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Am Fam Physician. 2022;106(5):557-564

Related Letter to the Editor: Compression Stockings May Reduce Postthrombotic Syndrome

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Edema is a common clinical sign that may indicate numerous pathologies. As a sequela of imbalanced capillary hemodynamics, edema is an accumulation of fluid in the interstitial compartment. The chronicity and laterality of the edema guide evaluation. Medications (e.g., antihypertensives, anti-inflammatory drugs, hormones) can contribute to edema. Evaluation should begin with obtaining a basic metabolic panel, liver function tests, thyroid function testing, brain natriuretic peptide levels, and a urine protein/creatinine ratio. Validated decision rules, such as the Wells and STOP-Bang (snoring, tired, observed, pressure, body mass index, age, neck size, gender) criteria, can guide decision-making regarding the possibility of venous thromboembolic disease and obstructive sleep apnea, respectively. Acute unilateral lower-extremity edema warrants immediate evaluation for deep venous thrombosis with a d-dimer test or compression ultrasonography. For patients with chronic bilateral lower-extremity edema, duplex ultrasonography with reflux can help diagnose chronic venous insufficiency. Patients with pulmonary edema or elevated brain natriuretic peptide levels should undergo echocardiography to assess for heart failure. Lymphedema is often a clinical diagnosis; lymphoscintigraphy can be performed if the diagnosis is unclear. Treatment of edema is specific to the etiology. Diuretics are effective but should be used only for systemic causes of edema. Ruscus extract and horse chestnut seed demonstrate moderate-quality evidence to improve edema from chronic venous insufficiency. Compression therapy is effective for most causes of edema.

Edema is a frequent manifestation of systemic illness resulting in maldistribution of total body water. Total body water is divided into intracellular (two-thirds) and extracellular (one-third) compartments. The extracellular compartment is further divided into plasma (one-fourth) and interstitial fluid (three-fourths). Edema is characterized by excess fluid accumulation in the interstitial compartment and occurs because of an imbalance of capillary hemodynamics as a result of one or more of the following mechanisms: increased oncotic pressure of the interstitial space, increased intravascular hydrostatic pressure, increased permeability of the endothelial barrier, decreased oncotic pressure within the capillary, or poor lymphatic drainage.1,2 Although edema is often localized to the extremities, fluid may also accumulate throughout the entire body (anasarca).2

Clinical recommendation Evidence rating Comments
Patients with lower-extremity edema should be stratified based on location (unilateral vs. bilateral) and time course (acute/subacute vs. chronic) of the condition.5,6 C Clinical reviews and consensus expert opinion
Initial laboratory workup for patients with lower-extremity edema should include brain natriuretic peptide levels, thyroid-stimulating hormone, liver function tests, basic metabolic panel, and urine protein/creatinine ratio.57 C Clinical reviews and consensus expert opinion
A high Wells score is the most useful clinical feature in diagnosing acute deep venous thrombosis (LR+ = 5.2) and should be used in patients with acute unilateral lower-extremity edema.16,17 A Systematic review and meta-analysis of randomized controlled trials
The STOP-Bang criteria are a validated tool to screen for obstructive sleep apnea and should be used in patients with chronic bilateral lower-extremity edema.24 C Validated clinical decision rule with disease-oriented outcome
For patients with chronic edema, venous duplex ultrasonography with reflux can diagnose chronic venous insufficiency (and differentiate it from lymphedema).8,25 C Clinical reviews and consensus expert opinion
An ankle-brachial index should be performed in patients with lower-extremity edema and high suspicion of peripheral artery disease before recommending compression stockings.8 C Clinical reviews and consensus expert opinion
In patients with diuretic-resistant congestive heart failure with persistent lower-extremity edema, torsemide (Demadex) is more effective than furosemide (Lasix) in reducing the risk of hospitalization and cardiac mortality.44 A Systematic review and meta-analysis of randomized controlled trials

Although limited data are available on the prevalence of lower-extremity edema, recent estimates indicate that approximately 20% of adults older than 50 years have edema.3 Peripheral edema is a common finding in primary care and can be diagnostically challenging. Edema may be a sign of unrecognized systemic disease and can result in functional impairment. Although often characterized as edema, lipedema is more correctly described as maldistribution of fat in the extremities.4 This article focuses on diagnosing and treating localized edema, particularly in the lower extremities.

