Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury

Phase 1

Completed

• Conditions: Subarachnoid Hemorrhage; Ischemic Stroke; Subdural Hematoma; Traumatic Brain Injury; Intracerebral Hemorrhage; Fever
• Interventions: Drug: Bromocriptine 5 MG; Drug: Acetaminophen 650 MG

• Registration Number: NCT03496545
• Lead Sponsor: University of California, San Francisco

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.

Study Timeline

• Study First Submitted: 2018-03-17
• Study First Submitted QC: 2018-04-05
• Study First Posted: 2018-04-12
• Study Start: 2018-11-30
• Primary Completion: 2019-11-02
• Study Completion: 2019-11-02
• Results First Submitted: 2021-05-25
• Status Verified: 2021-06
• Results First Submitted QC: 2021-06-22
• Last Update Submitted: 2021-06-22
• Results First Posted: 2021-06-24
• Last Update Posted: 2021-06-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 47

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bromocriptine and Acetaminophen	Bromocriptine 5 MG	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.
Acetaminophen	Acetaminophen 650 MG	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	Acetaminophen 650 MG	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Total Time to First Temperature < 37.5ºC	48 hours	Time in minutes it took after medication administration for the temperature to reach \< 37.5ºC.
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.
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.

Trial Locations

Locations (2)

Zuckerberg San Francisco General Hospital and Trauma Center; 🇺🇸 San Francisco, California, United States

University of California, San Francisco Medical Center - Parnassus; 🇺🇸 San Francisco, California, United States