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One function of the lymphatic system is to return excess fluid and protein from interstitial spaces to the blood vascular system. Since lymphatic vessels often lack a basement membrane, they can resorb molecules too large for venous uptake. Mechanisms of clinical edema include increased arteriovenous capillary filtration and reduced interstitial fluid absorption. Causes of increased capillary filtration include increased hydrostatic pressure in capillaries, decreased tissue pressure, and increased membrane permeability. Reduced interstitial fluid resorption can be caused by decreased plasma oncotic pressure, increased oncotic pressure of tissue fluid, and lymphatic obstruction.
Lymphedema is categorized as either primary or secondary. Primary lymphedema is caused by congenital absence or abnormalities of lymphatic tissue and is relatively rare. Secondary lymphedema is generally caused by obstruction or interruption of the lymphatic system, which usually occurs at proximal limb segments (i.e., lymph nodes) due to infection, malignancy, or scar tissue (See Table 1).[1] The pelvic and inguinal groups of nodes in the lower extremities and the axillary nodes of the upper extremities are the primary sites of obstruction.
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Table 1. Lymph Drainage Failure
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Mechanism
Reduced lymph-conducting Hypertrophy or hyperplasia
pathways of lymphatic vessels Functional Obstructed
failure lymphatics
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Possible causes
Aplasia or hypoplasia Lymphangiomatosis, Valvular Lymph node
of whole vessel lymphatic malformations failure abnormalities
(e.g.,
fibrosis)
Acquired obliteration Megalymphatics Disordered "Scarring"
of lymphatic lumen contractility from
(e.g., lymphangio- lymphaden-
thrombosis, lymphangitis) ectomy,
radiation
therapy or
infection
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Adapted from Mortimer PS: The pathophysiology of lymphedema. Cancer 83(12
suppl 2): 2798-2802, 1998.
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It has been assumed that lymphedematous limbs contain interstitial fluids with higher protein concentrations than plasma. However, a recent report found a negative correlation between protein concentration and arm edema.[3] Concomitant venous obstruction has also been observed in patients with lymphedematous limbs. An investigation of venous outflow using duplex Doppler ultrasound revealed venous abnormalities in more than 60% of cases.[4] Additional studies suggest that local vasodilatory control may be altered, although not on a sustained basis.[5] Further work in this area is needed to better discern the pathophysiology of lymphedema.
A second type of acute lymphedema may occur within 6 to 8 weeks postoperatively, possibly as a result of acute lymphangitis or phlebitis. There is no associated venous thrombosis in these cases. This pattern of lymphedema may also be seen during the course of radiation treatment of a limb or its associated lymphatic drainage route. The affected area is tender, warm or hot, and erythematous. This type of lymphedema can usually be successfully treated with limb elevation and anti-inflammatory medication, although more involved treatments may be necessary. The first two acute forms do not necessarily portend chronic swelling after their resolution.
A third type of acute lymphedema is an erysipeloid form, occurring after an insect bite, or minor injury or burn. It is often superimposed on a chronic edematous limb. The affected area is erythematous, very tender and hot. This form of edema often requires limb elevation and antibiotics. Compression pumping or wrapping is contraindicated during acute stages of infection. Many clinicians will permit treatment once severe erythema or blistering has resolved. Mild erythema can persist following an infection.
The fourth and most common type of lymphedema is usually insidious and is not always associated with erythema. Discomfort of the skin or aching in the proximal segments (neck/shoulders for upper extremity, lumbar spine/hips for lower extremity) may be noted due to stretch of the soft tissues or muscular overuse and postural changes caused by increased limb weight. This type has a variable onset and is frequently apparent 18 to 24 months after surgery. It may appear a few months or many years after cancer treatment.
