Subarachnoid Hemorrhage, Subdural Hematoma, Traumatic Brain Injury, Ischemic Stroke, Fever, Intracerebral Hemorrhage
Conditions
Keywords
fever, central fever, neurogenic fever, hyperthermia, bromocriptine, subarachnoid hemorrhage, SAH, subdural hematoma, SDH, intracerebral hemorrhage, ICH, traumatic brain injury, TBI, ischemic stroke
Brief summary
The purpose of this study is to evaluate the antipyretic effect of bromocriptine in critically-ill patients with acute neurologic injury and fever from infectious and non-infectious etiologies.
Detailed description
In patients with acute neurologic injury such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke, fever has been found to be an independent predictor of poor outcome including increased mortality rates, longer hospital stays, depressed level of consciousness, and worse functional outcomes. Our current antipyretic therapy of acetaminophen and sometimes nonsteroidal anti-inflammatory drugs are not very effective and external cooling requires sedatives and other medications to prevent shivering and pain. Bromocriptine is a dopamine D2 receptor agonist which acts at the hypothalamus, a specific area of the brain that regulates body temperature. Fevers of both central and infectious etiologies must be regulated through the hypothalamus and we have evidence that bromocriptine has an antipyretic effect at the hypothalamus; thus, we hypothesize that bromocriptine could be used safely and more broadly to treat all fevers in the acute setting and not just refractory central fevers in this patient population. Here, we propose to evaluate the acute antipyretic effects of bromocriptine in this critically-ill population through a pilot, open label, blinded endpoint, randomized controlled trial. In both enrolling centers, University of California, San Francisco Medical Center Parnassus (UCSF) and Zuckerberg San Francisco General Hospital, every patient who is admitted to the neurointensive care unit for an anticipated stay of greater than 48 hours with a diagnosis of subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke will be screened and consented. If they have a temperature reading ≥ 38.3 ºC, the investigational pharmacy will randomize them to the control arm of acetaminophen or the intervention arm of acetaminophen and bromocriptine for 48 hours. We will continuously measure their temperature and other vitals data. Retrospectively, we will review imaging and labs ordered to work up infectious etiologies of fever. The ICU nurse will do a 5 minute assessment every shift during the 48 hour study period for side effects. The temperature data will be analyzed between the two study arms.
Interventions
DRUGBromocriptine 5 MG
Bromocriptine 5 mg every 4 hours PO/NG/FT
Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The data analyst who will analyze the data from each patient will be masked to what medication(s) the patients received.
Intervention model description
open label, blinded endpoint, randomized (1:1) controlled trial with two arms: control - acetaminophen and intervention - acetaminophen and bromocriptine.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* age ≥18 years old * weight ≥ 40 kg * one reading of body temperature ≥ 38.3 ºC * diagnosis of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, subdural hematoma, or ischemic stroke * admission to the Intensive Care Unit at UCSF Medical Center or Zuckerberg San Francisco General Hospital.
