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The Effect of Goal-Directed Therapy on Patient Morbidity and Mortality After Traumatic Brain Injury: Results From the Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial*

Merck, Lisa H. MD, MPH1; Yeatts, Sharon D. PhD2; Silbergleit, Robert MD3; Manley, Geoffrey T. MD, PhD4; Pauls, Qi MS2; Palesch, Yuko PhD2; Conwit, Robin MD5; Le Roux, Peter MD6; Miller, Joseph MD, MS7; Frankel, Michael MD8; Wright, David W. MD9

doi: 10.1097/CCM.0000000000003680
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Objectives: To estimate the impact of goal-directed therapy on outcome after traumatic brain injury, our team applied goal-directed therapy to standardize care in patients with moderate to severe traumatic brain injury, who were enrolled in a large multicenter clinical trial.

Design: Planned secondary analysis of data from Progesterone for the Treatment of Traumatic Brain Injury III, a large, prospective, multicenter clinical trial.

Setting: Forty-two trauma centers within the Neurologic Emergencies Treatment Trials network.

Patients: Eight-hundred eighty-two patients were enrolled within 4 hours of injury after nonpenetrating traumatic brain injury characterized by Glasgow Coma Scale score of 4–12.

Measurements and Main Results: Physiologic goals were defined a priori in order to standardize care across 42 sites participating in Progesterone for the Treatment of Traumatic Brain Injury III. Physiologic data collection occurred hourly; laboratory data were collected according to local ICU protocols and at a minimum of once per day. Physiologic transgressions were predefined as substantial deviations from the normal range of goal-directed therapy. Each hour where goal-directed therapy was not achieved was classified as a “transgression.” Data were adjudicated electronically and via expert review. Six-month outcomes included mortality and the stratified dichotomy of the Glasgow Outcome Scale-Extended. For each variable, the association between outcome and either: 1) the occurrence of a transgression or 2) the proportion of time spent in transgression was estimated via logistic regression model.

Results: For the 882 patients enrolled in Progesterone for the Treatment of Traumatic Brain Injury III, mortality was 12.5%. Prolonged time spent in transgression was associated with increased mortality in the full cohort for hemoglobin less than 8 gm/dL (p = 0.0006), international normalized ratio greater than 1.4 (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0003), and systolic blood pressure less than 90 mm Hg (p < 0.0001). In the patient subgroup with intracranial pressure monitoring, prolonged time spent in transgression was associated with increased mortality for intracranial pressure greater than or equal to 20 mm Hg (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0293), hemoglobin less than 8 gm/dL (p = 0.0220), or systolic blood pressure less than 90 mm Hg (p = 0.0114). Covariates inversely related to mortality included: a single occurrence of mean arterial pressure less than 65 mm Hg (p = 0.0051) or systolic blood pressure greater than 180 mm Hg (p = 0.0002).

Conclusions: The Progesterone for the Treatment of Traumatic Brain Injury III clinical trial rigorously monitored compliance with goal-directed therapy after traumatic brain injury. Multiple significant associations between physiologic transgressions, morbidity, and mortality were observed. These data suggest that effective goal-directed therapy in traumatic brain injury may provide an opportunity to improve patient outcomes.

1Departments of Emergency Medicine, Neurosurgery, and Diagnostic Imaging, The Warren Alpert Medical School of Brown University, Providence, RI.

2Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.

3Department of Emergency Medicine, University of Michigan, Ann Arbor, MI.

4Department of Neurosurgery, University of California at San Francisco, San Francisco, CA.

5National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD.

6Department of Neurosurgery, Main Line Health, Philadelphia, PA.

7Department of Emergency Medicine, Henry Ford Health System, Detroit, MI.

8Department of Neurology, Emory University School of Medicine, Atlanta, GA.

9Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA.

*See also p. 731.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Work by the authors on the Progesterone for the Treatment of Traumatic Brain Injury III clinical trial was supported, in part, by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NS062778, 5U10NS059032, and U01NS056975) and was conducted through the Neurological Emergencies Treatment Trials network.

Drs. Merck’s, Yeatts’s, Pauls’s, Palesch’s, Miller’s, and Wright’s institutions received funding from the National Institutes of Health (NIH) National Institute on Neurological Disorders and Stroke (NINDS). Drs. Merck, Yeatts, Silbergleit, Manley, Pauls, Palesch, Conwit, Le Roux, Miller, Frankel, and Wright received support for article research from the NIH. Dr. Yeatts’ institution received funding from Bard (for role on Data and Safety Monitoring Board), and she received funding from Genetech (for role on Potential of rTPA for Ischemic Strokes with Mild Symptoms [PRISMS] Trial Steering Committee) and the University of Michigan (for faculty role on the NINDS-funded Clinical Trials Methodology course). Drs. Silbergleit’s, Le Roux’s, and Frankel’s institutions received funding from the NIH. Drs. Silbergleit and Frankel disclosed off-label product use of progesterone for neuroprotection after traumatic brain injury (TBI). Dr. Pauls disclosed work for hire. Dr. Conwit disclosed government work. Dr. Wright’s institution received funding from the NIH/National Heart, Lung, and Blood Institute, the Department of Defense, and the National Football League; he received funding as an expert witness; and he disclosed that he is listed on a patent held by Emory University of progesterone for the treatment of TBI.

For information regarding this article, E-mail: lisa_merck@brown.edu

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