Vasopressor Modulation of Cerebral Autoregulation and Systemic Hemodynamics in Severe Traumatic Brain Injury: The REGULATE randomized controlled trial
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Background
Severe traumatic brain injury (TBI) frequently disrupts cerebral autoregulation, rendering cerebral perfusion pressure highly dependent on systemic hemodynamics. Vasopressors are a cornerstone of TBI management, yet norepineph-rine and vasopressin may exert divergent effects on cerebral autoregulation and systemic cardiovascular function. Their comparative impact in this population remains poorly defined.
Objective
The REGULATE trial is a randomized, controlled study designed to investigate the effects of norepinephrine, vasopressin, and their combination on cerebral autoregulation and advanced systemic hemodynamics in patients with severe TBI.
Methods
This quadruple-blinded, parallel-group trial will enroll 450 adults with severe TBI (Glasgow Coma Scale ≤ 8) requiring vasopressor support. Participants will be randomized (1:1:1) to norepinephrine, vasopressin, or combination therapy. Continuous 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 relationship between cerebral autoregulation and systemic hemodynamics. Secondary outcomes include cerebral oxygenation indices, intracranial pressure burden, vasopressor dose exposure, organ perfusion markers, adverse events, and clinical outcomes (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 autoregulation and systemic cardiovascular performance in severe TBI. Results are expected to inform individualized vasopressor strategies to optimize cerebral and systemic physiology while minimizing secondary injury.
Trial registration
ClinicalTrials.gov (forthcoming).
