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

• ClinicalTrials.gov Identifier: NCT01322048
• Recruitment Status: Completed
• First Posted: March 24, 2011
• Results First Posted: June 8, 2017
• Last Update Posted: August 17, 2017
• Sponsor: Vanderbilt University
• 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

Study Description

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 Design

• 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
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: December 2016

Arms and Interventions

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; Placebo	Drug: Placebo; Placebo IV q6h and Per Tube q12, both for 7 days

Outcome Measures

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) ]

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 64 Years (Child, Adult)
• Sexes Eligible for Study: All
• 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

Locations

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)

Investigators

• Principal Investigator: Mayur B Patel, MD, MPH; Vanderbilt University Medical Center

More Information

Additional Information:

Vanderbilt Multidisciplinary Traumatic Brain Injury Clinic (MTBIC) 

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

Patel MB, McKenna JW, Alvarez JM, Sugiura A, Jenkins JM, Guillamondegui OD, Pandharipande PP. 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. 2012 Sep 26;13:177. doi: 10.1186/1745-6215-13-177.

• Responsible Party: Mayur Patel, Assistant Professor of Surgery and Neurosurgery, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01322048
• Other Study ID Numbers: 110429
• First Posted: March 24, 2011
• 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; Agitation; Severe TBI; TBI; Catecholamines; Heart rate variability; Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Cognitive Impairment

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Hyperkinesis; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dyskinesias; Neurologic Manifestations; Propranolol; Clonidine; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Sympatholytics; Autonomic Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists