Ascites is a cardinal and debilitating complication in patients with acute-on-chronic liver failure (ACLF), significantly correlating with disease severity and poor prognosis. The underlying pathophysiology is driven by severe splanchnic arterial vasodilation, which reduces effective arterial blood volume and triggers compensatory neurohumoral activation. This cascade leads to profound sodium retention, renal vasoconstriction, and circulatory instability. Consequently, patients with ACLF frequently experience diuretic intolerance and are at elevated risk for severe complications, including electrolyte disturbances, acute kidney injury (AKI), and hepatorenal syndrome (HRS).

Current management strategies rely heavily on diuretics and albumin; however, the efficacy of diuretics is often limited by systemic hypotension and pre-existing renal impairment, leading to frequent treatment failure or diuretic-induced complications. Existing clinical guidelines lack definitive recommendations regarding the preemptive use of vasoconstrictors to stabilize hemodynamics before ascites becomes refractory. Midodrine, an oral alpha-1 adrenergic agonist, targets this circulatory dysfunction by increasing systemic vascular resistance and improving renal perfusion. This randomized controlled trial aims to evaluate the efficacy and safety of the early initiation of midodrine in achieving better control of ascites and preventing the progression to renal complications in patients with acute-on-chronic liver failure.

Inclusion Criteria:

1. Age ≥18 years.
2. ACLF
3. Ascites (Grade II/III).
4. Willing/able for salt restriction, labs, urine collections, and follow-ups; consent obtained.

Exclusion Criteria:

1. SCr ≥ 1.5 mg/dL OR ongoing AKI >stage I
2. Persistent or uncorrectable severe hyponatremia (Na ≤120 mEq/L), hyperkalemia (>6.0 mEq/L) or any other critical electrolyte imbalance.
3. Refractory ascites
4. Spontaneous bacterial peritonitis
5. Hepatic encephalopathy grade II-III.
6. Shock, need for IV vasopressors, SBP <90 mmHg or MAP <65 despite fluids/albumin.
7. Active GI bleed, uncontrolled infection/sepsis, or SBP at screening.
8. Severe cardiomyopathy, critical valvular disease, arrhythmias contraindicating α-agonists.
9. ACLF patients on Mechanical ventilation/ICU/ionotropes/High flow oxygen
10. Pregnancy, lactation.
11. Hypersensitivity/intolerance to midodrine.
12. Significant LUTS.