Emergency Department Triage of Traumatic Head Injury Using Brain
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ORIGINAL CONTRIBUTION Emergency Department Triage of Traumatic Head Injury Using a Brain Electrical Activity Biomarker: A Multisite Prospective Observational Validation Trial Daniel Hanley, MD, Leslie S. Prichep, PhD, Jeffrey Bazarian, MD, J. Stephen Huff, MD, Rosanne Naunheim, MD, John Garrett, MD, Elizabeth B. Jones, MD, David W. Wright, MD, John O’Neill, MD, Neeraj Badjatia, MD, Dheeraj Gandhi, MD, Kenneth C. Curley, MD, Richard Chiacchierini, PhD, Brian O’Neil, MD, and Dallas C. Hack, MD ABSTRACT Objectives: A brain electrical activity biomarker for identifying traumatic brain injury (TBI) in emergency department (ED) patients presenting with high Glasgow Coma Scale (GCS) after sustaining a head injury has shown promise for objective, rapid triage. The main objective of this study was to prospectively evaluate the From the Brain Injury Outcomes, The Johns Hopkins Medical Institutions (DH), Baltimore, MD; the Department of Psychiatry, New York University School of Medicine (LSP), New York, NY; BrainScope Company, Inc. (LSP), Bethesda, MD; the University of Rochester Medical Center (JB), Rochester, NY; the University of Virginia Health System (JSH), Charlottesville, VA; the Washington University Barnes Jewish Medical Center (RN), St. Louis, MO; the Baylor University Medical Center (JG), Dallas, TX; the University of Texas Memorial Hermann Hospital (EJ), Houston, TX; the Emory University School of Medicine and Grady Memorial Hospital (DW), Atlanta, GA; the Allegheny General Hospital (JO), Pittsburgh, PA; the R. Adams Cowley Shock Trauma Center (NB), Baltimore, MD; the Department of Radiology, University of Maryland (DG), Baltimore, MD; Iatrikos Research and Development Strategies, LLC (KCC), Tampa, FL; the Department of Surgery, Uniformed Services University of the Health Sciences (KCC), Bethesda, MD; R. P. Chiacchierini Consulting, LLC (RC), Gaithersburg, MD; the Detroit Receiving Hospital (BO), Detroit, MI; and Brain Health (DCH), Harpers Ferry, WV. Received August 29, 2016; revision received January 25, 2017; accepted January 31, 2017. The authors have no relevant financial information or potential conflicts to disclose. This study was funded in part by a research contract from U.S. Army, contract W81XWH-14-C-1405, entitled, “Validation of Point-of-Care TBI Detection System for Head Injured Patients.” Data acquisition for this study was supported by research grants from BrainScope Co., Inc., to the clinical sites. JB, JSH, RN, JG, EBJ, DWW, JO, NB, and BO were all principal investigators at clinical data acquisition sites (University of Rochester Medical Center, Rochester, NY; University of Virginia Health System, Charlottesville, VA; Washington University Barnes Jewish Medical Center, St. Louis, MO; Baylor University Medical Center, Dallas, TX; University of Texas Memorial Hermann Hospital, Houston, TX; Emory University School of Medi- cine and Grady Memorial Hospital, Atlanta, GA; Allegheny General Hospital, Pittsburgh, PA; R. Adams Cowley Shock Trauma Center, Baltimore, MD; Detroit Receiving Hospital, Detroit, MI, respectively), whose institutions received research contracts from BrainScope Company, Inc., to sup- port subject recruitment, consenting and data acquisition. DH led the Brain Injury Outcomes (BIOS) Division of Johns Hopkins, the independent CRO for the trial. He is a member of the Medical Advisory Board of BrainScope Co., Inc., but receives no financial remuneration for this activity. DG served as an independent CT adjudicator, is associate professor and director of interventional neuroradiology at the University of Maryland, and receives salary from BIOS. LSP is employed by BrainScope as the chief scientificofficer and is a professor at NYU School of Medicine. LSP holds potential financial interest through patented technology licensed by BrainScope from NYU School of Medicine. DCH currently serves as a consultant to BrainScope Co., Inc., who at the time the study was conducted was coordinator of the Brain Health/Fitness Research Program at the U.S. Army Medical Research and Materiel Command. KCC currently serves as a consultant to BrainScope Co., Inc., who at the time the study was conducted was the Neurotrauma Research Portfolio Manager for Combat Casualty Care Research Program and Defense Health Program at the U.S. Army Medical Research and Materiel Command. RPC served as the independent consulting statistician to BrainScope Co., Inc., for this study. The views, opinions, and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation. In the conduct of research where humans are the subjects, the investigator(s) adhered to the policies regarding the protection of human