Peripheral Edema causes and treatment
Total body water is divided between the intracellular and extracellular spaces. The extracellular space, which comprises about one third of total body water, is composed of the intravascular plasma volume (25%) and the extravascular interstitial space (75%). Starling defined the physiologic forces involved in maintaining the balance of water between these two compartments, which include the gradient between intravascular and extravascular hydrostatic pressures, differences in oncotic pressures within the interstitial space and plasma, and the hydraulic permeability of the blood vessel wall.
The lymphatic system collects fluid and filtered proteins from the interstitial space and returns them to the vascular compartment. Major perturbations in this delicate homeostasis that favors net filtration out of the vascular space, or impaired return of fluid by lymphatics from the interstitial space, will result in edema.
Edema is defined as a palpable swelling caused by an increase in interstitial fluid volume. Edema, other than localized edema, does not become clinically apparent until the interstitial volume has increased by 2.5 to 3 liters.
There are two types of leg edema:
- Venous edema consists of excess low-viscosity, protein-poor interstitial fluid resulting from increased capillary filtration that cannot be accommodated by a normal lymphatic system.
- Lymph edema consists of excess protein rich interstitial fluid within the skin and subcutaneous tissue resulting from lymphatic dysfunction.
A third type, lipidema, is more accurately considered a form of fat maldistribution rather than true edema.
Increased venous pressures due to central or regional venous obstruction or to an expansion in plasma volume are transmitted to the capillary bed, thereby increasing hydrostatic pressure and predisposing to edema. Conversely, local auto regulation by smooth muscle sphincters on the pre-capillary (or arterial) side protect the capillary bed from increases in systemic arterial pres-sure, which explains why hypertensive patients do not have edema despite elevated blood pressure.
The major contributors to interstitial oncotic pressure are mucopolysaccharides, filtered proteins such as albumin, capillary wall protein permeability, and the rate of lymphatic clearance. Changes in capillary wall permeability are mediated by cytokines such as tumor necrosis factor, interleukin 1, and interleukin 10, as well as by circulating vasodilatory prostaglandins and nitric oxide. Increased vascular permeability is central to edema resulting from local inflammation (e.g., insect bites), allergic reactions, and burns.
Causes of Edema
In heart failure, an elevation in venous pressure caused by ventricular systolic or diastolic dysfunction increases capillary hydrostatic pressure. The resulting low-output state activates the aforementioned neurohumoral mechanisms that maintain arterial perfusion. If the resulting extravasation of fluid out paces the ability of the lymphatic system to return this fluid to the vascular space, edema will result. With left ventricular failure, this manifests as pulmonary edema; whereas with right ventricular failure, this leads to peripheral edema. The severity of the edema may be disproportionate to the degree of central venous pressure elevation depending on factors such as immobility, posture, and venous insufficiency.
Constrictive Pericarditis/ Restrictive Cardiomyopathy
The signs of both constrictive pericarditis and restrictive cardiomyopathy are similar to those of right heart failure, namely elevated jugular venous pressure, hepatic congestion, ascites, and peripheral edema, and their onset may be insidious. Patients with elevated neck veins often receive a misdiagnosis of primary hepatic cirrhosis. A possible diagnosis of constriction or restriction should be considered in a patient presenting with unexplained edema, elevated jugular venous pressure, and relatively preserved systolic function. Although echocardiography may provide indirect evidence, more invasive studies such as right heart catheterization or tissue biopsy are often necessary to make a conclusive diagnosis.
The nephrotic syndrome comprises a group of disorders that are characterized by severe proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Nephrotic proteinuria is often caused by diabetic nephropathy, although it may result from primary glomerular disease or less common conditions. Although the syndrome has been long recognized, the mechanism of edema formation is still debated. The long held “under fill” theory postulates that edema results from reduced colloid oncotic pressure due to massive protein loss by the kidneys, which leads to translocation of water into the interstitial space.
Although this may occur in children with acute nephrosis, it is not the likely mechanism in most adults. In fact, most patients with nephrotic syndrome have increased neurohumoral hormone levels. These findings suggest that primary salt retention by the kidneys has substantial effects in most patients. The low plasma oncotic pressure increases the amount of edema that is observed for any increase in plasma volume and central venous pressure. Therefore, estimation of the central venous pressure is very important as a guide to diuretic therapy. If the plasma volume is reduced very rapidly with diuretics, patients can develop acute renal failure while having substantial edema.
Hypoproteinemia can occur in several conditions other than nephrotic syndrome, although the mechanism of edema formation may be similar. These etiologies include severe nutritional deficiency (e.g., kwashiorkor), protein losing enteropathies, and severe liver disease where hepatic synthetic function is impaired. Albumin is important for maintaining plasma oncotic pressure, and a level below 2 g/dL of plasma often results in edema.
End stage liver disease results in profound salt and water retention. Although most of this fluid retention manifests in the peritoneal cavity as ascites, peripheral edema may become prominent in later stages, particularly when there is severe hypoalbuminemia. As in heart failure, decreased “effective” circulating volume initiates a neurohumoral cascade of events leading to increased sodium and water reabsorption by the kidneys. This decrease is, in part, the result of splanchnic vasodilatation and arterio-venous fistula formation throughout the body that reduce vascular resistance. Unlike heart failure, cardiac output is normal or elevated in this form of high-output failure.
