Edema - Pathophysiology and Treatment

Donald E. Kohan, M.D., Ph.D.

General Concepts

Edema is defined as soft tissue swelling due to expansion of the interstitial volume. Edema can be localized or generalized. The normal distribution of body water is illustrated below.

1. Generalized edema involves an increase in extracellular fluid only (18% of body weight). Some extracellular fluid compartments, termed transcellular fluids (cerebrospinal fluid, intraocular fluid and joint fluid) do not communicate freely with the rest of the body.

EXAMPLE: A 70 kg adult has an ECF volume of 12.6 L (18% of body weight). If 2.5 L of fluid is added to this compartment alone, there is a 20% increase in interstitial fluid, but only a 3.5% increase in body weight. This amount could result in detectable edema.

2. Generalized edema is due to increases in both total body water and sodium. If just water is retained, it distributes throughout the total body water compartment (60% of body weight) and edema will not usually form. However, if sodium is retained as well, it is confined to the extracellular spaces. The increased osmolality due to sodium retains water in the ECF.

3. Generalized edema can occur with low, normal, or high serum sodium concentration. Serum sodium concentration, per se, does not reflect total body sodium. Increased total body sodium can occur with a low, normal or high serum sodium concentration.

Mechanisms maintaining interstitial fluid volume

The volume of interstitial fluid is determined by Starling's Law: Hydrostatic Pressure (capillary - tissue) - Oncotic pressure (capillary - tissue) = net fluid movement out of capillary into interstitium.

Oncotic pressure = osmotic pressure created by plasma protein molecules that are impermeable across the capillary membrane.

Causes of generalized edema

I. Decreased oncotic pressure
Nephrotic syndrome
Cirrhosis
Malnutrition

II. Increased vascular permeability to proteins
Angioneurotic edema (usually allergic)

III. Increased hydrostatic pressure
Congestive heart failure
Cirrhosis

IV. Obstruction of lymph flow
Congestive heart failure

V. Inappropriate renal sodium and water retention
Renal failure
Nephrotic syndrome

Except for increased vascular permeability to proteins, virtually every clinical situation in which edema is manifest requires the kidneys to reabsorb supranormal amounts of sodium and water.

Effective arterial blood volume (EABV)

The concept of EABV is crucial in understanding why the kidney retains sodium and water. EABV is an abstract term that refers to the adequacy of the arterial blood volume to "fill" the capacity of the arterial vasculature. Normal EABV exists when the ratio of cardiac output to peripheral resistance maintains venous return and cardiac output at normal levels. EABV can be reduced, therefore, by factors which reduce actual arterial blood volume (hemorrhage, dehydration), increase arterial vascular capacitance (cirrhosis, sepsis) or reduce cardiac output (congestive heart failure). EABV can be reduced in the setting of low, normal, or high actual blood volume. Whenever EABV falls, the kidney is triggered to retain sodium and water. The mechanisms involved are:

1. Reduced renal blood flow. When EABV is reduced, renal blood flow is reduced. In addition, volume receptors in large arterial vessels are activated, leading to increased renal sympathetic tone and decreased renal blood flow. When renal blood flow is reduced, the kidney retains sodium and water by the following mechanisms (see figure below):

a. An increase in proximal tubule salt and water reabsorption. Reduced renal blood flow is perceived by the kidney as a fall in blood pressure. To compensate, renin is produced by the juxtaglomerular apparatus, leading to increased angiotensin II formation. Angiotensin II causes predominantly efferent arteriole constriction which increases filtration fraction (ratio of GFR to renal blood flow) and elevates oncotic pressure at the end of the glomerular capillary. The increased oncotic pressure enhances proximal tubule fluid reabsorption.

b. Enhanced distal sodium and water reabsorption. The increase in angiotensin II stimulates the adrenal gland to release aldosterone. Aldosterone stimulates sodium retention by the collecting duct.

2. Antidiuretic hormone (ADH). Volume receptors in the arterial tree

Edema formation in congestive heart failure (CHF)

CHF implies a primary failure of the pumping ability of the heart. When the heart begins to fail, blood backs up in the venous system, while arterial volume is initially reduced. This reduction in arterial filling (or, in effect, EABV) is detected by arterial volume receptors, triggering sympathetic nerve-mediated vasoconstriction in an attempt to restore the ratio of cardiac output to vascular capacitance. The net result of this vasoconstriction is that the brain, heart and lungs continue to receive as much blood flow as possible. In contrast, blood flow to the kidney and other organs is reduced, having been shunted to the organs necessary for immediate survival. Thus, EABV is reduced and the kidney begins to retain sodium and water.

In more severe degrees of CHF, the patients can become hyponatremic. This occurs because more water is retained by the kidney than is sodium. In this setting, serum ADH levels are markedly elevated, resulting in a very concentrated urine. Additionally, proximal tubule sodium and water reabsorption are very high, permitting relatively little water to reach the urine. Finally, ADH stimulates thirst, resulting in increased water intake.

Edema formation in cirrhosis

Cirrhosis of the liver is defined as increased fibrous tissue in the liver associated with regeneration of focal areas of damaged liver parenchyma. If severe, scarring and distortion of normal liver architecture can lead to marked hepatic dysfunction. This, in turn, can cause sodium retention and edema formation by the following mechanisms which lower EABV (see figure):

1. Decreased total peripheral resistance may be the most important causative factor for renal sodium retention in cirrhosis. Total blood volume is usually increased in cirrhotics, even before obvious edema formation. It appears that the damaged liver fails to degrade or overproduces vasodilating factors. These factors lead primarily to a marked fall in mesenteric (splanchnic) vascular resistance and blood pooling. This lowers EABV, activating compensatory mechanisms such as sympathetic nerves and the renin-angiotensin-aldosterone system.

2. Increased portal pressure (portal hypertension) is due to obstruction of blood flow in the portal vein. This causes increased hydrostatic pressure in the splanchnic circulation and accumulation of fluid in the peritoneal space, a condition known as ascites.

3. Decreased hepatic albumin synthesis causes hypoalbuminemia and decreased plasma oncotic pressure, enhancing movement of fluid into the interstitium.

Edema formation in nephrotic syndrome

The nephrotic syndrome is defined as a glomerular disease which results in proteinuria (urinary protein losses of ≥ 3.5 gm/day), hypoproteinemia, edema, and hyperlipidemia. Most patients with nephrotic syndrome have an expanded plasma volume due to an intrinsic, as yet unidentified, defect in renal sodium and water excretion. Hypoalbuminemia due to urinary protein losses favors fluid movement from the intravascular to the interstitial compartment and exacerbates edema formation in the nephrotic syndrome. In some patients, urinary protein loss and hypoalbuminemia can be so severe that plasma volume becomes reduced, leading to renal hypoperfusion and further stimulating sodium and water retention (see figure).

- Diagnosis and management

Rationale for treatment

Excessive fluid in the extracellular space can markedly impair normal organ function. Edema of the skin, particularly in the lower extremities can be painful, interferes with normal blood circulation, impairs wound healing, increases the likelihood of infection, and is unattractive. Ascites can impair normal respiration, decrease venous blood return to the heart, and promotes intraperitoneal infection. Pulmonary edema interferes with respiratory gas exchange and is a major cause of morbidity and mortality. Most importantly, edema is a sign of an underlying disease process which needs to be treated.

Differential diagnosis

FENa (fractional excretion of sodium) = Urine/Plasma sodium concentration
Urine/Plasma creatinine concentration

FENa <> 1.0 can be seen in volume expanded states, such as too much intravenous or oral sodium and water, and reduced renal mass. It is also seen in patients taking diuretics.

The treatment of edema should neither begin nor end with the administration of diuretics. The basic approaches to treatment are as follows.

1. First, treat the underlying disease.
2. Decrease sodium and water intake, either dietary or intravenous.
3. Increase excretion of sodium and water
a. Diuretics - remember, these are palliative, not curative.
b. Bed rest, local pressure

4. Do not make the disease worse. Other than treatment of severe pulmonary edema, treatment of edema is not usually an emergency. The use of all diuretics entails one major risk: excessive diuresis. Overdiuresis causes volume depletion, hypotension, inadequate organ perfusion and a host of complications. USE CAUTION!

Fluid restriction

An edema forming patient typically loses little sodium from his/her body - about 15 mEq/day in urine, sweat and stool combined. Placing a patient on a low salt diet (about 1 gm per day) gives an intake of sodium of about 17 mEq/day. Thus restricting dietary salt often does not decrease edema, it only prevents edema from becoming worse.

A major problem in hospitalized patients is those receiving intravenous fluids. In many patients, an intravenous line containing some sodium chloride is kept running continuously. Typically, the lowest rate that keeps a vein patent is 500 ml/day. Even using the a low sodium concentration (l/4 normal saline), the patient is given 19 mEq sodium/day. Thus, intravenous fluids can be a major cause of edema in hospitalized patients with problems excreting sodium.

Diuretics

Diuretics inhibit sodium and water reabsorption in the nephron. Several classes of diuretics are available that have different sites of action, potencies and side effects. Diuretics will be discussed in detail after the lectures on edema, water metabolism, and potassium homeostasis.

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