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

Trials

Pratik P Pandharipande²  Oscar D Guillamondegui¹  Judith M Jenkins¹  Ayaka Sugiura¹  JoAnn M Alvarez³  John W McKenna¹  Mayur B Patel¹ 

[1] 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;Vanderbilt University Medical Center, Division of Critical Care, Department of Anesthesia, 1211 21st Avenue South, 526 Medical Arts Building, Nashville, TN, 37212, USA;Vanderbilt University School of Medicine, Department of Biostatistics, 1161 21st Avenue South D-2220 Medical Center North, Nashville, TN, 37232-2158, USA

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

Others  :  1095310
DOI  :  10.1186/1745-6215-13-177

 received in 2012-06-01, accepted in 2012-09-03,  发布年份 2012

【 摘 要 】

Background

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.

Methods/Design

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.

Discussion

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

ClinicalTrials.gov NCT01322048

【 授权许可】

   
2012 Patel et al.; licensee BioMed Central Ltd.

【 图 表 】

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