Peripheral oedema

Peripheral oedema is clinically detectable swelling of the soft tissues, usually of the feet, ankles and legs, due to excess interstitial fluid. It is detected when interstitial volume rises by 2.5 to 3 litres or more. It may be bilateral (systemic or gravitational causes) or unilateral (local venous, lymphatic or inflammatory causes), pitting or non pitting, acute or chronic. This article covers bilateral leg swelling and generalised oedema.

Clinical relevance. Oedema is a sign, not a diagnosis, and it can signal serious heart, liver or kidney disease, hypoalbuminaemia, thyroid disease or malignancy. Common causes are venous insufficiency, drugs, and heart failure in older adults.

Classification by mechanism (Starling forces and lymph flow).

• Raised capillary hydrostatic pressure: heart failure, venous insufficiency, venous obstruction, salt and water retention (kidney disease, drugs), pregnancy, prolonged standing or sitting.
• Reduced plasma oncotic pressure: nephrotic syndrome, cirrhosis, protein losing enteropathy, malnutrition (kwashiorkor), severe sepsis, critical illness.
• Increased capillary permeability: sepsis, burns, allergic and angioedema reactions, capillary leak syndrome, vasculitis, interleukin 2 therapy, snake bite, inflammation.
• Impaired lymphatic drainage: primary lymphoedema, secondary lymphoedema (cancer treatment, filariasis, infection, trauma, obesity), lipoedema (fat disorder with secondary lymphoedema).
• Drug induced fluid retention: dihydropyridine calcium channel blockers, NSAIDs, corticosteroids, thiazolidinediones, gabapentin and pregabalin, minoxidil, fludrocortisone, oestrogens, antidepressants, monoamine oxidase inhibitors, hormonal agents, ciclosporin and tacrolimus.
• Endocrine: hypothyroidism (myxoedema, non pitting), hyperthyroidism (pretibial myxoedema), Cushing syndrome, hyperaldosteronism (rarely).

Pitting versus non pitting. Pitting oedema leaves an indentation after 5 seconds of firm pressure (grade 1, 2 mm, to grade 4, over 8 mm and lasting over 2 minutes). Non pitting oedema suggests lymphoedema, lipoedema, myxoedema or chronic venous disease with fibrosis.

History.

• Onset (days, weeks, months), progression, distribution (feet, legs, thighs, genitals, abdomen, face, eyes), laterality, diurnal pattern. Swelling worse by evening and relieved by elevation suggests gravitational or venous oedema; morning facial puffiness suggests nephrotic syndrome.
• Associated symptoms in heart failure: breathlessness, orthopnoea, cough, reduced exercise tolerance.
• Kidney disease: foamy urine, haematuria, reduced urine output.
• Liver disease: jaundice, abdominal distension, easy bruising, haematemesis.
• Hypothyroidism: weight gain, constipation, cold intolerance, hoarseness.
• Venous disease: heaviness, varicose veins, skin changes, ulcers.
• Protein loss and malnutrition: diarrhoea, weight loss, poor appetite.
• Inflammation and cellulitis: fever, pain, redness.
• Past history: heart disease, hypertension, kidney or liver disease, thyroid disease, diabetes, cancer and its treatment (surgery, radiotherapy, lymph node removal), venous thrombosis, filariasis exposure, HIV, tuberculosis, rheumatic fever, pregnancy.
• Drugs: amlodipine and nifedipine, NSAIDs, steroids, pioglitazone, gabapentin, pregabalin, minoxidil, hormones, antidepressants, ciclosporin, tacrolimus, imatinib, and dose changes; salt and fluid intake; alcohol.
• Occupation and posture (prolonged sitting or standing), travel, immobility, diet.
• Pregnancy and menstrual cycle (premenstrual swelling).

Examination.

• Vital signs, weight, body mass index, waist, blood pressure, heart rate, rhythm, saturation.
• Oedema: pitting grade, level (ankle, shin, thigh, sacrum, scrotum, abdominal wall), symmetry, skin (shiny, tense, weeping, ulceration, varicosities, haemosiderin staining, lipodermatosclerosis, hyperkeratosis).
• Stemmer sign: inability to pinch the skin fold at the base of the second toe; positive in lymphoedema. Also look at the foot (squared toes, hump on dorsum).
• Jugular venous pressure and hepatojugular reflux, heart sounds (third sound, murmurs, pericardial knock), basal crackles, pleural effusion, signs of pulmonary hypertension.
• Abdomen: ascites, hepatomegaly, splenomegaly, spider naevi, palmar erythema, caput medusae, masses.
• Face and eyes: periorbital oedema, thyroid and eye signs, pallor, jaundice, clubbing.
• Pulses, capillary refill, ankle brachial pressure index before compression.
• Skin and nodes: inguinal and pelvic nodes, scars, radiation changes.
• Pregnancy: blood pressure, proteinuria, hyperreflexia.

