Generalised Oedema

Generalised oedema (anasarca) is widespread accumulation of fluid in the interstitial space affecting dependent areas, face and serous cavities. It occurs when capillary hydrostatic pressure rises, plasma oncotic pressure falls, capillary permeability increases, lymphatic drainage is impaired, or tubular sodium retention expands the extracellular fluid volume.

Main causes by mechanism:

• Increased hydrostatic pressure: heart failure, constrictive pericarditis, kidney failure, venous obstruction, fluid overload, calcium channel blockers
• Reduced oncotic pressure: nephrotic syndrome, cirrhosis, protein losing enteropathy, malnutrition (kwashiorkor), extensive burns
• Increased permeability: sepsis, anaphylaxis, capillary leak, angioedema
• Sodium retention: acute nephritic syndrome, NSAIDs, corticosteroids, minoxidil, thiazolidinediones, oestrogens
• Endocrine: hypothyroidism (non-pitting myxoedema), hyperthyroidism, Cushing syndrome
• Idiopathic cyclical oedema in women

Nephrotic syndrome is the most clinically important kidney cause: proteinuria above 3.5 g daily, serum albumin below 30 g/L, oedema and hyperlipidaemia. The mechanism combines underfilling (reduced oncotic pressure) and primary tubular sodium retention.

• Distribution and tempo: periorbital in nephrotic and nephritic syndromes (morning); dependent oedema in heart failure and venous disease; ascites predominant in cirrhosis; generalised with serous effusions in nephrotic syndrome
• Pitting oedema that indents after 5 seconds of pressure (grade by depth: 1+ is 2 mm and 4+ is 8 mm with sustained indentation); non-pitting suggests lymphatic obstruction or myxoedema
• Cardiac: raised JVP, third heart sound, hepatomegaly
• Hepatic: jaundice, spider naevi, ascites, caput medusae
• Nephrotic: frothy urine, xanthelasma, leuconychia (Muehrcke lines)
• Thyroid, nutritional and skin signs

Red flags: dyspnoea, respiratory distress, oliguria, sudden unilateral limb swelling (venous thrombosis, a particular risk in nephrotic syndrome), hypertension with haematuria, abdominal pain with ascites (spontaneous bacterial peritonitis), facial swelling with stridor (angioedema), hypotension.

• Urinalysis and urinary protein:creatinine ratio; spot ratio above 300 mg/mmol confirms nephrotic range
• Serum albumin, creatinine, urea and electrolytes, lipids, liver function and INR
• Natriuretic peptide, ECG, echocardiography
• Thyroid function, HbA1c, full blood count, urinalysis for haematuria
• Hepatitis B and C, HIV, antinuclear antibody, complement, serum protein electrophoresis with free light chains, anti-PLA2R antibody, ANCA if indicated
• Stool alpha-1 antitrypsin clearance for protein losing enteropathy
• Chest radiograph, abdominal ultrasound with Doppler for ascites and liver disease, renal vein thrombosis, lower limb Doppler if unilateral swelling
• Renal biopsy for adult nephrotic syndrome without diabetes

Differentials: localised oedema (venous, lymphatic), lipoedema, obesity, drug induced oedema, pregnancy related oedema.

General measures

• Sodium restriction below 2 g daily; fluid restriction 1 to 1.5 L daily if sodium is below 125 mmol/L; leg elevation; compression stockings for venous disease once arterial disease is excluded.
• Stop causal drugs: amlodipine (switch to a different class), NSAIDs, pioglitazone, corticosteroids where possible.

Diuretic therapy

• Furosemide 40 to 80 mg orally daily, doubling every 24 to 48 hours until effective, to a usual ceiling of 160 mg twice daily orally; in renal impairment or gut oedema use intravenous 80 to 200 mg boluses or an infusion of 10 to 40 mg/h.
• Add metolazone 2.5 to 5 mg or hydrochlorothiazide 25 to 50 mg for resistance (monitor potassium and sodium daily).
• Spironolactone 100 to 400 mg daily in cirrhosis; maintain a ratio of spironolactone 100 mg to furosemide 40 mg.
• Weight loss target: 0.5 to 1 kg daily; ascites without peripheral oedema should not exceed 0.5 kg daily.
• Avoid over diuresis: reduce or hold diuretics for postural hypotension, creatinine rise above 30%, sodium below 125 mmol/L or potassium below 3.0 mmol/L.

Specific

• Nephrotic syndrome: ACE inhibitor or angiotensin receptor blocker (ramipril 2.5 to 10 mg daily); atorvastatin 20 to 40 mg; prophylactic anticoagulation (enoxaparin 40 mg daily; warfarin target INR 2 to 3) when albumin is below 20 g/L with additional risk, such as membranous nephropathy; treat the underlying lesion: prednisolone 1 mg/kg daily (maximum 80 mg) for minimal change disease for up to 16 weeks.
• Diuretic resistant nephrotic oedema: albumin 20% 100 mL with furosemide 40 mg intravenously, repeated every 12 to 24 hours for up to 3 days, only if albumin is below 20 g/L and with caution for pulmonary oedema.
• Cirrhosis: large volume paracentesis with albumin 8 g for each litre removed when more than 5 L is drained; spironolactone and furosemide; treat precipitants.
• Heart failure: loop diuretic, ACE inhibitor or angiotensin receptor neprilysin inhibitor, beta blocker, mineralocorticoid antagonist, SGLT2 inhibitor.
• Hypothyroidism: levothyroxine 1.6 microg/kg daily (25 to 50 microg initial in older adults and cardiac disease).
• Malnutrition: refeeding with phosphate, thiamine and potassium monitoring.

Emergency. Pulmonary oedema: sit upright and give oxygen, continuous positive airway pressure, furosemide intravenous and glyceryl trinitrate. Anaphylaxis or angioedema: intramuscular adrenaline 0.5 mg (500 microg) repeated every 5 minutes. Sepsis with capillary leak: restrictive fluids with vasopressors.

Refer to nephrology for proteinuria above 50 mg/mmol with oedema, renal impairment or suspected glomerulonephritis; to cardiology for cardiac failure; to hepatology for ascites with portal hypertension.

Special groups. Pregnancy: new generalised oedema with hypertension and proteinuria indicates pre-eclampsia. Older adults: start diuretic doses low and monitor sodium, potassium and creatinine every 3 to 5 days.