Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury

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 ≥ 50 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