Resuscitative Endocrinology:Single-dose Clinical Uses for Estrogen-Traumatic Brain Injury
Condition: Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      Each year in the United States alone, a third of a million persons are hospitalized for
      traumatic brain injury (TBI), of whom approximately 1/4 die. Most are less than 30 years of
      age. Not only are the health care costs staggering for both initial care and rehabilitation,
      but the societal loss in terms of economic impact reaches into the billions of dollars
      annually in the U.S. alone. Despite advances in neurosurgical interventions and intensive
      care management, many survivors do not fully recover. A significant cause of this mortality
      and morbidity is thought due to potentially preventable secondary injury, namely oxidant
      injury, inflammation, and apoptosis in the penumbra (the area of brain surrounding the
      primary lesion, which is at-risk, but potentially salvageable), beginning in the first few
      hours after the severe traumatic event.

      Despite the current bleak outlook for many of these patients, a series of animal
      investigations have uncovered a promising solution to the problem of the secondary injury
      seen in severe TBI and other similar processes, namely the early administration of estrogen,
      a strong anti-oxidant, anti-inflammatory and anti-apoptotic compound. Based on these
      encouraging results from animal studies, the investigators hypothesize that early
      administration of IV Premarin® in patients with severe TBI will safely reduce secondary brain
      injury, improve neurological outcomes, and improve survival.
    

Detailed description: 
      Early estrogen treatment has been tested in a myriad of animal models of resuscitation
      ranging from TBI and stroke to spinal cord injury, trauma-related hemorrhage, and sepsis. In
      these scenarios, studies using old and young, male and female animals found estrogen to be a
      strikingly effective therapy. Importantly, various animal studies examining brain injury
      sizes via radiological imaging and sophisticated immunofluorescent techniques have revealed
      significant protective effects of IV estrogen given post-injury, noting decreases in injury
      size of up to 65% in those receiving estrogen compared with those not receiving it.
      Furthermore, this beneficial effect is seen in all body tissues in both males and females.
      Only one identified TBI study to date did not show similar efficacy. A rodent model of TBI
      found that all females, in all three groups (those receiving no treatment, placebo, and
      estrogen) inexplicably died.

      Mechanisms of Estrogen's Neuroprotection The use of estrogen as an acute resuscitation drug
      for severe brain injury has been extensively investigated in animal models. The mechanisms of
      estrogen's protective effects are numerous, including prevention of propogation of oxidant
      injury, anti-inflammatory properties in all major organs in the body, and mitochondria
      stabilization.

      Importantly, the following studies find that estrogen exerts significant neuroprotective
      effects aimed at many of the mechanisms implicated in devastating secondary brain injury in
      TBI, including:

      Brain Ischemia and Reperfusion Intracerebral Hemorrhage (a frequent component of traumatic
      brain injury) Impaired Cerebral Blood Flow Cerebral Vasospasm Cerebral Metabolic Dysfunction,
      including mitochondrial dysfunction with reduction of ATP production Cerebral Excitotoxicity
      and Blood Brain Barrier Preservation Cerebral Oxidant Injury Cerebral Edema Cerebral
      Inflammation Apoptosis

      The protective effects of estrogen may initially appear counterintuitive in light of the
      recent WHI and HERS trials which studied long-term, oral, low-dose administration of estrogen
      in older, significantly-post menopausal women. In contrast, the proposed study utilizes a
      one-time resuscitative dose of IV estrogen administered rapidly following the injury. From a
      safety standpoint, there are a hundred-million women years of safety data for estrogen's
      clinical use, and safe use has been documented in men with prostate cancer, uremic bleeding,
      liver transplantation, and spine surgery. Any safety concerns, such as clotting effects found
      with long-tem, orally administered estrogen would not be expected when administered one time
      through an IV dose. Estrogen, when administered IV, avoids the first pass effect in the
      liver, and does not trigger the ER-α mediated pro-thrombotic effects seen with oral
      administration. Therefore, it is felt that this acute, IV single-dose administration of
      estrogen will convey the protective benefits seen in animal studies without side effects
      implicated with long-term oral use in humans.

      Finally, estrogen is not the only sex steroid implicated in resuscitation. While estrogen has
      been the most frequently studied sex steroid in animal resuscitation models, progesterone too
      is thought to have potential neuroprotective effects. There is a recently published clinical
      pilot trial of IV progesterone as an acute resuscitative therapy for TBI patients, which
      indicates potentially promising clinical results without negative safety findings, thereby
      also poising this sex steroid for future multi-center trials.

      In summary, we believe that there are compelling reasons to evaluate estrogen as an acute
      intervention in patients with traumatic brain injury given the benefit demonstrated in animal
      studies of brain injury, and safety data in humans prescribed estrogen for other indications.
      But we are aware that there are no published data related to use of a single dose of IV
      estrogen in injured patients in the acute setting. Therefore we have conceptualized our trial
      with frequent evaluation of patient safety through an organized Data Safety Monitoring
      Committee.

      Potential participants include patients between the ages of 18 and 55 years who are admitted
      to Parkland Memorial Hospital or Baylor University Medical Center with a presumed diagnosis
      of severe traumatic brain injury. This young population was chosen for several reasons:

        1. This population represents the most frequent patient with TBI (young).

        2. This population filters out confounders such as chronic, age-related illnesses. Upon
           admission to the Emergency Department and evaluation of the patient in light of study
           criteria, qualified participants will be randomized to receive a single dose of 0.5
           mg/kg Premarin® IV or placebo. One 7cc tube of blood and available urine will be drawn
           for baseline values prior to study drug administration. Those patients who require the
           placement of a ventriculostomy by a neurosurgeon for therapeutic treatment will also
           have one 7cc test tube of blood and available urine from the foley catheter drawn at the
           time the ventriculostomy is placed. Upon placement of the ventriculostomy, cerebral
           spinal fluid that would otherwise be discarded will be collected. These fluids will be
           centrifuged and frozen within one hour of collection, and the blood, CSF and urine
           analyzed in batches for markers of injury and repair. These samples will then be
           serially collected on an every four hour schedule over the first 24 hours, then every 8
           hours for the following 4 days. CSF collection will end early if the ventriculostomy is
           removed for clinical reasons. Clinically-relevant patient progress (such as vital signs,
           Glasgow Coma Scale (GCS), partial pressure of carbon dioxide in the arterial blood
           (PaCO2), intracranial pressure (ICP), and temperature), clinically required
           interventions, neuro-imaging results, and demographics will be monitored and tracked.

      For assessing length of time in coma and orientation, we will administer the Galveston
      Orientation and Amnesia Test (GOAT) daily until the patient successfully completes the test,
      for up to 2 months.

      Longer-term neurological outcomes will be measured at discharge, 28 days, 3 and 6 months
      post-injury utilizing the Disability Rating Scale, Glasgow Outcome Score-Extended (GOSE), and
      Functional Status Examination. These outcomes measures will be collected by the research
      staff via telephone interviews if the patient has been discharged. The Disability Rating
      Scale (DRS), Glasgow Outcome Scale-Extended GOSE, and Functional Status Examination are well
      validated in the literature for follow-up in patients with TBI. These tests can be easily
      administered over the phone to either the patient or the caregiver.
    

Intervention name(s): Premarin IV; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): One time dose of Premarin IV; One time dose of Placebo
Other intervention name(s): IV Estrogen; Infivite Multivitamin
Intervention MeSH terms: Estrogens; Estrogens, Conjugated (USP)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment