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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01322048
Recruitment Status : Completed
First Posted : March 24, 2011
Results First Posted : June 8, 2017
Last Update Posted : August 17, 2017
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

Brief Summary:

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

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (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
Study Start Date : August 2011
Primary Completion Date : January 2015
Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Ventilator-free Days [ Time Frame: Baseline to day 28 ]

Secondary Outcome Measures :
  1. Plasma Norepinephrine Levels [ Time Frame: Post-treatment (t=Day 8) ]

Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): 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

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
First Posted: March 24, 2011    Key Record Dates
Results First Posted: June 8, 2017
Last Update Posted: August 17, 2017
Last Verified: July 2017

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

Keywords provided by Mayur Patel, Vanderbilt University:
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
Brain Injuries, Traumatic
Craniocerebral Trauma
Trauma, Nervous System
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Adrenergic Agents
Adrenergic beta-Antagonists
Adrenergic Antagonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents
Sensory System Agents
Peripheral Nervous System Agents
Autonomic Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists