19.

Pathophysiology and etiology of edema in adults

TOPIC OUTLINE
Pathophysiology and etiology of edema in adults
INTRODUCTION
Author Section Editor Deputy Editor
PATHOPHYSIOLOGY OF EDEMA
Burton D Rose, MD Richard H Sterns, MD John P Forman, MD,
FORMATION
MSc
Capillary hemodynamics
Edema formation Disclosures
- Increased capillary hydraulic pressure
- Hypoalbuminemia
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This
- Increased capillary permeability
topic last updated: Tue Apr 21 00:00:00 GMT 2009 (More)
- Lymphatic obstruction or myxedema
Safety factors and etiology of edema in adults INTRODUCTION — Edema is defined as a palpable swelling
Pathophysiology Find produced
Patient byPrint
Renal sodium retention expansion of the interstitial fluid volume. A variety of clinical conditions are
The compensated state associated with the development of edema, including heart failure,
ETIOLOGY cirrhosis, and the nephrotic syndrome (table 1).
Heart failure Some patients have localized edema. This can be caused by a variety of
Drug-induced edema
conditions including venous obstruction, as occurs with deep vein
Refeeding edema
thrombosis or venous stasis, acute left ventricular failure (which is a form
INFORMATION FOR PATIENTS
of venous obstruction), and allergic reactions (such as laryngeal edema).
REFERENCES
This topic will review the pathophysiology and etiology of generalized
GRAPHICSView All edematous states. The clinical manifestations, diagnosis, and therapy of
FIGURES edema are discussed separately. (See "Clinical manifestations and
Renin in HF diagnosis of edema in adults" and "General principles of the treatment of
Frank Starling curves in HF edema in adults" and "Treatment of refractory edema in adults".)
TABLES
PATHOPHYSIOLOGY OF EDEMA FORMATION — There are two basic steps
Major causes of edema
involved in edema formation:
Different Starlings forces

RELATED TOPICS An alteration in capillary hemodynamics that favors the movement

Actions of angiotensin II on the heart of fluid from the vascular space into the interstitium.
Chapter 7B: Exchange of water between The retention of dietary or intravenously administered sodium and
plasma and interstitial fluid
water by the kidneys.
Clinical features of primary
aldosteronism
The importance of the kidneys in the development of edema should not be
Clinical features, diagnosis, and long- underestimated. Edema (other than localized edema as with an allergic
term prognosis of preeclampsia
reaction) does not become clinically apparent until the interstitial volume
Clinical manifestations and diagnosis of
has increased by at least 2.5 to 3 liters. Since the normal plasma volume is
edema in adults
only about 3 liters, it is clear that patients would develop marked
Excitation-contraction coupling in
hemoconcentration and shock if the edema fluid were derived only from
myocardium
the plasma.
General principles of the treatment of
edema in adults These complications do not occur because of the following sequence:
Hyponatremia in patients with cirrhosis
Idiopathic edema The initial movement of fluid from the vascular space into the
Idiopathic systemic capillary leak interstitium reduces the plasma volume and consequently tissue
syndrome perfusion.
Lymphedema: Etiology, clinical
manifestations, and diagnosis In response to these changes, the kidney retains sodium and water.
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 Some of this fluid stays in the vascular space, returning the plasma
19.3 volume toward normal. However, the alteration in capillary
hemodynamics results in most of the retained fluid entering the
interstitium and eventually becoming apparent as edema.

The net effect is a marked expansion of the total extracellular volume (as
TOPIC OUTLINE edema) with maintenance of the plasma volume at closer to normal levels.
This example also illustrates an important point that must be considered
INTRODUCTION
when treating a patient with edema. Renal sodium and water retention in
PATHOPHYSIOLOGY OF EDEMA
FORMATION most edematous states is an appropriate compensation in that it restores
Capillary hemodynamics tissue perfusion, even though it also augments the degree of edema.
Edema formation Removing the edema fluid with diuretic therapy will improve symptoms due
- Increased capillary hydraulic pressure to edema but may diminish tissue perfusion, occasionally to clinically
- Hypoalbuminemia significant levels. (See "General principles of the treatment of edema in
- Increased capillary permeability adults".)
- Lymphatic obstruction or myxedema
Pathophysiology
The hemodynamic effects are somewhat different when the primary
Safety factors and etiology of edema in adults Find Patient Print
abnormality is inappropriate renal fluid retention. In this setting, both the
Renal sodium retention
The compensated state plasma and interstitial volumes are expanded and there are no deleterious
hemodynamic effects from removal of the excess fluid. This is an example
ETIOLOGY
of overfilling of the vascular tree which most often occurs with primary
Heart failure
Drug-induced edema renal disease
Refeeding edema Capillary hemodynamics — The exchange of fluid between the plasma and
INFORMATION FOR PATIENTS the interstitium is determined by the hydraulic and oncotic pressures in
REFERENCES each compartment. The relationship between these parameters can be
expressed by Starling's law [1,2]:
GRAPHICSView All
FIGURES Net filtration  =   LpS   x   (Δ hydraulic pressure   -   Δ oncotic pressure)
Renin in HF
                         =   LpS   x   [(Pcap  -   Pif)   -   s(πcap   -   πif)]
Frank Starling curves in HF
TABLES where Lp is the unit permeability (or porosity) of the capillary wall, S is the
Major causes of edema surface area available for fluid movement, Pcap and Pif are the capillary
Different Starlings forces and interstitial fluid hydraulic pressures, πcap and πif are the capillary and
interstitial fluid oncotic pressures, and s represents the reflection
RELATED TOPICS
coefficient of proteins across the capillary wall (with values ranging from 0
Actions of angiotensin II on the heart if completely permeable to 1 if completely impermeable). The interstitial
Chapter 7B: Exchange of water between oncotic pressure is derived primarily from filtered plasma proteins and to a
plasma and interstitial fluid lesser degree proteoglycans in the interstitium. (See "Chapter 7B: Exchange
Clinical features of primary of water between plasma and interstitial fluid".)
aldosteronism
Clinical features, diagnosis, and long- Approximate normal values in the skeletal muscle capillary are shown in
term prognosis of preeclampsia this table (table 2). As can be seen, the mean capillary hydraulic pressure
Clinical manifestations and diagnosis of (17 mmHg), which pushes fluid out of the capillary, and the plasma oncotic
edema in adults pressure (28 mmHg), which pulls fluid into the vascular space, are
Excitation-contraction coupling in quantitatively the most important. There is normally a small mean gradient
myocardium of about 0.3 mmHg favoring filtration out of the vascular space; the fluid
General principles of the treatment of that is filtered is then returned to the systemic circulation by the lymphatics
edema in adults so that fluid accumulation in the interstitium is prevented.
Hyponatremia in patients with cirrhosis
Starling's forces are substantially different in some other organs, such as
Idiopathic edema
the liver [3]. The hepatic sinusoids are highly permeable to proteins; as a
Idiopathic systemic capillary leak
result, the capillary and interstitial oncotic pressures are roughly equal and
syndrome
there is little transcapillary oncotic pressure gradient [2]. The net effect is
Lymphedema: Etiology, clinical
that the hydraulic pressure gradient favoring filtration is essentially
manifestations, and diagnosis
unopposed. To some degree, filtration is minimized by a lower capillary
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 hydraulic pressure than in skeletal muscle, since approximately two-thirds
19.3
of hepatic blood flow is derived from the portal vein, a low-pressure
system. However, edema does not normally occur, because the filtered fluid
is again removed by the lymphatics.

