CHAPTER 7: EDEMA

About one-third of total-body water is confined to the extracellular space. Approximately 75% of the latter is interstitial fluid, and the remainder is the plasma. The forces that regulate the disposition of fluid between these two components of the extracellular compartment frequently are referred to as the Starling forces. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid tend to promote movement of fluid from the vascular to the extravascular space. By contrast, the colloid oncotic pressure contributed by plasma proteins and the hydrostatic pressure within the interstitial fluid promote the movement of fluid into the vascular compartment. As a consequence, there is movement of water and diffusible solutes from the vascular space at the arteriolar end of the capillaries. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillaries and by way of the lymphatics. These movements are usually balanced so that there is a steady state in the sizes of the intravascular and interstitial compartments, yet a large exchange between them occurs. However, if either the capillary hydrostatic pressure is increased and/or the oncotic pressure is reduced, a further net movement of fluid from intravascular to the interstitial spaces will take place.

Edema is defined as a clinically apparent increase in the interstitial fluid volume, which develops when Starling forces are altered so that there is increased flow of fluid from the vascular system into the interstitium. Edema due to an increase in capillary pressure may result from an elevation of venous pressure caused by obstruction to venous and/or lymphatic drainage. An increase in capillary pressure may be generalized, as occurs in heart failure, or it may be localized to one extremity when venous pressure is elevated due to unilateral thrombophlebitis (see below). The Starling forces also may be imbalanced when the colloid oncotic pressure of the plasma is reduced owing to any factor that may induce hypoalbuminemia, as when large quantities of protein are lost in the urine such as in the nephrotic syndrome (see below), or when synthesis is reduced in a severe catabolic state.

Edema may also result from damage to the capillary endothelium, which increases its permeability and permits the transfer of proteins into the interstitial compartment. Injury to the capillary wall can result from drugs (see below), viral or bacterial agents, and thermal or mechanical trauma. Increased capillary permeability also may be a consequence of a hypersensitivity reaction and of immune injury. Damage to the capillary endothelium is presumably responsible for inflammatory edema, which is usually nonpitting, localized, and accompanied by other signs of inflammation—i.e., erythema, heat, and tenderness.

In many forms of edema, despite the increase in extracellular fluid volume, the effective arterial blood volume, a parameter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by pooling of blood in the splanchnic veins (as in cirrhosis), and by hypoalbuminemia (Fig. 7-1A). As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to or intensifying edema.

The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α₂-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties, particularly on the renal efferent arterioles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle.

The renin-angiotensin-aldosterone system (RAAS) operates as both a hormonal and paracrine system. Its activation causes sodium and water retention and thereby contributes to edema formation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptor enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the collecting tubule, further favoring edema formation. In patients with heart failure, not only is aldosterone secretion elevated but the biologic half-life of the hormone is prolonged secondary to the depression of hepatic blood flow, which reduces its hepatic catabolism and increases further the plasma level of the hormone. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a moderate diuresis in edematous states.

The secretion of arginine vasopressin (AVP) occurs in response to increased intracellular osmolar concentration, and, by stimulating V₂ receptors, AVP increases the reabsorption of free water in the distal tubules and collecting ducts of the kidneys, thereby increasing total-body water. Circulating AVP is elevated in many patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.

This potent peptide vasoconstrictor is released by endothelial cells. Its concentration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema.

Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a polypeptide; a high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. The closely related brain natriuretic peptide (pre-prohormone BNP) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic ­receptor-A, which causes: (1) excretion of sodium and water by augmenting glomerular filtration rate, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arterioles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states.

Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, the natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edematous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness.

A weight gain of several kilograms usually precedes overt manifestations of generalized edema, and a similar weight loss from diuresis can be induced in a slightly edematous patient before “dry weight” is achieved. Anasarca refers to gross, generalized edema. Ascites and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema.

Edema is recognized by the persistence of an indentation of the skin after pressure; this is known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening. Edema may also be recognized by puffiness of the face, which is most readily apparent in the periorbital areas.

The differences among the major causes of generalized edema are shown in Table 7-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions.

Heart failure

(See also Chap. 19) In heart failure, the impaired systolic emptying of the ventricle(s) and/or the impairment of ventricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, the heightened tone of the sympathetic nervous system causes renal vasoconstriction and reduction of glomerular filtration. In mild heart failure, a small increment of total blood volume may repair the deficit of effective arterial volume through the operation of Starling’s law of the heart, in which an increase in ventricular diastolic volume promotes a more forceful contraction and may thereby maintain the cardiac output. However, if the cardiac disorder is more severe, sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous pressure and causing edema (Fig. 7-1).

The presence of heart disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with evidence of cardiac failure, such as dyspnea, basilar rales, venous distention, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as echocardiography may be helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body.

Edema of renal disease

(See also Chap. 15) The edema that occurs during the acute phase of glomerulonephritis is characteristically associated with hematuria, proteinuria, and hypertension. Although some evidence supports the view that the fluid retention is due to increased capillary permeability, in most instances, the edema results from primary retention of sodium and water by the kidneys owing to renal insufficiency. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with edema due to acute renal failure commonly have arterial hypertension as well as pulmonary congestion on chest roentgenogram, often without considerable cardiac enlargement, but they may not develop orthopnea. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water.

