Crit Care Med. 2019 May;47(5):623-631

# 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 L, Yeatts S, Silbergleit R, Manley G, Pauls Q, Palesch Y, Conwit R, Le Roux P, Miller J, Frankel M, Wright D

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.