The alveolar capillaries also have a relatively low capillary hydraulic

pressure (due to perfusion from the low-pressure system in the right
TOPIC OUTLINE ventricle) and are more permeable than skeletal muscle to proteins,
INTRODUCTION resulting in a lesser transcapillary oncotic pressure gradient [4]. The clinical
PATHOPHYSIOLOGY OF EDEMA significance of this difference will be discussed below.
FORMATION
Edema formation — The development of edema requires an alteration in
Capillary hemodynamics
one or more of Starling's forces in a direction that favors an increase in net
Edema formation
- Increased capillary hydraulic pressure filtration. This can be produced by an elevation in capillary hydraulic
- Hypoalbuminemia pressure, capillary permeability, or interstitial oncotic pressure, or by a
- Increased capillary permeability reduction in the plasma oncotic pressure (table 1). Edema can also be
- Lymphatic obstruction or myxedema induced by lymphatic obstruction, since the fluid that is normally filtered is
Pathophysiology
Safety factors and etiology of edema in adults not returned to the systemic circulation. Find Patient Print
Renal sodium retention
Increased capillary hydraulic pressure — Capillary hydraulic pressure,
The compensated state
although generated by cardiac contraction, is relatively insensitive to
ETIOLOGY
alterations in arterial pressure. This stability is due to autoregulatory
Heart failure
changes in resistance at the precapillary sphincter, which determine the
Drug-induced edema
extent to which the arterial pressure is transmitted to the capillary. If the
Refeeding edema
arterial pressure is increased, for example, the sphincter constricts,
INFORMATION FOR PATIENTS
minimizing the elevation in capillary hydraulic pressure and preventing the
REFERENCES
development of edema.
GRAPHICSView All
In contrast, the resistance at the venous end of the capillary is not well
FIGURES regulated. Consequently, changes in venous pressure result in parallel
Renin in HF alterations in capillary hydraulic pressure. The venous pressure is
Frank Starling curves in HF increased in two settings: (1) when the blood volume is expanded,
TABLES augmenting the volume in the venous system, and (2) when there is venous
Major causes of edema obstruction. Examples of edema due to volume expansion include heart
Different Starlings forces failure and renal disease; edema due to venous obstruction is commonly
RELATED TOPICS
seen with cirrhosis of the liver, in which there is a marked increase in
hepatic sinusoidal pressure, and with deep venous thrombosis in the lower
Actions of angiotensin II on the heart
extremities. Effective venous obstruction also occurs with acute pulmonary
Chapter 7B: Exchange of water between
edema due to diastolic dysfunction, a setting in which compliance of the
plasma and interstitial fluid
heart is dramatically reduced.
Clinical features of primary
aldosteronism Hypoalbuminemia — Hypoalbuminemia due to albumin loss in the urine
Clinical features, diagnosis, and long- in the nephrotic syndrome or to decreased hepatic albumin synthesis is
term prognosis of preeclampsia another potential cause of edema. However, chronic hypoalbuminemia
Clinical manifestations and diagnosis of alone may be insufficient to induce edema (see 'Safety factors' below).
edema in adults
Excitation-contraction coupling in Increased capillary permeability — An increase in capillary permeability
myocardium due to vascular injury promotes the development of edema both directly
General principles of the treatment of and by permitting albumin to move into the interstitium, thereby
edema in adults diminishing the oncotic pressure gradient. This problem may be operative
Hyponatremia in patients with cirrhosis in the following clinical settings:
Idiopathic edema
Burns, in which both histamine and oxygen free radicals can induce
Idiopathic systemic capillary leak
syndrome microvascular injury [5].
Lymphedema: Etiology, clinical Therapy with recombinant human interleukin-2 or vascular
manifestations, and diagnosis
endothelial growth factor, which appear to directly increase capillary
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 permeability [6,7].
19.3
Episodic idiopathic capillary leak syndromes, which may be
mediated by increased expression of interleukin-2 receptors on
circulating mononuclear cells or by increased generation of kinins [8-
10]. Affected patients often have an associated monoclonal
gammopathy and, during episodes, have a massive leak of proteins
TOPIC OUTLINE and fluids out of the vascular space with the hematocrit rising
INTRODUCTION acutely to as high as 70 to 80 percent [10]. The mortality rate is high
PATHOPHYSIOLOGY OF EDEMA in this disorder. Preliminary evidence suggests that the combination
FORMATION of aminophylline (an inhibitor of phosphodiesterase) and
Capillary hemodynamics terbutaline (a relatively selective ß2-adrenergic agonist) may prevent
Edema formation episodes [10,11] and therefore improve survival [8,11]. It is not clear,
- Increased capillary hydraulic pressure however, why these drugs are effective. Prolonged survival may
- Hypoalbuminemia provide more time for progression to multiple myeloma; in one
- Increased capillary permeability series of 11 patients followed for a mean of 6.4 years, three died —
- Lymphatic obstruction or myxedema
one during an attack and two from multiple myeloma [8]. (See
Pathophysiology
Safety factors and etiology of edema in adults Find Patient Print
"Idiopathic systemic capillary leak syndrome".)
Renal sodium retention
The compensated state Any of the conditions associated with the adult respiratory distress
ETIOLOGY syndrome. In this disorder, ischemia- or sepsis-induced release of
Heart failure cytokines, such as interleukin-1 or tumor necrosis factor, may play
Drug-induced edema an important role in the increase in pulmonary capillary permeability,
Refeeding edema at least in part via the recruitment of neutrophils [12,13].
INFORMATION FOR PATIENTS
REFERENCES Capillary permeability is moderately increased in patients with
diabetes mellitus [14,15]. This abnormality may be mediated in part
GRAPHICSView All by hyperglycemia-induced accumulation of advanced glycosylation
FIGURES end products derived from the combination of glucose with
Renin in HF circulating proteins [16]. The net effect is to enhance the severity of
Frank Starling curves in HF edema which, in these patients, is usually due to heart failure or the
TABLES nephrotic syndrome.
Major causes of edema
Different Starlings forces The malnutrition syndrome kwashiorkor may be another example of
edema due in part to increased capillary permeability. Although
RELATED TOPICS edema has often been ascribed to hypoalbuminemia (see Safety
Actions of angiotensin II on the heart factors below), it has been suggested that increased generation of
Chapter 7B: Exchange of water between cysteinyl leukotrienes may be of primary importance in the edema of
plasma and interstitial fluid kwashiorkor by increasing capillary permeability [17].
Clinical features of primary
aldosteronism Lymphatic obstruction or myxedema — Lymphatic obstruction is an
Clinical features, diagnosis, and long- unusual cause of edema (called lymphedema). It is most often due to
term prognosis of preeclampsia radical lymph node dissection for malignancy (eg, breast cancer). (See
Clinical manifestations and diagnosis of "Lymphedema: Etiology, clinical manifestations, and diagnosis".)
edema in adults
With hypothyroidism (myxedema), on the other hand, there is a marked
Excitation-contraction coupling in
myocardium increase in the interstitial accumulation of albumin and other proteins [18].
Although this may be due in part to an elevation in capillary permeability,
General principles of the treatment of
edema in adults the excess interstitial protein and fluid would normally be returned to the
systemic circulation by the lymphatics. However, lymphatic flow is low or
Hyponatremia in patients with cirrhosis
normal in myxedema [18], not increased as in other edematous states [19].
Idiopathic edema
This may be due to binding of the filtered proteins to excess interstitial
Idiopathic systemic capillary leak
mucopolysaccharides, thereby preventing their removal by the lymphatics
syndrome
[18].
Lymphedema: Etiology, clinical
manifestations, and diagnosis
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 19.3

