A Guide to Peripheral Oedema

PEER REVIEWED FEATURE 2 CPD POINTS A guide to peripheral oedema GAYATHRI KUMARASINGHE MB BS, FRACP GERARD CARROLL AM, MB BS(Hons), FRACP, FCSANZ Peripheral oedema is a nonspecific symptom with a wide range of potential causes. A systematic time-efficient review of the patient will aid in differentiating the benign from the more serious causes, guide initial investigations and determine who can be managed in the community and who requires specialist referral or hospitalisation.

eripheral oedema is a nonspecific finding common to a KEY POINTS wide range of medical conditions and can therefore pose a diagnostic challenge. The causes range from benign • The differential diagnosis of peripheral oedema is wide, conditions that can be managed in the community to requiring a systematic approach for diagnosis and Pmajor organ failure requiring specialist referral or hospitali- management. sation. A systematic review of the patient and rational, cost- • Initial assessment of whether the oedema is generalised effective investigations are recommended as initial steps in or localised is essential to tailor the differential diagnosis. management. • Patients whose condition is stable with localised disease processes can be investigated and managed in the Here we outline conditions that can cause peripheral oedema, community. details of history taking and examination, and baseline invest • Patients with signs of advanced heart failure or of hepatic igations aimed at refining the differential diagnosis and guiding or renal disease require early specialist involvement or management and referral. hospital admission. • Constrictive pericarditis is a medical emergency that can Physiological mechanisms of peripheral oedema present with peripheral oedema. A high index of suspicion Peripheral oedema is most commonly caused by extravasation is required and patients with suggestive signs should be of fluid from the vasculature into the interstitium as a result of referred for urgent cardiologist review. altered vascular haemodynamics. Starling described the physiological mechanisms causing peripheral oedema as:1 • increased intravascular hydrostatic pressure • decreased intravascular or plasma oncotic (colloid osmotic) pressure • increased vascular permeability. MedicineToday 2015; 16(6): 26-34 Any one or more of these factors can underlie peripheral oedema (Figure 1). 2 Other important causes of peripheral oedema include: Dr Kumarasinghe is a Consultant Cardiologist at the Mater Hospital, Sydney. • impaired lymphatic flow Copyright _Layout 1 17/01/12 1:43 PM Page 4 Professor Carroll is a Consultant Physician and Cardiologist at Riverina • pregnancy IAN LISHMAN/JUICE IMAGES/DIOMEDIA.COM LISHMAN/JUICE IAN

Cardiology, Wagga Wagga, and the Mater Hospital, Sydney, NSW. • physiological changes, such as cyclical premenstrual changes. ©

26 MedicineToday ❙ JUNE 2015, VOLUME 16, NUMBER 6 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2015. Causes of peripheral oedema Conditions that are associated with gen- Decreased Increased Precapillary interstitial interstitial eralised or localised peripheral oedema sphincter hydrostatic oncotic are summarised in Figure 2. pressure pressure

Generalised peripheral oedema Vein Heart failure Artery

Heart failure is a common and serious Lymphatics Lymphoedema cause of generalised peripheral oedema (Figure 3). Left heart failure – either sys- Increased capillary Increased Decreased plasma hydrostatic pressure capillary oncotic pressure tolic or diastolic – can cause pulmonary • Venous obstruction permeability • Malabsorption oedema, giving rise to dyspnoea. Right • Hepatic cirrhosis • Nephrotic syndrome heart failure causes peripheral oedema, • Heart failure • Liver failure pleural effusions and sometimes ascites, • Constrictive • Malnutrition which can be exacerbated by severe tri- pericarditis • Restrictive cuspid regurgitation. cardiomyopathy In heart failure, the inability of the • Renal failure heart to effectively circulate blood volume • Pregnancy throughout the body leads to increased venous pressure that is transmitted to the Figure 1. Changes in vascular haemodynamics underlying peripheral oedema. capillaries. This causes extravasation of Adapted from Cho S. Am J Med 2002; 113: 580-586.2 electrolytes and fluid into the interstitium, producing oedema. A low-output state and hypoperfusion of vital organs lead to Localised oedema Generalised oedema neurohormonal activation, which aims to restore circulatory homeostasis but in effect worsens cardiac failure and exacer- Myxoedema bates oedema. Neurohormonal activation includes stimulation of the sympathetic nervous system, which leads to peripheral Heart failure vasoconstriction and increases cardiac Lymphoedema Constrictive pericarditis inotropy and chronotropy, thereby Restrictive cardiomyopathy increasing afterload and cardiac work. The release of additional neurohormones Hepatic cirrhosis of the renin–angiotensin–aldosterone Nephrotic syndrome system causes sodium and water retention, End-stage renal failure while arginine vasopressin (AVP) causes Acute renal failure further water retention and peripheral vasoconstriction. The natriuretic peptides, atrial (ANP) Nutritional deficiency and B-type (BNP), are markers of atrial Lipoedema and ventricular distension and are elevated in heart failure. Serum BNP levels can Pregnancy Premenstrual disorder therefore be used to determine whether heart failure is the cause of peripheral Venous incompetence oedema. Deep vein thrombosis Medications

