Chapter 036.

Edema
Depending on its cause and mechanism, edema may be localized or have a
generalized distribution; it is recognized in its generalized form by puffiness of the
face, which is most readily apparent in the periorbital areas, and by the persistence
of an indentation of the skin following 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. When the ring on a finger fits more snugly than in the
past or when a patient complains of difficulty in putting on shoes, particularly in the
evening, edema may be present.

Pathogenesis

About one-third of total-body water is confined to the extracellular space.

Approximately 75% of the latter, in turn, is interstitial fluid and the remainder is the
plasma.

Starling Forces

The forces that regulate the disposition of fluid between these two components of the
extracellular compartment are frequently referred to as the Starling forces. The
hydrostatic pressure within the vascular system and the colloid oncotic pressure in
the interstitial fluid tend to promote movement of fluid from the vascular to the
extravascular space. On the other hand, the colloid oncotic pressure contributed by
plasma proteins and the hydrostatic pressure within the interstitial fluid, referred to
as the tissue tension, promote the movement of fluid into the vascular compartment.

As a consequence of these forces, there is a 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. Unless these channels are obstructed,
lymph flow rises with increases in net movement of fluid from the vascular
compartment to the interstitium. These flows are usually balanced so that a steady
state exists in the sizes of the intravascular and interstitial compartments, and, yet,
a large exchange between them occurs. However, should either the hydrostatic or
oncotic pressure gradient be altered significantly, a further net movement of fluid
between the two components of the extracellular space will take place. The
development of edema, then, depends on one or more alterations in the Starling
forces so that there is increased flow of fluid from the vascular system into the
interstitium or into a body cavity.

Edema due to an increase in capillary pressure may result from an elevation of

venous pressure due to obstruction to venous and/or lymphatic drainage. An
increase in capillary pressure may be generalized, as occurs in congestive heart
failure (see below). The Starling forces may also be imbalanced when the colloid
oncotic pressure of the plasma is reduced, owing to any factor that may induce
hypoalbuminemia, such as severe malnutrition, liver disease, loss of protein into the
urine or into the gastrointestinal tract, or a severe catabolic state. Edema may be
localized to one extremity when venous pressure is elevated due to unilateral
thrombophlebitis (see below).
Capillary Damage

Edema may also result from damage to the capillary endothelium, which increases its
permeability and permits the transfer of protein into the interstitial compartment.
Injury to the capillary wall can result from drugs, viral or bacterial agents, and
thermal or mechanical trauma. Increased capillary permeability may also be a
consequence of a hypersensitivity reaction and is characteristic 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
inflammationredness, heat, and tenderness.

Reduction of Effective Arterial Volume

In many forms of edema, the effective arterial blood volume, a parameter that
represents the filling of the arterial tree, is reduced. Underfilling of the arterial tree
may be caused by a reduction of cardiac output and/or systemic vascular resistance.
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 retention of salt and, therefore, of water, ultimately leading to
edema.

Renal Factors and the Renin-Angiotensin-Aldosterone (RAA) System

(See also Chap. 336) In the final analysis, renal retention of Na+ is central to the
development of generalized 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 (Chap. 336). Renin is an enzyme
with a molecular mass of about 40,000 Da that acts on its substrate,
angiotensinogen, an 2-globulin synthesized by the liver, to release angiotensin I, a
decapeptide, which is broken down to angiotensin II (AII), an octapeptide. AII has
generalized vasoconstrictor properties; it is especially active on the efferent
arterioles. This efferent arteriolar constriction reduces the hydrostatic pressure in the
peritubular capillaries, while 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 RAA system has long been recognized as a hormonal system; however, it also
operates locally. Intrarenally produced AII contributes to glomerular efferent
arteriolar constriction, and this "tubuloglomerular feedback" causes salt and water
retention. These renal effects of AII are mediated by activation of AII type 1
receptors, which can be blocked by specific antagonists [angiotensin receptor
blockers (ARBs)].

The mechanisms responsible for the increased release of renin when renal blood flow
is reduced include: (1) a baroreceptor response in which reduced renal perfusion
results in incomplete filling of the renal arterioles and diminished stretch of the
juxtaglomerular cells, a signal that increases the elaboration and/or release of renin;
(2) reduced glomerular filtration, which lowers the NaCl load reaching the distal renal
tubules and the macula densa, cells in the distal convoluted tubules that act as
chemoreceptors and that signal the neighboring juxtaglomerular cells to secrete
renin; and (3) activation of the -adrenergic receptors in the juxtaglomerular cells by
the sympathetic nervous system and by circulating catecholamines, which also
stimulates renin release. These three mechanisms generally act in concert to
enhance Na+ retention and, thereby, contribute to the formation 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
Na+ reabsorption (and K+excretion) by the collecting tubule. In patients with heart
failure, not only is aldosterone secretion elevated but the biologic half-life of
aldosterone is prolonged, which increases further the plasma level of the hormone. A
depression of hepatic blood flow, especially during exercise, is responsible for
reduced hepatic catabolism of aldosterone. The activation of the RAA system is most
striking in the early phase of acute, severe heart failure and is less intense in
patients with chronic, stable, compensated heart failure.

