at the 
hip, the examiner should record the score as 
untestable (UN), and clearly write the 
explanation for this choice. 
0 = No drift; leg holds 30-degree position 
for full 5 seconds.  
1 = Drift; leg falls by the end of the 5-
second period but does not hit bed.  
2 = Some effort against gravity; leg falls to 
bed by 5 seconds, but has some effort 
against gravity.  
3 = No effort against gravity; leg falls to 
bed immediately.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
________________  
6a. Left Leg  
 
6b. Right Leg 
 
7. Limb Ataxia: This item is aimed at finding 
evidence of a unilateral cerebellar lesion. Test 
with eyes open. In case of visual defect, 
ensure testing is done in intact visual field. 
The finger-nose-finger and heel-shin tests are 
performed on both sides, and ataxia is scored 
only if present out of proportion to weakness. 
Ataxia is absent in the patient who cannot 
understand or is paralyzed. Only in the case of 
amputation or joint fusion, the examiner 
should record the score as untestable (UN), 
and clearly write the explanation for this 
choice. In case of blindness, test by having the 
patient touch nose from extended arm 
position. 
0 = Absent.  
1 = Present in one limb.  
2 = Present in two limbs.  
UN = Amputation or joint fusion, explain: 
________________ 
 
8. Sensory: Sensation or grimace to pinprick 
when tested, or withdrawal from noxious 
stimulus in the obtunded or aphasic patient. 
Only sensory loss attributed to stroke is 
scored as abnormal and the examiner should 
test as many body areas (arms [not hands], 
legs, trunk, face) as needed to accurately 
check for hemisensory loss. A score of 2, 
“severe or total sensory loss,” should only be 
given when a severe or total loss of sensation 
can be clearly demonstrated. Stuporous and 
aphasic patients will, therefore, probably 
score 1 or 0. The patient with brainstem stroke 
who has bilateral loss of sensation is scored 2. 
If the patient does not respond and is 
quadriplegic, score 2. Patients in a coma (item 
1a=3) are automatically given a 2 on this item. 
0 = Normal; no sensory loss.  
1 = Mild-to-moderate sensory loss; patient 
feels pinprick is less sharp or is dull on the 
affected side; or there is a loss of 
superficial pain with pinprick, but patient 
is aware of being touched.  
2 = Severe to total sensory loss; patient is 
not aware of being touched in the face, 
arm, and leg. 
 
9. Best Language: For this scale item, the 
patient is asked to describe what is happening 
in the attached picture, to name the items on 
0 = No aphasia; normal.  
1 = Mild-to-moderate aphasia; some 
obvious loss of fluency or facility of 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
58 
the attached naming sheet and to read from 
the attached list of sentences. Comprehension 
is judged from responses here, as well as to all 
of the commands in the preceding general 
neurological exam. If visual loss interferes 
with the tests, ask the patient to identify 
objects placed in the hand, repeat, and 
produce speech. The intubated patient should 
be asked to write. The patient in a coma (item 
1a=3) will automatically score 3 on this item. 
The examiner must choose a score for the 
patient with stupor or limited cooperation, but 
a score of 3 should be used only if the patient 
is mute and follows no one-step commands. 
comprehension, without significant 
limitation on ideas expressed or form of 
expression. Reduction of speech and/or 
comprehension, however, makes 
conversation about provided materials 
difficult or impossible. For example, in 
conversation about provided materials, 
examiner can identify picture or naming 
card content from patient’s response.  
2 = Severe aphasia; all communication is 
through fragmentary expression; great 
need for inference, questioning, and 
guessing by the listener. Range of 
information that can be exchanged is 
limited; listener carries burden of 
communication. Examiner cannot identify 
materials provided from patient response.  
3 = Mute, global aphasia; no usable speech 
or auditory comprehension. 
10. Dysarthria: If patient is thought to be 
normal, an adequate sample of speech must be 
obtained by asking patient to read or repeat 
words from the attached list. If the patient has 
severe aphasia, the clarity of articulation of 
spontaneous speech can be rated. Only if the 
patient is intubated or has other physical 
barriers to producing speech, the examiner 
should record the score as untestable (UN), 
and clearly write an explanation for this 
choice. Do not tell the patient why he or she is 
being tested. 
0 = Normal.  
1 = Mild-to-moderate dysarthria; patient 
slurs at least some words and, at worst, can 
be understood with some difficulty.  
2 = Severe dysarthria; patient's speech is 
so slurred as to be unintelligible in the 
absence of or out of proportion to any 
dysphasia, or is mute/anarthric.  
UN = Intubated or other physical barrier, 
explain:___________________________ 
 
11. Extinction and Inattention: Sufficient 
information to identify neglect may be 
obtained during the prior testing. If the patient 
has a severe visual loss preventing visual 
double simultaneous stimulation, and the 
cutaneous stimuli are normal, the score is 
normal. If the patient has aphasia but does 
appear to attend to both sides, the score is 
normal. The presence of visual spatial neglect 
or anosognosia may also be taken as evidence 
of abnormality. Since the abnormality is 
scored only if present, the item is never 
untestable. 
0 = No abnormality.  
1 = Visual, tactile, auditory, spatial, or 
personal inattention or extinction to 
bilateral simultaneous stimulation in one 
of the sensory modalities.  
2 = Profound hemi-inattention or 
extinction to more than one modality; does 
not recognize own hand or orients to only 
one side of space. 
 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
59 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
60 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
61 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
62 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
63 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
64 
19.4. 
World Federation of Neurological Societies Grading Scale for Subarachnoid 
Hemorrhage 
 
GRADE 
Glasgow Coma Scale 
Motor Deficit 
I 
15 
Absent 
II 
14-13 
Absent 
III 
14-13 
Present 
IV 
12-7 
Absent or Present 
V 
6-3 
Absent or Present 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
65 
19.5. 
Intracerebral Hemorrhage Score 
 
Test/Scale/Finding 
Score 
Glasgow Coma Score 
• 3 – 4 
• 5 – 12 
• 13 - 15 
 
+2 
+1 
0 
Age ≥80 years 
+1 
ICH Volume ≥30ml 
+1 
Intraventricular Hemorrhage 
+1 
Infratentorial Origin of Hemorrhage 
+1 
TOTAL SCORE 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
66 
19.6. 
Intensive Care Delirium Screening Checklist 
 
• 
Score your patient over the entire shift.  Components don’t all need to be present at the 
same time. 
• 
Components #1 through #4 require a focused bedside patient assessment.  This cannot be 
completed when the patient is deeply sedated or comatose (i.e., SAS = 1; RASS =-4 or -5). 
• 
Components #5 through #8 are based on observations throughout the entire shift.  
Information from the prior 24 hours (i.e., from 1-2 nursing shifts) should be obtained for 
components #7 and #8. 
 
Give a score of 1 to each of the 8 items below if the patient clearly meets the criteria defined in the 
scoring instructions. 
ASSESSMENT 
SCORING INSTRUCTIONS 
 
SCORE 
1.Altered Level 
of 
Consciousness* 
 
• Deep sedation/coma over entire shift [SAS=1, 2; RASS= -4,-5] 
• Agitation [SAS = 5, 6, or 7; RASS= 1-4] at any point 
• Normal wakefulness [SAS = 4; RASS = 0] over the entire shift 
• Light sedation: no recent sedatives [SAS = 3; RASS= -1, -2, -3] 
• Light sedation: recent sedatives [SAS = 3; RASS= -1, -2, -3] 
Not assessable 
= 1 point 
= 0 points 
= 1 point 
= 0 points 
 
2.Inattention 
 
• Difficulty following instructions or  
• Easily distracted by external stimuli or 
• Difficulty in shifting focus 
(Does the patient follow you with their eyes?) 
1 Point if any 
present 
 
3.Disorientation 
 
• Mistake in time, place, person 
(Does the patient recognize their caregiver?) 
(Does the patient know what kind of place they are in?) 
1 Point for any 
abnormality 
 
4.Hallucination/ 
delusions/ 
psychosis 
 
• Unequivocal manifestation of hallucinations or of behavior probably 
due to hallucinations (e.g., catching non-existent object) 
• Delusions 
• Gross impairment in reality testing 
(Is the patient inappropriately afraid of the people or things around 
them?) 
1 Point for any 
 
5.Psychomotor 
agitation or 
retardation 
 
• Hyperactivity requiring additional sedatives or restraints in order to 
control potential dangerousness (e.g. pulling out IV lines, hitting 
staff) 
• Hypoactive or clinically noticeable psychomotor slowing or 
retardation 
1 Point if any 
are present 
 
6.Inappropriate 
speech or mood 
 
• Inappropriate, disorganized or incoherent speech 
• Inappropriate mood or display of emotion related to events or 
situation 
(Is the patient apathetic, or inappropriately demanding?) 
1 Point if any 
are present 
 
7.Sleep 
wake/cycle 
disturbance 
 
• Sleeping less than 4 hours at night or  
• Waking frequently at night (do not consider wakefulness initiated by 
medical staff or loud environment) or  
• Sleeping during most of day 
1 Point if any 
are present 
 
8.Symptom 
fluctuation 
(1 Point if 
present) 
• Fluctuation of any of the above items over a 24 hour period (e.g., 
from one shift to another). 
1 Point if 
present 
 
TOTAL SCORE 
(0-8/8): 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
67 
19.7. 
Barthel Index 
 
Guidelines 
a. The index should be used as a record of what a patient does, not as a record of 
what a patient could do. 
b.The main aim is to establish degree of independence from any help, physical or 
verbal, however minor and for whatever reason. 
c. The need for supervision renders the patient not independent. 
d.A patient's performance should be established using the best available evidence. 
Asking the patient, friends/relatives and nurses are the usual sources, but direct 
observation and common sense are also important.  However direct testing is not 
needed. 
e. Usually the patient's performance over the preceding 24-48 hours is important, 
but occasionally longer periods will be relevant. 
f. Middle categories imply that the patient supplies over 50 per cent of the effort. 
g.Use of aids to be independent is allowed. 
 
