What is the recommended dosing and safety considerations for spironolactone in treating fluid overload?

Spironolactone Dosing for Fluid Overload in Cirrhotic Ascites

For patients with cirrhosis and ascites, start spironolactone 100 mg combined with furosemide 40 mg as a single morning oral dose, maintaining the 100:40 ratio to optimize natriuresis while preventing electrolyte disturbances. 1, 2, 3

Initial Dosing Strategy

• Begin with spironolactone 100 mg plus furosemide 40 mg orally once daily in the morning for all patients with cirrhotic ascites and fluid overload 1, 2
• Administer both medications together as a single morning dose to maximize adherence and minimize nocturia 2
• Use the oral route exclusively in cirrhotic patients—intravenous furosemide causes acute reductions in glomerular filtration rate and should be avoided 1, 4, 2
• Spironolactone alone (without furosemide) should only be used in patients with minimal fluid overload due to its long half-life and hyperkalemia risk 1

Dose Escalation Protocol

If weight loss is inadequate after 3–5 days, increase both drugs simultaneously while maintaining the 100:40 ratio:

Current Dose (Spironolactone/Furosemide)	Next Step	Maximum Dose
100 mg / 40 mg	150 mg / 60 mg	400 mg / 160 mg
150 mg / 60 mg	200 mg / 80 mg
200 mg / 80 mg	300 mg / 120 mg
300 mg / 120 mg	400 mg / 160 mg

• Escalate every 3–5 days based on weight loss and natriuresis 1, 2
• The maximum dose is spironolactone 400 mg and furosemide 160 mg daily—exceeding these doses indicates diuretic resistance requiring large-volume paracentesis 1, 2
• Maintaining the 100:40 ratio prevents both hypokalemia (from excessive loop diuretic) and hyperkalemia (from excessive aldosterone antagonist) 1, 2

Target Weight Loss and Monitoring

• Aim for 0.5 kg/day weight loss in patients without peripheral edema 1, 2
• Aim for 1.0 kg/day weight loss in patients with peripheral edema 1, 2
• Exceeding these targets increases risk of intravascular volume depletion, prerenal azotemia, and hepatic encephalopathy 1, 2

Monitoring schedule:

• Check electrolytes (sodium, potassium) and creatinine at day 3, week 1, then monthly for 3 months 1, 2
• Measure daily morning weight before breakfast and after voiding 1, 2
• Monitor blood pressure regularly to detect hypotension 1, 2

Electrolyte Management Algorithm

Situation	Action
Hypokalemia (K < 3.0 mmol/L)	Temporarily reduce or hold furosemide; continue spironolactone [1,2]
Hyperkalemia (K > 5.5 mmol/L)	Reduce or stop spironolactone; furosemide may be continued alone temporarily [1,2]
Severe hyponatremia (Na < 120–125 mmol/L)	Stop both diuretics immediately—this is an absolute contraindication [1,2]

Absolute Contraindications to Spironolactone

Do not initiate or must immediately discontinue spironolactone if:

• Serum creatinine > 2.5 mg/dL 2
• Serum sodium < 120–125 mmol/L 1, 2
• Baseline serum potassium > 5.0 mmol/L 2, 3
• Overt hepatic encephalopathy without another precipitating factor 2
• Acute kidney injury (creatinine rise > 0.3 mg/dL within 48 hours) 2
• Anuria (no urine output) 1, 2
• Marked hypovolemia or hypotension 1, 2

Dietary Sodium Restriction

• Enforce strict sodium intake < 2 g/day (88 mmol/day, equivalent to 5 g salt/day) 1, 2
• This translates to a no-added-salt diet with avoidance of precooked meals 1
• Sodium restriction is as crucial as pharmacologic therapy—intake > 4 g/day can completely negate diuretic efficacy 1, 2
• Provide nutritional counseling on sodium content in foods 1
• Maintain protein intake of 1.2–1.5 g/kg/day to prevent malnutrition 2
• Fluid restriction is not necessary when serum sodium is within normal range 2

Mechanism and Rationale

• Spironolactone is a competitive aldosterone antagonist acting at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted tubule 1
• Secondary aldosteronism plays a major role in renal sodium retention in cirrhosis, making spironolactone more effective than furosemide alone (95% vs 52% response rate) 1
• The 100:40 ratio optimizes natriuresis while maintaining normokalemia 1, 2
• High doses (up to 400 mg/day) are required in cirrhosis because hyperaldosteronism is severe, and the natriuretic response is competitive with aldosterone levels 5, 6

Definition and Management of Refractory Ascites

Ascites is refractory when it persists despite:

• Maximum tolerated doses (spironolactone 400 mg + furosemide 160 mg daily) for at least one week 2
• Sodium restriction < 5 g/day 2

Management of refractory ascites:

1. Perform large-volume paracentesis with albumin replacement (8 g albumin per liter of fluid removed) 1, 2
2. Restart diuretics 1–2 days after paracentesis to prevent rapid re-accumulation 2
3. Refer promptly for liver transplantation evaluation, irrespective of MELD score 2

Common Pitfalls to Avoid

• Do not use spironolactone as monotherapy in patients with significant ascites—combination therapy from the start is superior 1
• Do not exceed 400 mg spironolactone or 160 mg furosemide daily—higher doses signal treatment failure, not inadequate dosing 1, 2
• Do not use intravenous furosemide in cirrhotic patients—oral bioavailability is excellent and IV administration causes acute GFR reduction 1, 4, 2
• Do not continue diuretics if severe hyponatremia, progressive renal failure, or worsening hepatic encephalopathy develops 1, 2
• Avoid NSAIDs and COX-2 inhibitors—they impair diuretic response and increase renal injury risk 2

Adverse Effects and Monitoring

• Adverse events occur in 19–33% of patients on diuretics, with almost half requiring dose reduction or discontinuation 1
• Hepatic encephalopathy occurs in up to 25% of hospitalized patients treated with diuretics 1
• Renal impairment occurs in 14–20%, especially in the absence of peripheral edema—usually moderate and reversible with diuretic discontinuation 1
• Hyponatremia occurs in 8–30% and relates to impaired free water excretion 1
• Hyperkalemia occurs in up to 11% with spironolactone 1
• Gynecomastia and antiandrogen effects occur with spironolactone but not with eplerenone 1, 7, 8
• Amiloride (10–40 mg/day) can substitute for spironolactone in patients with tender gynecomastia, though it is less effective 1

Heart Failure Dosing (For Comparison)

• In heart failure, spironolactone is initiated at 12.5–25 mg daily (or every other day) for cardioprotective effects, not natriuresis 1, 3
• The dose may increase to 50 mg daily if tolerated 1, 3
• These low doses (25–50 mg/day) provide mortality benefit through anti-fibrotic effects, not diuretic action 6
• Natriuretic doses (> 50 mg/day) are required for volume overload in heart failure, similar to cirrhosis 6