Dermatitis Constrictive pericarditis and restrictive Cellulitis cardiomyopathy Constrictive pericarditisCopyright and _Layout restrictive 1 17/01/12 Figure 1:43 2. PMCauses Page of 4generalised and localised peripheral oedema. PHOTOBANK GALLERY/SHUTTERSTOCK PHOTOBANK

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a. Normal heart b. Dilated cardiomyopathy cardiac tamponade, which is a cardiac emergency. If there is any clinical suspicion of tamponade (e.g. dyspnoea, elevated jugular venous pressure and signs of right heart failure) then patients require urgent cardiology referral.

Hepatic cirrhosis End-stage liver disease predominantly causes ascites, but patients also often present with bipedal oedema. Oedema arises due to: • severe hypoalbuminaemia • salt and water retention • formation of multiple arteriovenous c. Constrictive pericarditis d. Restrictive cardiomyopathy fistulae. Ascites can be severe, and care is needed when performing paracentesis to prevent sudden fluid shifts. Plasma volume and oncotic pressure should be maintained by administering intrave- nous 20% concentrated albumin while performing slow paracentesis over a few days.

Renal disease Nephrotic syndrome, acute renal failure and end-stage renal failure can all give rise to peripheral oedema. Nephrotic syndrome is characterised by peripheral Thickened pericardium Stiff heart muscle © CHRIS WIKOFF, 2015 oedema in association with high-level Figures 3a to d. Cardiac conditions that can cause peripheral oedema. a. Healthy heart. proteinuria, low serum albumin levels and b. Dilated cardiomyopathy with poor systolic and diastolic function of the heart, causing high serum cholesterol levels. Diabetic peripheral oedema. c. Constrictive pericarditis causing impaired venous return. d. Restrictive cardiomyopathy causing impaired relaxation of the heart and diastolic heart failure. nephropathy is a common cause of proteinuria in adults. Acute renal failure caused by severe renal insults and end- of peripheral oedema but are important therapy, malignancy and idiopathic stage renal failure can be associated with differential diagnoses to consider (Figure causes. Worldwide, the most common oliguria or anuria accompanied by fluid 3). Patients with either of these conditions cause is tuberculosis. retention, generalised oedema and present with dyspnoea and elevated jugular The causes of restrictive cardiomyo- elevated central venous pressure. venous pressure and often have signs of pathy include: hepatic congestion and ascites as well as • infiltrative diseases such as amyloid Medications peripheral oedema. Echocardiography osis and haemochromatosis Peripheral oedema is a common side effect usually shows normal left ventricular • connective tissue diseases such as of medications, including: systolic function, but Doppler readings can scleroderma • calcium channel blockers (e.g. be used to diagnose pericardial constriction • hypertrophic cardiomyopathy. dihydropyridines such as nifedipine, or restriction. Both constrictive pericarditis and amlodipine, felodipine and lercan- In Australia, the more common causes restrictive cardiomyopathy require imag- idipine, and nondihydropyridines of constrictive pericarditis include con- ing and right heart catheterisation for such as verapamil and diltiazem) nective tissue diseases,Copyright recurrent _Layout acute 1 17/01/12 definitive 1:43 PM diagnosis. Page 4 • vasodilators (e.g. minoxidil and less pericarditis, previous surgery or radiation Constrictive pericarditis can cause commonly hydralazine)