TOPIC OUTLINE
Safety factors — Since there is normally a small gradient favoring filtration,
it might be expected that only a minor change in these hemodynamic
INTRODUCTION
forces would lead to edema. However, experimental and clinical
PATHOPHYSIOLOGY OF EDEMA observations indicate that there must be at least a 15 mmHg increase in
FORMATION
the gradient favoring filtration before edema can be detected [1,2]. Three
Capillary hemodynamics
factors contribute to this protective response.
Edema formation
- Increased capillary hydraulic pressure
Lymphatic flow and contractility increase in the presence of tissue
- Hypoalbuminemia
edema, which remove some of the excess filtrate [20,21]. With
- Increased capillary permeability
- Lymphatic obstruction or myxedema pulmonary edema due to heart failure, for example, the rate of
Pathophysiology
Safety factors and etiology of edema in adults increase in lung liquid accumulation at any given
Find elevation
Patientin Print
Renal sodium retention pulmonary capillary pressure is related to the functional capacity of
The compensated state the lymphatics which is influenced by both individual factors and the
ETIOLOGY acuteness of the hemodynamic change [22]. With acute rises in
Heart failure pulmonary capillary pressures, the pulmonary lymphatic system
Drug-induced edema does not have an increased capacity to remove fluid; as a result,
Refeeding edema pulmonary edema occurs at pulmonary artery capillary pressures as
INFORMATION FOR PATIENTS low as 18 mmHg. In contrast, patients with chronic heart failure have
REFERENCES an increased lymphatic capacity and do not develop pulmonary
edema until much higher pulmonary capillary pressures (eg, >25
GRAPHICSView All mmHg) are reached.
FIGURES
Fluid entry into the interstitium will eventually raise the interstitial
Renin in HF
hydraulic pressure [1].
Frank Starling curves in HF
TABLES Fluid entry into the interstitium also lowers the interstitial oncotic
Major causes of edema pressure, both by dilution and by lymphatic-mediated removal of
Different Starlings forces interstitial proteins. As an example, interstitial oncotic pressure falls
RELATED TOPICS to very low levels in heart failure, while the plasma oncotic pressure
is relatively normal [23]. The associated increase in the
Actions of angiotensin II on the heart
transcapillary oncotic pressure gradient (πcap - πif) counterbalances
Chapter 7B: Exchange of water between
the rise in capillary hydraulic pressure, thereby minimizing the
plasma and interstitial fluid
degree of edema formation.
Clinical features of primary
aldosteronism
The reduction in interstitial oncotic pressure has important implications for
Clinical features, diagnosis, and long-
the role of hypoalbuminemia in edema formation and for the tendency of
term prognosis of preeclampsia
edema to form at different sites. The normal interstitial oncotic pressure in
Clinical manifestations and diagnosis of
edema in adults subcutaneous tissue in humans may be as high as 12 to 15 mmHg [24,25].
As a result, a gradual fall in plasma oncotic pressure in the nephrotic
Excitation-contraction coupling in
myocardium syndrome, for example, will be associated with a parallel decline in the
interstitial oncotic pressure due to less entry of albumin into the
General principles of the treatment of
edema in adults interstitium. The net effect is that the transcapillary oncotic pressure
Hyponatremia in patients with cirrhosis gradient is initially maintained with little tendency to edema formation.
Thus, in the absence of severe hypoalbuminemia, edema in the nephrotic
Idiopathic edema
syndrome and renal disease is primarily due to renal sodium retention. (See
Idiopathic systemic capillary leak
"Mechanism and treatment of edema in nephrotic syndrome".)
syndrome
Lymphedema: Etiology, clinical Similar considerations concerning hypoalbuminemia-induced edema apply
manifestations, and diagnosis to the pulmonary circulation. The alveolar capillaries appear to have a
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 greater baseline permeability to albumin and therefore a higher interstitial
19.3
oncotic pressure of about 18 mmHg [2,4]. This leads to a larger safety
factor against edema due to hypoalbuminemia than seen in skeletal
muscle, since there can be a greater parallel decline in the interstitial
oncotic pressure. Thus, in the absence of a concurrent rise in left atrial and
pulmonary capillary pressures, pulmonary edema is not usually seen with
hypoalbuminemia, even at a plasma albumin concentration acutely low
TOPIC OUTLINE
enough to induce peripheral edema [26].
INTRODUCTION
PATHOPHYSIOLOGY OF EDEMA The response is appreciably different after the rapid administration of large
FORMATION volumes of saline to patients with marked hypovolemia, a condition in
Capillary hemodynamics which a low plasma albumin concentration can predictably cause edema.
Edema formation In this setting, there is acute dilutional hypoalbuminemia without time for
- Increased capillary hydraulic pressure the interstitial albumin concentration to fall. As a result, the transcapillary
- Hypoalbuminemia oncotic pressure gradient is reduced and peripheral edema can occur
- Increased capillary permeability before the restoration of normal intracardiac filling pressures.
- Lymphatic obstruction or myxedema
Safety factors and etiology of edema in adults Renal sodium retention — As noted above, the retention
Pathophysiology Find of fluid by the Print
Patient
Renal sodium retention kidney in edematous states can represent an appropriate compensatory
The compensated state response to effective arterial or circulating volume depletion or an
ETIOLOGY inappropriate manifestation of renal disease [26,27]. In most instances, the
Heart failure effective circulating volume is directly proportional to the cardiac output.
Drug-induced edema Thus, when the cardiac output is reduced because of underlying cardiac
Refeeding edema disease, the kidney attempts to restore the effective circulating volume by
INFORMATION FOR PATIENTS retaining sodium and water.
REFERENCES
However, effective tissue perfusion and the cardiac output are not always
GRAPHICSView All related, since the former can also be reduced by a decrease in peripheral
vascular resistance [28]. As an example, creation of an arteriovenous
FIGURES
fistula is associated with no initial change in cardiac output, yet tissue
Renin in HF
Frank Starling curves in HF perfusion is reduced since the blood flowing through the fistula is
bypassing the capillary circulation. In response to this hemodynamic
TABLES
change, the kidney retains sodium and water, thereby increasing the blood
Major causes of edema
Different Starlings forces volume and cardiac output [29]. The new steady state is characterized by a
cardiac output that exceeds the baseline level by an amount equal to the
RELATED TOPICS flow rate through the fistula.
Actions of angiotensin II on the heart
A common clinical correlate of this experiment occurs in patients with
Chapter 7B: Exchange of water between
cirrhosis and ascites, who frequently have an elevated cardiac output [30].
plasma and interstitial fluid
Despite this, they behave as if they are volume depleted, as evidenced by
Clinical features of primary
avid renal sodium retention and a progressive rise in secretion of the three
aldosteronism
hypovolemic hormone — renin, norepinephrine, and antidiuretic hormone
Clinical features, diagnosis, and long-
term prognosis of preeclampsia (ADH) [28,31,32]. (See "Hyponatremia in patients with cirrhosis".)
Clinical manifestations and diagnosis of The disparity between the high cardiac output and the renal and
edema in adults neurohumoral responses in cirrhosis is due both to splanchnic
Excitation-contraction coupling in vasodilatation and to the presence of multiple arteriovenous fistulas
myocardium throughout the body, such as spider angiomata in the skin. The net effect is
General principles of the treatment of a marked fall in systemic vascular resistance and a reduction in systemic
edema in adults
blood pressure [28,33]. Much of the cardiac output is circulating
Hyponatremia in patients with cirrhosis ineffectively as there is a progressive reduction in renal and eventually
Idiopathic edema musculocutaneous perfusion [34].
Idiopathic systemic capillary leak
syndrome The renal sodium and water retention seen in heart failure or cirrhosis
Lymphedema: Etiology, clinical results from both a hypovolemia-induced fall in GFR and, more importantly,
manifestations, and diagnosis an increase in tubular reabsorption. The latter is mediated by increases in
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 the activity of the renin-angiotensin-aldosterone and sympathetic nervous
19.3
systems [28,35,36].

