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Background: Cushing's reflex usually results from intracranial hypertension. Although Cushing's sign can implicate severe traumatic brain injury (TBI) in injured patients, no major investigations have been made. The purpose of this study was to assess the predictability of life-threatening brain injury requiring immediate neurosurgical intervention (LT-BI) among trauma patients with Cushing's sign in the prehospital setting., Methods: This was a retrospective study using data from the Japan Trauma Data Bank from the period of 2010 to 2014. Patients 16 years old or older with blunt mechanisms of injury who were transported directly from the scene and Glasgow Coma Scale for eye opening of one in the prehospital setting were included. LT-BI was defined as patients requiring burr hole evacuation or craniotomy within 24 h of hospital arrival and patients who were non-survivors due to isolated severe TBI. Prehospital systolic blood pressure (pSBP) and heart rate (pHR) were assessed using area under the receiver operating characteristic curve (AUROC) and multiple logistic regression analysis to predict LT-BI., Results: Of 6332 eligible patients, 1859 (29%) exhibited LT-BI. AUROC of LT-BI using pSBP and pHR was 0.666 (95% confidence interval (CI); 0.652-0.681, P < 0.001), and 0.578 (95% CI; 0.563-0.594, P < 0.001), respectively. AUROC of pSBP was the highest among the 60 ≤ pHR ≤ 99 subgroup, of which AUROC was 0.680 (95% CI; 0.662-0.699, P < 0.001). Multiple logistic regression analysis showed that the higher the pSBP and the lower the pHR, the more likely that the patients had LT-BI. In a group with pSBP ≥ 180 mmHg and pHR ≤ 59 beats/min, the odds ratio and 95% CI of LT-BI after adjusting for age, sex, and severity of injuries to other body regions was 4.77 (2.85-7.97), P < 0.001 was compared with the reference group, which was defined as patients with normal vital signs., Discussion: Our study has found that the combination of hypertension and bradycardia, which are the components of Cushing's sign without eye opening in the prehospital setting was a weak but a significant predictor of LT-BI, or death due to possible isolated severe TBI., Conclusions: Prehospital Cushing's sign with disturbed level of consciousness in trauma patients was a weak but significant predictor of the need for immediate neurosurgical intervention.