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Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Early triage and treatment after TBI have been shown to improve outcome. Identifying patients at risk for increased intracranial pressure (ICP) via baseline computed tomography (CT) , however, has not been validated previously in a prospective dataset. We hypothesized that acute CT findings of elevated ICP, combined with direct ICP measurement, hold prognostic value in terms of six-month patient outcome after TBI. Data were obtained from the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECTIII) multi-center clinical trial. Baseline CT scans for 881 participants were individually reviewed by a blinded central neuroradiologist. Five signs of elevated ICP were measured (sulcal obliteration, lateral ventricle compression, third ventricle compression, midline shift, and herniation). Associations between signs of increased ICP and outcomes (six-month functional outcome and death) were assessed. Secondary analyses of 354 patients with recorded ICP monitoring data available explored the relationships between hemorrhage phenotype/anatomic location, sustained ICP ≥20 mm Hg, and surgical intervention(s). Univariate and multi-variate logistic/linear regressions were performed; p < 0.05 is defined as statistically significant. Imaging characteristics associated with ICP in this cohort include sulcal obliteration (p = 0.029) and third ventricular compression (p = 0.039). Univariate regression analyses indicated that increasing combinations of the five defined signs of elevated ICP were associated with death, poor functional outcome, and time to death. There was also an increased likelihood of death if patients required craniotomy (odds ratio [OR] = 4.318, 95% confidence interval [1.330–16.030]) or hemicraniectomy (OR = 2.993 [1.109–8.482]). On multi-variate regression analyses, hemorrhage location was associated with death (posterior fossa, OR = 3.208 [1.120–9.188] and basal ganglia, OR = 3.079 [1.178–8.077]). Volume of hemorrhage >30 cc was also associated with increased death, OR = 3.702 [1.575–8.956]). The proportion of patient hours with sustained ICP ≥20 mm Hg, and maximum ICP ≥20 mm Hg were also directly correlated with increased death (OR = 6 4.99 [7.731–635.51]; and OR = 1.025 [1.004–1.047]), but not with functional outcome. Poor functional outcome was predicted by concurrent presence of all five radiographic signs of elevated ICP (OR = 4.44 [1.514–14.183]) and presence of frontal lobe (OR = 2.951 [1.265–7.067]), subarachnoid (OR = 2.231 [1.067–4.717]), or intraventricular (OR = 2.249 [1.159–4.508]) hemorrhage. Time to death was modulated by total patient days of elevated ICP ≥20 mm Hg (effect size = 3.424 [1.500, 5.439]) in the first two weeks of hospitalization. Sulcal obliteration and third ventricular compression, radiographic signs of elevated ICP, were significantly associated with measurements of ICP ≥20 mm Hg. These radiographic biomarkers were significantly associated with patient outcome. There is potential utility of ICP-related imaging variables in triage and prognostication for patients after moderate-severe TBI. [ABSTRACT FROM AUTHOR]