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Introduction: Guidance exists for initiating vasopressors in shock, but little supports their weaning. Midodrine has been investigated as an adjunct to facilitate vasopressor weaning; however, current studies do not explore the comparative effectiveness of different dosing regimens. This study aims to evaluate whether a higher or lower dose of midodrine is more effective in reducing norepinephrine requirements during the weaning process. Methods: A single-center, retrospective chart review was conducted. The primary outcome was time to discontinue norepinephrine after the addition of either a high-dose (greater than 30 mg) or low-dose (30 mg or less) of midodrine. Secondary outcomes were ICU length of stay, percent decrease in norepinephrine rate after 24 hours of midodrine, the proportion of patients discharged on midodrine, and development of bradycardia. A subgroup analysis was performed comparing patients whose midodrine was titrated vs no titration. Results: Of 203 patients reviewed, 42 met inclusion criteria: 6 in the high-dose group and 36 in the low-dose group. Median time to wean norepinephrine was 95.7 hours (IQR 19.2–259.7) in the high-dose group versus 30.8 hours (IQR 16.1–46.2) in the low-dose group (p=0.659), showing no significant difference. In the subgroup analysis, the non-titration group had a shorter weaning time (22.8 hours, IQR 12.1–35.9) compared to the titration group (70.2 hours, IQR 34.2–107.8; p=0.022). Overall, 19 patients (45.2%) were discharged on midodrine, and 11 (26.2%) developed bradycardia. Titration did not significantly impact norepinephrine weaning. Conclusions: This is the first study to compare dosing strategies of midodrine for norepinephrine weaning. The primary endpoint showed no statistically significant difference between high-and low-dose groups. A notable proportion of patients were discharged on midodrine, and bradycardia was a common adverse event.