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.

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.

Inclusion Criteria:

• Age: 16 years to 64 years
• Glasgow Coma Scale score less than or equal to 8 (Severe TBI) with injury on CT
• Screen within 24 hours of injury

Exclusion Criteria:

• Pre-existing heart disease (i.e. coronary heart disease)
• Pre-existing cardiac dysrhythmia
• Allergy to study drugs
• Penetrating brain injury
• Pre-existing brain dysfunction (i.e. prior severe TBI, debilitating stroke)
• Impending brain herniation (i.e. loss of bilateral corneal reflexes)
• Craniectomy or craniotomy
• Spinal cord injury
• Myocardial injury
• Severe liver disease
• Current use of beta-blockers and/or alpha-2-agonist
• Withdrawal of care expected in 24 hours
• Prisoners
• Pregnant women
• Unable to follow-up through final visit