Of the total fluids in the human body, twothirds reside inside the cell (i.e., intracellular fluid) and one-third resides outside the cells [i.e., extracellular fluid (ECF)]. The patient with generalized edema has an excess of ECF. The ECF resides in two locations: in the vascular compartment (plasma fluid) and between the cells of the body, but outside of the vascular compartment (interstitial fluid). In the vascular compartment, approximately 85% of the fluid resides on the venous side of the circulation and 15% on the arterial side (Table 1-1). An excess of interstitial fluid constitutes edema. On applying digital pressure, the interstitial fluid can generally be moved from the area of pressure, leaving an indentation; this is described as pitting edema. This demonstrates that the excess interstitial fluid can move freely within its space between the body’s cells. If digital pressure does not cause pitting in the edematous patient, then interstitial fluid cannot move freely. Such nonpitting edema can occur with lymphatic obstruction (i.e., lymphedema) or regional fibrosis of subcutaneous tissue, which may occur with chronic venous stasis.

Although generalized edema always signifies an excess of ECF, specifically in the interstitial compartment, the intravascular volume may be decreased, normal, or increased. For example, because two-thirds of ECF resides in the interstitial space and only one-third in the intravascular compartment, a rise in total ECF volume may occur as a consequence of excess interstitial fluid (i.e., generalized edema) although intravascular volume is decreased.

A. Starling’s law states that the rate of fluid movement across a capillary wall is proportional to the hydraulic permeability of the capillary, the transcapillary hydrostatic pressure difference, and the transcapillary oncotic pressure difference. As shown in Figure 1-1, under normal conditions, fluid leaves the capillary at the arterial end because the transcapillary hydrostatic pressure difference favoring transudation exceeds the transcapillary oncotic pressure difference, which favors fluid resorption. In contrast, fluid returns to the capillary at the venous end because the transcapillary oncotic pressure difference exceeds the hydrostatic pressure difference. Because serum albumin is the major determinant of capillary oncotic pressure, which acts to maintain fluid in the capillary, hypoalbuminemia can lead to excess transudation of fluid from the vascular to interstitial compartment. Although hypoalbuminemia might be expected to lead commonly to edema, several factors act to buffer the effects of hypoalbuminemia on fluid transudation. First, an
increase in transudation tends to dilute interstitial fluid, thereby reducing the interstitial protein concentration. Second, increases in interstitial fluid volume increase interstitial hydrostatic pressure. Third, the lymphatic flow into the jugular veins, which returns transudated fluid to the circulation, increases. In fact, in cirrhosis, where hepatic fibrosis causes high capillary hydrostatic pressures in association with hypoalbuminemia, the lymphatic flow can increase 20-fold to 20 L/day, attenuating the tendency to accumulate interstitial fluid. When these buffering factors are overwhelmed,
interstitial fluid accumulation can lead to edema. This generally occurs when serum albumin concentration (<2.0 g/L), and thus oncotic pressure, is quite low. Another factor that must be borne in mind as a cause of edema is an increase in the fluid permeability of the capillary wall (an increase in hydraulic conductivity). This increase is the cause of edema associated with hypersensitivity reactions and angioneurotic edema, and it may be a factor in edema associated with diabetes mellitus and idiopathic cyclic edema.

B. These comments refer to generalized edema (i.e., an increase in total-body interstitial fluid), but it should be noted that such edema may still have a predilection for specific areas of the body for various reasons. With cirrhosis, edema formation has a predilection for abdominal cavity because of portal hypertension as has already been mentioned. With the normal hours of upright posture, an accumulation of the edema fluid in the lower extremities should be expected, whereas excessive hours of bed rest in the supine position predispose to edema accumulation in the sacral and periorbital areas of the body. The physician must also be aware of the potential presence of localized edema, which must be differentiated from generalized edema.

