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

Traumatic Brain Injury Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01322048
• Other study ID #: 110429
• Status: Completed
• Phase: Phase 2
• First received: March 2, 2011
• Last updated: June 7, 2017
• Start date: August 2011
• Est. completion date: December 2016

Study information

• Verified date: June 2017
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: December 2016
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Craniocerebral Trauma
• Hyperkinesis
• Trauma, Nervous System
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

Drug:
• IV Propranolol and Per Tube Clonidine
1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days
• Placebo
Placebo IV q6h and Per Tube q12, both for 7 days

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Vanderbilt University	Eastern Association for the Surgery of Trauma (EAST), Vanderbilt Institute for Clinical and Translational Research (CTSA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ventilator-free Days		Baseline to day 28
Secondary	Plasma Catecholamine Levels		Baseline, Post-treatment (t=Day 8)
Secondary	24h Urinary Catecholamine Levels		Baseline, Post-treatment (t=Day 8)
Secondary	Daily Percentage of Low Heart Rate Variability (HRV) Intervals	Critically low range of HRV defined as 0.3 - 0.6 beats per minute.	Baseline to ICU Discharge (average t = Day 14)
Secondary	Change in Low Frequency to High Frequency Ratio From Heart Rate Variability Analysis	Response to autonomic cold pressor testing after treatment	Post-treatment (t= Day 8 )
Secondary	RASS Score	Richmond Agitation-Sedation Score	Twice daily to hospital discharge (average t = Day 30)
Secondary	Agitation Behavior Scale (ABS) Score	Agitation Behavior Scale for TBI	Twice daily to hospital discharge (average t = Day 30)
Secondary	Glasgow Coma Scale (GCS) Score	Glasgow Coma Scale	Twice daily to hospital discharge (average t = Day 30)
Secondary	Daily Pulse Pressure Variability	Standard deviation of the 5 minute means of pulse pressure	Baseline to ICU discharge (average t = Day 14)
Secondary	Coma-free Days		Baseline to hospital discharge (average t = Day 30)
Secondary	ICU Length of Stay	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	Baseline to ICU discharge (average t = Day 14)
Secondary	Hospital Length of Stay		Baseline to hospital discharge (average t = Day 30)
Secondary	Quality of Life After Brain Injury (QOLIBRI)	Quality of Life after Brain Injury (QOLIBRI)	3 months, 12 months
Secondary	Extended Glasgow Outcome Scale (GOSE)	Assessment of mortality and disability in TBI patients	At 3 months, 12 months
Secondary	Neuropsychological Assessment	Assessed using a battery of cognitive tests.	At hospital discharge (average t = Day 30), 3 months, 12 months
Secondary	Adjunct Medication Use	quantification of beta-blockers, alpha-2-agonists, analgesics, sedatives, and antipsychotics used throughout hospitalization	Baseline to hospital discharge (average t = Day 30)
Secondary	Cardiac Complications	Composite measure of any dysrhythmias (other than asymptomatic bradycardia and sinus tachycardia), myocardial infarction, and/or cardiac arrest.	Baseline to ICU discharge (average t = Day 14)
Secondary	Patient Health Questionnaire (PHQ-9)	Assessment for Depression after TBI	3 months, 12 months
Secondary	Rancho Los Amigos Level of Cognitive Functioning	Cognitive Function at Discharge	At hospital discharge (average t = Day 30)
Secondary	Cerebral Blood Velocity	Transcranial Doppler Sonogram of Cerebral Blood Velocity	Baseline, Post-treatment (t=Day 8)

External Links

•   Principal Investigator
•   Vanderbilt Multidisciplinary Traumatic Brain Injury Clinic (MTBIC)