TOPIC OUTLINE
The compensated state — Although the renin-angiotensin-aldosterone
system undoubtedly contributes to sodium retention in disorders such as
INTRODUCTION
heart failure and cirrhosis, the plasma renin activity is normal in some
PATHOPHYSIOLOGY OF EDEMA patients with these disorders [36,37]. A partial explanation for this
FORMATION
seemingly paradoxical finding is that the patient has entered a
Capillary hemodynamics
compensated state in which the initial fluid retention has increased venous
Edema formation
return to the heart, thereby allowing systemic hemodynamics to be
- Increased capillary hydraulic pressure
- Hypoalbuminemia stabilized (at least in the resting state) and removing the stimulus for
- Increased capillary permeability continued renin release [35,36]. This sequence is depicted in Figure 1 which
- Lymphatic obstruction or myxedema shows the changes that occur with chronic thoracic inferior vena cava
Pathophysiology
Safety factors and etiology of edema in adults constriction, an experimental model that simulates the Findchanges seen in Print
Patient
Renal sodium retention heart failure in humans (figure 1) [35]. The new steady state seen after six
The compensated state to seven days is characterized by plasma volume expansion, but
ETIOLOGY normalization of the systemic blood pressure, urinary sodium excretion,
Heart failure and renin and aldosterone release.
Drug-induced edema
In many patients, however, stable heart failure is associated with a
Refeeding edema
persistent reduction in cardiac output and it is not clear why renin levels
INFORMATION FOR PATIENTS
should be normal [35]. One possible explanation is that circulating levels
REFERENCES
may not reflect the degree of activation of tissue renin-angiotensin
GRAPHICSView All systems. (See "Actions of angiotensin II on the heart".)
FIGURES ETIOLOGY — The most common causes of generalized edema seen by the
Renin in HF clinician are:
Frank Starling curves in HF
TABLES Heart failure
Major causes of edema Cirrhosis
Different Starlings forces Nephrotic syndrome and other forms of renal disease
Premenstrual edema and pregnancy
RELATED TOPICS
The pathogenesis of edema in heart failure will be reviewed here because it
Actions of angiotensin II on the heart
illustrates many of the mechanisms described above [38]. The unusual
Chapter 7B: Exchange of water between
causes of drug-induced edema and refeeding edema will also be briefly
plasma and interstitial fluid
reviewed. The pathogenesis of edema in the last three of these conditions
Clinical features of primary
aldosteronism is discussed separately as is the uncommon disorder idiopathic edema,
which is generally seen in young women. (See "Pathogenesis of ascites in
Clinical features, diagnosis, and long-
term prognosis of preeclampsia patients with cirrhosis" and "Mechanism and treatment of edema in
nephrotic syndrome" and "Clinical features, diagnosis, and long-term
Clinical manifestations and diagnosis of
edema in adults prognosis of preeclampsia" and "Idiopathic edema".)
Excitation-contraction coupling in Heart failure — Heart failure can be produced by a variety of disorders,
myocardium
including coronary artery disease, hypertension, the cardiomyopathies,
General principles of the treatment of valvular disease, and cor pulmonale. The edema in the different causes of
edema in adults
heart failure is due to an increase in venous pressure that produces a
Hyponatremia in patients with cirrhosis parallel rise in capillary hydraulic pressure. Despite the similarity in
Idiopathic edema pathogenesis, the site of edema accumulation is variable and is dependent
Idiopathic systemic capillary leak upon the nature of the cardiac disease [39]:
syndrome
Lymphedema: Etiology, clinical Coronary, hypertensive heart disease, and left-sided valvular disease
manifestations, and diagnosis tend to preferentially impair left ventricular function. As a result,
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 patients with one of these disorders typically present with
19.3
pulmonary but not peripheral edema.