C. Although generalized edema may have a predilection for certain body sites, it is nevertheless a total-body phenomenon of excessive interstitial fluid. Localized edema, on the other hand, is caused by local factors and therefore is not a total-body phenomenon. Venous obstruction, as can occur with thrombophlebitis, may cause localized edema of one lower extremity. Lymphatic obstruction (e.g., from malignancy) can also cause an excessive accumulation of interstitial fluid and, therefore, localized edema. The physical examination of a patient with ankle edema should, therefore, include a search for venous incompetence (e.g., varicose veins) and for evidence of lymphatic disease. It should be recognized, however, that deep venous disease may not be detectable on physical examination and therefore may necessitate other diagnostic approaches (e.g., noninvasive ultrasonography). Therefore, if the venous disease is bilateral, the physician may mistakenly search for causes of generalized edema (e.g., cardiac failure and cirrhosis), when indeed the bilateral ankle edema is due to local factors. Pelvic lymphatic obstruction (e.g., malignancy) can also cause bilateral lower-extremity edema and thereby mimic generalized edema. Trauma, burns, inflammation, and cellulitis are other causes of localized edema.

The edematous patient has long presented a challenge in the understanding of body fluid volume regulation. In the healthy subject, if ECF is expanded by the administration of isotonic saline, the kidney will excrete the excessive amount of sodium and water, thereby returning ECF volume to normal. Such an important role of the kidney in volume regulation has been recognized for many years. What has not been understood, however, is why the kidneys continue to retain sodium and water in the edematous patient. It is understandable that when kidney disease is present and renal function is markedly impaired (i.e., acute or chronic renal failure), the kidney continues to retain sodium and water even to a degree causing hypertension and pulmonary edema. Much more perplexing are those circumstances in which the kidneys are known to be normal and yet continue to retain sodium and water in spite of the expansion of ECF and edema formation (e.g., cirrhosis and
congestive heart failure). For example, if the kidneys from a cirrhotic patient are transplanted to a patient with end-stage renal disease but without liver disease, excessive renal sodium and water retention no longer occur. The conclusion has emerged, therefore, that neither total ECF nor its interstitial component, both of which are expanded in the patient with generalized edema, is the modulator of renal sodium and water excretion. Rather, as Peters suggested in the 1950s, some body fluid compartment other than total ECF or interstitial fluid volume must be the regulator of renal sodium and water excretion.

A. The term effective blood volume was coined to describe this undefined, enigmatic body fluid compartment that signals the kidney, through unknown pathways, to retain sodium and water in spite of an expansion of total ECF. That the kidney must be responding to cardiac output was suggested, providing an explanation for sodium and water retention in low-output cardiac failure. This idea, however, did not provide a universal explanation for generalized edema because many patients with decompensated cirrhosis, who were avidly retaining sodium and water, were found to have normal or elevated cardiac output.

B. Total plasma or blood volume was then considered as a possible candidate for the effective blood volume modulating renal sodium and water excretion. However, it was soon apparent that expanded plasma and blood volumes were frequently present in the renal sodium- and water-retaining states, such as congestive heart failure and cirrhosis. The venous component of the plasma in the circulation has also been proposed as the modulator of renal sodium and water excretion and thereby of volume regulation, because a rise in the left atrial pressure is known to cause a water diuresis and natriuresis, mediated in part by a suppression of vasopressin and a decrease in neurally mediated renal vascular resistance. A rise in right and left atrial pressure has also been found to cause a rise in atrial natriuretic peptide. However, despite these effects on the low-pressure venous side of the circulation, renal sodium and water retention are hallmarks of congestive heart failure, a situation in which pressures in the atria and venous component of the circulation are routinely increased.

C. The arterial portion of body fluids (Table 1-1) is the remaining component that may be pivotal in the regulation of renal sodium and water excretion. More recently, the relationship between cardiac output and systemic arterial resistance [the effective arterial blood volume (EABV)] has been proposed as a predominant regulator of renal sodium and water reabsorption. This relationship establishes the “fullness” of the arterial vascular tree. In this context, a primary decrease in cardiac output or systemic arterial vasodilation, or a combination thereof, may cause arterial underfilling and thereby initiate and sustain a renal sodium- and water-retaining state, which leads to generalized edema. The sodium- and water-retaining states that are initiated by a decline in cardiac output are shown in Figure 1-2 and include (a) ECF volume depletion (e.g., diarrhea, vomiting, and hemorrhage); (b) low-output cardiac failure, pericardial tamponade, and constrictive pericarditis; (c) intravascular volume depletion secondary to protein loss and hypoalbuminemia (e.g., nephrotic syndrome, burns or other protein-losing dermopathies, and protein-losing enteropathy); and (d) increased capillary permeability (capillary leak syndrome). The causes of increased renal sodium
and water retention leading to generalized edema that are initiated by primary systemic arterial vasodilation are equally numerous and are shown in Figure 1-3. Severe anemia, beriberi, Paget’s disease, and thyrotoxicosis are causes of high-output cardiac failure that may lead to sodium and water retention by the normal kidney. A wide-open, large arteriovenous fistula,
hepatic cirrhosis, sepsis, pregnancy, and vasodilating drugs (e.g., minoxidil or hydralazine) are other causes of systemic arterial vasodilation that cause arterial underfilling and decrease renal sodium and water excretion.

D. Two major compensatory processes protect against arterial underfilling, as defined by the interrelationship of cardiac output and systemic arterial vascular resistance. One compensatory process is very rapid and consists of a neurohumoral and systemic hemodynamic response. The other is slower and involves renal sodium and water retention. In the edematous patient, these compensatory responses have occurred to varying degrees depending on the time point when the patient is seen during the clinical course. Because of the occurrence of the rapid hemodynamic compensatory responses, mean arterial pressure is a poor index of the integrity of the arterial circulation. Whether a primary fall in cardiac output or systemic arterial vasodilation is the initiator of arterial underfilling, the compensatory responses are quite similar. As depicted in Figures 1-2 and 1-3, the common neurohumoral response to a decreased EABV involves the stimulation of three vasoconstrictor pathways, namely the sympathetic nervous system, angiotensin, and vasopressin. In addition to direct effects, the sympathetic nervous system also increases angiotensin and vasopressin because increases in central sympathetic hypothalamic input and β-adrenergic stimulation through the renal nerves are important components of the increased non-osmotic vasopressin release and stimulation of renin secretion, respectively. With a primary fall in cardiac output or primary systemic arterial vasodilation, secondary increases in systemic arterial vascular resistance or cardiac output occur, respectively, to acutely maintain arterial pressure. This rapid compensation allows time for the slower renal sodium and water retention to occur and further attenuate arterial circulatory underfilling. With a decrease in ECF volume, such as occurs with acute gastrointestinal losses, sufficient sodium and water retention can occur to restore cardiac output to normal and therefore terminate renal sodium and water retention before edema forms. Such may not be the case with low-output cardiac failure because even these compensatory responses may not restore cardiac output totally to normal.

1. Therefore, the neurohumoral and renal sodium- and water-retaining mechanisms persist as important compensatory processes in maintaining EABV. However, neither the acute nor the chronic compensatory mechanisms are successful in restoring cardiac contractility or reversing cardiac tamponade or constrictive pericardial tamponade. Compensatory renal sodium and water retention occurs with an expansion of the venous side of the circulation as arterial vascular filling improves but does not return to normal. The resultant rise in venous pressure enhances capillary hydrostatic pressure and thereby transudation of fluid into the interstitial fluid, with resultant edema formation. In hypoalbuminemia and the capillary leak syndrome, excessive transudation of fluid occurs across the capillary bed and also prevents the restoration of cardiac output; therefore, continuous renal sodium and water retention occurs and causes edema formation.

2. Systemic arterial vasodilation, the other major initiator of arterial underfilling, also generally cannot be totally reversed by the compensatory mechanisms and therefore may lead to edema formation.
Systemic arterial vasodilation results in dilation of precapillary arteriolar sphincters, thereby increasing capillary hydrostatic pressure and probably capillary surface area. A larger proportion of retained sodium and water is therefore transudated across the capillary bed into the interstitium in these edematous disorders (Fig. 1-3).