History and Physical Examination

A detailed history can help narrow the differential diagnosis of edema. Time course and location of symptoms should be determined to help stratify patients based on chronic (more than three months) or acute/subacute (less than three months) edema, as well as unilateral or bilateral edema5 (Table 157). The presence of pain suggests deep venous thrombosis (DVT), chronic venous insufficiency (CVI), or complex regional pain syndrome. Patients with CVI report aching and heaviness of extremities.8 Edema that worsens with prolonged standing suggests an underlying venous etiology. The presence of dyspnea or orthopnea should prompt consideration for congestive heart failure (CHF), whereas heat intolerance, fatigue, and weight loss may suggest Graves disease.57

AcuteDeep venous thrombosis*
Insect or animal bite
Ruptured Baker cyst
Superficial venous thrombosis
Trauma (e.g., ruptured muscle, compartment syndrome, fracture)
Acute congestive heart failure*
Acute cirrhosis
Acute renal failure
Proximal deep venous thrombosis (e.g., inferior vena cava thrombosis)
ChronicChronic venous insufficiency*
Complex regional pain syndrome
Postthrombotic syndrome
Proximal vein compression
Chronic congestive heart failure, cirrhosis, or nephrotic syndrome*
Chronic venous insufficiency*
Pulmonary hypertension*
Obstructive sleep apnea
Thyroid disease

Risk factors for DVT should be assessed, including a history of venous thromboembolism, active malignancy, immobilization, or recent surgery.9 Previous radiation or surgery to an extremity may disrupt lymphatic drainage, resulting in lymph-edema.4 A comprehensive review of the patient’s medication list is essential because medications may cause or contribute to edema (Table 2).57,10

Medication classExamples
AntihypertensivesAmlodipine (Norvasc), beta blockers, clonidine, diltiazem, hydralazine, minoxidil, nifedipine
Anti-inflammatory drugsCorticosteroids, nonsteroidal anti-inflammatory drugs
ChemotherapyCyclophosphamide, cyclosporine (Sandimmune), docetaxel (Taxotere), gemcitabine, targeted immunotherapy
GabapentinoidsGabapentin (Neurontin), pregabalin (Lyrica)
HormonesEstrogen (Estratest), progesterone, testosterone
ThiazolidinedionesPioglitazone (Actos)
OtherAcyclovir, antipsychotics, monoamine oxidase inhibitors

On physical examination, nonpitting edema suggests pretibial myxedema or later stages of lymphedema, whereas pitting edema is associated with CVI, DVT, or early lymphedema. Pitting edema has been classically graded on a 1 to 4 scale based on depth and rebound time; however, this scale lacks reliability and reproducibility.11 Erythema and tenderness suggest DVT, superficial venous thrombosis, cellulitis, or stasis dermatitis. Lipedema is typically tender, whereas lymphedema often is not. Bilateral lower-extremity edema that spares the dorsum of the feet is highly suggestive of lipedema4 (Figure 1). Stemmer sign, the inability to pinch up a fold of skin of the dorsal second toe, is pathognomonic for advanced lymphedema.4 Skin changes such as stasis dermatitis, hyperpigmentation, medial ankle ulceration, or lipodermatosclerosis (inflammation of subcutaneous fat leading to hyperpigmentation and thickening) are seen in CVI8 (Figure 2). Prominent venous vessels such as telangiectasias, reticular veins, and varicose veins are also common in CVI.8 Hyperkeratosis or verrucous lesions are suggestive of lymphedema4 (Figure 312). Crescent-shaped ecchymosis of the ankle may suggest a ruptured Baker (popliteal) cyst or gastrocnemius muscle.7 The presence of an S3 heart sound (positive likelihood ratio [LR+] = 11.0), abdominojugular reflux (LR+ = 6.4), or jugular venous distention (LR+ = 5.1) increases the likelihood of CHF.13 Common findings for cirrhosis include ascites (LR+ = 7.2) and spider nevi (LR+ = 4.3).14

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