Oral Midodrine as an Adjunct to Accelerate Vasopressor Liberation in Septic Shock: A Prospective Randomized Controlled Trial

INTRODUCTION: Septic shock is the most prevalent form of circulatory failure in critically ill patients, often necessitating prolonged vasopressor support to maintain adequate mean arterial pressure(1). While intravenous vasopressors are effective, they pose risks such as tissue ischemia, require invasive monitoring, and may prolong ICU stays(2). Oral midodrine, an α1-adrenergic agonist, has shown promise in reducing the duration of IV vasopressor therapy by improving vascular tone and facilitating hemodynamic stability(3). However, evidence regarding its effectiveness and safety in critically ill patients remains limited and inconsistent. OBJECTIVES: To assess the effect of oral midodrine administration on weaning from vasopressor requirement in critically ill adult patients in septic shock using the Vasoactive inotropic score (VIS) score. MATERIALS AND METHODS: This prospective, double-masked, randomized controlled trial was conducted in a tertiary care ICU. Adults aged 18–80 years with septic shock requiring at least two vasopressor agents (norepinephrine ≥0.2 mcg/kg/min and vasopressin ≤0.04 U/min) were randomized to receive either oral midodrine 10 mg every 8 hours (Midodrine group, n=51) or an identical placebo (Placebo group, n=51). Both groups received standard septic shock management, including fluid resuscitation, antibiotics, and IV vasopressors titrated to maintain a target MAP ≥65 mmHg. The primary outcome was the time to de-escalation from dual vasopressor support to a single low-dose vasopressor (norepinephrine ≤0.15 mcg/kg/min). Secondary outcomes included total time to complete vasopressor discontinuation, vasoactive-inotropic score (VIS) trends, length of ICU stay, and ICU mortality. Bradycardia episodes (HR<50/min) and thyroid/adrenal function were also monitored. RESULTS: A total of 102 patients were analyzed (51 in each arm). There were no significant differences in baseline demographics, severity scores (APACHE II, qSOFA), or comorbidities between groups. Time to reduce to a single low-dose vasopressor was similar in both groups (17.8 ± 7.1 hours Midodrine vs. 19.3 ± 9.1 hours Placebo, p=0.347) depicted in Figure 1. Although the Midodrine group demonstrated a significantly lower VIS at the 30-hour mark (p=0.023), no other VIS time points or maximum VIS differed significantly. The total time to completely discontinue vasopressors was also comparable (23.6 ± 7.2 hours Midodrine vs. 25.7 ± 9.8 hours Placebo, p=0.241). Unexpectedly, ICU length of stay was longer in the Midodrine group (7.9 ± 5.6 days vs. 6.1 ± 3.0 days, p=0.039). ICU mortality rates were similar (19.6% Midodrine vs. 21.6% Placebo, p=0.807). Bradycardia episodes were more frequent with midodrine (33.3% vs. 17.6%), though no significant differences in cortisol, TSH, T3, or T4 levels were noted. CONCLUSION: In this cohort of patients with septic shock requiring dual vasopressor therapy, adjunctive oral midodrine did not shorten the time to vasopressor de-escalation or reduce overall vasopressor requirements. Although midodrine transiently improved VIS at 30 hours, it was associated with more frequent bradycardia and a longer ICU stay. Larger, multicenter trials are warranted to clarify midodrine's role in vasopressor weaning and patient-centered outcomes in septic shock. KEYWORDS: Septic shock, Midodrine, Vasopressor weaning, ICU, Vasoactive-inotropic score, Randomized controlled trial.