Chronic lymphedema is the most difficult of all types of edema to reverse, due to the nature of its pathophysiology. A cycle is started, wherein the deficient lymphatic system of the limb is incapable of compensating for the increased demand for fluid drainage. This condition may occur subsequent to any of the following: tumor recurrence or progression in the nodal area, infection and/or injury of lymphatic vessels, immobility, radiation injury to lymphatic structures, surgery, unsuccessful management of early lymphedema, or venous obstruction due to thrombosis.
Early in the course of developing lymphedema, the patient experiences soft, pitting edema that may be easily improved by limb elevation, gentle exercise and elastic support. Continual and progressive lymphostasis, however, causes dilation of the lymph vessels and backflow of fluid to the tissue beds. Collagen proteins accumulate, further increasing colloid osmotic tissue pressure, leading to enhanced fluid flow from the vascular capillaries into the interstitial space. The stasis of fluid and protein stimulates inflammation and macrophage activity as the body attempts to degrade the excess proteins. Fibrosis of the interstitial connective tissue by fibrinogen and fibroblasts causes the development of the brawny, stiff, nonpitting lymphedema that no longer responds to elevation, gentle exercise, or elastic compression garments. Chronic lymphedema gradually becomes nonpitting.
Lymphedematous tissues have a lower oxygen content, a greater distance between lymph vessels due to fluid accumulation and swelling, impaired lymphatic clearance, and depressed macrophage function, rendering patients at increased risk of infection and cellulitis. Since there is no other route for tissue protein transport, treatment for patients with advanced lymphedema with chronic fibrosis is more difficult than when treated earlier. Additionally, once these tissues are stretched, edema recurs more readily.
Generalized lymphedema may also occur subsequent to hypoalbuminemia with low plasma oncotic pressure due to (a) inadequate oral nutrition (secondary to anorexia, nausea, vomiting, depression, chemotherapy); (b) decreased intestinal absorption of protein or abnormal protein synthesis/anabolism; (c) protein loss due to leakage of blood, ascites, effusions, or surgical drains; or (d) contributing medical conditions leading to hypoalbuminemia (e.g., diabetes, kidney malfunction, hypertension, congestive heart failure, liver disease).
Patients at risk for lymphedema are those with:
Approximately 50% of patients with minimal edema report a feeling of heaviness or fullness of the extremity. Assessment of the patient with edema includes a history and physical examination. The history should include information regarding past surgeries, postoperative complications, prior radiation treatments, the time interval from radiation or surgery to the onset of symptoms, and intervening variables in the presence or severity of symptoms. The quality and behavior of the edema (fluctuation with position, progression over time) should be assessed. History of trauma or infection should be determined. In addition, information concerning current medications may be important.[1] Edema is not detectable clinically until the interstitial volume reaches 30% above normal. The following scale may be clinically useful:
Patients should also be assessed for knowledge of their disease and the potential for developing lymphedema. Deficient lymphatic drainage due to node dissection and/or radiation therapy predisposes the affected limb to serious infection. Even minor infection of the limb may lead to significant lymphedema.
Patients should understand the potential of developing lymphedema and should be instructed on limb and skin care following surgery and/or radiation therapy. (See list of Considerations for Patient Teaching below) It should be stressed that there is no empirical evidence for these or similar recommendations, although advice to avoid injury and infection in the affected limb seems intuitive. Lymphedema may occur as late as 30 or more years after surgery. Breast cancer patients who comply with instruction on skin care and exercises following mastectomy show a significantly lower incidence of lymphedema.[1]
Lymphatic drainage is improved by tissue compression from muscular contractions during exercise. In exercise, muscles squeeze the soft tissue causing lymph to travel proximally to the vascular system.[2] Therefore, exercise is important in the prevention of lymphedema. Breast cancer patients should be instructed on hand and arm exercises following mastectomy. Patients who undergo operative procedures affecting pelvic lymph node drainage should be instructed in how to perform appropriate leg and ankle exercises. The physician should determine how soon the exercise is initiated following surgery. Physiatrists or therapy professionals should be consulted for a tailored program of exercises for each patient.
Because the recovery rate is increased when lymphedema is detected early,[2] patients should be taught to recognize the early signs of edema and to report any of the following symptoms to their doctor: feelings of tightness in the extremity; shoes that don't fit; decreased strength; pain, aching, or heaviness; redness, swelling, or signs of infection. Rings may become tight as well, but patients are discouraged from wearing them on the side of risk.
Considerations for Teaching Patients Prevention and Control of Lymphedema
1. Keep arm or leg elevated above the level of the heart, when possible.
Avoid rapid circular movements that cause centrifugal pooling of fluid in
distal parts of the limb.
2. Clean and lubricate the skin of the extremity daily.
3. Avoid injury and infection of the affected limb:
6. Practice prescribed exercises, as instructed.
7. Keep regular follow-up appointments with your physician.
8. Closely observe all areas of the limb daily for signs of problems.
Surgical interventions are not recommended as they are not generally successful in curing lymphedema. Several techniques have been tried, such as staged excision of the skin and subcutaneous tissue with or without skin grafting and the Thompson dermal flap, which combines excision of edematous tissue with burying a shaved dermal flap to establish continuity between the superficial and deep lymphatic vessels. These methods have minimal success and high complication rates of skin necrosis, infection, and sensory difficulties.[6] The oncology patient is usually not a suitable candidate for these techniques.
Compression garments
Compression garments should always cover the entire area of edema. For example, a stocking that reaches only to the knee tends to become tight and occludes lymphatic and venous return if there is significant edema in the thigh. Extremity pumps that use intermittent sequential pneumatic compression may also be helpful in the management of the edematous limb, though many feel such pumps are ineffective and potentially counterproductive. The cuff is alternately inflated and deflated according to a controlled time cycle. This action increases fluid flow in the veins and lymphatic vessels and prevents the accumulation of residual fluid in the limb. Compression pumps should be used only under the supervision of a trained health care professional. High external pressure can damage superficial lymphatic vessels. Furthermore, when using compression pumps and other techniques, caution should be taken if there is a potential for residual tumor which some theorize may be mobilized into venous or lymphatic channels.
Pharmacologic therapy
Pharmacologic therapy uses antibiotics to treat and prevent bacterial cellulitis and lymphangitis. Other drugs that have been used include diuretics, anticoagulants, pantothenic acid, pyridoxine, and hyaluronidase. These drugs have no proven therapeutic value and may cause adverse reactions.[7]
It is important to determine the specific etiology of the swelling and to treat it appropriately. Infection is a frequent sequela of edema and causes increased capillary permeability, which increases protein deposition in the tissues. If an infection is diagnosed, appropriate antibiotics should be given that are effective against gram-positive cocci and, less frequently, fungal infections. Laboratory data (e.g., CBC) should be evaluated. Because massage and techniques to encourage drainage would be contraindicated if venous thrombosis is present, diagnostic tests may be indicated to distinguish vascular blockage from deep vein thrombosis. If thrombosis is found, anticoagulation therapy should be given.
Coumarin (Chemical Abstracts Service registry number 91-64-5; NSC 8774; systematic name 2H-1-Benzopyran-2-one, also referred to as 5,6-benzo-[a]-pyrone), is a compound that has been studied for the management of high protein lymphedemas such as those associated with local and regional treatments for neoplastic diseases.[8,9]
In the United States, dietary supplements are regulated as food not drugs. Premarket approval by the Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not required to be reviewed for manufacturing consistency, and no specific standards for dose or purity exist, there may be considerable variation from lot to lot for all products marketed as dietary supplements.
Coumarin was formerly used in the United States as a fixative and flavoring agent in foods and as a pharmaceutical excipient. In response to investigations by coumarin manufacturers that demonstrated the compound caused liver toxicity in animals when used in amounts comparable to or greater than that appearing in human foods, it was reclassified by the U.S. Food and Drug Administration (FDA) in 1954 as a food adulterant. Since that time, its addition to human foods has been prohibited and importation of coumarin-containing foodstuffs from outside the United States is not permitted. Coumarin is marketed for medical use in several European countries, but its therapeutic use has not been approved in the United States or Canada.
