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Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial

Mayur B Patel12*, John W McKenna2, JoAnn M Alvarez3, Ayaka Sugiura2, Judith M Jenkins2, Oscar D Guillamondegui2 and Pratik P Pandharipande14

Author Affiliations

1 Veterans Affairs (VA) Tennessee Valley Healthcare System, Nashville VA Medical Center, 1310 24th Avenue South, Nashville, TN, 37212, USA

2 Vanderbilt University Medical Center, Division of Trauma & Surgical Critical Care, Department of Surgery, 1211 21st Avenue South, 404 Medical Arts Building, Nashville, TN, 37212, USA

3 Vanderbilt University School of Medicine, Department of Biostatistics, 1161 21st Avenue South D-2220 Medical Center North, Nashville, TN, 37232-2158, USA

4 Vanderbilt University Medical Center, Division of Critical Care, Department of Anesthesia, 1211 21st Avenue South, 526 Medical Arts Building, Nashville, TN, 37212, USA

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Trials 2012, 13:177  doi:10.1186/1745-6215-13-177

Published: 26 September 2012



Severe TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.


The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.


The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.

Trial registration NCT01322048

Traumatic brain injury; Sympathetic hyperactivity; Sympathetic storm; Autonomic dysfunction; Adrenergic blockade; Beta-blocker; Alpha2-agonist; Propranolol; Clonidine; Agitation