Medications may cause, or exacerbate, peripheral edema. Anti hypertensive drugs such as calcium channel blockers and direct vasodilators are most frequently implicated. Of the calcium channel blockers, the dihydropyridines are more likely to induce peripheral edema than are the phenylalkylamine or benzothiazepine classes, purportedly because of more selective arteriolar vasodilatation. The direct vasodilators such asminoxidil and diazoxide enhance renal sodium reabsorption through their blood pressure effect and activation of the reninangiotensin-aldosterone system. Angiotensin-converting enzyme inhibitors, in contrast, early cause dependent edema, suggesting that in other vasodilators angiotensin may play a central role in edema formation.
Troglitazone, rosiglitazone, and pioglitazone have been associated with peripheral and pulmonary edema, and are generally contraindicated in patients with New York Heart Association class III or IV heart failure. The edema is partly attributed to the 6% to 8% increase in plasma volume associated with use of these drugs. The mechanism of edema formation, however, is not known. Hence, use of these drugs in patients with milder forms of heart failure must be weighed against the potential risk of worsening volume overload. Such patients should be monitored for changes in weight and fluid status.
Peripheral edema is evident in 80% of normal pregnancies, half of which involve the lower extremities. The majority of this weight gain occurs during the second trimester. Several factors conducive to edema formation are present in the gravid patient, such as increased plasma volume and sodium retention, decreased plasma protein concentration, increased capillary hydrostatic pressure late in pregnancy because of mechanical compression of the internal vena cava and iliac veins, increased antinatriuretic hormones such as aldosterone and desoxycorticosterone, and activation of the reninangiotensin-aldosterone system.
Chronic Venous Insufficiency
Chronic venous insufficiency often results from longstanding venous valvular incompetence that leads to venous hypertension. The most common cause of valvular incompetence is the sequela of prior clinical or occult deep venous thromboses. As the thrombosis heals, valves are destroyed, leading to incompetency and venous wall distortion.
The edema may be unilateral or bilateral, although it is often asymmetric. Early in its course, it is soft and pitting, where as in the later stages, chronic venous and dermal changes such as varicosities, in duration, fibrosis, and pigmentation develop. Symptoms may be exacerbated by heat or prolonged sitting or standing. The extremities are susceptible to secondary complications such as dermatitis, cellulitis, and stasis ulceration. Venous stasis ulcers typically occur around the medial malleoli
Lymphedema results from impaired lymphatic transport leading to the pathologic accumulation of protein rich lymphatic fluid in the interstitium, most commonly in the extremities. Secondary lymphadema is the most common form. In the United States, edema of the upper extremity after axillary lymph node dissection is the most common cause of acquired lymphadema, whereas filariasis is the most common cause worldwide, affecting more than 90 million people.
With longstanding lymph stasis, cutaneous and sub-cutaneous fibrosis develops into the classic, indurated peau d’orange appearance of the skin. There is preferential swelling of the dorsum of the foot, with a characteristic “squared-off” appearance to the toes. This swelling results in the inability to tent the skin on the dorsum of the digits of the affected extremity, also known as Stemmer’s sign. Depending on the etiology, the edema may be unilateral or bilateral. Even when bilateral, it is common for the lymphedema to be asymmetric in severity.
Lipedema is commonly mistaken for peripheral edema or lymphedema. In this condition, the leg swelling is due to abnormal accumulation of fatty substances in the sub-cutaneous tissues, characteristically sparing the feet, and found almost exclusively in young women. The onset is usually insidious and often becomes apparent shortly after puberty. The lack of involvement of the feet and the absence of Stemmer’s sign help to distinguish lipedema from lymphedema.
Peripheral edema may occur in the setting of hyperthyroidism or hypothyroidism, although it is more common with thyroid hormone deficiency, occurring in about half of all patients with myxedema. Localized edema of the eyelids, face, and dorsum of the hand are noted more frequently. There are numerous direct and indirect biochemical responses to hypothyroidism that affect nearly all organ systems, and the mechanism of myxedema is not fully understood. At the capillary level, there is increased permeability resulting in the accumulation of proteins and mucopolysaccharides in the interstitium, followed by sodium and water. There is a concomitant expansion in total body water and sodium
“Idiopathic edema” describes a poorly understood syndrome of abnormal fluid retention that primarily affects premenopausal women. In attempts to describe its primary features, the condition has also been termed cyclical edema, periodic edema, fluid retention syndrome, or orthostatic edema. The key features are periodic episodes of edema in women who have weight changes that are not clearly related to the menstrual cycle.
Symptoms are usually described as swelling of the hands, legs, or face, or abdominal bloating, which may be real, or perceived by the patient. By definition, its diagnosis is made after excluding other organic causes of water retention. It is most common in the third and fourth decades of life. Psychologic and emotional disturbances are common comorbid conditions. Concomitant misuse of diuretics or laxatives is also common in patients with this disorder.
Treatment requires the recognition and management of underlying conditions that predispose to the formation of edema. Only by correcting the disruptions in Starling forces that lead to the cascade of water retention can the cycle be halted and the process reversed. In many cases, the elimination of edema is not possible, whereas in some it is not desirable. A combination of patient education, sodium restriction, and, when appropriate, the use of diuretics are often required.
Loop diuretics are usually the most effective for diuresis. Because their plasma half-lives are short (e.g., 1 hour for bumetanide, 1.5 to 2 hours for furosemide, 3 to 4 hours for torsemide), several doses are required per day to maintain natriuresis. The maximal response to each loop diuretic is patient specific; hence, a threshold level of the drug at the site of action must be attained for maximal response. Exceeding this threshold dose will not result in greater diuresis. Similarly, if an adequate dose fails to achieve a response, changing to a different loop diuretic will not be efficacious because the mechanisms of action are the same