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

This study is currently recruiting participants.
Verified May 2013 by Vanderbilt University
Sponsor:
Collaborators:
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
ClinicalTrials.gov Identifier:
NCT01322048
First received: March 2, 2011
Last updated: May 1, 2013
Last verified: May 2013
History of Changes
  Purpose

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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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:

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Ventilator-free days [ Time Frame: Baseline to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma Catecholamine Levels [ Time Frame: Baseline, Post-treatment (t=Day 8) ] [ Designated as safety issue: No ]
  • 24h Urinary Catecholamine Levels [ Time Frame: Baseline, Post-treatment (t=Day 8) ] [ Designated as safety issue: No ]
  • Daily percentage of low heart rate variability (HRV) intervals [ Time Frame: Baseline to ICU Discharge (average t = Day 14) ] [ Designated as safety issue: No ]
    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 ) ] [ Designated as safety issue: No ]
    Response to autonomic cold pressor testing after treatment

  • RASS score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
    Richmond Agitation-Sedation Score

  • Agitation Behavior Scale (ABS) score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
    Agitation Behavior Scale for TBI

  • Glasgow Coma Scale (GCS) score [ Time Frame: Twice daily to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
    Glasgow Coma Scale

  • Daily pulse pressure variability [ Time Frame: Baseline to ICU discharge (average t = Day 14) ] [ Designated as safety issue: No ]
    Standard deviation of the 5 minute means of pulse pressure

  • Coma-free days [ Time Frame: Baseline to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
  • ICU Length of Stay [ Time Frame: Baseline to ICU discharge (average t = Day 14) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
  • Quality of Life after Brain Injury (QOLIBRI) [ Time Frame: 3 months, 12 months ] [ Designated as safety issue: No ]
    Quality of Life after Brain Injury (QOLIBRI)

  • Extended Glasgow Outcome Scale (GOSE) [ Time Frame: At 3 months, 12 months ] [ Designated as safety issue: No ]
    Assessment of mortality and disability in TBI patients

  • Neuropsychological Assessment [ Time Frame: At hospital discharge (average t = Day 30), 3 months, 12 months ] [ Designated as safety issue: No ]
    Assessed using a battery of cognitive tests.

  • Adjunct medication use [ Time Frame: Baseline to hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Assessment for Depression after TBI

  • Rancho Los Amigos Level of Cognitive Functioning [ Time Frame: At hospital discharge (average t = Day 30) ] [ Designated as safety issue: No ]
    Cognitive Function at Discharge

  • Cerebral Blood Velocity [ Time Frame: Baseline, Post-treatment (t=Day 8) ] [ Designated as safety issue: No ]
    Transcranial Doppler Sonogram of Cerebral Blood Velocity


Estimated Enrollment: 100
Study Start Date: August 2011
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2016 (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
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.

  Eligibility

Ages Eligible for Study:   16 Years to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01322048

Contacts
Contact: Mayur B Patel, MD, MPH mayur.b.patel@Vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37212
Contact: Mayur B Patel, MD, MPH         mayur.b.patel@Vanderbilt.edu    
Principal Investigator: Mayur B Patel, MD, MPH            
Sponsors and Collaborators
Vanderbilt University
Vanderbilt Institute for Clinical and Translational Research (CTSA)
Eastern Association for the Surgery of Trauma (EAST)
Investigators
Principal Investigator: Mayur B Patel, MD, MPH Vanderbilt University
  More Information

Additional Information:
Principal Investigator  This link exits the ClinicalTrials.gov site
Vanderbilt Multidisciplinary Traumatic Brain Injury Clinic (MTBIC)  This link exits the ClinicalTrials.gov site

No publications provided by Vanderbilt University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Mayur Patel, Assistant Professor of Surgery and Neurosurgery, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01322048     History of Changes
Other Study ID Numbers: 110429
Study First Received: March 2, 2011
Last Updated: May 1, 2013
Health Authority: United States: Institutional Review Board

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

Additional relevant MeSH terms:
Craniocerebral Trauma
Wounds and Injuries
Brain Injuries
Hyperkinesis
Trauma, Nervous System
Nervous System Diseases
Brain Diseases
Central Nervous System Diseases
Dyskinesias
Neurologic Manifestations
Signs and Symptoms
Adrenergic Agents
Clonidine
Propranolol
Adrenergic alpha-Agonists
 Adrenergic beta-Antagonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Adrenergic Agonists
Adrenergic Antagonists
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Analgesics

ClinicalTrials.gov processed this record on June 18, 2013