Continuing Education Activity

Anasarca is a medical condition in which there is a severe generalized accumulation of fluid or edema in the interstitial space. This accumulation of fluid occurs when capillary filtration exceeds the amount of fluid removed via lymphatic drainage or a change in the oncotic pressure from low protein states. It is caused by a variety of clinical conditions including heart failure, renal failure, liver failure, or conditions involving the lymphatic system. This activity reviews the causes, pathophysiology, presentation of anasarca and stresses the importance of the interprofessional team in its management.

Objectives:

• Identify the etiology of anasarca.
• Review the presentation of a patient with anasarca.
• Summarize the treatment and management options available for anasarca
• Explain interprofessional team strategies for improving care coordination and outcomes in patients with anasarca.

Introduction

Anasarca and edema both are defined as an increase, swelling, or expansion of interstitial fluid volume. This accumulation of fluid in the interstitial space occurs as the capillary filtration exceeds the amount of fluid take out by lymphatic drainage. When edema is massive and generalized, it is called anasarca and it can be caused by a variety of clinical conditions like heart failure, renal failure, liver failure, or problems with the lymphatic system. In this article, we will refer to the term anasarca when referring to instances of the severe form of edema as not every patient with edema has anasarca. The manifestation of anasarca in patients can vary, but it usually becomes clinically apparent as the interstitial volume exceeds 2.5 -3.0 liters.[1][2][3]

Etiology

The most common causes of anasarca include heart failure, cirrhosis, conditions cause a low albumin state, renal dieases like nephrotic syndrome, and pregnancy. Other causes of anasarca are venous obstruction, burns, trauma, malignancy etc.

Epidemiology

The epidemiology of anasarca is not well studied as it is a common complaint among the patients with various different medical conditions. Anasarca is noted in higher frequency in patients with organ dysfunction as well in post-operative patients. In a study of 241 patients who underwent major abdominal surgery, around 29% of patients developed postoperative anasarca. [4]

Pathophysiology

Anasarca develops as a response to an elevation in capillary hydraulic pressure, increased capillary permeability, a lower plasma oncotic pressure, or a combination of these changes. Anasarca also can be secondary to lymphatic obstruction leading to retained fluid in the interstitial space. The following are the clinical conditions for the various mechanisms described.[5][6]

• An elevation in capillary hydraulic pressure
  • Heart failure, kidney disease, early cirrhosis, pregnancy, drugs (i.e. amlodipine)
  • Venous obstruction or insufficiency states like DVT, hepatic venous congestion 
• Increased capillary permeability
  • Burns, trauma, sepsis, allergic reactions, malignant ascites
• Lymphatic obstruction
  • Malignancy, Post lymph node dissection
• Hypoalbuminemia
  • Nephrotic syndrome, liver disease, malnutrition

As a first step, when the fluid moves from the vascular space to the interstitium, it reduces the plasma volume. This reduces tissue perfusion which then causes retention of sodium and water by the kidneys which leads to a cascade of effects worsening fluid retention. Some of the excess fluid gained will be retained in the intravascular compartment. However, the alteration in capillary hemodynamics results in most of the retained fluid entering the interstitium and, eventually, becoming apparent as edema or anasarca.

History and Physical

The history should include the underlying comorbidities, the timing of the development of the edema and anasarca, positional changes, whether it is unilateral or bilateral, and medication history. Chronic accumulation of more generalized edema is caused by the onset or exacerbation of systemic conditions such as congestive heart failure (CHF), renal disease, or hepatic disease. Dependent edema caused by venous insufficiency is more likely to improve with elevation and deteriorate with dependency. Edema associated with decreased plasma oncotic pressure (e.g., malabsorption, liver failure, nephrotic syndrome) does not change with dependency.

The physical examination can aid in establishing the diagnosis. The exam should be focused on identifying the pattern of edema – peripheral vs. pulmonary edema, pitting vs. non-pitting edema, and the presence of jugular venous distension. Below are the exam findings of common clinical conditions that can cause anasarca.

Patients with pulmonary edema complain primarily of dyspnea that can be worsened at rest and upon exertion as well as orthopnea, cough, and chest pain. Common physical examination findings can reveal pulmonary findings like crackles or rhonchi, cardiac findings indicating volume overload, or heart failure like an S3 gallop. Peripheral edema is usually detected by the presence of pitting after pressure is applied to the edematous region. Pitting reflects the movement of the excess interstitial water in response to pressure. It is usually seen in dependent areas like the lower extremities in ambulatory patients and over the sacrum in patients who are bed-bound. Scrotal edema can also be seen in males when the edema is more severe like cases of anasarca. Non-pitting edema more commonly suggests lymphatic obstruction or hypothyroidism. Acute onset of unexplained unilateral leg edema should raise the possibility of deep vein thrombosis (DVT). Cirrhotic patients from any cause can develop ascites and then edema in the lower extremities because of an increase in venous pressure below the diseased liver. The presence of other signs of portal hypertension, such as distended abdominal wall veins and splenomegaly, also is suggestive of a primary hepatic disease. 

The cause of edema and anasarca sometimes can be determined by noting changes in skin temperature, color, and texture. Acute DVT and cellulitis may produce increased warmth over the affected area. The deposition of hemosiderin or chronic venous insufficiency often causes the skin to have a brawny, reddish hue and commonly involves the medial malleolus. As venous insufficiency progresses, it can result in lipodermatosclerosis which is associated with marked sclerotic and hyperpigmented tissue and characterized by fibrosis and hemosiderin deposition that can lead to venous ulcers over the medial malleolus. The ulcers may progress to deep, weeping erosions. Myxedema from hypothyroidism presents with a generalized, dry, thick skin with nonpitting periorbital edema and yellow to orange skin discoloration over the knees, elbows, palms, and soles. Pretibial myxedema occurs in patients with thyroid disease and is characterized by bilateral, asymmetric, nonpitting, scaly thickening, and induration of the skin. These ulcers may be violaceous or slightly pigmented (yellow-brown) and often have an orange-peel appearance. The most frequent location of pretibial myxedema is over the lower legs, especially the pretibial areas or the dorsum of the foot.

Evaluation

The initial evaluation should include basic blood and urine samples. A complete blood count (CBC), comprehensive metabolic panel (CMP), and a urinalysis (UA) can all give an initial broad overview of potential pathologies leading to the cause of the anasarca. The CMP can help assess renal function, albumin level, and liver function (AST and ALT). Dipstick testing principally detects albumin and would need an additional protein sulfosalicylic acid precipitation test (SAS) to detect globulins and Bence-Jones proteins. A urine protein/creatinine ratio or 24-hr urine for protein can obviate the need for SAS testing. The finding of a markedly positive dipstick for protein in combination with hypoalbuminemia and clinical edema is virtually diagnostic of a nephrotic syndrome. Additional testing through measuring a brain natriuretic peptide (BNP) can give clues like underlying CHF. Chest radiography is helpful in cardiac enlargement, pulmonary edema, and pleural effusions.

If warranted, a cardiac echo can evaluate the ventricular function, assess for the presence of a pericardial effusion, and aid in the diagnosis of cardiac disease. Echocardiography can also be used to evaluate pulmonary arterial pressures for patients with known or suspected obstructive sleep apnea and lower extremity edema. Venous ultrasonography is the imaging of choice in the evaluation of suspected DVT. Duplex ultrasonography also can be used to confirm a chronic venous insufficiency. The most commonly used radiographic technique in patients with renal dysfunction or proteinuria is the use of renal ultrasonography. Ultrasonography allows the clinician to characterize kidney size and assess for cystic renal disease and hydronephrosis.[7][8]

Magnetic resonance angiography with venography of the lower extremity and pelvis can be used to evaluate for intrinsic or extrinsic pelvic or thigh DVT. Left iliac vein compression by the right iliac artery (May-Thurner syndrome) should be suspected in women who are 18 and 30 years of age and present with edema of the left lower extremity. Lymphoscintigraphy is the method of choice for evaluating lymphedema when the diagnosis cannot be made clinically.  MRI may aid in the diagnosis of musculoskeletal etiologies like a gastrocnemius tear or popliteal cyst. T1-weighted magnetic resonance lymphangiography can visualize the lymphatic channels when lymphedema is suspected.

