Fever, Intracerebral Hemorrhage, Ischemic Stroke, Subarachnoid Hemorrhage
Conditions
Keywords
Targeted Temperature Management
Brief summary
This study will assess the impact of fever prevention on fever burden and short- and long-term neurologic outcomes in brain injured patients. Half of the subjects will undergo fever prevention using a targeted temperature management system and half of the subjects will be treated for fever should it develop.
Detailed description
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 will be treated with standard fever care measures according to a step-wise algorithm, consisting primarily of intermittent antipyretics (e.g., acetaminophen) and cooling blankets and, when necessary, advanced targeted temperature management devices.
Interventions
Prophylactic normothermia
OTHERStandard Care
No intervention to control temperature unless fever occurs
Sponsors
Yale University
Boston University
C. R. Bard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Admitted with a primary neurological diagnosis of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage 2. Prior to onset of acute symptoms, was considered functionally independent (mRS 0-2) 3. Meets disease-specific criteria
Exclusion criteria
1. Fever (≥38°C) prior to study enrollment 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 3. Has a pre-morbid condition with poor likelihood of survival to 6 months 4. Has a pre-morbid mRS ≥3 5. Diagnosed with brain death 6. Is undergoing therapeutic hypothermia therapy 7. Has sustained neurological injury felt to be catastrophic with little chance of recovery 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) 9. Has poor skin integrity or poor tissue perfusion 10. Participation in a concurrent investigational / interventional study (medical device or drug)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fever Burden | Up to 14 days | Daily average fever burden (°C-hour) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Other Neurologic Outcomes: NIH Stroke Scale Mid-Term | 6-months post injury | NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome. |
| Major Adverse Events | From date of randomization until end of study, assessed up to 12 months | MAEs defined as one of the following: pneumonia, sepsis, malignant cerebral edema, death |
| Number of Participants With Infection | From date of randomization until hospital discharge, assessed up to 30 days | Healthcare associated infection |
| Number of Subjects With Shivering | Up to 14 days | Shivering greater than or equal to 1 on the Bedside Shivering Assessment Scale (BSAS). BSAS scores range from 0-3 with 0 indicating no shivering noted and 3 indicating severe shivering involving gross movements of the trunk and upper and lower extremities. |
| Primary Neurologic Outcome: Modified Rankin Scale Short-Term | 3-months post injury | Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death. |
| Other Neurologic Outcomes: NIH Stroke Scale Short-Term | 3-months post injury | NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome. |
| Other Neurologic Outcomes: Barthel Index Short-Term | 3-months post injury | Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome. |
| Other Neurologic Outcomes: Glasgow Outcome Scale Extended Short-Term | 3-months post injury | Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome. |
| Other Neurologic Outcomes: Montreal Cognitive Assessment Short-Term | 3-months post injury | Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome. |
| Primary Neurologic Outcome: Modified Rankin Scale Mid-Term | 6-months post injury | Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death. |
| Other Neurologic Outcomes: Barthel Index Mid-Term | 6-months post injury | Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome. |
| Other Neurologic Outcomes: Glasgow Outcome Scale Extended Mid-Term | 6-months post injury | Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome. |
| Other Neurologic Outcomes: Montreal Cognitive Assessment Mid-Term | 6-months post injury | Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome. |
| Primary Neurologic Outcome: Modified Rankin Scale Long-Term | 12-months post injury | Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death. |
| Adverse Events | From date of randomization until hospital discharge, assessed up to 30 days | An untoward medical occurrence, unintended disease or injury, or unanticipated complication |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 7-day (or hospital discharge); 3-, 6-, and 12-months | Mortality |
| Hospital Length of Stay | From date of randomization until hospital discharge, assessed up to 90 days | Overall hospitalization duration |
| ICU Length of Stay | From date of randomization until ICU discharge | ICU Duration |
Countries
Australia, Austria, Germany, South Korea, Switzerland, United States
Participant flow
Pre-assignment details
Subjects screen failed after signing consent (n=9): Disease-specific criteria (Not met) = 3 Fever at time of study = 1 Fever for more than one hour or one instance prior to study enrollment = 3 Fever at time of randomization = 1 Aneurysmal SAH confirmed within 24 hours of symptom onset = 1
Participants by arm
| Arm | Count |
|---|---|
| Fever Prevention Fever will be prevented using a surface targeted temperature management system
Targeted Temperature Management: Prophylactic normothermia | 339 |
| Standard Care Standard care in which fever may spontaneously develop
Standard Care: No intervention to control temperature unless fever occurs | 338 |
| Total | 677 |
Baseline characteristics
| Characteristic | Fever Prevention | Standard Care | Total |