ACTIVITY  
SCORE 
FEEDING 
0 = unable 
5 = needs help cutting, spreading butter, etc., or requires 
modified diet 
10 = independent 
 
BATHING 
0 = dependent 
5 = independent (or in shower) 
 
GROOMING 
0 = needs to help with personal care 
5 = independent face/hair/teeth/shaving (implements  
      provided) 
 
DRESSING 
0 = dependent 
5 = needs help but can do about half unaided 
10 = independent (including buttons, zips, laces, etc.) 
 
BOWELS 
0 = incontinent (or needs to be given enemas) 
5 = occasional accident 
10 = continent 
 
BLADDER 
0 = incontinent, or catheterized and unable to manage alone 
5 = occasional accident 
10 = continent 
 
TOILET USE 
0 = dependent 
5 = needs some help, but can do something alone 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
68 
10 = independent (on and off, dressing, wiping) 
TRANSFERS (BED TO CHAIR AND BACK) 
0 = unable, no sitting balance 
5 = major help (one or two people, physical), can sit 
10 = minor help (verbal or physical) 
15 = independent 
 
MOBILITY (ON LEVEL SURFACES) 
0 = immobile or < 50 yards 
5 = wheelchair independent, including corners, >50 yards 
10 = walks with help of one person (verbal or physical) >50 
yards 
15 = independent (may use any aid; e.g., cane) >50 yards 
 
STAIRS 
0 = unable 
5 = needs help (verbal, physical, carrying aid) 
10 = independent 
 
TOTAL (0–100) 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
69 
19.8. 
Glasgow Outcome Scale Extended 
 
DESCRIPTION 
SCORE 
Dead 
1 
Vegetative State (VS) 
2 
Lower Severe Disability (Lower SD) 
3 
Upper Severe Disability (Upper SD) 
4 
Lower Moderate Disability (Lower MD) 
5 
Upper Moderate Disability (Upper MD) 
6 
Lower Good Recovery (Lower GR) 
7 
Upper Good Recovery (Upper GR) 
8 
 
Structured Interview for GOS-E 
Consciousness: 
 
1. Is the head-injured person able to obey simple commands or say any 
words? 
_____Yes          _____No (VS) 
Note: anyone who shows the ability to obey even simple commands or utter any word or 
communicate specifically in any other way is no longer considered to be in vegetative 
state. Eye movements are not reliable evidence of meaningful responsiveness. Corroborate 
with 
nursing staff and/or other caretakers. Confirmation of VS requires full assessment. 
Independence at Home: 
 
2a. Is the assistance of another person at home essential every day for some 
activities of daily living? 
_____Yes          _____No      If no, go to 3 
Note: for a NO answer they should be able to look after themselves at home for 24 hours if 
necessary, though they need not actually look after themselves. Independence includes the 
ability to plan for and carry out the following activities: getting washed, putting on clean 
clothes without prompting, preparing food for themselves, dealing with callers and 
handling minor domestic crises. The person should be able to carry out activities without 
needing prompting or reminding and should be capable of being left alone overnight. 
 
2b. Do they need frequent help of someone to be around at home most of 
the time? 
_____Yes (Lower SD)         _____No (Upper SD) 
Note: for a NO answer they should be able to look after themselves at home up to eight 
hours during the day if necessary, though they need not actually look after themselves 
 
2c. Was the patient independent at home before the injury? 
_____Yes          _____No 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
70 
Independence Outside Home: 
 
3a. Are they able to shop without assistance? 
_____Yes          _____No (Upper SD) 
Note: this includes being able to plan what to buy, take care of money themselves and 
behave appropriately in public. They need not normally shop, but must be able to do so. 
 
3b. Were they able to shop without assistance before? 
_____Yes          _____No 
 
4a. Are they able to travel locally without assistance? 
_____Yes          _____No (Upper SD) 
Note: they may drive or use public transport to get around. Ability to use a taxi is 
sufficient, provided the person can phone for it themselves and instruct the driver. 
 
4b. Were they able to travel locally without assistance before the injury? 
_____Yes          _____No 
 
Work: 
 
5a. Are they currently able to work (or look after others at home) to their 
previous capacity? 
_____Yes If yes, go to 6         _____No 
 
5b. How restricted are they? 
     a. Reduced work capacity?                                            _____ a (Upper MD) 
     b. Able to work only in a sheltered workshop or           _____ b (Lower MD) 
        non-competitive job or currently unable to work? 
 
5c. Does the level of restriction represent a change in respect to the pre-
trauma situation? 
_____Yes          _____No 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
71 
Social and Leisure Activities: 
 
6a. Are they able to resume regular social and leisure activities outside 
home? 
_____Yes If yes, go to 7          _____No 
Note: they need not have resumed all their previous leisure activities, but should not be 
prevented by physical or mental impairment. If they have stopped the majority of activities 
because of loss of interest or motivation, then this is also considered a disability. 
 
6b. What is the extent of restriction on their social and leisure activities? 
     a. Participate a bit less: at least half as often as before injury  _____ a (Lower 
GR) 
     b. Participate much less: less than half as often                       _____ b (Upper 
MD) 
     c. Unable to participate: rarely, if ever, take part                    _____ c (Lower 
MD) 
 
6c. Does the extent of restriction in regular social and leisure activities 
outside home represent  a change in respect or pre-trauma 
_____Yes          _____No 
 
Family and Friendships: 
 
7a. Has there been family or friendship disruption due to psychological 
problems? 
_____Yes          _____No If no, go to 8 
Note: typical post-traumatic personality changes are: quick temper, irritability, anxiety, 
insensitivity to others, mood swings, depression and unreasonable or childish behavior. 
 
7b. What has been the extent of disruption or strain? 
     a. Occasional - less than weekly                                              _____a (Lower 
GR) 
     b. Frequent - once a week or more, but not tolerable              _____ b (Upper 
MD) 
     c. Constant - daily and intolerable                                           _____ c (Lower 
MD) 
 
7c. Does the level of disruption or strain represent a change in respect to 
pre-trauma situation? 
_____Yes          _____No 
Note: if there were some problems before injury, but these have become markedly worse 
since the injury then answer yes to question 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
72 
Return to Normal Life: 
 
8a. Are there any other current problems relating to the injury which affect 
daily life? 
_____Yes (Lower GR)         _____No (Upper GR) 
Note: other typical problems reported after head injury: headaches, dizziness, sensitivity to 
noise or light, slowness, memory failures and concentration problems. 
 
8b. If similar problems were present before the injury, have these become 
markedly worse? 
_____Yes          _____No 
 
9. What is the most important factor in outcome? 
     _____ a. Effects of head injury 
     _____ b. Effects of illness or injury to another part of the body 
     _____ c. A mixture of these 
 
Note: Extended GOS grades are shown beside responses on the assessment form. 
The overall rating is based on the lowest outcome category indicated. 
Areas in which there has been no change with respect to the pre-trauma situation 
are ignored when the overall rating is made. 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
73 
19.9. 
Montreal Cognitive Assessment 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
74 
19.10. Instructions for Use 
 
 
  
    
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
75 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
76 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
77 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
78 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
79 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
80 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
81 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
82 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
83 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
84 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
85 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
86 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
87 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
88 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
89 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
90 
 
19.11. Guidelines for Treatment of Patients with Ischemic Stroke 
 
Adapted from: Guidelines for Early Management of Patients With Acute Ischemic 
Stroke: A Guideline for Healthcare Professionals From the American Heart 
Association/American Stroke Association (2013) 
 
Classification/Level of Evidence Scheme 
• 
Class I: Benefit>>>Risk; Procedure/treatment SHOULD be performed/administered 
• 
Class IIa: Benefit >> Risk; IT IS REASONABLE to perform procedure/administer 
treatment 
• 
Class IIb: Benefit≥Risk; Procedure/treatment MAY BE CONSIDERED 
• 
Class III: No Benefit OR Harm; Procedure/treatment is NOT 
RECOMMENDED/SHOULD NOT BE PERFORMED  
 
• 
Evidence Level A: Data derived from multiple randomized clinical trials or meta-
analyses 
• 
Evidence Level B: Data derived from a single randomized trial or non-randomized 
studies 
• 
Evidence Level C: Only consensus opinion of experts, case studies, or standard of 
care 
 
 
RECOMMENDATIONS 
 
Emergency Evaluation and Diagnosis of Acute Ischemic Stroke (AIS) 
1. An organized protocol for the emergency evaluation of patients with suspected 
stroke is recommended (Class I; Level of Evidence B). The goal is to complete an 
evaluation and to begin fibrinolytic treatment within 60 minutes of the patient’s arrival 
in an ED. Designation of an acute stroke team that includes physicians, nurses, and 
laboratory/radiology personnel is encouraged. Patients with stroke should have a 
careful clinical assessment, including neurological examination.  
2. The use of a stroke rating scale, preferably the NIHSS, is recommended (Class I; 
Level of Evidence B).  
3. A limited number of hematologic, coagulation, and biochemistry tests are 
recommended during the initial emergency evaluation, and only the assessment of 
blood glucose must precede the initiation of intravenous rtPA (Class I; Level of 
Evidence B).  
4. Baseline electrocardiogram assessment is recommended in patients presenting with 
acute ischemic stroke but should not delay initiation of intravenous rtPA (Class I; 
Level of Evidence B). 
5. Baseline troponin assessment is recommended in patients presenting with acute 
ischemic stroke but should not delay initiation of intravenous rtPA (Class I; Level of 
Evidence C). 
6. The usefulness of chest radiographs in the hyperacute stroke setting in the absence 
of evidence of acute pulmonary, cardiac, or pulmonary vascular disease is unclear. If 
obtained, they should not unnecessarily delay administration of fibrinolysis (Class IIb; 
Level of Evidence B). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
91 
 
Early Diagnosis: Brain and Vascular Imaging 
Recommendations for Patients With Acute Cerebral Ischemic Symptoms That Have Not Yet 
Resolved 
 
1. Emergency imaging of the brain is recommended before initiating any specific 
therapy to treat acute ischemic stroke (Class I; Level of Evidence A). In most 
instances, NECT will provide the necessary information to make decisions about 
emergency management.  
2. Either NECT or MRI is recommended before intra- venous rtPA administration to 
exclude ICH (absolute contraindication) and to determine whether CT 
hypodensity or MRI hyperintensity of ischemia is present (Class I; Level of 
Evidence A).  
3. Intravenous fibrinolytic therapy is recommended in the setting of early ischemic 
changes (other than frank hypodensity) on CT, regardless of their extent (Class I; 
Level of Evidence A).  
4. A noninvasive intracranial vascular study is strongly recommended during the 
initial imaging evaluation of the acute stroke patient if either intra-arterial 
fibrinolysis or mechanical thrombectomy is contemplated for management but 
should not delay intravenous rtPA if indicated (Class I; Level of Evidence A). 
5. In intravenous fibrinolysis candidates, the brain imaging study should be 
interpreted within 45 minutes of patient arrival in the ED by a physician with 
expertise in reading CT and MRI studies of the brain parenchyma (Class I; Level 
of Evidence C). 
6. CT perfusion and MRI perfusion and diffusion imaging, including measures of 
infarct core and penumbra, may be considered for the selection of patients for 
acute reperfusion therapy beyond the time windows for intravenous fibrinolysis. 
These techniques provide additional information that may improve diagnosis, 
mechanism, and severity of ischemic stroke and allow more informed clinical 
decision making (Class IIb; Level of Evidence B).  
7. Frank hypodensity on NECT may increase the risk of hemorrhage with 
fibrinolysis and should be considered in treatment decisions. If frank hypodensity 
involves more than one third of the MCA territory, intravenous rtPA treatment 
should be withheld (Class III; Level of Evidence A).  
 
Recommendations for Patients With Cerebral Ischemic Symptoms That Have Resolved 
 
1. Noninvasive imaging of the cervical vessels  should be performed routinely as  
part of the  evaluation of patients with suspected TIAs (Class I; Level of Evidence 
A).  
2. Noninvasive imaging by means of CTA or MRA of the intracranial vasculature is 
recommended to exclude the presence of proximal intracranial stenosis and/or 
occlusion (Class I; Level of Evidence A) and should be obtained when knowledge 
of intracranial stenoocclusive disease will alter management. Reliable diagnosis 
of the presence and degree of intracranial stenosis requires the performance of 
catheter angiography to confirm abnormalities detected with non- invasive 
testing.  
3. Patients with transient ischemic neurological symptoms should undergo 
neuroimaging evaluation within 24 hours of symptom onset or as soon as 
possible in patients with delayed presentations. MRI, including DWI, is the 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
92 
preferred brain diagnostic imaging modality. If MRI is not available, head CT 
should be performed (Class I; Level of Evidence B).  
 
General Supportive Care and Treatment of Acute Complications 
1. Cardiac monitoring is recommended to screen for atrial fibrillation and other 
potentially serious cardiac arrhythmias that would necessitate emergency cardiac 
interventions. Cardiac monitoring should be performed for at least the first 24 hours 
(Class I; Level of Evidence B).  
2. Patients who have elevated blood pressure and are otherwise eligible for treatment 
with intravenous rtPA should have their blood pressure carefully lowered (Table  1) 
so that their systolic blood pressure is <185 mm Hg and their diastolic blood 
pressure is <110 mm Hg (Class I; Level of Evidence B) before fibrinolytic therapy is 
initiated. If medications are given to lower blood pressure, the clinician should be 
sure that the blood pressure is stabilized at the lower level before beginning 
treatment with intravenous rtPA and maintained below 180/105 mm Hg for at least 
the first 24 hours after intravenous rtPA treatment.  
3. Airway support and ventilatory assistance are recommended for the treatment of 
patients with acute stroke who have decreased consciousness or who have bulbar 
dysfunction that causes compromise of the airway (Class I; Level of Evidence C).  
4. Supplemental oxygen should be provided to maintain oxygen saturation >94% 
(Class I; Level of Evidence C).  
5. Sources of hyperthermia (temperature >38°C) should be identified and treated, and 
antipyretic medications should be administered to lower temperature in hyperthermic 
patients with stroke (Class I; Level of Evidence C).  
6. Until other data become available, consensus exists that the previously described 
blood pressure recommendations should be followed in patients undergoing other 
acute interventions to recanalize occluded vessels, including intra-arterial fibrinolysis 
(Class I; Level of Evidence C).  
7. In patients with markedly elevated blood pressure who do not receive fibrinolysis, a 
reasonable goal is to lower blood pressure by 15% during the first 24 hours after 
onset of stroke. The level of blood pressure that would mandate such treatment is 
not known, but consensus exists that medications should be withheld unless the 
systolic blood pressure is >220 mm Hg or the diastolic blood pressure is >120 mm 
Hg (Class I; Level of Evidence C).  
8. Hypovolemia should be corrected with intravenous normal saline, and cardiac 
arrhythmias that might be reducing cardiac output should be corrected (Class I; Level 
of Evidence C). 
9. Hypoglycemia (blood glucose <60 mg/dL) should be treated in patients with acute 
ischemic stroke (Class I; Level of Evidence C). The goal is to achieve 
normoglycemia. 
10. Evidence from one clinical trial indicates that initiation of antihypertensive therapy 
within 24 hours of stroke is relatively safe. Restarting antihypertensive medications is 
reasonable after the first 24 hours for patients who have preexisting hypertension 
and are neurologically stable unless a specific contraindication to restarting 
treatment is known (Class IIa; Level of Evidence B). 
11. No data are available to guide selection of medications for the lowering of blood 
pressure in the setting of acute ischemic stroke. The antihypertensive medications 
and doses included in Table 1 are reasonable choices based on general consensus 
(Class IIa; Level of Evidence C).  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
93 
12. Evidence indicates that persistent in-hospital hyperglycemia during the first 24 hours 
after stroke is associated with worse outcomes than normoglycemia, and thus, it is 
reasonable to treat hyperglycemia to achieve blood glucose levels in a range of 140 
to 180 mg/dL and to closely monitor to prevent hypoglycemia in patients with acute 
ischemic stroke (Class IIa; Level of Evidence C). 
13. The management of arterial hypertension in patients not undergoing reperfusion 
strategies remains challenging. Data to guide recommendations for treatment are 
inconclusive or conflicting. Many patients have spontaneous declines in blood 
pressure during the first 24 hours after onset of stroke. Until more definitive data are 
available, the benefit of treating arterial hypertension in the setting of acute ischemic 
stroke is not well established (Class IIb; Level of Evidence C). Patients who have 
malignant hypertension or other medical indications for aggressive treatment of 
blood pressure should be treated accordingly.  
14. Supplemental oxygen is not recommended in nonhypoxic patients with acute 
ischemic stroke (Class III; Level of Evidence B).   
 
