Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury
Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury
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.
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