DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Traumatic Brain Injury
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.
|Brain Injuries Craniocerebral Trauma Trauma, Nervous System Traumatic Brain Injury||Drug: IV Propranolol and Per Tube Clonidine Drug: Placebo||Phase 2|
|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|
- Ventilator-free Days [ Time Frame: Baseline to day 28 ]
- 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
|Study Start Date:||August 2011|
|Study Completion Date:||December 2016|
|Primary Completion Date:||January 2015 (Final data collection date for primary outcome measure)|
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 IV q6h and Per Tube q12, both for 7 days
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01322048
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37212|
|Principal Investigator:||Mayur B Patel, MD, MPH||Vanderbilt University Medical Center|