Intravenous Fibrinolysis 
1. Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected 
patients who may be treated within 3 hours of onset of ischemic stroke (Class I; 
Level of Evidence A). Physicians should review the criteria outlined in Tables 2 and 3 
(which are modeled on those used in the NINDS Trial) to determine the eligibility of 
the patient. A recommended regimen for observation and treatment of patients who 
receive intravenous rtPA is described in Table 4. 
2. In patients eligible for intravenous rtPA, benefit of therapy is time dependent, and 
treatment should be initiated as quickly as possible. The door-to-needle time (time of 
bolus administration) should be within 60 minutes from hospital arrival (Class I; Level 
of Evidence A) 
3. Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for 
administration to eligible patients who can be treated in the time period of 3 to 4.5 
hours after stroke onset (Class I; Level of Evidence B). The eligibility criteria for 
treatment in this time period are similar to those for people treated at earlier time 
periods within 3 hours, with the following additional exclusion criteria: patients >80 
years old, those taking oral anticoagulants regardless of INR, those with a baseline 
NIHSS score >25, those with imaging evidence of ischemic injury involving more 
than one third of the MCA territory, or those with a history of both stroke and 
diabetes mellitus. 
4. Intravenous rtPA is reasonable in patients whose blood pressure can be lowered 
safely (to below 185/110 mm Hg) with antihypertensive agents, with the physician 
assessing the stability of the blood pressure before starting intravenous rtPA (Class 
I; Level of Evidence B). 
5. In patients undergoing fibrinolytic therapy, physicians should be aware of and 
prepared to emergently treat potential side effects, including bleeding complications 
and angioedema that may cause partial airway obstruction (Class I; Level of 
Evidence B).  
6. Intravenous rtPA is reasonable in patients with a seizure at the time of onset of 
stroke if evidence suggests that residual impairments are secondary to stroke and 
not a postictal phenomenon (Class IIa; Level of Evidence C). 
7. The effectiveness of sonothrombolysis for treatment of patients with acute stroke is 
not well established (Class IIb; Level of Evidence B). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
94 
8. The usefulness of intravenous administration of tenecteplase, reteplase, 
desmoteplase, urokinase, or other fibrinolytic agents and the intravenous 
administration of ancrod or other defibrinogenating agents is not well established, 
and they should only be used in the setting of a clinical trial (Class IIb; Level of 
Evidence B). 
9. The effectiveness of intravenous treatment with rtPA is not well established (Class 
IIb; Level of Evidence C) and requires further study for patients who can be treated in 
the time period of 3 to 4.5 hours after stroke but have 1 or more of the following 
exclusion criteria: (1) patients >80 years old, (2) those taking oral anticoagulants, 
even with INR ≤1.7, (3) those with a baseline NIHSS score >25, or (4) those with a 
history of both stroke and diabetes mellitus. 
10. Use of intravenous fibrinolysis in patients with conditions of mild stroke deficits, 
rapidly improving stroke symptoms, major surgery in the preceding 3 months, and 
recent myocardial infarction may be considered, and potential increased risk should 
be weighed against the anticipated benefits (Class IIb; Level of Evidence C). These 
circumstances require further study.  
11. The intravenous administration of streptokinase for treatment of stroke is not 
recommended (Class III; Level of Evidence A). 
12. The use of intravenous rtPA in patients taking direct thrombin inhibitors or direct 
factor Xa inhibitors may be harmful and is not recommended unless sensitive 
laboratory tests such as aPTT, INR, plate- let count, and ECT, TT, or appropriate 
direct factor Xa activity assays are normal, or the patient has not received a dose of 
these agents for >2 days (assuming normal renal metabolizing function). Similar 
consideration should be given to patients being considered for intra-arterial rtPA 
(Class III; Level of Evidence C). Further study is required. 
 
Endovascular Interventions 
1. Patients eligible for intravenous rtPA should receive intravenous rtPA even if intra-
arterial treatments are being considered (Class I; Level of Evidence A). 
2. Intra-arterial fibrinolysis is beneficial for treatment of carefully selected patients with 
major ischemic strokes of <6 hours’ duration caused by occlusions of the MCA who 
are not otherwise candidates for intravenous rtPA (Class I; Level of Evidence B). The 
optimal dose of intra-arterial rtPA is not well established, and rtPA does not have 
FDA approval for intra-arterial use. 
3. As with intravenous fibrinolytic therapy, reduced time from symptom onset to 
reperfusion with intra-arterial therapies is highly correlated with better clinical 
outcomes, and all efforts must be undertaken to minimize delays to definitive therapy 
(Class I; Level of Evidence B).  
4. Intra-arterial treatment requires the patient to be at an experienced stroke center  
with rapid access to cerebral angiography and qualified interventionalists. An 
emphasis on expeditious assessment and treatment should be made. Facilities are 
encouraged to define criteria that can be used to credential individuals who can 
perform intra-arterial revascularization procedures. Outcomes on all patients should 
be tracked (Class I; Level of Evidence C). 
5. When mechanical thrombectomy is pursued, stent retrievers such as Solitaire FR 
and Trevo are generally preferred to coil retrievers such as Merci (Class I; Level of 
Evidence A). The relative effectiveness of the Penumbra System versus stent 
retrievers is not yet characterized. 
6. The Merci, Penumbra System, Solitaire FR, and Trevo thrombectomy devices can be 
useful in achieving recanalization alone or in combination with pharmacological 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
95 
fibrinolysis in carefully selected patients (Class IIa; Level of Evidence B). Their ability 
to improve patient outcomes has not yet been established. These devices should 
continue to be studied in randomized controlled trials to determine the efficacy of 
such treatments in improving patient out-comes. 
7. Intra-arterial fibrinolysis or mechanical thrombectomy is reasonable in patients who 
have contraindications to the use of intravenous fibrinolysis (Class IIa; Level of 
Evidence C).  
8. Rescue intra-arterial fibrinolysis or mechanical thrombectomy may be reasonable 
approaches to recanalization in patients with large-artery occlusion who have not 
responded to intravenous fibrinolysis. Additional randomized trial data are needed 
(Class IIb; Level of Evidence B). 
9. The usefulness of mechanical thrombectomy devices other than the Merci retriever, 
the Penumbra System, Solitaire FR, and Trevo is not well established (Class IIb; 
Level of Evidence C). These devices should be used in the setting of clinical trials. 
10. The usefulness of emergent intracranial angioplasty and/or stenting is not well 
established. These procedures should be used in the setting of clinical trials (Class 
IIb; Level of Evidence C).  
11. The usefulness of emergent angioplasty and/or stenting of the extracranial carotid or 
vertebral arteries in unselected patients is not well established (Class IIb; Level of 
Evidence C). Use of these techniques may be considered in certain circumstances, 
such as in the treatment of acute ischemic stroke resulting from cervical 
atherosclerosis or dissection (Class IIb; Level of Evidence C). Additional randomized 
trial data are needed. 
 
Anticoagulants 
1. At present, the usefulness of argatroban or other thrombin inhibitors for treatment of 
patients with acute ischemic stroke is not well established (Class IIb; Level of 
Evidence B). These agents should be used in the setting of clinical trials. 
2. The usefulness of urgent anticoagulation in patients with severe stenosis of an 
internal carotid artery ipsilateral to an ischemic stroke is not well established (Class 
IIb; Level of Evidence B).  
3. Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting 
neurological worsening, or improving outcomes after acute ischemic stroke, is not 
recommended for treatment of patients with acute ischemic stroke (Class III; Level of 
Evidence A). 
4. Urgent anticoagulation for the management of non- cerebrovascular conditions is not 
recommended for patients with moderate-to-severe strokes because of an increased 
risk of serious intracranial hemorrhagic complications (Class III; Level of Evidence 
A). 
5. Initiation of anticoagulant therapy within 24 hours of treatment with intravenous rtPA 
is not recommended (Class III; Level of Evidence B).  
 
Antiplatelet Agents 
1. Oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after 
stroke onset is recommended for treatment of most patients (Class I; Level of 
Evidence A).  
2. The usefulness of clopidogrel for the treatment of acute ischemic stroke is not well 
established (Class IIb; Level of Evidence C). Further research testing the usefulness 
of the emergency administration of clopidogrel in the treatment of patients with acute 
stroke is required.  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
96 
3. The efficacy of intravenous tirofiban and eptifibatide is not well established, and 
these agents should be used only in the setting of clinical trials (Class IIb; Level of 
Evidence C).  
4. Aspirin is not recommended as a substitute for other acute interventions for 
treatment of stroke, including intravenous rtPA (Class III; Level of Evidence B).  
5. The administration of other intravenous antiplatelet agents that inhibit the 
glycoprotein IIb/IIIa receptor is not recommended (Class III; Level of Evidence B). 
Further research testing the usefulness of emergency administration of these 
medications as a treatment option in patients with acute ischemic stroke is required. 
6. The administration of aspirin (or other antiplatelet agents) as an adjunctive therapy 
within 24 hours of intravenous fibrinolysis is not recommended (Class III; Level of 
Evidence C).  
 
Volume Expansion, Vasodilators, and Induced Hypertension 
1. In exceptional cases with systemic hypotension producing neurological sequelae, a 
physician may pre- scribe vasopressors to improve cerebral blood flow. If drug-
induced hypertension is used, close neurological and cardiac monitoring is 
recommended (Class I; Level of Evidence C). 
2. The administration of high-dose albumin is not well established as a treatment for 
most patients with acute ischemic stroke until further definitive evidence regarding 
efficacy becomes available (Class IIb; Level of Evidence B).  
3. At present, use of devices to augment cerebral blood flow for the treatment of 
patients with acute ischemic stroke is not well established (Class IIb; Level of 
Evidence B). These devices should be used in the setting of clinical trials.  
4. The usefulness of drug-induced hypertension in patients with acute ischemic stroke 
is not well established (Class IIb; Level of Evidence B). Induced hypertension should 
be performed in the setting of clinical trials. 
5. Hemodilution by volume expansion is not recommended for treatment of patients 
with acute ischemic stroke (Class III; Level of Evidence A).  
6. The administration of vasodilatory agents, such as pentoxifylline, is not 
recommended for treatment of patients with acute ischemic stroke (Class III; Level of 
Evidence A).  
 
