Vasopressor Modulation of Cerebral Autoregulation and Systemic Hemodynamics in Severe Traumatic Brain Injury: The REGULATE randomized controlled trial

Background: Severe traumatic brain injury (TBI) frequently disrupts cerebral auto-regulation, rendering cerebral perfusion pressure highly dependent on systemic he-modynamics. Vasopressors are a cornerstone of TBI management, yet norepineph-rine and vasopressin may exert divergent effects on cerebral autoregulation and sys-temic cardiovascular function. Their comparative impact in this population remains poorly defined. Objective: The REGULATE trial is a randomized, controlled study designed to in-vestigate the effects of norepinephrine, vasopressin, and their combination on cere-bral autoregulation and advanced systemic hemodynamics in patients with severe TBI. Methods: This quadruple-blinded, parallel-group trial will enroll 450 adults with se-vere TBI (Glasgow Coma Scale ≤ 8) requiring vasopressor support. Participants will be randomized (1:1:1) to norepinephrine, vasopressin, or combination therapy. Con-tinuous multimodal monitoring will include intracranial pressure, arterial pressure, near-infrared spectroscopy, and advanced cardiac output assessment. Co-primary outcomes are (1) cerebral autoregulation, quantified as the area under the curve of the pressure reactivity index over 48 hours, and (2) systemic hemodynamics, defined as the area under the curve of cardiac output and effective arterial elastance over 48 hours. A prespecified interaction analysis will evaluate treatment effects on the rela-tionship between cerebral autoregulation and systemic hemodynamics. Secondary outcomes include cerebral oxygenation indices, intracranial pressure burden, vaso-pressor dose exposure, organ perfusion markers, adverse events, and clinical out-comes (mortality, ICU length of stay, neurological recovery at 3 months). Conclusions: REGULATE is the first adequately powered trial to systematically compare norepinephrine, vasopressin, and their combination on cerebral autoregula-tion and systemic cardiovascular performance in severe TBI. Results are expected to inform individualized vasopressor strategies to optimize cerebral and systemic phys-iology while minimizing secondary injury.