Cor pulmonale, in contrast, is initially associated with pure right

ventricular failure, resulting in prominent edema in the lower
extremities and perhaps ascites.

TOPIC OUTLINE Cardiomyopathies tend to produce equivalent involvement of both

INTRODUCTION the right and left ventricles, often leading to the simultaneous onset
of pulmonary and peripheral edema.
PATHOPHYSIOLOGY OF EDEMA
FORMATION
Capillary hemodynamics In acute pulmonary edema due to a myocardial infarction or ischemia, the
Edema formation left ventricular disease results in elevations in left ventricular end-diastolic
- Increased capillary hydraulic pressure and left atrial pressures, which are transmitted back through the pulmonary
- Hypoalbuminemia veins to the pulmonary capillaries. In general, the pulmonary capillary
- Increased capillary permeability pressure must exceed 18 to 20 mmHg (normal equals 5 to 12 mmHg)
- Lymphatic obstruction or myxedema before acute pulmonary edema occurs [40].
Pathophysiology
Safety factors and etiology of edema in adults Find Patient Print
The pathogenesis of edema formation is somewhat different in chronic
Renal sodium retention
The compensated state heart failure. In this setting, the increase in capillary pressure is a result of
plasma volume expansion, not solely the obstructive effect of a diseased
ETIOLOGY
heart. This is called the forward hypothesis of heart failure, in which the
Heart failure
Drug-induced edema primary event is a reduction in cardiac output [28,41]. This decrease in
Refeeding edema tissue perfusion leads to activation of the sympathetic and renin-
INFORMATION FOR PATIENTS angiotensin systems, which tend to promote sodium and water retention;
they also tend to increase vascular resistance and cardiac inotropy in an
REFERENCES
effort to restore tissue perfusion [42,43]. (See "Pathophysiology of heart
GRAPHICSView All failure: Neurohumoral adaptations".)
FIGURES The net effect in patients with relatively well-preserved cardiac function is
Renin in HF an initially mild impairment in sodium-excretory ability. Edema is often
Frank Starling curves in HF absent at this time, unless there is a high level of sodium intake [44]. With
TABLES more advanced disease, however, forward output can be restored only by
Major causes of edema plasma volume expansion and intracardiac filling pressures that are high
Different Starlings forces enough to promote edema formation.
RELATED TOPICS
Similar considerations apply to high-output heart failure due, for example,
Actions of angiotensin II on the heart to hyperthyroidism (where the hypermetabolic state leads to an increase in
Chapter 7B: Exchange of water between energy requirements) or to arteriovenous fistulas (where blood flowing
plasma and interstitial fluid through the fistulas is bypassing the capillary circulation). In these
Clinical features of primary conditions, the patients still behave as if they are effectively volume
aldosteronism depleted, since the cardiac output is inappropriately low in relation to tissue
Clinical features, diagnosis, and long- needs [29,45].
term prognosis of preeclampsia
Clinical manifestations and diagnosis of The effect of fluid retention on cardiac function is illustrated in Figure 1
edema in adults (figure 2) [38]. The upper curve represents the normal Frank-Starling
Excitation-contraction coupling in relationship between stroke volume and left ventricular end-diastolic
myocardium pressure (LVEDP), in which increasing cardiac stretch enhances cardiac
General principles of the treatment of contractility [34]. (See "Pathophysiology of heart failure: Left ventricular
edema in adults pressure-volume relationships".) The development of mild cardiac failure
Hyponatremia in patients with cirrhosis (middle curve) will, if the sympathetic stimulation of cardiac function is
Idiopathic edema insufficient, lower both stroke volume and cardiac output (line AB). The
Idiopathic systemic capillary leak ensuing renal sodium and water retention can reverse these abnormalities,
syndrome since the increments in plasma volume and LVEDP will augment cardiac
Lymphedema: Etiology, clinical contractility (line BC).
manifestations, and diagnosis
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 At this point, the patient is in a new steady state of compensated heart
19.3
failure in which the stroke volume and cardiac output are normal, sodium
excretion matches sodium intake, and the activity of the renin-angiotensin-
aldosterone system has returned to normal (figure 1) [35,36]. The
restoration of tissue perfusion in this setting has occurred only after there
has been an elevation in the LVEDP, perhaps to a level sufficient to produce
pulmonary edema.
TOPIC OUTLINE
INTRODUCTION There are several points that deserve emphasis in this simple example of
PATHOPHYSIOLOGY OF EDEMA mild to moderate heart failure:
FORMATION
Capillary hemodynamics It demonstrates again the dual effects of fluid retention in
Edema formation edematous states: a beneficial increment in cardiac output and a
- Increased capillary hydraulic pressure potentially harmful elevation in venous pressure.
- Hypoalbuminemia
- Increased capillary permeability It illustrates that vascular congestion (that is, an elevated LVEDP)
- Lymphatic obstruction or myxedema and a low cardiac output do not have to occur together in patients
Pathophysiology
Safety factors and etiology of edema in adults with heart disease. At point B, the patient is inFind
a low-output
Patientstate but
Print
Renal sodium retention there is no congestion; at point C, the patient is congested but has a
The compensated state normal cardiac output.
ETIOLOGY
The Frank-Starling relationship varies with exercise. Patients with
Heart failure
Drug-induced edema moderate heart disease may have a normal cardiac output at rest,
Refeeding edema but may be unable to increase it adequately with even mild exertion
INFORMATION FOR PATIENTS [46]. This relative decrease in tissue perfusion can lead sequentially
to further neurohumoral activation, renal vasoconstriction and
REFERENCES
ischemia, sodium retention, and ultimately edema [47,48]. In this
GRAPHICSView All setting, limiting physical activity may produce substantial
FIGURES improvement. Simply assuming the supine position for 1 to 2 h, for
Renin in HF example, maximizes the cardiac output in relation to tissue needs.
Frank Starling curves in HF This can induce as much as a 40 percent rise in glomerular filtration
TABLES rate and a doubling of the natriuretic response to a diuretic [49].
Major causes of edema
Patients with mild to moderate heart disease may have no edema
Different Starlings forces
with dietary sodium restriction, but may retain sodium and possibly
RELATED TOPICS become edematous if given a sodium load [44]. Suppose points A
Actions of angiotensin II on the heart and C in Figure 3 reflect the hemodynamic state on a low-sodium
diet (figure 1). An increase in sodium intake will initially expand the
Chapter 7B: Exchange of water between
plasma and interstitial fluid intravascular volume and raise the LVEDP. In the normal subject
Clinical features of primary (point A) who is still on the ascending limb of the Frank-Starling
aldosteronism curve, the increase in filling pressure will enhance stroke volume and
Clinical features, diagnosis, and long- cardiac output, which will then promote the excretion of the excess
term prognosis of preeclampsia sodium. In contrast, a similar elevation in the LVEDP in the patient
Clinical manifestations and diagnosis of with heart failure (point C), who is on a flatter part of the curve, will
edema in adults produce less of an increment both in cardiac output and
Excitation-contraction coupling in consequently in sodium excretion. Limiting dietary sodium intake in
myocardium this setting may be sufficient to alleviate the edema.
General principles of the treatment of
edema in adults The situation is somewhat different with severe heart failure (figure 2). At
Hyponatremia in patients with cirrhosis this time, the plateau in stroke volume occurs earlier and at a lower level
Idiopathic edema than in mild heart failure, and increasing the LVEDP cannot normalize the
stroke volume. Two factors appear to account for this plateau.
Idiopathic systemic capillary leak
syndrome
The heart may simply have reached its maximum capacity to
Lymphedema: Etiology, clinical
manifestations, and diagnosis increase contractility in response to increasing stretch. In vitro
studiesUpToDate.
suggest Did
thatUpToDate
this abnormality may result fromYes
decreased
Major side effects and safety of calcium Help improve answer your question? No
 calcium affinity for and therefore binding to troponin C and from
19.3
decreased calcium availability within the myocardial cells [50]. (See
"Excitation-contraction coupling in myocardium".)