|---|---|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 13.22 | 60.4 years STANDARD_DEVIATION 13.86 | 60.7 years STANDARD_DEVIATION 13.54 |
| Baseline Severity High (NIHSS ≥17, ICH ≥3, or WFNS ≥IV) | 156 Participants | 158 Participants | 314 Participants |
| Baseline Severity Low (NIHSS <17, ICH ≤2, or WFNS ≤III) | 182 Participants | 180 Participants | 362 Participants |
| BMI | 28.51 kg/m^2 STANDARD_DEVIATION 6.829 | 28.60 kg/m^2 STANDARD_DEVIATION 6.827 | 28.56 kg/m^2 STANDARD_DEVIATION 6.823 |
| Clinical Diagnosis Intracerebral Hemmorrhage (ICH) | 111 Participants | 112 Participants | 223 Participants |
| Clinical Diagnosis Ischemic Stroke (IS) | 128 Participants | 126 Participants | 254 Participants |
| Clinical Diagnosis Subarachnoid Hemorrhage (SAH) | 100 Participants | 100 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 26 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 307 Participants | 312 Participants | 619 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 68 Participants | 66 Participants | 134 Participants |
| Race (NIH/OMB) Black or African American | 56 Participants | 68 Participants | 124 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) White | 204 Participants | 189 Participants | 393 Participants |
| Region of Enrollment Austria | 19 participants | 18 participants | 37 participants |
| Region of Enrollment Germany | 32 participants | 30 participants | 62 participants |
| Region of Enrollment South Korea | 55 participants | 57 participants | 112 participants |
| Region of Enrollment Switzerland | 10 participants | 9 participants | 19 participants |
| Region of Enrollment United States | 223 participants | 224 participants | 447 participants |
| Sex: Female, Male Female | 177 Participants | 168 Participants | 345 Participants |
| Sex: Female, Male Male | 162 Participants | 170 Participants | 332 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 75 / 339 | 77 / 338 |
| other Total, other adverse events | 122 / 331 | 48 / 336 |
| serious Total, serious adverse events | 150 / 331 | 132 / 336 |
Outcome results
Primary
Fever Burden
Daily average fever burden (°C-hour)
Time frame: Up to 14 days
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Fever Burden | 0.37 °C-hour | Standard Deviation 0.961 |
| Standard Care | Fever Burden | 0.73 °C-hour | Standard Deviation 1.075 |
Secondary
Adverse Events
An untoward medical occurrence, unintended disease or injury, or unanticipated complication
Time frame: From date of randomization until hospital discharge, assessed up to 30 days
Population: As Treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fever Prevention | Adverse Events | Any Adverse Event during the Acute Phase | 933 Adverse Events |
| Fever Prevention | Adverse Events | Any Adverse Event after the acute phase | 71 Adverse Events |
| Fever Prevention | Adverse Events | Serious Adverse Event during the acute phase | 287 Adverse Events |
| Fever Prevention | Adverse Events | Serious Adverse Event after the acute phase | 68 Adverse Events |
| Standard Care | Adverse Events | Serious Adverse Event after the acute phase | 88 Adverse Events |
| Standard Care | Adverse Events | Any Adverse Event during the Acute Phase | 764 Adverse Events |
| Standard Care | Adverse Events | Serious Adverse Event during the acute phase | 223 Adverse Events |
| Standard Care | Adverse Events | Any Adverse Event after the acute phase | 97 Adverse Events |
Secondary
Major Adverse Events
MAEs defined as one of the following: pneumonia, sepsis, malignant cerebral edema, death
Time frame: From date of randomization until end of study, assessed up to 12 months
Population: As Treated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fever Prevention | Major Adverse Events | MAE through 3 months | 213 Major Adverse Events |
| Fever Prevention | Major Adverse Events | MAE through 6 months | 228 Major Adverse Events |
| Fever Prevention | Major Adverse Events | MAE through 12 months | 235 Major Adverse Events |
| Standard Care | Major Adverse Events | MAE through 3 months | 201 Major Adverse Events |
| Standard Care | Major Adverse Events | MAE through 6 months | 227 Major Adverse Events |
| Standard Care | Major Adverse Events | MAE through 12 months | 241 Major Adverse Events |
Secondary
Number of Participants With Infection
Healthcare associated infection
Time frame: From date of randomization until hospital discharge, assessed up to 30 days
Population: As Treated
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fever Prevention | Number of Participants With Infection | 112 Participants |
| Standard Care | Number of Participants With Infection | 116 Participants |
Secondary
Number of Subjects With Shivering
Shivering greater than or equal to 1 on the Bedside Shivering Assessment Scale (BSAS). BSAS scores range from 0-3 with 0 indicating no shivering noted and 3 indicating severe shivering involving gross movements of the trunk and upper and lower extremities.
Time frame: Up to 14 days
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fever Prevention | Number of Subjects With Shivering | 283 Participants |
| Standard Care | Number of Subjects With Shivering | 82 Participants |
Secondary
Other Neurologic Outcomes: Barthel Index Mid-Term
Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome.
Time frame: 6-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Barthel Index Mid-Term | 65.4 Barthel Index Score | Standard Deviation 35.96 |
| Standard Care | Other Neurologic Outcomes: Barthel Index Mid-Term | 69.0 Barthel Index Score | Standard Deviation 35.26 |
Secondary
Other Neurologic Outcomes: Barthel Index Short-Term
Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome.