Adverse effects commonly associated with coumarin include mild nausea and diarrhea.[8] Liver toxicity has been reported in up to 6% of treated patients.[10-13] Patients typically present with increased serum concentrations of hepatic transaminases, with or without coincidentally increased serum bilirubin.[14,15] Aberrant laboratory values generally resolve within a few weeks after coumarin treatment is discontinued; however, liver pathology may be progressive and fulminant despite withdrawal of the compound.[16] Long-term toxicity data are sparse for patients who have received continuous treatment for up to 2 years. The clinical toxicity of longer durations of coumarin treatment has not been investigated. Animal toxicology studies have shown that the incidence of coumarin-induced hepatotoxicity is highly variable between species.[17] Reports of hepatic toxicity in humans have led to coumarin's removal from the market in some European countries as well as in Australia.
In one study, coumarin, administered as tablets for oral use at a daily dose of 400 mg, was shown to partially reverse edema fluid accumulation, to reduce the size of swollen extremities, and to decrease the discomfort associated with lymphedema.[8] A double-blind, placebo-controlled, crossover study in 140 women with lymphedema of the arm following treatment for breast cancer, however, demonstrated that coumarin was not more effective than placebo in the treatment of lymphedema. This study also found a higher (6%) incidence of coumarin-associated hepatic toxicity and concluded that coumarin was not a safe or effective treatment for lymphedema.[9,13]
Diuretics encourage vascular fluid depletion, but they do nothing for excess protein deposits and could hasten connective tissue fibrosis.[18] Therefore, diuretics should be used with caution and only for the treatment of excess vascular fluid due to other causes.
Dietary management
The nutritional status of the patient should be evaluated and supportive measures instituted as required. Hypoalbuminemia encourages fluid to pass into interstitial tissues with excess protein and higher colloid osmotic pressure. The serum albumin level should be kept above 2.5 g/dL. The patient's weight should be monitored, and patients should be encouraged to eat protein-rich foods and supplements.
Pain management
Patients with lymphedema may experience pain as a result of pressure on nerve endings or as a result of atrophy or muscle contractures during movement.[1] Following assessment, pain may be managed with non-opioid analgesics, relaxation techniques, mild to strong opioid analgesics, adjuvant drugs (e.g., amitriptyline), and/or transcutaneous electrical nerve stimulation (TENS). The most successful treatment, however, is reduction of the lymphedema.
Complications
Edematous tissues are less well nourished and more prone to necrosis during immobility. Therefore, patients with lymphedema should be monitored for areas of skin breakdown, especially over bony prominences.
Excess pressure on inguinal or pelvic lymphatics may indicate pelvic metastasis with subsequent interference of bladder emptying. Pressure, in conjunction with regular narcotics, may cause problems with bowel elimination. Patient bladder and bowel status should be monitored for signs of urinary retention or constipation.
Another study highlighted the factors associated with psychologic distress within a group of patients who developed upper extremity lymphedema after breast cancer treatment. Risk factors for poor adjustment to the condition include poor social support, use of an avoidant and reclusive style of coping (some women seek to avoid social situations in which their lymphedema causes a constant reminder of their cancer experience), and the presence of pain of any intensity.[19] Group and individual counseling that provides specific information about preventive measures, the role of diet and exercise, advice for selecting comfortable and flattering clothing, and emotional support can be helpful to women coping with lymphedema.
The cause of lymphangiosarcoma is unknown. Clinically, it presents as single or multiple, bluish-red hemorrhagic nodules on the edematous limb with proximal and distal progression. Initially, there is a solitary, purple-red focus in the skin of the limb, slightly raised, macular or nodular, and usually described by the patient as a "bruise." Later, satellite tumors arise, and the nodules grow. Death usually results from metastatic (usually pulmonary) and residual growths.[1]
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