Clinical trial NCT02957331
Conditions: Brain Injuries, Traumatic
Sponsor: University of Tennessee
Start date: 2016-01-01; Completion date: 2018-05-01
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is test the effect of beta-adrenergic blockade on mortality in patients with traumatic brain injury with the hypothesis being that the addition of beta blockade to the treatment regime of this patient population will lower mortality and supress the catecholamine surge that accompanies traumatic brain injury as compared to those who do not receive beta blockade.

Half the patients will be randomized to receive propranolol and half will be randomized to receive no beta blocker.

Detailed description:
The use of Beta-adrenergic blockade is not currently the standard of care of patients with traumatic brain injury. Traumatic brain injury is a common problem in our society with greater than 1.5 million cases occurring annually and over 50,000 deaths per year in the civilian population in the United States. Medical therapy has long consisted of monitoring intracranial pressure and supportive measures designed to limit intracranial pressure. Two retrospective observational studies completed at the University of Tennessee demonstrate that the addition of beta-adrenergic blockage to the treatment of the traumatic brain injury lessens mortality. The basis for conducting this study was established by retrospective data showing no harm to patients receiving Inderal and potential benefit. Available data, including data from the University of Tennessee, are retrospective and are limited to simple exposure to the drug. The proposed study will attempt to further quantify the effect by dosing with the drug to actual beta-blockade instead of simple exposure to the drug.

The effect of propranolol at the dosing levels used in this research will be determined by measurement of urinary catecholamines in both study arms and comparison of the actual effect of the drug on the catecholamine surge that occurs following traumatic brain injury will be determined.

Additionally, the effect of healthcare disparities on outcomes in patients with traumatic brain injury will be measured. Outcomes will be stratified by payer status and ethnicity to determine the effect each of these variables has on outcomes.

Arms: arm 1: One half of qualifying and consenting subjects will be randomized to receive propranolol. This group will receive study drug 3 times daily (every 8 hours) starting at 20 mg. The dosage may be increased by up to 60 mg/day divided over three daily doses (or an additional 20 mg/dose) as necessary until the heart rate is less than 100. Study drug will be held for hypotension (systolic \<100) or bradycardia (heart rate \<60 beats per minute). The maximum daily dose for the treatment of hypertension of 640 mg will not be exceeded in this study. arm 2: Non beta blockade arm will receive standard of care treatment and will not receive beta blockade. If a subject randomized to no Inderal develops hypertension and increased heart rate, he/she will be treated according to standard of care by the trauma team caring for the patient.
Interventions: intervention 1: Propranolol
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Beta-Adrenergic Blockade for Attenuation of Catecholamine Surge Following 
Traumatic Brain Injury:  A Randomized Pilot Trial 
 
Thomas J. Schroeppel, MD, MS1, John P. Sharpe, MD, MS2,  
Charles P. Shahan MD, MS2, L. Paige Clement, PharmD3, Louis J. Magnotti, MD2, 
Marilyn Lee, PharmD4, Michael Muhlbauer, MD5, Jordan A. Weinberg, MD6  
Elizabeth A. Tolley, PhD7 Martin A. Croce, MD2, Timothy C. Fabian, MD2 
 
1- Department of Trauma and Acute Care Surgery, UCHealth – Memorial Hospital. 
Colorado Springs, CO, USA. 
2- Department of Surgery, University of Tennessee Health Science Center, 
Memphis, TN, USA.   
3- Department of Pharmacy, University of Colorado Health – Memorial Hospital. 
Colorado Springs, CO, USA. 
4- Department of Pharmacy, Regional One Health, Memphis, TN, USA. 
5- Department of Neurosurgery, University of Tennessee Health Science Center, 
Memphis, TN, USA.   
6- Trauma Administration, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 
USA. 
7- Department of Preventive Medicine, University of Tennessee Health Science 
Center, Memphis, TN, USA. 
 
jsharpe6@uthsc.edu 
cshahan@uthsc.edu 
lesley.clement@uchealth.org 
lmagnott@uthsc.edu 
mlee@regionalonehealth.org 
mmuhlbauer@semmes-murphey.com 
Jordan.Weinberg@DignityHealth.org 
mcroce@uthsc.edu 
tfabian@uthsc.edu 
btolley@uthsc.edu 
 
This study was supported by grants from the University of Tennessee Health Science 
Center Institute for Research, Innovation, Synergy, and Equity (iRISE) and the Semmes-
Murphey Foundation.  No additional funding or conflicts to report.  Clinicaltrials.gov - 
NCT02957331.  Document updated September 19, 2019. 
 
