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Introduction: Acute aortic syndromes (AAS) demand rapid reduction in heart rate (HR) and systolic blood pressure (SBP) to limit complications and reduce mortality. Clinical guidelines recommend urgent intravenous beta-blockade to achieve a target HR of 60 to 80 beats per minute and SBP less than 120 mmHg as first-line therapy. The purpose of this study was to compare achievement of predefined hemodynamic goals and drug utilization patterns between esmolol and labetalol infusions in patients with AAS. Methods: This was a retrospective, multi-center cohort study of adult patients who were admitted between January 2020 and May 2025 with confirmed AAS. Patients who received either infusions of esmolol or labetalol as initial beta-blocker therapy were included. Each beta-blocker exposure was treated as an independent episode, allowing inclusion of patients who received both agents or resumed therapy after procedural interruption. The primary objective of this study was to compare incidence of failure to achieve predefined hemodynamic goals between esmolol and labetalol infusions in patients with AAS. Results: A total of 89 patients contributed to 114 drug exposure episodes (esmolol n=90; labetalol n=24). Failure to achieve HR goal occurred in 20.4% of esmolol episodes compared to 12.5% with labetalol (p=0.599). SBP goal was unmet in 18.4% of esmolol episodes, while all labetalol episodes met SBP goal (p=0.067). Use of a secondary vasoactive agent was more common with esmolol (50%) versus labetalol (21%; p=0.01). Transition from esmolol to labetalol occurred in 15.7% of patients, versus labetalol to esmolol in 1.1% of patients (p< 0.01). Esmolol was associated with a higher median volume per day (1.5L vs 0.7L; p< 0.01). Conclusions: In this retrospective crossover analysis of AAS, there was a higher proportion of esmolol infusions that failed to achieve hemodynamic goals compared to labetalol, but no statistically significant differences were observed. Labetalol was associated with a lower rate of secondary vasoactive agent use, fewer therapy changes, and reduced drug volume requirements compared to esmolol.