28 MedicineToday ❙ JUNE 2015, VOLUME 16, NUMBER 6 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2015. • NSAIDs high-output cardiac failure in patients venous return. This may present with • corticosteroids with severe hyperthyroidism. bilateral peripheral oedema but is often • antidepressants asymmetrical. Acute deep vein thrombo- • oestrogens and progesterones Severe nutritional deficiency sis is associated with unilateral swelling, • thiazolidinediones (e.g. pioglitazone, Peripheral oedema can arise due to low pain and at times erythema. Varicose rosiglitazone). serum albumin and protein levels in veins are a sign of venous incompetence The mechanism by which calcium conditions such as protein-losing entero but not necessarily associated with periph- channel blockade causes peripheral pathies, severe nutritional deficiencies eral oedema. oedema is through unopposed arteriolar (e.g. kwashiorkor, which is uncommon in vasodilatation with continued venular Australia), severe liver disease and severe Dermatitis and cellulitis constriction. These effects may be min- heart failure. In severe heart failure, Localised skin irritation can lead to an imised by administering calcium channel ‘cardiac cachexia’ can result from low inflammatory cell infiltrate activated by blockers at night and co-administering albumin and protein levels caused by inflammatory cytokines, such as tumour ACE inhibitors or angiotensin receptor malabsorption from an oedematous necrosis factor alpha and interleukin-8, antagonists. Diuretics should not be used gastrointestinal tract. A clue to a mal and increased vascular permeability. This to treat peripheral oedema caused by nourished state (even in a person who is is usually associated with erythema and medications. not thin) is the combination of low albu- pruritus; however, dermatitis or eczema min level and lymphocytopenia. occurring bilaterally in the lower extrem- Pregnancy ities can mimic peripheral oedema from Peripheral oedema is common in preg- Obesity-related oedema other causes. Dermatitis is therefore an nancy and is usually seen in the second Oedema is a common finding in over- important differential diagnosis to keep and third trimesters. Salt and water are weight and obese individuals. The causes in mind. retained to increase plasma volume to are not always clear and can be multifac- Localised oedema associated with pain meet the increased cardiac output required torial. For example, chronic venous insuf- and erythema are the presenting features for the fetus and placenta. Compression ficiency, impairment of the lymphatic of cellulitis. Patients may also have fever. of the inferior vena cava and iliac veins system as well as impaired cardiac, res- A history of trauma or pruritus points can exacerbate peripheral oedema in the piratory or renal function can be found towards cellulitis as the most likely cause. later stages of pregnancy. in obesity and can contribute to oedema. Obesity-related oedema should again be Lipoedema Cyclical or premenstrual oedema a diagnosis of exclusion. Lipoedema is caused by accumulation Generalised oedema is relatively common of fatty deposits, most commonly in the in women during the premenstrual stage Localised oedema lower extremities. It can be bilateral and of the menstrual cycle. Premenstrual The causes of localised oedema are also mistaken for lymphoedema or venous oedema occurs cyclically in the week important differential diagnoses in patients incompetence, but is differentiated from preceding menstruation and is a diagnosis presenting with peripheral oedema. them by the absence of pitting and of of exclusion in women with normal serum involvement of the feet. albumin levels, no elevation of jugular Lymphatic obstruction venous pressure and no evidence of renal, In Australia, lymphoedema is most com- Patient assessment hepatic or cardiac disease. monly caused by destruction of the local Knowledge of the common causes and lymph nodes by surgery (e.g. mastectomy differential diagnoses of peripheral oedema Thyroid disease with axillary lymph node clearance) or should aid in formulating a comprehensive Myxoedema can occur in patients with radiotherapy. Worldwide, the more com- yet time-efficient, systematic review of the severe hypothyroidism (e.g. Hashimoto’s mon cause is filariasis. In lymphoedema, patient. It is important to exclude the more thyroiditis). Myxoedema is nonpitting the skin has a tethered peau d’orange serious differential diagnoses, such as heart and caused by dermatological changes, appearance and oedema is commonly, but failure, hepatic or renal disease, and in with deposition of glycosaminoglycans, not always, unilateral. patients with acute localised oedema, deep rather than altered vascular haemody- vein thrombosis. namics. Pretibial myxoedema can also Venous incompetence or deep vein occur in a minority of patients with thrombosis History Graves’ disease andCopyright hyperthyroidism. _Layout 1 17/01/12 Venous 1:43 incompetencePM Page 4 or a history of deep Points to cover in history taking in a patient Peripheral oedema can be a feature of vein thrombosis can lead to impaired with peripheral oedema are listed in the

