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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acetaminophen | Active Comparator | 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. |
|
| Bromocriptine and Acetaminophen | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bromocriptine 5 MG | Drug | Bromocriptine 5 mg every 4 hours PO/NG/FT |
|
| Measure | Description | Time Frame |
|---|---|---|
| Temperature Burden | Mean total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication. | over 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Nursing assessment at every shift during 48 hour study period after first drug administration |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Judy H Ch'ang, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zuckerberg San Francisco General Hospital and Trauma Center | San Francisco | California | 94110 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21503807 | Background | 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. | |
| 15841455 | Background | 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. |
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There is no plan to make IPD available to other researchers as this data is very specific to this study.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Bromocriptine and Acetaminophen |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 17, 2021 |
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open label, blinded endpoint, randomized (1:1) controlled trial with two arms: control - acetaminophen and intervention - acetaminophen and bromocriptine.
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The data analyst who will analyze the data from each patient will be masked to what medication(s) the patients received.
| Acetaminophen 650 MG | Drug | Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours |
|
|
| 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. | 48 hours |
| Total Time to First Temperature < 37.5ºC | Time in minutes it took after medication administration for the temperature to reach < 37.5ºC. | 48 hours |
| University of California, San Francisco Medical Center - Parnassus |
| San Francisco |
| California |
| 94143 |
| United States |
| 28816118 | Background | Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal sympathetic hyperactivity: the storm after acute brain injury. Lancet Neurol. 2017 Sep;16(9):721-729. doi: 10.1016/S1474-4422(17)30259-4. |
| 12140674 | Background | Weimar C, Ziegler A, Konig IR, Diener HC. Predicting functional outcome and survival after acute ischemic stroke. J Neurol. 2002 Jul;249(7):888-95. doi: 10.1007/s00415-002-0755-8. |
| 19521083 | Background | Sung CY, Lee TH, Chu NS. Central hyperthermia in acute stroke. Eur Neurol. 2009;62(2):86-92. doi: 10.1159/000222778. Epub 2009 Jun 12. |
| 12184856 | Background | Jiang JY, Gao GY, Li WP, Yu MK, Zhu C. Early indicators of prognosis in 846 cases of severe traumatic brain injury. J Neurotrauma. 2002 Jul;19(7):869-74. doi: 10.1089/08977150260190456. |
| 18514828 | Background | 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. |
| 8110595 | Background | Maher J, Hachinski V. Hypothermia as a potential treatment for cerebral ischemia. Cerebrovasc Brain Metab Rev. 1993 Winter;5(4):277-300. |
| 1389956 | Background | Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev. 1992 Fall;4(3):189-225. |
| 19450568 | 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. |
| 8837806 | 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. |
| 3693428 | 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. |
| 17940175 | 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. |
| 10713016 | Background | Marik PE. Fever in the ICU. Chest. 2000 Mar;117(3):855-69. doi: 10.1378/chest.117.3.855. |
| 26982342 | Background | 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. |
| 28348904 | 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. |
| 22876068 | 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. |
| 20190667 | 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. |
| 26436473 | 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. |
| 28319467 | Background | 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. |
| 25643903 | Background | 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. |
| 18723420 | Background | 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 Nov;39(11):3029-35. doi: 10.1161/STROKEAHA.108.521583. Epub 2008 Aug 21. |
| 17314332 | Background | 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. |
| 7482646 | Background | 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. |
| 12415441 | Background | Stocchetti N, Rossi S, Zanier ER, Colombo A, Beretta L, Citerio G. Pyrexia in head-injured patients admitted to intensive care. Intensive Care Med. 2002 Nov;28(11):1555-62. doi: 10.1007/s00134-002-1513-1. Epub 2002 Oct 4. |
| 11014424 | Background | Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion DW. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery. 2000 Oct;47(4):850-5; discussion 855-6. doi: 10.1097/00006123-200010000-00011. |
| 15241093 | Background | Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004 Jul;32(7):1489-95. doi: 10.1097/01.ccm.0000129484.61912.84. |
| 12629243 | Background | 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. |
| 9663190 | Background | 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. |
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. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Temperature Burden | Mean total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication. | Posted | Mean | Standard Deviation | Temperature in degrees Celsius | over 48 hours |
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| |||||||||||||||||||||||||||||
| 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. | 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. | Posted | Count of Participants | Participants | Nursing assessment at every shift during 48 hour study period after first drug administration |
|
| ||||||||||||||||||||||||||||||
| 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. | Posted | Mean | Inter-Quartile Range | Minutes | 48 hours |
|
| ||||||||||||||||||||||||||||||
| Secondary | Total Time to First Temperature < 37.5ºC | Time in minutes it took after medication administration for the temperature to reach < 37.5ºC. | Posted | Mean | Inter-Quartile Range | Minutes | 48 hours |
|
|
48 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 21 | 0 | 21 | 17 | 21 |
| EG001 | 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. | 1 | 26 | 1 | 26 | 23 | 26 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization | General disorders | Non-systematic Assessment | The participant went to the OR and when the participant was released, the participant's neurological exam was not at baseline and the family did not want to continue participation in the study. |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood pressure decrease | Cardiac disorders | Non-systematic Assessment |
| ||
| Hypotension required treatment | Cardiac disorders | Non-systematic Assessment |
| ||
| Orthostasis | Cardiac disorders | Non-systematic Assessment |
| ||
| Headache | General disorders | Non-systematic Assessment |
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| Nausea | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Judy Ch'ang, MD | Weill Cornell Medicine | (212) 746-2596 | jhc9010@med.cornell.edu |
| Apr 8, 2021 |
| Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 12, 2019 | Jun 22, 2021 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D006408 | Hematoma, Subdural |
| D000070642 | Brain Injuries, Traumatic |
| D000083242 | Ischemic Stroke |
| D005334 | Fever |
| D002543 | Cerebral Hemorrhage |
| D000084462 | Hyperthermia |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D020198 | Intracranial Hemorrhage, Traumatic |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D006406 | Hematoma |
| D014947 | Wounds and Injuries |
| D001930 | Brain Injuries |
| D020521 | Stroke |
| D001832 | Body Temperature Changes |
| D012816 | Signs and Symptoms |
| D018882 | Heat Stress Disorders |
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| ID | Term |
|---|---|
| D001971 | Bromocriptine |
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D004879 | Ergotamines |
| D004876 | Ergot Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D004873 | Ergolines |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
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| Male |
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| Black |
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| Hispanic |
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| Asian/Pacific Islander |
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| Other |
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