subjects as prescribed by Code of Federal Regulations (CFR) Title 45, Volume 1, Part 46; Title 32, Chapter 1, Part 219; and Title 21, Chapter 1, Part 50 (Protection of Human Subjects). The trial (Validation of TBI Detection System for Head Injured Patients [B-AHEAD III]) was registered on ClinicalTrials.gov (NCT02367300; https://c linicaltrials.gov/ct2/show/NCT02367300?term=BrainScope&rank=5; date referenced Jun 17, 2016). Supervising Editor: Peter D. Panagos, MD. Address for correspondence and reprints: Leslie S. Prichep, PhD; e-mail: [email protected]. ACADEMIC EMERGENCY MEDICINE 2017;24:617–627. © 2017 by the Society for Academic Emergency Medicine ISSN 1069-6563 617 doi: 10.1111/acem.13175 PII ISSN 1069-6563583 618 Hanley et al. • ED TRIAGE OF TBI USING A BRAIN ELECTRICAL ACTIVITY BIOMARKER efficacy of an automated classification algorithm to determine the likelihood of being computed tomography (CT) positive, in high-functioning TBI patients in the acute state. Methods: Adult patients admitted to the ED for evaluation within 72 hours of sustaining a closed head injury with GCS 12 to 15 were candidates for study. A total of 720 patients (18–85 years) meeting inclusion/exclusion criteria were enrolled in this observational, prospective validation trial, at 11 U.S. EDs. GCS was 15 in 97%, with the first and third quartiles being 15 (interquartile range = 0) in the study population at the time of the evaluation. Standard clinical evaluations were conducted and 5 to 10 minutes of electroencephalogram (EEG) was acquired from frontal and frontal–temporal scalp locations. Using an a priori derived EEG-based classification algorithm developed on an independent population and applied to this validation population prospectively, the likelihood of each subject being CT+ was determined, and performance metrics were computed relative to adjudicated CT findings. Results: Sensitivity of the binary classifier (likely CT+ or CT–) was 92.3% (95% confidence interval [CI] = 87.8%– 95.5%) for detection of any intracranial injury visible on CT (CT+), with specificity of 51.6% (95% CI = 48.1%– 55.1%) and negative predictive value (NPV) of 96.0% (95% CI = 93.2%–97.9%). Using ternary classification (likely CT+, equivocal, likely CT–) demonstrated enhanced sensitivity to traumatic hematomas (≥1 mL of blood), 98.6% (95% CI = 92.6%–100.0%), and NPV of 98.2% (95% CI = 95.5%–99.5%). Conclusion: Using an EEG-based biomarker high accuracy of predicting the likelihood of being CT+ was obtained, with high NPV and sensitivity to any traumatic bleeding and to hematomas. Specificity was significantly higher than standard CT decision rules. The short time to acquire results and the ease of use in the ED environment suggests that EEG-based classifier algorithms have potential to impact triage and clinical management of head-injured patients. he Centers for Disease Control and Prevention at the expense of very low specificity,10–12 contributing T estimates that traumatic brain injury (TBI) to potential long-term health risks associated with over- accounts for over 2.5 million emergency department scanning.10,13 Care pathways that reduce the radiation (ED) visits annually in the United States.1 ED visits exposure risks and allow for screening of mTBI for TBI have increased by 29.1% over the period from patients in nonhospital settings could provide substan- 2006 to 2010, a time when ED visits overall increased tial benefit to mTBI patients. only 3.6%.2 Not included are another 1.6 to 3.8 mil- Previous studies of traumatic hematomas in mild to lion annually who sustain sports related TBI and do moderate head-injured populations, suggest extremely not seek emergency medical care3 and TBI in the mili- high sensitivity to CT-positive (CT+) cases with mea- tary. TBI treatment is time-sensitive, and early identifi- surable blood, using a classification algorithm based cation is associated with reduced morbidity and on brain electrical activity.14,15 In studies comparing improved outcomes.4 Robust, quantitative tools for brain electrical activity classifiers for TBI with standard screening do not currently exist in practice. Nonethe- practice decision rules for CT in the ED, an electroen- less, the rapid, objective, and accurate identification cephalogram (EEG) marker was reported to have speci- and triage of head-injured persons with such a tool ficity and negative predictive value (NPV) greatly could significantly contribute to improved care and exceeding those of the standard decision rules, while outcome. maintaining equivalent sensitivity.16,17 Currently, computed tomography (CT) scan is the The present, observational, multisite, prospective, pragmatically accepted criterion standard for identify- clinical trial evaluated the feasibility of using