The Frank-Starling relationship actually applies to left ventricular

end-diastolic volume, since it is the stretching of cardiac muscle that
is responsible for the enhanced contractility. The more easily
TOPIC OUTLINE measured LVEDP is used clinically since, in relatively normal hearts,
INTRODUCTION pressure and volume vary in parallel. However, cardiac compliance
PATHOPHYSIOLOGY OF EDEMA may be greatly reduced with severe heart disease [51]. As a result, a
FORMATION small increase in volume produces a large elevation in LVEDP, but no
Capillary hemodynamics substantial stretching of the cardiac muscle and therefore little
Edema formation change in cardiac output [52].
- Increased capillary hydraulic pressure
- Hypoalbuminemia Drug-induced edema — Certain drugs can induce edema by enhancing
- Increased capillary permeability renal sodium reabsorption (table 1). In the past, this was most likely to
- Lymphatic obstruction or myxedema occur with potent direct vasodilators such as minoxidil and diazoxide,
Pathophysiology
Safety factors and etiology of edema in adults which are now infrequently used [53-55]. Patients treated
Find Patient Print
with minoxidil, for
Renal sodium retention
example, often require therapy with high doses of a loop diuretic (such as
The compensated state
160 to 240 mg of furosemide) to prevent edema formation.
ETIOLOGY
Heart failure The mechanism by which these agents stimulate sodium retention is
Drug-induced edema uncertain. The fall in blood pressure itself probably plays an important role
Refeeding edema both directly and by activating the renin-angiotensin-aldosterone and
INFORMATION FOR PATIENTS sympathetic nervous systems, both of which stimulate sodium retention
REFERENCES [53,56]. The ability of sympatholytic agents to directly diminish renin
release and of angiotensin converting enzyme inhibitors to diminish
GRAPHICSView All angiotensin II production may explain why these drugs do not produce
FIGURES edema even though they lead to an equivalent reduction in blood pressure.
Renin in HF
Frank Starling curves in HF Peripheral edema occurs in 4 to 6 percent of diabetic patients treated with
a thiazolidinedione such as pioglitazone or rosiglitazone (compared to 1 to
TABLES
2 percent with placebo) and in a higher percentage of patients with a
Major causes of edema
Different Starlings forces history of heart failure or those also treated with insulin. The mechanism is
stimulation of sodium reabsorption by the sodium channels in the luminal
RELATED TOPICS membrane of collecting tubule cells, which is the same site stimulated by
Actions of angiotensin II on the heart aldosterone. (See "Thiazolidinediones in the treatment of diabetes
Chapter 7B: Exchange of water between mellitus", section on 'Fluid retention/heart failure'.)
plasma and interstitial fluid
Other causes of drug-induced edema include:
Clinical features of primary
aldosteronism
Calcium channel blockers, particularly the dihydropyridines in which
Clinical features, diagnosis, and long-
leakage out of the capillary due to dilatation of the precapillary
term prognosis of preeclampsia
sphincter appears to be of primary importance [57]. (See "Major side
Clinical manifestations and diagnosis of
effects and safety of calcium channel blockers".)
edema in adults
Excitation-contraction coupling in Nonsteroidal antiinflammatory drugs inhibit renal prostaglandin
myocardium synthesis and can exacerbate edema in patients with underlying
General principles of the treatment of heart failure or cirrhosis [58]. (See "NSAIDs: Electrolyte
edema in adults
complications".)
Hyponatremia in patients with cirrhosis
Idiopathic edema Fludrocortisone is a synthetic mineralocorticoid used in the
Idiopathic systemic capillary leak treatment of hypoaldosteronism and orthostatic hypotension.
syndrome Although this drug initially causes fluid retention, edema is unusual
Lymphedema: Etiology, clinical because of the phenomenon of mineralocorticoid escape. (See
manifestations, and diagnosis "Clinical features of primary aldosteronism".)
Major side effects and safety of calcium Help improve UpToDate. Did UpToDate answer your question? Yes No
 Estrogens (alone or in oral contraceptives) may promote sodium
19.3 retention, primarily in patients with impaired estrogen metabolism
due to hepatic disease [59,60].

