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DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Traumatic Brain Injury

This study has been completed.
Vanderbilt Institute for Clinical and Translational Research (CTSA)
Eastern Association for the Surgery of Trauma (EAST)
Information provided by (Responsible Party):
Mayur Patel, Vanderbilt University Identifier:
First received: March 2, 2011
Last updated: March 27, 2017
Last verified: March 2017

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.

Condition Intervention Phase
Brain Injuries
Craniocerebral Trauma
Trauma, Nervous System
Traumatic Brain Injury
Drug: IV Propranolol and Per Tube Clonidine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Severe Traumatic Brain Injury, A Pilot Randomized Clinical Trial Using Propranolol and Clonidine

Resource links provided by NLM:

Further study details as provided by Vanderbilt University Medical Center:

Primary Outcome Measures:
  • Ventilator-free days [ Time Frame: Baseline to hospital discharge (average t = Day 30) ]

Secondary Outcome Measures:
  • Plasma Catecholamine Levels [ Time Frame: Baseline, Post-treatment (t=Day 8) ]
  • 24h Urinary Catecholamine Levels [ Time Frame: Baseline, Post-treatment (t=Day 8) ]
  • Daily percentage of low heart rate variability (HRV) intervals [ Time Frame: Baseline to ICU Discharge (average t = Day 14) ]
    Critically low range of HRV defined as 0.3 - 0.6 beats per minute.

  • Change in Low frequency to high frequency ratio from heart rate variability analysis [ Time Frame: Post-treatment (t= Day 8 ) ]
    Response to autonomic cold pressor testing after treatment

  • RASS score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ]
    Richmond Agitation-Sedation Score

  • Agitation Behavior Scale (ABS) score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ]
    Agitation Behavior Scale for TBI

  • Glasgow Coma Scale (GCS) score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ]
    Glasgow Coma Scale

  • Daily pulse pressure variability [ Time Frame: Baseline to ICU discharge (average t = Day 14) ]
    Standard deviation of the 5 minute means of pulse pressure

  • Coma-free days [ Time Frame: Baseline to hospital discharge (average t = Day 30) ]
  • ICU Length of Stay [ Time Frame: Baseline to ICU discharge (average t = Day 14) ]
    Time to ICU discharge, represented by readiness for ICU discharge indicated by a physician order for transfer to a lower level of care even if a bed availability problems prevent actual discharge from the ICU

  • Hospital length of stay [ Time Frame: Baseline to hospital discharge (average t = Day 30) ]
  • Quality of Life after Brain Injury (QOLIBRI) [ Time Frame: 3 months, 12 months ]
    Quality of Life after Brain Injury (QOLIBRI)

  • Extended Glasgow Outcome Scale (GOSE) [ Time Frame: At 3 months, 12 months ]
    Assessment of mortality and disability in TBI patients

  • Neuropsychological Assessment [ Time Frame: At hospital discharge (average t = Day 30), 3 months, 12 months ]
    Assessed using a battery of cognitive tests.

  • Adjunct medication use [ Time Frame: Baseline to hospital discharge (average t = Day 30) ]
    quantification of beta-blockers, alpha-2-agonists, analgesics, sedatives, and antipsychotics used throughout hospitalization

  • Cardiac Complications [ Time Frame: Baseline to ICU discharge (average t = Day 14) ]
    Composite measure of any dysrhythmias (other than asymptomatic bradycardia and sinus tachycardia), myocardial infarction, and/or cardiac arrest.

  • Patient Health Questionnaire (PHQ-9) [ Time Frame: 3 months, 12 months ]
    Assessment for Depression after TBI

  • Rancho Los Amigos Level of Cognitive Functioning [ Time Frame: At hospital discharge (average t = Day 30) ]
    Cognitive Function at Discharge

  • Cerebral Blood Velocity [ Time Frame: Baseline, Post-treatment (t=Day 8) ]
    Transcranial Doppler Sonogram of Cerebral Blood Velocity

Estimated Enrollment: 100
Study Start Date: August 2011
Study Completion Date: December 2016
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Adrenergic Blockade
Propranolol and Clonidine
Drug: IV Propranolol and Per Tube Clonidine
1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days
Placebo Comparator: Placebo
Drug: Placebo
Placebo IV q6h and Per Tube q12, both for 7 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.


Ages Eligible for Study:   16 Years to 64 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its identifier: NCT01322048

United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
Sponsors and Collaborators
Vanderbilt University
Vanderbilt Institute for Clinical and Translational Research (CTSA)
Eastern Association for the Surgery of Trauma (EAST)
Principal Investigator: Mayur B Patel, MD, MPH Vanderbilt University Medical Center
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Mayur Patel, Assistant Professor of Surgery and Neurosurgery, Vanderbilt University Identifier: NCT01322048     History of Changes
Other Study ID Numbers: 110429
Study First Received: March 2, 2011
Last Updated: March 27, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Vanderbilt University Medical Center:
Sympathetic Hyperactivity
Traumatic Brain Injury
Severe TBI
Heart rate variability
Adrenergic alpha-Agonists
Adrenergic beta-Antagonists
Cognitive Impairment

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Trauma, Nervous System
Craniocerebral Trauma
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Adrenergic Agents
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antihypertensive Agents
Autonomic Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-Antagonists
Adrenergic Antagonists
Anti-Arrhythmia Agents
Vasodilator Agents processed this record on April 21, 2017