Nephrotic syndrome and other hypoalbuminemic states

The primary alteration in the nephrotic syndrome is a diminished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine. With severe hypoalbuminemia (<35 g/L) and the consequent reduced colloid osmotic pressure, the sodium and water that are retained cannot be restrained within the vascular compartment, and total and effective arterial blood volumes decline. This process initiates the edema-forming sequence of events described above, including activation of the RAAS. The nephrotic syndrome may occur during the course of a variety of kidney diseases, which include glomerulonephritis, diabetic glomerulosclerosis, and hypersensitivity reactions. The edema is diffuse, symmetric, and most prominent in the dependent areas; as a consequence, periorbital edema is most prominent in the morning.

Hepatic cirrhosis

This condition is characterized in part by hepatic venous outflow blockade, which in turn expands the splanchnic blood volume and increases hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal sodium retention and causes a reduction of effective arterial blood volume. These alterations are frequently complicated by hypoalbuminemia secondary to reduced hepatic synthesis of albumin, as well as peripheral arterial vasodilation. These effects reduce the effective arterial blood volume further, leading to activation of the RAAS and renal sympathetic nerves and to release of AVP, endothelin, and other sodium-and water-retaining mechanisms (Fig. 7-1B). The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Initially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system and obstructed hepatic lymphatics, i.e., in the peritoneal cavity (causing ascites). In later stages, particularly when there is severe hypoalbuminemia, peripheral edema may develop. A sizable accumulation of ascitic fluid may increase intraabdominal pressure and impede venous return from the lower extremities and contribute to the accumulation of edema of the lower extremities.

The excess production of prostaglandins (PGE₂ and PGI₂) in cirrhosis attenuates renal sodium retention. When the synthesis of these substances is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), renal function may deteriorate, and this may increase sodium retention further.

Drug-induced edema

A large number of widely used drugs can cause edema (Table 7-2). Mechanisms include renal vasoconstriction (NSAIDs and cyclosporine), arteriolar dilation (vasodilators), augmented renal sodium reabsorption (steroid hormones), and capillary damage.

Edema of nutritional origin

A diet grossly deficient in protein over a prolonged period may produce hypoproteinemia and edema. The latter may be intensified by the development of beriberi heart disease, which also is of nutritional origin, in which multiple peripheral arteriovenous fistulae result in reduced effective systemic perfusion and effective arterial blood volume, thereby enhancing edema formation (Fig. 7-1B). Edema may actually become intensified when famished subjects are first provided with an adequate diet. The ingestion of more food may increase the quantity of sodium ingested, which is then retained along with water. So-called refeeding edema also may be linked to increased release of insulin, which directly increases tubular sodium reabsorption. In addition to hypoalbuminemia, hypokalemia and caloric deficits may be involved in the edema of starvation.

In this condition, the hydrostatic pressure in the capillary bed upstream (proximal) of the obstruction increases so that an abnormal quantity of fluid is transferred from the vascular to the interstitial space. Since the alternative route (i.e., the lymphatic channels) also may be obstructed or maximally filled, an increased volume of interstitial fluid in the limb develops (i.e., there is trapping of fluid in the interstitium of the extremity). The displacement of large quantities of fluid into a limb may occur at the expense of the blood volume in the remainder of the body, thereby reducing effective arterial blood volume and leading to the retention of NaCl and H₂O until the deficit in plasma volume has been corrected.

Localized edema due to venous or lymphatic obstruction may be caused by thrombophlebitis, chronic lymphangitis, resection of regional lymph nodes, and filariasis, among other causes. Lymphedema is particularly intractable because restriction of lymphatic flow results in increased protein concentration in the interstitial fluid, a circumstance that aggravates fluid retention.

Other causes of edema

These causes include hypothyroidism (myxedema) and hyperthyroidism (pretibial myxedema secondary to Graves’ disease), the edema in which is typically nonpitting and due to deposition of hyaluronic acid and, in Graves’ disease, lymphocytic infiltration and inflammation; exogenous hyperadrenocortism; pregnancy; and administration of estrogens and vasodilators, particularly dihydropyridines such as nifedipine.

The distribution of edema is an important guide to its cause. Edema associated with heart failure tends to be more extensive in the legs and to be accentuated in the evening, a feature also determined largely by posture. When patients with heart failure are confined to bed, edema may be most prominent in the presacral region. Severe heart failure may cause ascites that may be distinguished from the ascites caused by hepatic cirrhosis by the jugular venous pressure, which is usually elevated in heart failure and normal in cirrhosis.

Edema resulting from hypoproteinemia, as occurs in the nephrotic syndrome, characteristically is generalized, but it is especially evident in the very soft tissues of the eyelids and face and tends to be most pronounced in the morning owing to the recumbent posture assumed during the night. Less common causes of facial edema include trichinosis, allergic reactions, and myxedema. Edema limited to one leg or to one or both arms is usually the result of venous and/or lymphatic obstruction. Unilateral paralysis reduces lymphatic and venous drainage on the affected side and may also be responsible for unilateral edema. In patients with obstruction of the superior vena cava, edema is confined to the face, neck, and upper extremities in which the venous pressure is elevated compared with that in the lower extremities.