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myxoedema and severe nutritional defi- considered when a raised jugular venous HISTORY TAKING IN A PATIENT WITH PERIPHERAL OEDEMA ciencies should be kept in mind. Pain and pressure and dyspnoea are combined with fevers suggest an infective cause such as a history of connective tissue disease, Current illness cellulitis. Altered mentation can point to recurrent pericarditis, multiple cardiac • Duration of oedema (Is it acute or severe hepatic or renal disease but can also surgeries, uraemia caused by renal failure chronic? Does it improve overnight?) be due to delirium in elderly patients, or, less commonly in the western world, • Other symptoms caused by any of the conditions discussed tuberculosis. –– dyspnoea above. –– oliguria or anuria Other signs of systemic disease –– fatigue, lethargy Physical examination The patient should be examined for ascites –– appetite changes, weight loss Distribution of oedema and jaundice. Patients with hepatic cirrho- –– pain Examination of a patient with peripheral sis typically have ascites caused by the –– fever oedema should focus initially on the loca- failure of hepatic synthesis of albumin –– altered mentation tion and distribution of the oedema. combined with portal hypertension. • Pregnancy status, menstrual history Bipedal oedema can be due to any of the Ascites is also common in severe right (if relevant) causes of generalised oedema discussed heart failure. Past history above. Unilateral limb oedema can be due Oedema caused by thyroid disease is • Previous episodes of peripheral to any of the causes of localised oedema, associated with: oedema such as lymphoedema, unilateral venous • signs of hair loss or coarse hair and • History of systemic or other disease disease, severe dermatitis or cellulitis. sweating (hypothyroidism) or –– cardiac disease (e.g. heart failure, Oedema that extends from the lower limbs • ophthalmopathy and features of myocardial infarction, pericarditis, to involve the scrotum and abdomen indi- hyperthyroidism (Graves’ disease). cardiac surgery) cates advanced cardiac, hepatic or renal –– hypertension disease. Skin features –– hepatic disease Lymphoedema, myxoedema and lipoedema –– renal disease Jugular venous pressure are typically nonpitting. Lipoedema involv- –– diabetes –– thyroid disease The jugular venous pressure is the key ing the legs typically spares the feet. –– connective tissue disease physical sign in assessing generalised A history of pruritus and mild to mod- –– tuberculosis oedema. If the jugular venous pressure is erate oedema localised to the legs or arms • History of malignancy, previous elevated then right heart failure, constric- suggests dermatitis. Erythema and pain radiotherapy or surgery tive pericarditis, restrictive cardiomyopathy on palpation suggest cellulitis but can also • History of venous incompetence and general fluid overload states, such as be caused by deep vein thrombosis. severe renal dysfunction, should be con- Risk factors and family history sidered. A normal jugular venous pressure Investigations • Risk factors for deep vein thrombosis suggests a cause ‘below the diaphragm’. Investigations should be tailored to the • Alcohol history differential diagnosis formulated after his- • Family history of heart failure Cardiorespiratory system tory taking and examination. Features of Medications A cardiorespiratory examination should the history that suggest specific diagnoses • Especially calcium channel blockers, be undertaken to detect: and suggested investigations are summa- vasodilators, NSAIDs, corticosteroids, • third or fourth heart sounds rised in the Table. Patients who have nor- antidepressants, oestrogens and • cardiac murmurs mal examination results apart from progesterones, thiazolidinediones • crepitations in the lungs peripheral oedema and are taking a calcium • pleural effusions channel blocker or other medication Box. The presence of dyspnoea points • pitting bipedal oedema. known to cause peripheral oedema may towards a cardiac cause. A history of olig- The presence of these signs may indi- not require investigation but only cessation uria or anuria points towards a renal cause cate heart failure or restrictive cardio of the medication and review within a few but may also be due to severe heart failure. myopathy. Pleural effusions may also days. Evidence of cellulitis or dermatitis Fatigue, lethargy and changes in appetite occur in the presence of protein-losing also warrants treatment without specific accompanying severe generalised oedema states such as nephrotic syndrome or immediate investigations. suggest advanced cardiac,Copyright hepatic _Layout or renal1 17/01/12 malabsorption. 1:43 PM Page 4 Conversely, if advanced cardiac, hepatic disease. Less common causes such as Constrictive pericarditis should be or renal disease is suspected then referral

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TABLE. CAUSES OF PERIPHERAL OEDEMA, SUGGESTIVE FEATURES OF THE HISTORY is warranted for specialist review or to the AND RECOMMENDED INVESTIGATIONS AND REFERRAL emergency department, depending on the Causes Suggestive features Investigations, referral severity of the presenting symptoms.