Neuroprotective Agents 
1. Among patients already taking statins at the time of onset of ischemic stroke, 
continuation of statin therapy during the acute period is reasonable (Class IIa; Level 
of Evidence B).  
2. The utility of induced hypothermia for the treatment of patients with ischemic stroke 
is not well established, and further trials are recommended (Class IIb; Level of 
Evidence B).  
3. At present, transcranial near-infrared laser therapy is not well established for the 
treatment of acute ischemic stroke (Class IIb; Level of Evidence B), and further trials 
are recommended.  
4. At present, no pharmacological agents with putative neuroprotective actions have 
demonstrated efficacy in improving outcomes after ischemic stroke, and therefore, 
other neuroprotective agents are not recommended (Class III; Level of Evidence A).  
5. Data on the utility of hyperbaric oxygen are inconclusive, and some data imply that 
the intervention may be harmful. Thus, with the exception of stroke secondary to air 
embolization, this intervention is not recommended for treatment of patients with 
acute ischemic stroke (Class III; Level of Evidence B).  
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
97 
 
Surgical Interventions 
1. The usefulness of emergent or urgent CEA when clinical indicators or brain imaging 
suggests a small infarct core with large territory at risk (e.g., penumbra), 
compromised by inadequate flow from a critical carotid stenosis or occlusion, or in 
the case of acute neurological deficit after CEA, in which acute thrombosis of the 
surgical site is suspected, is not well established (Class IIb; Level of Evidence B).  
2. In patients with unstable neurological status (either stroke-in-evolution or crescendo 
TIA), the efficacy of emergent or urgent CEA is not well established (Class IIb; Level 
of Evidence B). 
 
General Acute Care After Hospitalization 
1. The use of comprehensive specialized stroke care (stroke units) that incorporates 
rehabilitation is recommended (Class I; Level of Evidence A).  
2. Patients with suspected pneumonia or UTIs should be treated with appropriate 
antibiotics (Class I; Level of Evidence A).  
3. Subcutaneous administration of anticoagulants is recommended for treatment of 
immobilized patients to prevent DVT (Class I; Level of Evidence A).  
4. The use of standardized stroke care order sets is recommended to improve general 
management (Class I; Level of Evidence B).  
5. Assessment of swallowing before the patient begins eating, drinking, or receiving 
oral medications is recommended (Class I; Level of Evidence B).  
6. Patients who cannot take solid food and liquids orally should receive NG, 
nasoduodenal, or PEG tube feedings to maintain hydration and nutrition while under- 
going efforts to restore swallowing (Class I; Level of Evidence B).  
7. Early mobilization of less severely affected patients and measures to prevent 
subacute complications of stroke are recommended (Class I; Level of Evidence C).  
8. Treatment of concomitant medical diseases is recommended (Class I; Level of 
Evidence C).  
9. Early institution of interventions to prevent recurrent stroke is recommended (Class I; 
Level of Evidence C).  
10. The use of aspirin is reasonable for treatment of patients who cannot receive 
anticoagulants for DVT prophylaxis (Class IIa; Level of Evidence A).  
11. In selecting between NG and PEG tube routes of feeding in patients who cannot take 
solid food or liquids orally, it is reasonable to prefer NG tube feeding until 2 to 3 
weeks after stroke onset (Class IIa; Level of Evidence B).  
12. The use of intermittent external compression devices is reasonable for treatment of 
patients who cannot receive anticoagulants (Class IIa; Level of Evidence B).  
13. Routine use of nutritional supplements has not been shown to be beneficial (Class 
III; Level of Evidence B).  
14. Routine use of prophylactic antibiotics has not been shown to be beneficial (Class III; 
Level of Evidence B).  
15. Routine placement of indwelling bladder catheters is not recommended because of 
the associated risk of catheter-associated UTIs (Class III; Level of Evidence C).  
 
Treatment of Acute Neurological Complications 
1. Patients with major infarctions are at high risk for complicating brain edema and 
increased ICP. Measures to lessen the risk of edema and close monitoring of the 
patient  for  signs  of  neurological worsening during the first days after stroke are 
recommended (Class I; Level of Evidence A). Early transfer of patients at risk for 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
98 
malignant brain edema to an institution with neurosurgical expertise should be 
considered.  
2. Decompressive surgical evacuation of a space-occupying cerebellar infarction is 
effective in preventing and treating herniation and brain stem compression (Class I; 
Level of Evidence B).  
3. Decompressive surgery for malignant edema of the cerebral hemisphere is effective 
and potentially lifesaving (Class I; Level of Evidence B). Advanced patient age and 
patient/family valuations of achievable outcome states may affect decisions 
regarding surgery.  
4. Recurrent seizures after stroke should be treated in a manner similar to other acute 
neurological conditions, and antiepileptic agents should be selected by specific 
patient characteristics (Class I; Level of Evidence B). 
5. Placement of a ventricular drain is useful in patients with acute hydrocephalus 
secondary to ischemic stroke (Class I; Level of Evidence C).  
6. Although aggressive medical measures have been recommended for treatment of 
deteriorating patients with malignant brain edema after large cerebral infarction, the 
usefulness of these measures is not well established (Class IIb; Level of Evidence 
C).  
7. Because of lack of evidence of efficacy and the potential to increase the risk of 
infectious complications, corticosteroids (in conventional or large doses) are not 
recommended for treatment of cerebral edema and increased ICP complicating 
ischemic stroke (Class III; Level of Evidence A). 
8. Prophylactic use of anticonvulsants is not recommended (Class III; Level of Evidence 
C).  
 
 
Table 1. 
Potential Approaches to Arterial Hypertension in Acute Ischemic Stroke Patients Who Are 
Candidates for Acute Reperfusion Therapy 
 
Patient otherwise eligible for acute reperfusion therapy except that BP is >185/110 mm Hg: 
• 
Labetalol 10–20 mg IV over 1–2 minutes, may repeat 1 time; or 
• 
Nicardipine 5 mg/h IV, titrate up by 2.5 mg/h every 5–15 minutes, maximum 15 mg/h; when desired 
BP reached, adjust to maintain proper BP limits; or 
• 
Other agents (hydralazine, enalaprilat, etc.) may be considered when appropriate 
 
If BP is not maintained at or below 185/110 mm Hg, do not administer rtPA  
 
Management of BP during and after rtPA or other acute reperfusion therapy to maintain BP at or 
below180/105 mm Hg: 
• 
Monitor BP every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 
hours, and then every hour for 16 hours 
• 
If systolic BP >180–230 mm Hg or diastolic BP >105–120 mm Hg: Labetalol 10 mg IV followed 
by continuous IV infusion 2–8 mg/min; or 
• 
Nicardipine 5 mg/h IV, titrate up to desired effect by 2.5 mg/h every 5–15 minutes, maximum 15 
mg/h 
• 
If BP not controlled or diastolic BP >140 mm Hg, consider IV sodium nitroprusside 
 
BP indicates blood pressure; IV, intravenously; and rtPA, recombinant tissue- type plasminogen activator. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
99 
Table 2. 
Inclusion and Exclusion Characteristics of Patients With Ischemic Stroke Who Could Be 
Treated With IV rtPA Within 3 Hours From Symptom Onset 
 
Inclusion criteria: 
• 
Diagnosis of ischemic stroke causing measurable neurological deficit 
• 
Onset of symptoms <3 hours before beginning treatment 
• 
Aged ≥18 years 
Exclusion criteria: 
• 
Significant head trauma or prior stroke in previous 3 months 
• 
Symptoms suggest subarachnoid hemorrhage 
• 
Arterial puncture at noncompressible site in previous 7 days 
• 
History of previous intracranial hemorrhage 
• 
Intracranial neoplasm, arteriovenous malformation, or aneurysm 
• 
Recent intracranial or intraspinal surgery 
• 
Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) 
• 
Active internal bleeding 
• 
Acute bleeding diathesis, including but not limited to Platelet count <100 000/mm³ 
• 
Heparin received within 48 hours, resulting in abnormally elevated aPTT greater than the upper limit 
of normal 
• 
Current use of anticoagulant with INR >1.7 or PT >15 seconds 
• 
Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive 
laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity 
assays) 
• 
Blood glucose concentration <50 mg/dL (2.7 mmol/L) 
• 
CT demonstrates multilobar infarction (hypodensity >1/3 cerebral hemisphere) 
Relative exclusion criteria: 
• 
Recent experience suggests that under some circumstances—with careful consideration and 
weighting of risk to benefit—patients may receive fibrinolytic therapy despite 1 or more relative 
contraindications. Consider risk to benefit of IV rtPA administration carefully if any of these relative 
contraindications are present: 
o 
Only minor or rapidly improving stroke symptoms (clearing spontaneously) 
o Pregnancy 
o 
Seizure at onset with postictal residual neurological impairments 
o 
Major surgery or serious trauma within previous 14 days 
o 
Recent gastrointestinal or urinary tract hemorrhage (within previous 21 days) 
o 
Recent acute myocardial infarction (within previous 3 months) 
_________________________________________________ 
The checklist includes some FDA-approved indications and contraindications for administration of IV rtPA for acute ischemic stroke. 
Recent guideline revisions have modified the original FDA-approved indications. A physician with expertise in acute stroke care may 
modify this list. 
Onset time is defined as either the witnessed onset of symptoms or the time last known normal if symptom onset was not witnessed. 
In patients without recent use of oral anticoagulants or heparin, treatment with IV rtPA can be initiated before availability of 
coagulation test results but should be discontinued if INR is >1.7 or PT is abnormally elevated by local laboratory  standards. 
In patients without history of thrombocytopenia, treatment with IV rtPA can be initiated before availability of platelet count but should be 
discontinued if platelet count is <100 000/mm³. 
aPTT indicates activated partial thromboplastin time; CT, computed tomography; ECT, ecarin clotting time;FDA, Food and 
Drug Administration; INR, international normalized ratio; IV, intravenous; PT, partial thromboplastin time; rtPA, recombinant tissue 
plasminogen activator; and TT, thrombin time. 
 
