title: 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.
abstract: 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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01322048.
authors.affiliation: Veterans Affairs-VA, Tennessee Valley Healthcare System, Nashville VA Medical Center, 1310 24th Avenue South, Nashville, TN 37212, USA. mayur.b.patel@Vanderbilt.edu
authors.forename: Mayur B
authors.initials: MB
authors.lastname: Patel
authors.forename: John W
authors.initials: JW
authors.lastname: McKenna
authors.forename: JoAnn M
authors.initials: JM
authors.lastname: Alvarez
authors.forename: Ayaka
authors.initials: A
authors.lastname: Sugiura
authors.forename: Judith M
authors.initials: JM
authors.lastname: Jenkins
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Guillamondegui
authors.forename: Pratik P
authors.initials: PP
authors.lastname: Pandharipande
mesh_terms: D000320:Adrenergic Fibers / Q000187:drug effects* / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001930:Brain Injuries / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D002395:Catecholamines / Q000097:blood / Q000652:urine; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015600:Glasgow Coma Scale; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D011433:Propranolol / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D012107:Research Design; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013714:Tennessee; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D002395:Catecholamines; D011433:Propranolol; D003000:Clonidine