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Hyperosmolar therapy is a mainstay in the acute medical management of traumatic brain injury (TBI). Emerging literature suggests that a hyperosmolar state may lead to thrombotic complications. The primary objective of this study was to investigate associations between hypertonic saline (HTS) and the outcome of deep venous thrombosis (DVT) in pediatric patients with severe TBI.This is a single-center retrospective cohort study of 58 patients admitted to the intensive care unit at a Level 1 pediatric trauma center between January 2010 and June 2013. Main measurements included volume of HTS administration, serum sodium levels, DVT confirmed with ultrasonography, survival at 30 days postinjury, and Glasgow Outcome Scale.The cumulative total bolus volume of HTS (mL/kg) given to each subject was associated with DVT (P = .01). Peak sodium level and 72-hour sustained sodium levels were associated with DVT (P = .05). A sustained sodium level of at least 160 mmol/L was associated with DVT (P = .02).In children with severe TBI, the total bolus volume of 3% HTS and sustained sodium levels greater than 160 mmol/L are independently associated with DVT.