Table 3. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
100 
Additional Inclusion and Exclusion Characteristics of Patients With Acute Ischemic Stroke Who 
Could Be Treated With IV rtPA Within 3 to 4.5 Hours From Symptom Onset 
 
Inclusion criteria 
• 
Diagnosis of ischemic stroke causing measurable neurological deficit 
• 
Onset of symptoms within 3 to 4.5 hours before beginning treatment 
Relative exclusion criteria 
• 
Aged >80 years 
• 
Severe stroke (NIHSS>25) 
• 
Taking an oral anticoagulant regardless of INR 
• 
History of both diabetes and prior ischemic stroke  
 
 
INR indicates international normalized ratio; IV, intravenous; NIHSS, National Institutes of Health Stroke 
Scale; and rtPA, recombinant tissue plasminogen activator. 
 
 
Table 4. 
Treatment of Acute Ischemic Stroke: Intravenous Administration of rtPA 
 
• 
Infuse 0.9 mg/kg (maximum dose 90 mg) over 60 minutes, with 10% of the dose given as a bolus 
over 1 minute. 
• 
Admit the patient to an intensive care or stroke unit for monitoring. 
• 
If the patient develops severe headache, acute hypertension, nausea, or vomiting or has a 
worsening neurological examination, discontinue the infusion (if IV rtPA is being administered) and 
obtain emergent CT scan. 
• 
Measure blood pressure and perform neurological assessments every 15 minutes during and 
after IV rtPA infusion for 2 hours, then every 30 minutes for 6 hours, then hourly until 24 hours after 
IV rtPA treatment. 
• 
Increase the frequency of blood pressure measurements if systolic blood pressure is >180 mm 
Hg or if diastolic blood pressure is >105 mm Hg; administer antihypertensive medications to 
maintain blood pressure. 
• 
Delay placement of nasogastric tubes, indwelling bladder catheters, or intra- arterial pressure 
catheters if the patient can be safely managed without them. 
• 
Obtain a follow-up CT or MRI scan at 24 hours after IV rtPA before starting anticoagulants or 
antiplatelet agents. 
 
CT indicates computed tomography; IV, intravenous; MRI, magnetic resonance imaging; and rtPA, 
recombinant tissue plasminogen activator 
 
 
 
 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
101 
19.12. Guidelines for Treatment of Patients with the Intracerebral Hemorrhage 
 
Adapted from: Guidelines for the Management of Spontaneous Intracerebral 
Hemorrhage (ICH): A Guideline for Healthcare Professionals From the American Heart 
Association/American Stroke Association (2010) 
 
 
Classification/Level of Evidence Scheme 
• 
Class I: Benefit>>>Risk; Procedure/treatment SHOULD be performed/administered 
• 
Class IIa: Benefit >> Risk; IT IS REASONABLE to perform procedure/administer 
treatment 
• 
Class IIb: Benefit≥Risk; Procedure/treatment MAY BE CONSIDERED 
• 
Class III: No Benefit OR Harm; Procedure/treatment is NOT 
RECOMMENDED/SHOULD NOT BE PERFORMED  
 
• 
Evidence Level A: Data derived from multiple randomized clinical trials or meta-
analyses 
• 
Evidence Level B: Data derived from a single randomized trial or non-randomized 
studies 
• 
Evidence Level C: Only consensus opinion of experts, case studies, or standard of 
care 
 
 
RECOMMENDATIONS 
 
Emergency Diagnosis and Assessment of ICH and Its Causes 
1. Rapid neuroimaging with CT or MRI is recommended to distinguish ischemic stroke 
from ICH (Class I; Level of Evidence: A).  
2. CT angiography and contrast-enhanced CT may be considered to help identify 
patients at risk for hematoma expansion (Class IIb; Level of Evidence: B), and CT 
angiography, CT venography, contrast-enhanced CT, contrast-enhanced MRI, 
magnetic resonance angiography, and magnetic resonance venography can be 
useful to evaluate for underlying structural lesions, including vascular malformations 
and tumors when there is clinical or radiological suspicion (Class IIa; Level of 
Evidence: B). 
 
Medical Treatment for ICH 
1. Patients with a severe coagulation factor deficiency or severe thrombocytopenia 
should receive appropriate factor replacement therapy or platelets, respectively 
(Class I; Level of Evidence: C). 
2. Patients with ICH whose INR is elevated due to OACs should have their warfarin 
withheld, receive therapy to replace vitamin K– dependent factors and correct the 
INR, and receive intravenous vitamin K (Class I; Level of Evidence: C).  
3. PCCs have not shown improved outcome compared with FFP but may have fewer 
complications compared with FFP and are reasonable to consider as an alternative 
to FFP (Class IIa; Level of Evidence: B).  
4. rFVIIa does not replace all clotting factors, and although the INR may be lowered, 
clotting may not be restored in vivo; therefore, rFVIIa is not routinely recommended 
as a sole agent for OAC reversal in ICH (Class III; Level of Evidence: C). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
102 
5. Although rFVIIa can limit the extent of hematoma expansion in noncoagulopathic 
ICH patients, there is an increase in thromboembolic risk with rFVIIa and no clear 
clinical benefit in unselected patients. Thus rFVIIa is not recommended in unselected 
patients. (Class III; Level of Evidence: A). Further research to determine whether any 
selected group of patients may benefit from this therapy is needed before any 
recommendation for its use can be made. 
6. The usefulness of platelet transfusions in ICH patients with a history of antiplatelet 
use is unclear and is considered investigational (Class IIb; Level of Evidence: B). 
7. Patients with ICH should have intermittent pneumatic compression for prevention of 
venous thromboembolism in addition to elastic stockings (Class I; Level of Evidence: 
B).  
8. After documentation of cessation of bleeding, low-dose subcutaneous low-molecular-
weight heparin or unfractionated heparin may be considered for prevention of venous 
thromboembolism in patients with lack of mobility after 1 to 4 days from onset (Class 
IIb; Level of Evidence: B). 
 
Blood Pressure 
1. Until ongoing clinical trials of BP intervention for ICH are completed, physicians must 
manage BP on the basis of the present incomplete efficacy evidence. Current 
suggested recommendations for target BP in various situations are listed in Table 1 
and may be considered (Class IIb; Level of Evidence: C).  
2. In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of 
systolic BP to 140 mm Hg is probably safe (Class IIa; Level of Evidence: B). 
 
 
Table 1. 
Suggested Recommended Guidelines for Treating Elevated BP in Spontaneous ICH 
 
 
1. If SBP is >200 mm Hg or MAP is >150 mm Hg, then consider aggressive reduction of BP with 
continuous intravenous infusion, with frequent BP monitoring every 5 min. 
2. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is the possibility of elevated ICP, then 
consider monitoring ICP and reducing BP using intermittent or continuous intravenous 
medications while maintaining a cerebral perfusion pressure >60 mm Hg. 
3. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is not evidence of elevated ICP, then 
consider a modest reduction of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg) using 
intermittent or continuous intravenous medications to control BP and clinically reexamine the 
patient every 15 min. 
 
 
Note that these recommendations are Class C. SBP indicates systolic blood pressure; MAP, mean arterial pressure. 
 
 
Management and Prevention of Secondary Brain Injury 
1. Initial monitoring and management of ICH patients should take place in an intensive 
care unit with physician and nursing neuroscience intensive care expertise (Class I; 
Level of Evidence: B). 
2. Glucose should be monitored and normoglycemia is recommended (Class I: Level of 
Evidence: C). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
103 
3. Clinical seizures should be treated with antiepileptic drugs (Class I; Level of 
Evidence: A).   
4. Continuous EEG monitoring is probably indicated in ICH patients with depressed 
mental status out of proportion to the degree of brain injury (Class IIa; Level of 
Evidence: B). 
5. Patients with a change in mental status who are found to have electrographic 
seizures on EEG should be treated with antiepileptic drugs (Class I; Level of 
Evidence: C).  
6. Prophylactic anticonvulsant medication should not be used (Class III; Level of 
Evidence: B). 
 
Procedures/Surgery 
1. Patients with a GCS score of <8, those with clinical evidence of transtentorial 
herniation, or those with significant IVH or hydrocephalus might be considered for 
ICP monitoring and treatment. A cerebral perfusion pressure of 50 to 70 mm Hg may 
be reasonable to maintain depending on the status of cerebral autoregulation (Class 
IIb; Level of Evidence: C).  
2. Ventricular drainage as treatment for hydrocephalus is reasonable in patients with 
decreased level of consciousness (Class IIa; Level of Evidence: B). 
 
Intraventricular Hemorrhage 
1. Although intraventricular administration of recombinant tissue-type plasminogen 
activator in IVH appears to have a fairly low complication rate, efficacy and safety of 
this treatment is uncertain and is considered investigational (Class IIb; Level of 
Evidence: B). 
 