Pramipexole, a dopamine-agonist utilized in patients with Parkinson

disease and restless legs syndrome, causes peripheral edema in
approximately 5 percent of patients; this effect appears to be dose-
TOPIC OUTLINE
related but the mechanism is uncertain [61].
INTRODUCTION
PATHOPHYSIOLOGY OF EDEMA Docetaxel, used in the treatment of metastatic breast cancer,
FORMATION produces fluid retention that is cumulative and often dose-limiting
Capillary hemodynamics [62-64]. However, with appropriate premedication (three to five days
Edema formation of oral corticosteroids, beginning 24 hours prior to dosing), higher
- Increased capillary hydraulic pressure cumulative doses can be administered before fluid retention occurs
- Hypoalbuminemia [64].
- Increased capillary permeability
- Lymphatic obstruction or myxedema Refeeding edema — Patients who have fasted for as little as three days
Pathophysiology
Safety factors and etiology of edema in adults retain sodium and may become edematous after refeeding Find Patient Print
with
Renal sodium retention
carbohydrates [65-70]. Insulin, which is induced with the renewed intake of
The compensated state
carbohydrates, results in enhanced reabsorption of sodium, thereby
ETIOLOGY
causing edema [68].
Heart failure
Drug-induced edema INFORMATION FOR PATIENTS — UpToDate offers two types of patient
Refeeding edema education materials, “The Basics” and “Beyond the Basics.” The Basics
INFORMATION FOR PATIENTS patient education pieces are written in plain language, at the 5th to
REFERENCES 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for
GRAPHICSView All
patients who want a general overview and who prefer short, easy-to-read
FIGURES materials. Beyond the Basics patient education pieces are longer, more
Renin in HF sophisticated, and more detailed. These articles are written at the 10th to
Frank Starling curves in HF 12th grade reading level and are best for patients who want in-depth
TABLES information and are comfortable with some medical jargon.
Major causes of edema
Different Starlings forces Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can
RELATED TOPICS
also locate patient education articles on a variety of subjects by searching
Actions of angiotensin II on the heart on “patient info” and the keyword(s) of interest.)
Chapter 7B: Exchange of water between
plasma and interstitial fluid Beyond the Basics topic (see "Patient information: Edema
Clinical features of primary (swelling)").
aldosteronism
Clinical features, diagnosis, and long-
term prognosis of preeclampsia Use of UpToDate is subject to the Subscription and License Agreement.
Clinical manifestations and diagnosis of
edema in adults
REFERENCES
Excitation-contraction coupling in
myocardium 1. Guyton, AC. Textbook of Medical Physiology, 8th ed, Saunders,
General principles of the treatment of Philadelphia, 1991, chap. 16.
edema in adults 2. Taylor AE. Capillary fluid filtration. Starling forces and lymph flow. Circ
Hyponatremia in patients with cirrhosis Res 1981; 49:557.
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Idiopathic systemic capillary leak microcirculation. Microvasc Res 1985; 30:251.
syndrome 4. Crandall ED, Staub NC, Goldberg HS, Effros RM. Recent developments
Lymphedema: Etiology, clinical in pulmonary edema. Ann Intern Med 1983; 99:808.
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Major side effects and safety of calcium Help improve UpToDate. Did UpToDate answer your question? Yes No
 . Belldegrun, A, Webb, D, Austin, HA III, et al. Effects of interleukin-2 on
renal function in patients receiving immunotherapy for advanced
19.3
cancer. Ann Intern Med 1987; 106:817.
7. Baumgartner I, Rauh G, Pieczek A, et al. Lower-extremity edema
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. Amoura Z, Papo T, Ninet J, et al. Systemic capillary leak syndrome:
TOPIC OUTLINE report on 13 patients with special focus on course and treatment. Am
INTRODUCTION J Med 1997; 103:514.
PATHOPHYSIOLOGY OF EDEMA 9. Cicardi M, Gardinali M, Bisiani G, et al. The systemic capillary leak
FORMATION syndrome: appearance of interleukin-2-receptor-positive cells during
Capillary hemodynamics attacks. Ann Intern Med 1990; 113:475.
Edema formation 10. Droder RM, Kyle RA, Greipp PR. Control of systemic capillary leak
- Increased capillary hydraulic pressure syndrome with aminophylline and terbutaline. Am J Med 1992;
- Hypoalbuminemia 92:523.
- Increased capillary permeability 11. Tahirkheli NK, Greipp PR. Treatment of the systemic capillary leak
- Lymphatic obstruction or myxedema syndrome with terbutaline and theophylline. A case series. Ann Intern
Pathophysiology
Safety factors and etiology of edema in adults Med 1999; 130:905. Find Patient Print
Renal sodium retention 12. Ohlsson K, Björk P, Bergenfeldt M, et al. Interleukin-1 receptor
The compensated state antagonist reduces mortality from endotoxin shock. Nature 1990;
348:550.
ETIOLOGY
Heart failure 13. Colletti LM, Remick DG, Burtch GD, et al. Role of tumor necrosis
Drug-induced edema factor-alpha in the pathophysiologic alterations after hepatic
ischemia/reperfusion injury in the rat. J Clin Invest 1990; 85:1936.
Refeeding edema
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GRAPHICSView All 15. Hommel E, Mathiesen ER, Aukland K, Parving HH. Pathophysiological
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Renin in HF
1 . Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications.
Frank Starling curves in HF Diabetes 1994; 43:836.
TABLES
17. Mayatepek E, Becker K, Gana L, et al. Leukotrienes in the
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Different Starlings forces
1 . Parving HH, Hansen JM, Nielsen SL, et al. Mechanisms of edema
RELATED TOPICS formation in myxedema--increased protein extravasation and
relatively slow lymphatic drainage. N Engl J Med 1979; 301:460.
Actions of angiotensin II on the heart
19. HOLLANDER W, REILLY P, BURROWS BA. Lymphatic flow in human
Chapter 7B: Exchange of water between subjects as indicated by the disappearance of 1-131-labeled albumin
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Clinical features of primary 20. Taylor AE. The lymphatic edema safety factor: the role of edema
