DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Traumatic Brain Injury
Condition: Brain Injuries; Craniocerebral Trauma; Trauma, Nervous System; Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Hyperkinesis; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      The investigators intend to determine the effect of adrenergic blockade on 1) short-term
      physiology, behavior, and cognition and 2) long-term neuropsychological outcomes after severe
      Traumatic Brain Injury (TBI).

      The primary hypothesis is that adrenergic blockade after severe TBI will be associated with
      increased ventilator-free days.
    

Detailed description: 
      Severe traumatic brain injury (TBI) is associated with sympathetic hyperactivity resulting in
      catecholamine excess, abnormal heart rate variability, agitation and sympathetic storms, deep
      white matter changes, and poor neuropsychological outcomes. Notably, persistent sympathetic
      hyperactivity after TBI results in higher days of mechanical ventilation and longer intensive
      care unit (ICU) length of stay (LOS). While there are data describing limited portions of
      this response, the full spectrum of sympathetic hyperactivity after severe TBI has not been
      systemically described or methodically intervened upon.

      We will perform a double-blinded, randomized, placebo-controlled pilot trial in a 100 patient
      cohort in which one group will receive centrally acting sympatholytic drugs, propranolol and
      clonidine, and the other group, placebo, within 48 hours of severe TBI. The length of therapy
      will be 7 days.

      The primary question studied is whether ventilator-free days will be increased after therapy.

      Secondary endpoints include plasma and urine catecholamine levels, heart rate and blood
      pressure variability, responses to autonomic cold pressor testing, assessments of coma,
      sedation, and agitation, sedative requirements, analgesic use, antipsychotic medication use,
      coma-free days, ventilator-free days, Intensive Care Unit (ICU) length of stay, and survival.
      Also, neuropsychological outcomes will be measured at ICU discharge, 3 months, and 12 months.

      Interim Analysis: At approximately 50% targeted accrual, n=46 randomized subjects, an interim
      analysis will be performed with A Priori (planned) futility and efficacy rules, which are
      DSMB and IRB approved.
    

Intervention name(s): IV Propranolol and Per Tube Clonidine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days; Placebo IV q6h and Per Tube q12, both for 7 days
Intervention MeSH terms: Propranolol; Clonidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Sympathetic Hyperactivity; Traumatic Brain Injury; Agitation; Severe TBI; TBI; Catecholamines; Heart rate variability; Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Cognitive Impairment