Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury
NCT ID: NCT03496545
Last Updated: 2021-06-24
Study Results
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Recruitment Status
COMPLETED
Clinical Phase
PHASE1/PHASE2
Total Enrollment
47 participants
Study Classification
INTERVENTIONAL
Study Start Date
2018-11-30
Study Completion Date
2019-11-02
Brief Summary
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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.
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Detailed Description
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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.
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.
Conditions
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Subarachnoid Hemorrhage
Subdural Hematoma
Traumatic Brain Injury
Ischemic Stroke
Fever
Intracerebral Hemorrhage
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
open label, blinded endpoint, randomized (1:1) controlled trial with two arms: control - acetaminophen and intervention - acetaminophen and bromocriptine.
Primary Study Purpose
TREATMENT
Blinding Strategy
SINGLE
Outcome Assessors
The data analyst who will analyze the data from each patient will be masked to what medication(s) the patients received.
Study Groups
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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.
Group Type
ACTIVE_COMPARATOR
Acetaminophen 650 MG
Intervention Type
DRUG
Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours
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.
Group Type
EXPERIMENTAL
Bromocriptine 5 MG
Intervention Type
DRUG
Bromocriptine 5 mg every 4 hours PO/NG/FT
Acetaminophen 650 MG
Intervention Type
DRUG
Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours
Interventions
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Bromocriptine 5 MG
Bromocriptine 5 mg every 4 hours PO/NG/FT
Intervention Type
DRUG
Acetaminophen 650 MG
Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours
Intervention Type
DRUG
Other Intervention Names
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parlodel
Tylenol
Eligibility Criteria
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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.
* 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
* 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
Minimum Eligible Age
18 Years
Maximum Eligible Age
100 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University of California, San Francisco
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Judy H Ch'ang, MD
Role: PRINCIPAL_INVESTIGATOR
University of California, San Francisco
Locations
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Zuckerberg San Francisco General Hospital and Trauma Center
San Francisco, California, United States
Site Status
University of California, San Francisco Medical Center - Parnassus
San Francisco, California, United States
Site Status
Countries
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United States
References
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Mullins ME, Empey M, Jaramillo D, Sosa S, Human T, Diringer MN. A prospective randomized study to evaluate the antipyretic effect of the combination of acetaminophen and ibuprofen in neurological ICU patients. Neurocrit Care. 2011 Dec;15(3):375-8. doi: 10.1007/s12028-011-9533-8.
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Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 2005 May;41(5):1179-97. doi: 10.1002/hep.20703. No abstract available.
Reference Type
BACKGROUND
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BACKGROUND
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Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin. 2008 May;26(2):585-603, xi. doi: 10.1016/j.ncl.2008.02.005.
Reference Type
BACKGROUND
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BACKGROUND
Durukan A, Marinkovic I, Strbian D, Pitkonen M, Pedrono E, Soinne L, Abo-Ramadan U, Tatlisumak T. Post-ischemic blood-brain barrier leakage in rats: one-week follow-up by MRI. Brain Res. 2009 Jul 14;1280:158-65. doi: 10.1016/j.brainres.2009.05.025. Epub 2009 May 18.
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BACKGROUND
Dietrich WD, Alonso O, Halley M, Busto R. Delayed posttraumatic brain hyperthermia worsens outcome after fluid percussion brain injury: a light and electron microscopic study in rats. Neurosurgery. 1996 Mar;38(3):533-41; discussion 541. doi: 10.1097/00006123-199603000-00023.
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BACKGROUND
Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987 Dec;7(6):729-38. doi: 10.1038/jcbfm.1987.127.
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BACKGROUND
Rabinstein AA, Sandhu K. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry. 2007 Nov;78(11):1278-80. doi: 10.1136/jnnp.2006.112730.
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Marik PE. Fever in the ICU. Chest. 2000 Mar;117(3):855-69. doi: 10.1378/chest.117.3.855.
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Samudra N, Figueroa S. Intractable Central Hyperthermia in the Setting of Brainstem Hemorrhage. Ther Hypothermia Temp Manag. 2016 Jun;6(2):98-101. doi: 10.1089/ther.2016.0004. Epub 2016 Mar 16.
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BACKGROUND
Natteru P, George P, Bell R, Nattanmai P, Newey CR. Central Hyperthermia Treated with Bromocriptine. Case Rep Neurol Med. 2017;2017:1712083. doi: 10.1155/2017/1712083. Epub 2017 Feb 28.
Reference Type
BACKGROUND
Kang SH, Kim MJ, Shin IY, Park DW, Sohn JW, Yoon YK. Bromocriptine for control of hyperthermia in a patient with mixed autonomic hyperactivity after neurosurgery: a case report. J Korean Med Sci. 2012 Aug;27(8):965-8. doi: 10.3346/jkms.2012.27.8.965. Epub 2012 Jul 25.
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BACKGROUND
Badjatia N, Fernandez L, Schmidt JM, Lee K, Claassen J, Connolly ES, Mayer SA. Impact of induced normothermia on outcome after subarachnoid hemorrhage: a case-control study. Neurosurgery. 2010 Apr;66(4):696-700; discussion 700-1. doi: 10.1227/01.NEU.0000367618.42794.AA.
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BACKGROUND
Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C, McGuinness S, Myburgh J, Weatherall M, Webb S, Beasley R; HEAT Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015 Dec 3;373(23):2215-24. doi: 10.1056/NEJMoa1508375. Epub 2015 Oct 5.
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Schell-Chaple HM, Liu KD, Matthay MA, Sessler DI, Puntillo KA. Effects of IV Acetaminophen on Core Body Temperature and Hemodynamic Responses in Febrile Critically Ill Adults: A Randomized Controlled Trial. Crit Care Med. 2017 Jul;45(7):1199-1207. doi: 10.1097/CCM.0000000000002340.
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Saxena M, Young P, Pilcher D, Bailey M, Harrison D, Bellomo R, Finfer S, Beasley R, Hyam J, Menon D, Rowan K, Myburgh J. Early temperature and mortality in critically ill patients with acute neurological diseases: trauma and stroke differ from infection. Intensive Care Med. 2015 May;41(5):823-32. doi: 10.1007/s00134-015-3676-6. Epub 2015 Feb 3.
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Fernandez A, Schmidt JM, Claassen J, Pavlicova M, Huddleston D, Kreiter KT, Ostapkovich ND, Kowalski RG, Parra A, Connolly ES, Mayer SA. Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology. 2007 Mar 27;68(13):1013-9. doi: 10.1212/01.wnl.0000258543.45879.f5. Epub 2007 Feb 21.
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Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, D'Alessandro R. Fever in acute stroke worsens prognosis. A prospective study. Stroke. 1995 Nov;26(11):2040-3. doi: 10.1161/01.str.26.11.2040.
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BACKGROUND
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Commichau C, Scarmeas N, Mayer SA. Risk factors for fever in the neurologic intensive care unit. Neurology. 2003 Mar 11;60(5):837-41. doi: 10.1212/01.wnl.0000047344.28843.eb.
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Albrecht RF 2nd, Wass CT, Lanier WL. Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc. 1998 Jul;73(7):629-35. doi: 10.1016/S0025-6196(11)64885-4.
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BACKGROUND
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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18-24766
Identifier Type: -
Identifier Source: org_study_id
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