Red flags.

• Rapid onset generalised oedema or weight gain over 2 kg in 3 days.
• Breathlessness at rest, orthopnoea, chest pain, hypoxia.
• Hypertension with headache, visual disturbance or proteinuria in pregnancy (pre-eclampsia).
• Nephrotic range proteinuria (over 3.5 g/day or urine protein to creatinine ratio over 350 mg/mmol), haematuria, oliguria, rising creatinine.
• Jaundice, ascites, encephalopathy, variceal bleeding.
• Fever with tender erythematous swelling.
• Unilateral swelling with pain or calf tenderness (venous thrombosis).
• Weight loss, mass, lymphadenopathy (malignancy, venous obstruction, lymphatic obstruction).
• Periorbital and facial swelling, stridor or voice change (angioedema).
• Leg ulceration with absent pulses or ischaemic signs.

Cardiac. Heart failure (reduced and preserved ejection fraction), right heart failure from pulmonary hypertension or chronic lung disease (cor pulmonale), constrictive pericarditis, restrictive cardiomyopathy, tricuspid regurgitation, severe valve disease, cardiac amyloidosis, high output failure (anaemia, thyrotoxicosis, beriberi, arteriovenous fistula, Paget disease).

Renal. Nephrotic syndrome (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, amyloidosis, lupus nephritis, HIV associated nephropathy, hepatitis B and C related, malaria and schistosomal glomerulopathy), nephritic syndrome (post streptococcal glomerulonephritis, IgA nephropathy), acute kidney injury, chronic kidney disease, renal sodium retention.

Hepatic and gastrointestinal. Cirrhosis and portal hypertension, hepatic vein obstruction (Budd-Chiari syndrome), protein losing enteropathy (inflammatory bowel disease, coeliac disease, intestinal lymphangiectasia), malabsorption, severe malnutrition (kwashiorkor), pancreatic insufficiency.

Venous and gravitational. Chronic venous insufficiency, varicose veins, post thrombotic syndrome, prolonged sitting or standing (dependent oedema), immobility, obesity, inferior vena cava obstruction, iliac vein compression, bilateral deep venous thrombosis, pelvic tumour.

Lymphatic. Primary lymphoedema (Milroy disease, Meige disease, lymphoedema praecox and tarda), secondary lymphoedema (after surgery, radiotherapy, malignant node infiltration, recurrent cellulitis, filariasis, podoconiosis, tuberculosis, trauma), lipoedema (symmetrical fat deposition sparing the feet), obesity related lymphoedema.

Drugs. Amlodipine, nifedipine, felodipine, NSAIDs and COX-2 inhibitors, corticosteroids, pioglitazone and rosiglitazone, gabapentin and pregabalin, minoxidil, hydralazine, fludrocortisone, oestrogens and progestogens, testosterone, antidepressants, ciclosporin, tacrolimus, imatinib, docetaxel, interleukin 2, and beta blockers (heart failure worsening).

Endocrine and metabolic. Hypothyroidism, Graves disease (pretibial myxoedema), Cushing syndrome, primary hyperaldosteronism, hypoalbuminaemia of any cause, diabetes.

Other. Pregnancy and pre-eclampsia, cyclical idiopathic oedema (women, fluctuating), allergic or hereditary angioedema, capillary leak syndrome, vasculitis, immobility after stroke, complex regional pain syndrome, refeeding oedema, high altitude, heat, and sepsis.

1. Establish pitting, distribution, laterality, tempo and drug history; weigh the patient as a baseline.
2. Initial tests for undifferentiated bilateral oedema: full blood count, urea, creatinine, electrolytes, albumin, liver function tests, glucose or HbA1c, lipid profile, thyroid stimulating hormone, 12 lead ECG.
3. Also request urinalysis (protein, blood) and urine albumin to creatinine ratio or protein to creatinine ratio. Natriuretic peptide is useful: NT-proBNP under 300 pg/mL makes heart failure unlikely.
4. Cardiac: echocardiography (ejection fraction, diastolic function, valves, right ventricular size, pulmonary pressure, pericardium, inferior vena cava), chest radiograph.
5. Renal: 24 hour urine protein or urine protein to creatinine ratio; renal ultrasound.
6. Serology and kidney biopsy (nephrotic syndrome in adults, rapid progression) with antinuclear antibody, complement C3 and C4, hepatitis B, hepatitis C and HIV tests, serum and urine protein electrophoresis with free light chains, phospholipase A2 receptor antibody.
7. Hepatic: liver ultrasound with Doppler, international normalised ratio, platelets, viral hepatitis serology, alpha fetoprotein, abdominal imaging, ascitic tap (serum ascites albumin gradient 11 g/L or more indicates portal hypertension).
8. Gastrointestinal: faecal alpha 1 antitrypsin clearance, stool studies, coeliac serology, endoscopy and biopsy when protein loss is suspected; nutritional assessment.
9. Venous and lymphatic: venous duplex ultrasound (reflux and obstruction), ankle brachial pressure index (compression is safe when the index is 0.8 or more), pelvic and abdominal imaging for obstruction.
10. Lymphoscintigraphy or magnetic resonance lymphangiography for lymphoedema. Blood film for microfilariae (night sample) and filarial antigen test (endemic areas).
11. Endocrine: thyroid function, cortisol tests, aldosterone to renin ratio when suggested.
12. Pregnancy: blood pressure, urine protein to creatinine ratio, liver enzymes and platelets.
13. Drug withdrawal test for suspected drug induced oedema (review at 2 to 4 weeks).