Exclusion criteria
* bromocriptine or acetaminophen hypersensitivity or allergy * known contraindication to bromocriptine- known ergot alkaloid hypersensitivity, known history of syncopal migraine * contraindication to nasogastric tube or swallowing pills * current diagnosis of acute liver failure, acute liver injury, or prior diagnosis of cirrhosis. acute presentation (\< 26 weeks), evidence of coagulation abnormality: international normalized ratio (INR) ≥ 2; evidence of liver damage: alanine aminotransferase (ALT) of 10 x normal value; and any degree of mental status alteration * currently being treated with intra or extravascular therapeutic hypothermia - or where therapeutic hypothermia treatment is anticipated during study period * hyperthermic syndromes: heat stroke, evidence of thyrotoxicosis, malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia * administration of acetaminophen or acetaminophen containing medications within 9 hours prior to fever presentation * administration of non-steroidal anti-inflammatory drugs (NSAIDs) within 6 hours prior to fever presentation or aspirin \> 300mg less than 1 hour prior to fever presentation. * pregnancy * extracorporeal blood circuit therapies: replacement therapy, extracorporeal life support (ventricular assist device, extracorporeal membrane oxygenation) during study period * anticipated ICU stay \< 48 hours' * creatinine clearance ≤ 30 * severe cardiovascular disease (especially unstable angina or severe valvular disease) * patients already taking bromocriptine for other indications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Temperature Burden | over 48 hours | Mean total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Nursing assessment at every shift during 48 hour study period after first drug administration | Episodes of symptomatic hypotension, including decrease in supine systolic and diastolic pressures of greater than 20mm and 10mm Hg respectively with patient reported accompanying symptoms of light headedness or dizziness and incidence of nausea and headache. |
| Total Time That Temperature is ≥ 38.3ºC | 48 hours | Time in minutes where the temperature is ≥ 38.3ºC during the 48 hours of control versus intervention administration. |
| Total Time to First Temperature < 37.5ºC | 48 hours | Time in minutes it took after medication administration for the temperature to reach \< 37.5ºC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acetaminophen Standard of care - acetaminophen 650mg every 4 hours PO/NG/FT (per oral, nasogastric tube, feeding tube) for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC. | 20 |
| Bromocriptine and Acetaminophen Bromocriptine 5mg every 4 hours PO/NG/FT for 48 hours and acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC. | 24 |
| Total | 44 |
Baseline characteristics
| Characteristic | Acetaminophen | Bromocriptine and Acetaminophen | Total |
|---|---|---|---|
| Age, Continuous | 56.5 years | 60.5 years | 59.5 years |
| Race/Ethnicity, Customized Asian/Pacific Islander | 4 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized Hispanic | 6 Participants | 9 Participants | 15 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 20 Participants | 24 Participants | 44 Participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 10 Participants | 16 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 1 / 26 |
| other Total, other adverse events | 17 / 21 | 23 / 26 |
| serious Total, serious adverse events | 0 / 21 | 1 / 26 |
Outcome results
Primary
Temperature Burden
Mean total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication.
Time frame: over 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetaminophen | Temperature Burden | 37.8 Temperature in degrees Celsius | Standard Deviation 0.5 |
| Bromocriptine and Acetaminophen | Temperature Burden | 37.7 Temperature in degrees Celsius | Standard Deviation 0.6 |
Secondary
Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache
Episodes of symptomatic hypotension, including decrease in supine systolic and diastolic pressures of greater than 20mm and 10mm Hg respectively with patient reported accompanying symptoms of light headedness or dizziness and incidence of nausea and headache.
Time frame: Nursing assessment at every shift during 48 hour study period after first drug administration
Population: Safety documents were not filled out by nursing staff for 4 patients, 3 from the acetaminophen group and 1 from the bromocriptine and acetaminophen group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Decrease in blood pressure | 12 Participants |
| Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Nausea | 2 Participants |
| Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Headache | 8 Participants |
| Bromocriptine and Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Decrease in blood pressure | 17 Participants |
| Bromocriptine and Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Nausea | 3 Participants |
| Bromocriptine and Acetaminophen | Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache | Headache | 12 Participants |
Secondary
Total Time That Temperature is ≥ 38.3ºC
Time in minutes where the temperature is ≥ 38.3ºC during the 48 hours of control versus intervention administration.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Total Time That Temperature is ≥ 38.3ºC | 216 Minutes |
| Bromocriptine and Acetaminophen | Total Time That Temperature is ≥ 38.3ºC | 300 Minutes |
Secondary
Total Time to First Temperature < 37.5ºC
Time in minutes it took after medication administration for the temperature to reach \< 37.5ºC.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Total Time to First Temperature < 37.5ºC | 253.5 Minutes |
| Bromocriptine and Acetaminophen | Total Time to First Temperature < 37.5ºC | 556 Minutes |