Time frame: 3-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Barthel Index Short-Term | 61.0 Barthel Index Score | Standard Deviation 36.35 |
| Standard Care | Other Neurologic Outcomes: Barthel Index Short-Term | 59.6 Barthel Index Score | Standard Deviation 38.14 |
Secondary
Other Neurologic Outcomes: Glasgow Outcome Scale Extended Mid-Term
Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome.
Time frame: 6-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Glasgow Outcome Scale Extended Mid-Term | 3.6 Glasgow Outcome Scale Extended Score | Standard Deviation 2.21 |
| Standard Care | Other Neurologic Outcomes: Glasgow Outcome Scale Extended Mid-Term | 3.6 Glasgow Outcome Scale Extended Score | Standard Deviation 2.22 |
Secondary
Other Neurologic Outcomes: Glasgow Outcome Scale Extended Short-Term
Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome.
Time frame: 3-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Glasgow Outcome Scale Extended Short-Term | 3.4 Glasgow Outcome Scale Extended Score | Standard Deviation 1.98 |
| Standard Care | Other Neurologic Outcomes: Glasgow Outcome Scale Extended Short-Term | 3.6 Glasgow Outcome Scale Extended Score | Standard Deviation 1.96 |
Secondary
Other Neurologic Outcomes: Montreal Cognitive Assessment Mid-Term
Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome.
Time frame: 6-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Montreal Cognitive Assessment Mid-Term | 19.1 MOCA Score | Standard Deviation 8.93 |
| Standard Care | Other Neurologic Outcomes: Montreal Cognitive Assessment Mid-Term | 20.0 MOCA Score | Standard Deviation 9.3 |
Secondary
Other Neurologic Outcomes: Montreal Cognitive Assessment Short-Term
Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome.
Time frame: 3-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: Montreal Cognitive Assessment Short-Term | 17.6 MOCA Score | Standard Deviation 9.42 |
| Standard Care | Other Neurologic Outcomes: Montreal Cognitive Assessment Short-Term | 19.1 MOCA Score | Standard Deviation 9.62 |
Secondary
Other Neurologic Outcomes: NIH Stroke Scale Mid-Term
NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome.
Time frame: 6-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: NIH Stroke Scale Mid-Term | 4.9 NIHSS Score | Standard Deviation 5.05 |
| Standard Care | Other Neurologic Outcomes: NIH Stroke Scale Mid-Term | 5.6 NIHSS Score | Standard Deviation 7.38 |
Secondary
Other Neurologic Outcomes: NIH Stroke Scale Short-Term
NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome.
Time frame: 3-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Other Neurologic Outcomes: NIH Stroke Scale Short-Term | 6.3 NIHSS Score | Standard Deviation 6.3 |
| Standard Care | Other Neurologic Outcomes: NIH Stroke Scale Short-Term | 6.7 NIHSS Score | Standard Deviation 8.22 |
Secondary
Primary Neurologic Outcome: Modified Rankin Scale Long-Term
Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.
Time frame: 12-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Primary Neurologic Outcome: Modified Rankin Scale Long-Term | 3.5 mRS score | Standard Deviation 1.58 |
| Standard Care | Primary Neurologic Outcome: Modified Rankin Scale Long-Term | 3.3 mRS score | Standard Deviation 1.64 |
Secondary
Primary Neurologic Outcome: Modified Rankin Scale Mid-Term
Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.
Time frame: 6-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Primary Neurologic Outcome: Modified Rankin Scale Mid-Term | 3.5 mRS score | Standard Deviation 1.5 |
| Standard Care | Primary Neurologic Outcome: Modified Rankin Scale Mid-Term | 3.4 mRS score | Standard Deviation 1.6 |
Secondary
Primary Neurologic Outcome: Modified Rankin Scale Short-Term
Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.
Time frame: 3-months post injury
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Primary Neurologic Outcome: Modified Rankin Scale Short-Term | 3.7 mRS score | Standard Deviation 1.41 |
| Standard Care | Primary Neurologic Outcome: Modified Rankin Scale Short-Term | 3.6 mRS score | Standard Deviation 1.43 |
Other Pre-specified
Hospital Length of Stay
Overall hospitalization duration
Time frame: From date of randomization until hospital discharge, assessed up to 90 days
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | Hospital Length of Stay | 25.3 Days | Standard Deviation 17.56 |
| Standard Care | Hospital Length of Stay | 22.9 Days | Standard Deviation 16.04 |
Other Pre-specified
ICU Length of Stay
ICU Duration
Time frame: From date of randomization until ICU discharge
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fever Prevention | ICU Length of Stay | 335.096 Hours | Standard Deviation 294.5559 |
| Standard Care | ICU Length of Stay | 312.949 Hours | Standard Deviation 287.09 |
Other Pre-specified
Mortality
Mortality
Time frame: 7-day (or hospital discharge); 3-, 6-, and 12-months
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fever Prevention | Mortality | 75 Participants |
| Standard Care | Mortality | 77 Participants |