Limits. Pitting oedema is not specific for cause. Albumin may be low in many conditions and does not by itself explain oedema unless under about 20 to 25 g/L. Natriuretic peptide may be normal in constrictive pericarditis and obese patients. Normal echocardiogram does not exclude right heart or pericardial disease.

Immediate priorities. Treat life threatening causes: acute heart failure, severe pre-eclampsia, acute kidney injury, tamponade, angioedema with airway threat (adrenaline 0.5 mg intramuscularly, then specific therapy), severe hypoalbuminaemia with sepsis.

General measures.

• Leg elevation higher than the heart for 30 minutes three or four times daily.
• Avoid prolonged standing or sitting; calf exercise; weight loss.
• Sodium restriction to under 2 g/day (5 g salt) in cardiac, renal and hepatic oedema.
• Stop or reduce the culprit drug where possible.
• Skin care with emollients and prompt treatment of infection.

Cardiac oedema.

• Loop diuretic: furosemide 20 to 40 mg orally once or twice daily (increase to 80 mg to 160 mg), bumetanide 0.5 to 2 mg, or torasemide 10 to 20 mg.
• For resistance, combine with spironolactone 25 to 50 mg daily or with metolazone 2.5 to 5 mg.
• Treat the cause: ACE inhibitor, beta blocker, mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitor in reduced ejection fraction; valve surgery; pericardiectomy; pulmonary vasodilators.
• Check urea, creatinine and electrolytes at 1 to 2 weeks.

Nephrotic syndrome.

• Salt restriction under 2 g sodium daily; fluid restriction 1 to 1.5 litres if hyponatraemic.
• Loop diuretic: furosemide 40 to 80 mg orally twice daily or intravenous infusion for resistant oedema, with metolazone 2.5 to 5 mg or spironolactone 50 to 100 mg daily.
• Albumin 20% (50 to 100 mL) intravenously with furosemide 40 mg only for diuretic resistant oedema in selected patients.
• Avoid rapid diuresis (maximum weight loss 0.5 to 1 kg a day).
• ACE inhibitor or angiotensin receptor blocker for proteinuria and blood pressure: ramipril 2.5 to 10 mg daily; statin (atorvastatin 20 to 40 mg).
• Anticoagulation with warfarin or direct oral anticoagulant for membranous nephropathy with albumin under 20 to 25 g/L, or any venous thromboembolism.
• Specific therapy by biopsy: minimal change disease, prednisolone 1 mg/kg daily (maximum 80 mg) for 4 to 16 weeks then taper. Membranous nephropathy, rituximab or cyclophosphamide with steroids. Focal segmental glomerulosclerosis, prednisolone with calcineurin inhibitor. Lupus nephritis, mycophenolate mofetil plus steroids.
• Treat infections (pneumococcal vaccination, prophylaxis in children) and secondary causes (hepatitis B antiviral therapy, HIV antiretroviral therapy, antimalarials, stop NSAIDs).

Hepatic oedema and ascites.

• Sodium restriction under 2 g/day.
• Spironolactone 100 mg with furosemide 40 mg each morning. Maintain the 100:40 ratio and increase every 3 to 5 days to a maximum of 400 mg and 160 mg.
• Weight loss goal 0.5 kg/day (1 kg if peripheral oedema).
• Paracentesis for tense ascites, with albumin 8 g/litre removed when over 5 litres.
• Stop NSAIDs, ACE inhibitors and angiotensin receptor blockers.
• Treat the cause (alcohol abstinence, antivirals).
• Refer for transjugular intrahepatic portosystemic shunt or transplantation in refractory cases.
• For spontaneous bacterial peritonitis, give albumin 1.5 g/kg on day 1 and 1 g/kg on day 3.

Venous insufficiency and gravitational oedema.

• Graduated compression stockings 20 to 30 mmHg (30 to 40 mmHg for severe disease) after confirming an ankle brachial pressure index of at least 0.8.
• Multilayer bandaging for ulcers; leg elevation; exercise and weight loss.
• Treat skin disease; endovenous ablation of incompetent veins.
• Avoid diuretics except for coexisting heart failure.
• Topical steroid for eczema (hydrocortisone 1% or mometasone).