Treatment / Management

Management of anasarca should be guided by the treatment of the underlying etiology but generally includes diuresis. Pulmonary edema is one of the few forms of generalized edema that is life-threatening and requires immediate therapy. In all other edematous states, removal of the excess fluid can proceed more slowly as it is not acutely life-threatening to the patient. In patients with generalized edema due to heart failure, nephrotic syndrome, or primary sodium retention, the edema fluid can be mobilized rapidly with help of loop or thiazide diuretics. In patients with anasarca, removing 2 to 3 liters or more of edema fluid in 24 hours can ordinarily be accomplished without a clinically significant reduction in plasma volume.

In patients with localized edema due to venous or lymphatic obstruction or malignant ascites, diuretic therapy can lead to volume depletion. Diuretic therapy in generalized edematous states and anasarca is usually begun with a loop diuretic, such as furosemide or bumetanide. In patients with cirrhosis and ascites, the two mainstays of treatment include sodium restriction and oral diuretics. The dietary sodium restriction would be less than 2000 mg/day [88 mmol/day] and diuretic therapy should be a combination of spironolactone and a loop diuretic like furosemide. The addition of spironolactone is preferred in the initial diuretic regimen as it helps to prevent hypokalemia. As hypokalemia predisposes to increased production of ammonia. The recommended initial dose is spironolactone 100-200 mg/d with furosemide at 20-40 mg/d. The diuretic dosage can be monitored with a random “spot” urine sodium concentration. Diuretics should be increased until the urine sodium concentration is greater than the potassium concentration. [9] Higher doses of diuretics may be required in patients with nephrotic syndrome, up to 1 mg/kg/day of furosemide and 2 mg/kg/day of spironolactone.[10][11] Some cases of idiopathic edema are diuretic-induced, and the initial approach in patients with idiopathic edema who are already on diuretics is to stop the diuretics for at least 2 to 3 weeks and encourage sodium restriction in diet.

The mainstays of therapy for lower-extremity edema due to venous insufficiency are mechanical therapies, including leg elevation and compression stockings with 20 to 30 mmHg for mild edema and 30 to 40 mmHg for severe edema complicated by ulceration. Compression therapy is contraindicated in patients with peripheral arterial disease. Local skin and wound care of venous ulcers is essential in preventing secondary cellulitis and dermatitis. Eczematous (stasis) dermatitis, characterized by dry, inflamed, scaling skin overlying superficial varicose veins, often occurs in patients with chronic venous insufficiency. Treatment includes daily hydration with emollients and short courses of topical steroid creams for severely inflamed skin. Primary lymphedema treatment involves complex decongestive physiotherapy, including manual lymphatic massage and multilayer bandages. The first goal is the improvement of fluid resorption and continues until achieving the maximum therapeutic response. The maintenance phase of treatment includes compression stockings at 30 to 40 mmHg. Pneumatic compression devices can be used to augment standard therapies. Surgical debulking or bypass procedures are limited to severe refractory cases. Diuretics are not demonstrated to be effective in the treatment of lymphedema.

Differential Diagnosis

• Autoimmune conditions like juvenile dermatomyositis [12]
• Congestive heart failure from any cause
• Hematological disorders like acute myeloid leukemia or rare causes like TAFRO [13]
• Kidney disease from any cause like:
  • Acute or Chronic kidney disease
  • IgA nephropathy
  • Membranoproliferative glomerulonephritis
  • Nephrotic syndrome
• Liver cirrhosis from any cause like alcohol abuse or hepatitis
• Lymphedema
• Medications: amlodipine [14]

• Pericardial effusion from any cause
• Pregnancy

Prognosis

Prognosis of anasarca depends on the underlying etiology. Reversible causes may carry favorable outcomes, whereas irreversible etiologies and malignancies have a poor prognosis. However in most of the situations, by the time anasarca has developed, the underlying problem has progressed beyond cure.

Complications

If left untreated, common complications include, but are not limited to skin ulcerations, skin infections, pulmonary edema, congestive heart failure, and even death.

Enhancing Healthcare Team Outcomes

Anasarca is a serious condition leading to generalized accumulation of fluid in the body. Because there are many causes of anasarca, it is best managed by an interprofessional team of healthcare workers. The nurse practitioner, physician assistant  and primary care giver should refer these patients to an internist because in many cases, admission is required to determine the diagnosis. A team approach for management is necessary with support of nurses and pharmacists. The outcomes of patients with anasarca is guarded, for those with failing organs, the mortality rates are very high. Even benign causes can require long-term admission and recovery is a very slow process.