E. Another reason why low cardiac output or systemic arterial vasodilation may lead to edema formation is the inability of patients with these disorders, as compared with healthy subjects, to escape from the sodium-retaining effect of aldosterone (Fig. 1-4). In the healthy subject receiving large exogenous doses of aldosterone or another mineralocorticoid hormone, ECF expansion is associated with a rise in the glomerular filtration rate and a decrease in proximal tubular sodium and water reabsorption, which leads to an increase in sodium and water delivery to the distal nephron site of aldosterone action. This increase in distal sodium delivery is the major mediator of escape from the sodium-retaining effect of mineralocorticoids in healthy subjects, thereby avoiding edema formation. In contrast, in patients with cirrhosis or cardiac failure, the renal vasoconstriction that accompanies the
compensatory neurohumoral response to arterial underfilling is associated with a decrease in distal sodium and water delivery to the distal nephron site of aldosterone action. This diminution in distal delivery, which occurs primarily because of a fall in the glomerular filtration rate and an increase in proximal tubular sodium reabsorption, results in a failure to escape from aldosterone and, therefore, causes edema formation. The importance of renal hemodynamics, particularly the glomerular filtration rate, in the aldosterone escape phenomena is emphasized by the observation that in pregnancy, a state of primary arterial vasodilation, aldosterone escape occurs despite arterial underfilling because of an associated 30% to 50% increase in the glomerular filtration rate. It still remains to be determined why pregnancy is associated with this large increase in the glomerular filtration rate, which occurs within 2 to 4 weeks of conception. However, there is evidence that an increase in relaxin may be involved. The increase in the filtration rate cannot be due to plasma volume expansion, because this does not occur until several weeks after conception. The higher filtered load of sodium, and therefore increased distal sodium load in pregnancy, no doubt allows the escape from the sodium-retaining effect of aldosterone which is elevated in normal pregnancy. The occurrence of aldosterone escape in pregnancy attenuates edema formation when compared with other edematous disorders.

The daily sodium intake in the United States is typically 4 to 6 g [1 g of sodium contains 43 mEq; 1 g of sodium chloride (NaCl) contains 17 mEq of sodium]. By not using added salt at meals, the daily sodium intake can be reduced to 4 g (172 mEq), whereas a typical “low-salt” diet contains 2 g (86 mEq). Diets that are even lower in NaCl content can be prescribed, but many individuals find them unpalatable. If salt substitutes are used, it is important to remember that these contain potassium chloride; therefore potassium-sparing diuretics (i.e., spironolactone, eplerenone, triamterene, and amiloride) should not be used with salt substitutes. Other drugs that increase serum potassium concentration must also be used with caution in the presence of salt substitute intake [i.e., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs)]. When prescribing dietary therapy for an edematous patient, it is important to emphasize that NaCl restriction is required, even if diuretic drugs are employed. The therapeutic potency of diuretic drugs varies inversely with dietary salt intake.

All commonly used diuretic drugs act by increasing urinary sodium excretion. They can be divided into five classes based on their predominant site of action along the nephron (Table 1-2). Osmotic diuretics (e.g., mannitol) and proximal diuretics (e.g., acetazolamide) are not employed as primary agents to treat edematous disorders. Loop diuretics (e.g., furosemide), distal convoluted tubule (DCT; e.g., hydrochlorothiazide) diuretics, and collecting duct diuretics (e.g., spironolactone), however, all play important but distinct roles in treating edematous patients. The goal of the diuretic treatment of edema is to reduce ECF volume and to maintain the ECF volume at the reduced level. This requires an initial natriuresis, but, at steady state, urinary NaCl excretion returns close to baseline despite continued diuretic administration. Importantly, an increase in sodium and water excretion does not prove therapeutic efficacy if ECF volume does not decline. Conversely, a return to “basal” levels of urinary

NaCl excretion does not indicate diuretic resistance. The continued efficacy of a diuretic is documented by the rapid return to ECF volume expansion that occurs if the diuretic is discontinued.