Corresponding Author: 
Thomas J. Schroeppel, MD, MS 
UCHealth - Memorial Hospital 
1400 E Boulder St, Ste 600 
Colorado Springs, CO, 80909 
Office:  (719) 364 6487 
Fax:  (719) 364 6488 
thomas.schroeppel@uchealth.org 


Methods 
A single-center prospective randomized controlled pilot trial was conducted at the 
Presley Regional Trauma Center at Regional One Health in Memphis, TN from 1/1/16 to 
12/13/17.  This hospital is the only trauma center in Memphis, serves as the only trauma 
center in the Mid-South area, and is a major teaching facility for the University of 
Tennessee Health Science Center.  The Mid-South is a geographic area of approximately 
3,500 square miles surrounding Memphis including western Tennessee, eastern Arkansas, 
northern Mississippi, and small portions of Missouri and Kentucky.  The trial is 
registered on clinicaltrials.gov (NCT02957331). After informed consent was obtained by 
one of the investigators or research nurses from the patient or legally authorized 
representative (LAR), patients were randomly assigned to either the treatment (PRO) or 
control arm using block randomization in groups of 4 to ensure equal group size.  This 
sequence was generated using SAS version 9.4 (SAS Institute, Cary, NC).  The study was 
not blinded due to the treatment effects and need for titration of the medication on 
physiologic parameters.  
The primary outcome was in-hospital mortality.  The secondary outcome was to 
examine the interaction between beta-blockade and catecholamines by measuring urinary 
catecholamines. A power analysis was performed using literature review to determine 
probable effect size.   Utilizing a 15% difference in mortality between groups, a sample 
of 99 patients per group would be required to power the study at 0.80.  This sample size 
would not be feasible at a single center.  Therefore, in lieu of performing a multi-center 
study with limited resources, we elected to perform a pilot study to determine study 


safety, feasibility, and effect size over a one-year period.  The enrollment was re-assessed 
after one year and still short of the goal, so the study was extended an additional year.   
 
Eligible patients for screening were 18 years or older with a TBI as determined by 
Glasgow Coma Scale score (GCS) less than 12 on admission and documented brain 
injury on head computed tomography scan.  Qualifying patients were randomized within 
72 hours of injury.  Exclusion criteria included patients with a significant injury in 
another body region (Abbreviated Injury Scale score >3), incarceration or gravidity, 
hepatic disease, home beta-blocker use, ongoing resuscitation or vasoactive medications, 
active acute coronary syndrome, and non-survivable injury as determined by 
neurosurgery review of imaging.  Data were extracted from the electronic medical 
record (Sorian, Cerner, Kansas City, MO) and the local trauma registry (NTRACS 
version 3.0, Digital Innovations, Forest Hill, MD).  Patients assigned to the PRO arm 
were dosed with propranolol starting at 20 mg three times daily (TID) by mouth or per 
feeding tube.  The dose of propranolol was increased daily in 20 mg TID increments (60 
mg/day total) until heart rate (HR) was less than 100 beats per minute (bpm) with 
maximum dose of 640 mg/day.  Parameters for holding the medication included HR less 
then 60 bpm or systolic blood pressure less than 100 mm Hg.  Patients assigned to the 
control arm were managed per institutional standard for TBI based on the Brain Trauma 
Foundation guidelines.27 Neither arm had additional beta-blockers withheld if the care 
team deemed that class of medication necessary for appropriate care.  Treatment duration 
for active study intervention was 14 days with a 48-hour taper of propranolol after the 
study period ended in the PRO arm.  Patients were followed during the hospital stay until 
death or discharge.   


 
Variables collected included demographics, severity of injury, severity of illness 
scores, physiologic parameters, operative interventions, hospital length of stay (LOS), 
intensive care unit length of stay (ICU LOS), discharge disposition, infectious morbidity, 
urinary catecholamines, and mortality. Urinary catecholamines were collected from 
discarded urine at study enrollment and then at study day (SD) 2, SD-5, SD-7, SD-10, 
and at the end of the study period (SD-14) or when the patient came off study.  The 
samples were stabilized with hydrochloric acid (HCl) and sent to a standard lab.  Timely 
acid stabilization of the urine specimens was required prior to shipping to the central lab 
for processing.  If HCl was not added to the specimen, unpredictable results were 
obtained that were not physiologically possible in vivo.  These values were excluded from 
analysis. Patients in the PRO arm were compared to the control using intent to treat 
analysis.  
 
Statistical analyses for categorical variables were compared using Chi-square tests 
or Fisher’s exact tests where appropriate.  Normally distributed continuous variables were 
compared using Student’s t-tests and non-normally distributed continuous variables were 
compared using Wilcoxon Rank Sums tests.  Effect size for mortality was calculated 
using the absolute difference between treatment groups.  A two-way mixed model III 
Analysis of the Variance (ANOVA) with repeated measures was used to estimate 
differences between the two treatment arms over time.  Using planned contrasts, the 
mean for each follow-up measurement was compared to SD-1 (i.e., randomization) for 
within-group contrasts and means at each assessment time were compared for between-
group contrasts. Because these contrasts were planned, no correction was made for 
multiple comparisons.  Output for the ANOVA is reported as Least Square Means 


(LSMeans) with standard error (±SE).  Finally, Kaplan-Meier survival analysis was 
performed to further examine mortality over time between groups. All statistical analyses 
were performed using SAS 9.4 (SAS Institute, Cary, NC).  The University of Tennessee 
Health Science Center and Regional One Health Institutional Review Boards approved 
the study.  A p value of less than 0.05 was considered significant.