Lymphoedema.

• Complex decongestive therapy: manual lymphatic drainage, multilayer compression bandaging, exercise, skin care, then compression garments for life; weight loss.
• Prompt antibiotics for cellulitis: flucloxacillin 500 mg to 1 g four times daily for 7 to 14 days; clarithromycin 500 mg twice daily if allergic to penicillin. Give prophylactic phenoxymethylpenicillin 250 to 500 mg twice daily for recurrent episodes.
• Filariasis: doxycycline 200 mg daily for 4 to 6 weeks plus hygiene. In endemic areas, give diethylcarbamazine 6 mg/kg daily for 12 days, or albendazole 400 mg with ivermectin 200 micrograms/kg, as local policy permits.
• Podoconiosis: foot hygiene, shoes and compression.
• Surgery (lymphovenous anastomosis) in selected cases.
• Diuretics are not useful.

Hypothyroidism. Levothyroxine 1.6 micrograms/kg daily (start 25 micrograms in older adults or coronary disease and increase every 4 to 6 weeks). Check thyroid stimulating hormone at 6 to 8 weeks.

Drug induced oedema.

• Reduce or stop the culprit if possible.
• Amlodipine can be reduced to 5 mg or replaced by an ACE inhibitor addition (which reduces oedema) or a different class.
• Switch NSAIDs to paracetamol 1 g every 6 hours (maximum 4 g, 3 g if frail or under 50 kg).
• Stop pioglitazone and review heart failure.
• Diuretics are often ineffective for dihydropyridine induced oedema.

Pregnancy. Reassure for physiological swelling; elevate legs, use compression stockings and exercise. Exclude pre-eclampsia (blood pressure 140/90 mmHg or more, proteinuria, headache, visual symptoms, epigastric pain, sudden facial or hand swelling) and venous thrombosis.

Idiopathic cyclical oedema. Salt restriction, avoid diuretic overuse, low dose spironolactone 25 to 50 mg daily in the second half of the cycle if needed.

Protein losing enteropathy and malnutrition. Treat the underlying disease. Use a high protein and medium chain triglyceride diet and nutritional rehabilitation. In kwashiorkor, refeed gradually with therapeutic milk F-75 then F-100 and micronutrients; avoid diuretics and albumin; treat infection and electrolyte deficits.

Angioedema. Stop ACE inhibitors. Give adrenaline 0.5 mg intramuscularly (allergic), chlorphenamine 10 mg intravenously and hydrocortisone 200 mg intravenously. For hereditary angioedema, give icatibant 30 mg subcutaneously or C1 esterase inhibitor 20 units/kg intravenously (adrenaline is not effective).

Monitoring. Daily weight and fluid balance in admission. Urea, creatinine and electrolytes within 1 to 2 weeks of diuretic changes and then every 3 to 6 months. Albumin, urine protein and blood pressure. Skin checks, review of drug list at each visit, and reassessment of limb circumference or volume.

Referral and escalation.

• Cardiology for suspected heart failure.
• Nephrology for nephrotic syndrome, acute kidney injury and unexplained proteinuria.
• Hepatology or gastroenterology for liver disease and protein loss.
• Vascular surgery for chronic venous disease with ulcer and obstruction.
• Lymphoedema service for primary or secondary lymphoedema.
• Endocrinology for thyroid disease; oncology if malignancy; dietitian.
• Obstetrics for pregnancy related swelling with hypertension.
• Infectious diseases and tropical medicine for filariasis.

Admission. Admit for anasarca with respiratory compromise, acute heart or kidney failure, severe nephrotic syndrome with complications (venous thrombosis, infection, hypovolaemia), decompensated cirrhosis, pre-eclampsia, cellulitis with systemic toxicity, severe hyponatraemia, or suspected malignant obstruction.

Safety netting. Return at once for breathlessness, chest pain, fainting, a rapidly enlarging swelling, reduced urine, a hot red tender limb with fever, a painful swollen single leg, severe headache or visual disturbance in pregnancy, jaundice or vomiting blood. Take daily morning weights; call if weight rises over 2 kg in 3 days.

Special groups.

• Children: nephrotic syndrome (minimal change disease), glomerulonephritis, malnutrition (kwashiorkor), heart failure and protein losing enteropathy. Use weight based diuretics.
• Older adults: venous insufficiency, drugs and heart failure. Watch for dehydration and electrolyte disturbance with diuretics.
• Pregnancy: physiological oedema is common, but sudden facial or hand swelling needs evaluation.
• Endemic regions: filariasis, podoconiosis, schistosomal and glomerular disease, malnutrition, rheumatic and Chagas heart disease, HIV nephropathy and tuberculous pericarditis are leading causes.