Clot Removal 
2. For most patients with ICH, the usefulness of surgery is uncertain (Class IIb; Level of 
Evidence: C). Specific exceptions to this recommendation follow. 
3. Patients with cerebellar hemorrhage who are deteriorating neurologically or who 
have brainstem compression and/or hydrocephalus from ventricular obstruction 
should undergo surgical removal of the hemorrhage as soon as possible (Class I; 
Level of Evidence: B).  Initial treatment of these patients with ventricular drainage 
alone rather than surgical evacuation is not recommended (Class III; Level of 
Evidence: C).  
4. For patients presenting with lobar clots >30 mL and within 1 cm of the surface, 
evacuation of supratentorial ICH by standard craniotomy might be considered (Class 
IIb; Level of Evidence: B).  
5. The effectiveness of minimally invasive clot evacuation utilizing either stereotactic or 
endoscopic aspiration with or without thrombolytic usage is uncertain and is 
considered investigational (Class IIb; Level of Evidence: B).  
6. Although theoretically attractive, no clear evidence at present indicates that ultra-
early removal of supratentorial ICH improves functional outcome or mortality rate. 
Very early craniotomy may be harmful due to increased risk of recurrent bleeding 
(Class III; Level of Evidence: B). 
 
 
Outcome Prediction and Withdrawal of Technological Support 
1. Aggressive full care early after ICH onset and postponement of new DNR orders until 
at least the second full day of hospitalization is probably recommended (Class IIa; 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
104 
Level of Evidence: B). Patients with preexisting DNR orders are not included in this 
recommendation. Current methods of prognostication in individual patients early after 
ICH are likely biased by failure to account for the influence of withdrawal of support 
and early DNR orders. Patients who are given DNR status at any point should 
receive all other appropriate medical and surgical interventions unless otherwise 
explicitly indicated. 
 
Prevention of Recurrent ICH 
2. In situations where stratifying a patient’s risk of recurrent ICH may affect other 
management decisions, it is reasonable to consider the following risk factors for 
recurrence: lobar location of the initial ICH, older age, ongoing anticoagulation, 
presence of the apolipoprotein E E2 or E4 alleles, and greater number of 
microbleeds on MRI (Class IIa; Level of Evidence: B).  
3. After the acute ICH period, absent medical contra- indications, BP should be well 
controlled, particularly for patients with ICH location typical of hypertensive 
vasculopathy (Class I; Level of Evidence: A).  
4. After the acute ICH period, a goal target of a normal BP of <140/90 (<130/80 if 
diabetes or chronic kidney disease) is reasonable (Class IIa; Level of Evidence: B). 
5. Avoidance of long-term anticoagulation as treatment for nonvalvular atrial fibrillation 
is probably recommended after spontaneous lobar ICH because of the relatively high 
risk of recurrence (Class IIa; Level of Evidence: B).  
6. Anticoagulation after nonlobar ICH and antiplatelet therapy after all ICH might be 
considered, particularly when there are definite indications for these agents (Class 
IIb; Level of Evidence: B).  
7. Avoidance of heavy alcohol use can be beneficial (Class IIa; Level of Evidence: B).  
8. There is insufficient data to recommend restrictions on use of statin agents or 
physical or sexual activity (Class IIb; Level of Evidence: C). 
 
Rehabilitation and Recovery 
1. Given the potentially serious nature and complex pattern of evolving disability, it is 
reasonable that all patients with ICH have access to multidisciplinary rehabilitation 
(Class IIa; Level of Evidence: B).  
2. Where possible, rehabilitation can be beneficial when begun as early as possible and 
continued in the community as part of a well-coordinated (seamless) program of 
accelerated hospital discharge and home-based resettlement to promote ongoing 
recovery (Class IIa; Level of Evidence: B). 
 
 
 
 
 
 
 
 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
105 
19.13. Guidelines for Treatment of Patients With Subarachnoid Hemorrhage 
 
Adapted from: Guidelines for the Management of Aneurysmal Subarachnoid 
Hemorrhage (aSAH); A Guideline for Healthcare Professionals From the American 
Heart Association/American Stroke Association (2012) 
 
 
Classification/Level of Evidence Scheme 
• 
Class I: Benefit>>>Risk; Procedure/treatment SHOULD be performed/administered 
• 
Class IIa: Benefit >> Risk; IT IS REASONABLE to perform procedure/administer 
treatment 
• 
Class IIb: Benefit≥Risk; Procedure/treatment MAY BE CONSIDERED 
• 
Class III: No Benefit OR Harm; Procedure/treatment is NOT 
RECOMMENDED/SHOULD NOT BE PERFORMED  
 
• 
Evidence Level A: Data derived from multiple randomized clinical trials or meta-
analyses 
• 
Evidence Level B: Data derived from a single randomized trial or non-randomized 
studies 
• 
Evidence Level C: Only consensus opinion of experts, case studies, or standard of 
care 
 
 
Recommendations 
 
Clinical Manifestations and Diagnosis of aSAH 
1. aSAH is a medical emergency that is frequently misdiagnosed. A high level of 
suspicion for aSAH should exist in patients with acute onset of severe headache 
(Class I; Level of Evidence B). 
2. Acute diagnostic workup should include noncontrast head CT, which, if 
nondiagnostic, should be followed by lumbar puncture (Class I; Level of Evidence B). 
3. CTA may be considered in the workup of aSAH. If an aneurysm is detected by CTA, 
this study may help guide the decision for type of aneurysm repair, but if CTA is 
inconclusive, DSA is still recommended (except possibly in the instance of classic 
perimesencephalic aSAH) (Class IIb; Level of Evidence C). 
4. Magnetic resonance imaging (fluid-attenuated inversion recovery, proton density, 
diffusion-weighted imaging, and gradient echo sequences) may be reasonable for 
the diagnosis of aSAH in patients with a nondiagnostic CT scan, although a negative 
result does not obviate the need for cerebrospinal fluid analysis (Class IIb; Level of 
Evidence C) 
5. DSA with 3-dimensional rotational angiography is indicated for detection of aneurysm 
in patients with aSAH (except when the aneurysm was previously diagnosed by a 
noninvasive angiogram) and for planning treatment (to determine whether an 
aneurysm is amenable to coiling or to expedite microsurgery) (Class I; Level of 
Evidence B). 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
106 
Medical Measures to Prevent Rebleeding After aSAH 
1. Between the time of aSAH symptom onset and aneurysm obliteration, blood 
pressure should be controlled with a titratable agent to balance the risk of stroke, 
hypertension-related rebleeding, and maintenance of cerebral perfusion pressure 
(Class I; Level of Evidence B). 
2. The magnitude of blood pressure control to reduce the risk of rebleeding has not 
been established, but a decrease in systolic blood pressure to <160 mm Hg is 
reasonable (Class IIa; Level of Evidence C).  
3. For patients with an unavoidable delay in obliteration of aneurysm, a significant risk 
of rebleeding, and no compelling medical contraindications, short-term (<72 hours) 
therapy with tranexamic acid or aminocaproic acid is reasonable to reduce the risk of 
early aneurysm rebleeding (Class IIa; Level of Evidence B). 
 
Surgical and Endovascular Methods of Treatment of Ruptured Cerebral Aneurysms 
1. Surgical clipping or endovascular coiling of the ruptured aneurysm should be 
performed as early as feasible in the majority of patients to reduce the rate of 
rebleeding after aSAH (Class I; Level of Evidence B). 
2. Complete obliteration of the aneurysm is recommended whenever possible (Class I; 
Level of Evidence B). 
3. Determination of aneurysm treatment, as judged by both experienced 
cerebrovascular surgeons and endovascular specialists, should be a multidisciplinary 
decision based on characteristics of the patient and the aneurysm (Class I; Level of 
Evidence C). 
4. For patients with ruptured aneurysms judged to be technically amenable to both 
endovascular coiling and neurosurgical clipping, endovascular coiling should be 
considered (Class I; Level of Evidence B). 
5. In the absence of a compelling contraindication, patients who undergo coiling or 
clipping of a ruptured aneurysm should have delayed follow-up vascular imaging 
(timing and modality to be individualized), and strong consideration should be given 
to retreatment, either by repeat coiling or microsurgical clipping, if there is a clinically 
significant (eg, growing) remnant (Class I; Level of Evidence B). 
6. Microsurgical clipping may receive increased consideration in patients presenting 
with large (>50 mL) intraparenchymal hematomas and middle cerebral artery 
aneurysms. Endovascular coiling may receive increased consideration in the elderly 
(>70 years of age), in those presenting with poor-grade (World Federation of 
Neurological Surgeons classification IV/V) aSAH, and in those with aneurysms of the 
basilar apex (Class IIb; Level of Evidence C). 
7. Stenting of a ruptured aneurysm is associated with increased morbidity and mortality, 
and should only be considered when less risky options have been excluded (Class 
III; Level of Evidence C). 
 
Anesthetic Management During Surgical and Endovascular Treatment 
1. Minimization of the degree and duration of intraoperative hypotension during 
aneurysm surgery is probably indicated (Class IIa; Level of Evidence B). 
2. There are insufficient data on pharmacological strategies and induced hypertension 
during temporary vessel occlusion to make specific recommendations, but there are 
instances when their use may be considered reasonable (Class IIb; Level of 
Evidence C). 
3. Induced hypothermia during aneurysm surgery is not routinely recommended but 
may be a reasonable option in selected cases (Class III; Level of Evidence B). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
107 
4. Prevention of intraoperative hyperglycemia during aneurysm surgery is probably 
indicated (Class IIa; Level of Evidence B). 
5. The use of general anesthesia during endovascular treatment of ruptured cerebral 
aneurysms can be beneficial in selected patients (Class IIa; Level of Evidence C). 
 