Increased quantities of aldosterone are secreted in heart failure and in other

edematous states, and blockade of the action of aldosterone by spironolactone (an
aldosterone antagonist) or amiloride (a blocker of epithelial Na+ channels) often
induces a moderate diuresis in edematous states. Yet, persistently augmented levels
of aldosterone (or other mineralocorticoids) alone do not always promote
accumulation of edema, as witnessed by the lack of striking fluid retention in most
instances of primary aldosteronism (Chap. 336). Furthermore, although normal
individuals retain some NaCl and water with the administration of potent
mineralocorticoids, such as deoxycorticosterone acetate or fludrocortisone, this
accumulation is self-limiting, despite continued exposure to the steroid, a
phenomenon known as mineralocorticoid escape. The failure of normal individuals
who receive large doses of mineralocorticoids to accumulate large quantities of
extracellular fluid and to develop edema is probably a consequence of an increase in
glomerular filtration rate (pressure natriuresis) and the action of natriuretic
substance(s) (see below). The continued secretion of aldosterone may be more
important in the accumulation of fluid in edematous states because patients with
edema secondary to heart failure, nephrotic syndrome, and hepatic cirrhosis are
generally unable to repair the deficit in effective arterial blood volume. As a
consequence, they do not develop pressure natriuresis.

Arginine Vasopressin (AVP)

(See also Chap. 334) The secretion of AVP occurs in response to increased
intracellular osmolar concentration, and by stimulating V2 receptors, AVP increases
the reabsorption of free water in the renal distal tubule and collecting duct, 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. Such patients fail to show the normal reduction of AVP with a
reduction of osmolality, contributing to edema formation and hyponatremia.

Endothelin

This potent peptide vasoconstrictor is released by endothelial cells; its concentration

is elevated in heart failure and contributes to renal vasoconstriction, Na+ retention,
and edema in heart failure.

Natriuretic Peptides
Atrial distention and/or a Na+ load cause 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. Release of ANP 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) arteriolar and venous dilation by antagonizing the
vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, ANP has the
capacity to oppose Na+ retention and arterial pressure elevation in hypervolemic
states.

The closely related brain natriuretic peptide (BNP) is stored primarily in ventricular
myocardium and is released when ventricular diastolic pressure rises. Its actions are
similar to those of ANP. Circulating levels of ANP and BNP are elevated in congestive
heart failure and in cirrhosis with ascites, but obviously not sufficiently to prevent
edema formation. In addition, in edematous states there is abnormal resistance to
the actions of natriuretic peptides.

Clinical Causes of Edema

Obstruction of Venous (and Lymphatic) Drainage of a Limb

In this condition the hydrostatic pressure in the capillary bed upstream (proximal) to
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) may also be obstructed or maximally filled, an increased volume of
interstitial fluid in the limb develops, i.e., there is trapping of fluid in the extremity.
Tissue tension rises in the affected limb until it counterbalances the primary
alterations in the Starling forces, at which time no further fluid accumulates. The net
effect is a local increase in the volume of interstitial fluid, causing local edema. The
displacement 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. This same sequence occurs in ascites and hydrothorax, in which fluid is
trapped or accumulates in the cavitary space, depleting the intravascular volume and
leading to secondary salt and fluid retention.

Congestive Heart Failure

(See also Chap. 227) In this disorder 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, and the aforementioned sequence of events (Fig. 36-1) is initiated.
In mild heart failure, a small increment of total blood volume may repair the deficit
of arterial volume and establish a new steady state. Through the operation of
Starling's law of the heart, an increase in ventricular diastolic volume promotes a
more forceful contraction and may thereby restore the cardiac output. However, if
the cardiac disorder is more severe, fluid retention continues, and the increment in
blood volume accumulates in the venous circulation. With reduction in cardiac
output, a decrease in baroreflex-mediated inhibition of the vasomotor center
activates renal vasoconstrictor nerves and the RAA system, causing Na+ and H2O
retention.
Figure 36-1

Sequence of events leading to the formation and retention of salt and

water and the development of edema. ANP, atrial natriuretic peptide; RPF, renal
plasma flow; GFR, glomerular filtration rate; ADH, antidiuretic hormone. Inhibitory
influences are shown by broken lines.

Incomplete ventricular emptying (systolic heart failure) and/or inadequate

ventricular relaxation (diastolic heart failure) both lead to an elevation of ventricular
diastolic pressure. If the impairment of cardiac function primarily involves the right
ventricle, pressures in the systemic veins and capillaries rise, augmenting the
transudation of fluid into the interstitial space and enhancing the likelihood of
peripheral edema. The elevated systemic venous pressure is transmitted to the
thoracic duct with consequent reduction of lymph drainage, further increasing the
accumulation of edema.

If the impairment of cardiac function (incomplete ventricular emptying and/or

inadequate relaxation) involves the left ventricle primarily, then pulmonary venous
and capillary pressures rise. Pulmonary artery pressure rises and this, in turn,
interferes with the emptying of the right ventricle, leading to an elevation of right
ventricular diastolic and of central and systemic venous pressures, thereby
enhancing the likelihood of the formation of peripheral edema. The elevation of