Generalised peripheral oedema Blood and urine tests Cardiac disease History of cardiac disease Chest x-ray, echocardiography, Patients presenting with less critical symp- cardiology referral • Systolic heart failure toms should undergo investigations, including: • Restrictive cardiomyopathy • serum electrolytes, urea and • Constrictive pericarditis creatinine levels • liver function tests, including Renal disease History of renal disease, Serum electrolytes, urea albumin level diabetes, hypertension and creatinine, lipids • Renal failure Urine protein ± renal tract • coagulation studies Nephrotic syndrome • ultrasound, referral to renal • full blood count physician • blood sugar level • thyroid-stimulating hormone level Hepatic disease History of hepatitis, alcohol Serum albumin, liver misuse function tests, INR, APTT, ± • spot urinalysis, looking for protein • Cirrhosis hepatic ultrasound, referral and glucose. to gastroenterologist Imaging Medication side effects Medication history Pleural effusions or lung crepitations • Calcium channel blockers detected on clinical examination warrant a posteroanterior and lateral chest x-ray. • Minoxidil These patients should also be referred for Corticosteroids • echocardiography to assess for the degree Thiazolidinediones • of heart failure, valvular disease and gross • NSAIDs pericardial abnormalities. • Hormonal treatment If history or examination findings or Thyroid disease History or symptoms of Serum TSH, free T4 and T3 initial blood test results suggest renal or thyrotoxicosis or hepatic disease then a renal tract or hepatic hypothyroidism ultrasound examination, respectively, is Pregnancy warranted. Patients with a suspected deep vein Cyclical (premenstrual) thrombosis should have a venous ultra- Severe nutritional Nutritional history Serum albumin and protein sound examination performed on the deficiencies same day.

Obesity B-type natriuretic peptide Localised peripheral oedema Measurement of the BNP level in blood can be valuable in determining whether a DVT History of risk factors for DVT Venous ultrasound, dopplers patient’s symptoms are caused by an exac- Venous incompetence Venous ultrasound, dopplers erbation of heart failure. A significant elevation in BNP associated with increasing Lymphatic obstruction History of surgery Lymphoscintogram dyspnoea can help with the diagnosis in a Dermatitis History of allergy, previous patient with multiple comorbidities. dermatitis Management Cellulitis Localised trauma, pain, No specific investigation tenderness required before treatment For patients with heart failure who do not require immediate hospital admission, Abbreviations: APTT=activatedCopyright partial _Layoutthromboplastin 1 17/01/12 time; DVT=deep 1:43 veinPM thrombosis; Page 4 INR=international normalised ratio; T3=tri-iodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone. treatment can be initiated with oral diuretics such as frusemide and potassium

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replacement pending review by a cardiologist. These patients should be advised to restrict fluids and adopt a low salt intake to prevent exacerbations, and to monitor their weight at home to detect early signs of fluid retention. Patients with constrictive pericarditis or signs of more advanced heart failure (such as a markedly raised jugular venous pressure associated with respiratory distress) require more urgent cardiology referral. Patients who have evidence of renal, hepatic or thyroid disease or nutritional deficiencies but whose condition is stable do not require hospitalisation but should have specialist involvement as early as possible. Management of patients with localised causes of oedema can be initiated in the community, and the patients reviewed to monitor progress. Treatments include anticoagulation for deep vein thrombosis, elevation for dependent oedema, compression stockings for isolated venous hypertension and antibiotics for cellulitis.

Conclusion The causes of peripheral oedema are varied, requiring a systematic approach to history taking and examination. Diagnosis is often a process of elimination of the common causes. Most patients who present early can be managed in the community. Patients with advanced cardiac, hepatic or renal disease with gross peripheral oedema warrant urgent specialist review or hospital admission. A high index of suspicion is required to detect rarer but potentially life-threatening causes of peripheral oedema, such as constrictive pericarditis. MT

References 1. Starling EH. Physiologic forces involved in the causation of dropsy. Lancet 1896; I: 1267-1270. 2. Cho S, Atwood JE. Peripheral edema. Am J Med 2002; 113: 580-586.

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