Management of Cerebral Vasospasm and Delayed Cerebral Ischemia (DCI) after aSAH 
1. Oral nimodipine should be administered to all patients with aSAH (Class I; Level of 
Evidence A). (It should be noted that this agent has been shown to improve 
neurological outcomes but not cerebral vasospasm. The value of other calcium 
antagonists, whether administered orally or intravenously, remains uncertain.) 
2. Maintenance of euvolemia and normal circulating blood volume is recommended to 
prevent DCI (Class I; Level of Evidence B). 
3. Prophylactic hypervolemia or balloon angioplasty before the development of 
angiographic spasm is not recommended (Class III; Level of Evidence B). (New 
recommendation) 
4. Transcranial Doppler is reasonable to monitor for the development of arterial 
vasospasm (Class IIa; Level of Evidence B). 
5. Perfusion imaging with CT or magnetic resonance can be useful to identify regions of 
potential brain ischemia (Class IIa; Level of Evidence B). 
6. Induction of hypertension is recommended for patients with DCI unless blood 
pressure is elevated at baseline or cardiac status precludes it (Class I; Level of 
Evidence B). 
7. Cerebral angioplasty and/or selective intra-arterial vasodilator therapy is reasonable 
in patients with symptomatic cerebral vasospasm, particularly those who are not 
rapidly responding to hypertensive therapy (Class IIa; Level of Evidence B). 
 
Management of Hydrocephalus Associated With aSAH 
1. aSAH-associated acute symptomatic hydrocephalus should be managed by 
cerebrospinal fluid diversion (EVD or lumbar drainage, depending on the clinical 
scenario) (Class I; Level of Evidence B).  
2. aSAH-associated chronic symptomatic hydrocephalus should be treated with 
permanent cerebrospinal fluid diversion (Class I; Level of Evidence C). 
3. Weaning EVD over >24 hours does not appear to be effective in reducing the need 
for ventricular shunting (Class III; Level of Evidence B). 
4. Routine fenestration of the lamina terminalis is not useful for reducing the rate of 
shunt-dependent hydrocephalus and therefore should not be routinely performed. 
(Class III; Level of Evidence B). 
 
Management of Seizures Associated With aSAH 
1. The use of prophylactic anticonvulsants may be considered in the immediate post-
hemorrhagic period (Class IIb; Level of Evidence B). 
2. The routine long-term use of anticonvulsants is not recommended (Class III; Level of 
Evidence B) but may be considered for patients with known risk factors for delayed 
seizure disorder, such as prior seizure, intracerebral hematoma, intractable hyper- 
tension, infarction, or aneurysm at the middle cerebral artery (Class IIb; Level of 
Evidence B). 
 
Management of Medical Complications Associated With aSAH 
1. Administration of large volumes of hypotonic fluids and intravascular volume 
contraction is not recommended after aSAH (Class III; Level of Evidence B). 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
108 
2. Monitoring volume status in certain patients with recent aSAH by some combination 
of central venous pressure, pulmonary wedge pressure, and fluid balance is 
reasonable, as is treatment of volume con- traction with crystalloid or colloid fluids 
(Class IIa; Level of Evidence B). 
3. Aggressive control of fever to a target of normothermia by use of standard or 
advanced temperature modulating systems is reasonable in the acute phase of 
aSAH (Class IIa; Level of Evidence B). 
4. Careful glucose management with strict avoidance of hypoglycemia may be 
considered as part of the general critical care management of patients with aSAH 
(Class IIb; Level of Evidence B). 
5. The use of packed red blood cell transfusion to treat anemia might be reasonable in 
patients with aSAH who are at risk of cerebral ischemia. The optimal hemoglobin 
goal is still to be determined (Class IIb; Level of Evidence B). 
6. The use of fludrocortisone acetate and hypertonic saline solution is reasonable for 
preventing and correcting hyponatremia (Class IIa; Level of Evidence B). 
7. Heparin-induced thrombocytopenia and deep venous thrombosis are relatively 
frequent complications after aSAH. Early identification and targeted treatment are 
recommended, but further research is needed to identify the ideal screening 
paradigms (Class I; Level of Evidence B).  
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
109 
19.14. Guide for Addressing Arctic Sun Water Temperature Below 25°C 
 
Note:  The following information is intended to assist the investigator/clinician in assessing 
an Arctic Sun water temperature ≤25°C.  Pictures of the Arctic Sun screen are provided for 
illustrative purposes only and may not represent what is observed in an actual clinical setting. 
 
 
Routine Assessment 
 
The Arctic Sun water temperature should be assessed hourly by the bedside nurse to 
determine if the system is working to cool the patient (water temperature for a normothermic 
patient is typically 28⁰-30⁰C).  If the water temperature is ≤25⁰C this could indicate that the 
subject is generating heat (fever or shivering). 
 
Assessing Potential Heat Generation 
 
Potential Shivering 
If the water temperature is ≤25⁰C, assess the patient for signs of shivering.  This can 
be performed by visually assessing the patient for obvious shivering and/or by 
palpation of the masseter, neck, or chest wall.  You may also look for irregularity of 
the baseline on your limb leads (any of the conductors connected to the 
electrocardiograph).  If shivering is detected or suspected, implement Tier 1 of the 
shiver control measures, or the next appropriate Tier if shiver control measures have 
already been implemented. (See section 6.10 of the protocol) 
 
Potential Fever 
If shivering is not detected or implementation of shiver control measures do not raise 
the water temperature (heat still being generated), you should consider a potential 
source of fever.  A fever work-up should be performed including any standard tests or 
diagnostic procedures performed as standard of care.  Empiric antimicrobials should 
be prescribed according to physician orders and in compliance with institutional 
guidance.  Please refer to Guidelines for evaluation of new fever in critically ill adult 
patients: 2008 update from the American College of Critical Care Medicine and the 
Infectious Diseases Society of America for additional recommendations. 
 
Other Potential Sources of Heat 
It is possible that heat can be generated from sources other than shivering or fever 
(e.g., heated ventilator).  If the water temperature remains low, check for other 
sources of heat generation and consider if additional action is necessary. 
 
 
Supplemental Information 
    
The Arctic Sun® Temperature Management System measures temperature in 0.01°C 
increments and can internally identify change before it shows on the display screen.  The 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
110 
Patient Temperature Trend Indicator reflects the rate of change in the patient’s temperature 
over the previous 5 minutes.  When assessing a patient, the clinician may refer to the Patient 
Temperature Trend Indicator for insight into patient heat generation which may be indicative 
of shivering or fever generation. 
Patient Trend Indicator 
 
 
The Patient Trend Indicator can be found in the upper center of the display screen.  Trends in 
temperature will be displayed in the following way:  
• 
Center bar- no change or less than 0.25°C change per hour 
• 
One arrow (up or down) - 0.25°C to 0.5°C change per hour 
• 
Two arrows (up or down) - 0.5°C to 0.75°C change per hour 
• 
Three arrows (up or down) - 0.75°C to 2.0°C change per hour 
• 
Four arrows (up or down) - > 2.0°C change per hour 
 
Example 1:  Thermoneutral 
 
 
Example 2: Patient Possibly Generating Heat 
 
 
 
 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0

Bard Medical Division 
 
FINAL 
Targeted Temperature Management 
 
March 9, 2020  
Protocol #BMD-1111 Version 7.0 
111 
19.15. Major Adverse Event Definition Guidance 
 
A.  Pneumonia Definition (Modified CDC Definition) 
 
Imaging Test Evidence 
Signs/Symptoms/Laboratory 
Two or more serial chest imaging 
test results with at least one of the 
following: 
New and persistent OR progressive 
and persistent 
• 
Infiltrate 
• 
Consolidation 
• 
Cavitation 
 
Note: In patients without underlying 
pulmonary or cardiac disease (e.g., 
respiratory distress syndrome, 
bronchopulmonary dysplasia, 
pulmonary edema, or chronic 
obstructive pulmonary disease), one 
definitive imaging test result is 
acceptable. 
For ANY PATIENT, at least one of the following: 
• 
Fever (>38.0°C or >100.4°F) OR Arctic Sun water 
temperature consistently below 25°C for at least 2 
hours despite all efforts to control potential 
shivering 
• 
Leukopenia (≤4000 WBC/mm3) or leukocytosis 
(>12,000 WBC/mm3) 
• 
For adults >70 years old, altered mental status with 
no other recognized cause 
 
And at least two of the following: 
• 
New onset of purulent sputum or change in 
character of sputum, or increased respiratory 
secretions, or increased suctioning requirements 
• 
New onset or worsening cough, or dyspnea, or 
tachypnea 
• 
Rales or bronchial breath sounds 
• 
Worsening gas exchange (e.g., O2 desaturations 
(e.g., PaO2/FiO2 <240), increased oxygen 
requirements, or increased ventilator demand) 
 
 
B.  Malignant Cerebral Edema Definition 
 
• Neurological deterioration that manifests after the first 8-12 hours after injury as 
measured by a standardized scale (e.g. NIHSS, GCS) 
• Evidence of mass effect or sulcal effacement, which may manifest as progressive 
midline shift on neuroimaging 
• Clinical attribution of deterioration to swelling 
 
C.  Sepsis Definition (From: The Third International Consensus Definitions for Sepsis and 
Septic Shock) 
 
• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host 
response to infection. 
• Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points 
consequent to the infection. 
BMD-1111--- Protocol | VV-TMF-28853
Downloaded on 01 Nov 2022
System Version Number 2.0