aldosteronism dependent lymphatic factors (EDLF). Lymphology 1990; 23:111.
Clinical features, diagnosis, and long-
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term prognosis of preeclampsia
lymphatic system in primary non-lymphogenic edema of the leg.
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Excitation-contraction coupling in 22. Szidon JP. Pathophysiology of the congested lung. Cardiol Clin 1989;
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General principles of the treatment of 23. Kwan T, Pintea M, Garcia Morino F, et al. Transcapillary oncotic
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Idiopathic edema 24. Fauchald P. Transcapillary colloid osmotic gradient and body fluid
Idiopathic systemic capillary leak volumes in renal failure. Kidney Int 1986; 29:895.
syndrome 25. Koomans HA, Kortlandt W, Geers AB, Dorhout Mees EJ. Lowered
Lymphedema: Etiology, clinical protein content of tissue fluid in patients with the nephrotic
manifestations, and diagnosis syndrome: observations during disease and recovery. Nephron 1985;
40:391.
Major side effects and safety of calcium Help improve UpToDate. Did UpToDate answer your question? Yes No
 2 . Zarins CK, Rice CL, Peters RM, Virgilio RW. Lymph and pulmonary
response to isobaric reduction in plasma oncotic pressure in
19.3
baboons. Circ Res 1978; 43:925.
27. Schrier RW. Body fluid volume regulation in health and disease: a
unifying hypothesis. Ann Intern Med 1990; 113:155.
2 . Schrier, RW. An odyssey into the milieu intériur: Pondering the
enigmas. J Am Soc Nephrol 1992; 1:1549.
TOPIC OUTLINE
29. EPSTEIN FH, FERGUSON TB. The effect of the formation of an
INTRODUCTION arteriovenous fistula upon blood volume. J Clin Invest 1955; 34:434.
PATHOPHYSIOLOGY OF EDEMA 30. KOWALSKI HJ, ABELMANN WH. The cardiac output at rest in
FORMATION Laennec's cirrhosis. J Clin Invest 1953; 32:1025.
Capillary hemodynamics
31. Pérez-Ayuso RM, Arroyo V, Camps J, et al. Evidence that renal
Edema formation prostaglandins are involved in renal water metabolism in cirrhosis.
- Increased capillary hydraulic pressure Kidney Int 1984; 26:72.
- Hypoalbuminemia
32. Henriksen JH, Bendtsen F, Gerbes AL, et al. Estimated central blood
- Increased capillary permeability volume in cirrhosis: relationship to sympathetic nervous activity, beta-
- Lymphatic obstruction or myxedema adrenergic blockade and atrial natriuretic factor. Hepatology 1992;
Pathophysiology
Safety factors and etiology of edema in adults 16:1163. Find Patient Print
Renal sodium retention 33. Fernandez-Seara J, Prieto J, Quiroga J, et al. Systemic and regional
The compensated state hemodynamics in patients with liver cirrhosis and ascites with and
ETIOLOGY without functional renal failure. Gastroenterology 1989; 97:1304.
Heart failure 34. Cohn JN. Blood pressure and cardiac performance. Am J Med 1973;
Drug-induced edema 55:351.
Refeeding edema 35. Watkins L Jr, Burton JA, Haber E, et al. The renin-angiotensin-
INFORMATION FOR PATIENTS aldosterone system in congestive failure in conscious dogs. J Clin
REFERENCES Invest 1976; 57:1606.
3 . Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the
GRAPHICSView All renin-angiotensin-aldosterone system to clinical state in congestive
FIGURES heart failure. Circulation 1981; 63:645.
Renin in HF 37. Chonko AM, Bay WH, Stein JH, Ferris TF. The role of renin and
Frank Starling curves in HF aldosterone in the salt retention of edema. Am J Med 1977; 63:881.
TABLES 3 . Rose, BD, Post, . Clinical Physiology of Acid-Base and Electrolyte
Major causes of edema Disorders, 5th ed, McGraw-Hill, New York, 2001, chap. 16.
Different Starlings forces 39. Blankfield RP, Finkelhor RS, Alexander JJ, et al. Etiology and diagnosis
of bilateral leg edema in primary care. Am J Med 1998; 105:192.
RELATED TOPICS
40. McHugh TJ, Forrester JS, Adler L, et al. Pulmonary vascular
Actions of angiotensin II on the heart congestion in acute myocardial infarction: hemodynamic and
Chapter 7B: Exchange of water between radiologic correlations. Ann Intern Med 1972; 76:29.
plasma and interstitial fluid 41. Warren, JV, Stead, EA. Fluid dynamics in chronic congestive heart
Clinical features of primary failure: An interpretation of the mechanisms producing the edema,
aldosteronism increased plasma volume, and elevated venous pressure in certain
patients with prolonged congestive failure. Arch Intern Med 1944;
Clinical features, diagnosis, and long-
73:138.
term prognosis of preeclampsia
42. Dzau VJ. Renal and circulatory mechanisms in congestive heart
Clinical manifestations and diagnosis of
failure. Kidney Int 1987; 31:1402.
edema in adults
Excitation-contraction coupling in 43. Packer M. Neurohormonal interactions and adaptations in congestive
myocardium heart failure. Circulation 1988; 77:721.
General principles of the treatment of 44. BRAUNWALD E, PLAUTH WH Jr, MORROW AG. A METHOD FOR THE
edema in adults DETECTION AND QUANTIFICATION OF IMPAIRED SODIUM
EXCRETION. RESULTS OF AN ORAL SODIUM TOLERANCE TEST IN
Hyponatremia in patients with cirrhosis NORMAL SUBJECTS AND IN PATIENTS WITH HEART DISEASE.
Idiopathic edema Circulation 1965; 32:223.
Idiopathic systemic capillary leak 45. Winaver J, Hoffman A, Burnett JC Jr, Haramati A. Hormonal
syndrome determinants of sodium excretion in rats with experimental high-
Lymphedema: Etiology, clinical output heart failure. Am J Physiol 1988; 254:R776.
manifestations, and diagnosis 4 . Reddy HK, Weber KT, Janicki JS, McElroy PA. Hemodynamic,
Major side effects and safety of calcium ventilatory
Help improve and metabolic
UpToDate. effects
Did UpToDate of light
answer your isometric
question? exercise
Yes in No
 patients with chronic heart failure. J Am Coll Cardiol 1988; 12:353.
19.3 47. Higgins CB, Vatner SF, Franklin D, Braunwald E. Effects of
experimentally produced heart failure on the peripheral vascular
response to severe exercise in conscious dogs. Circ Res 1972;
31:186.
4 . Millard RW, Higgins CB, Franklin D, Vatner SF. Regulation of the renal
circulation during severe exercise in normal dogs and dogs with
TOPIC OUTLINE experimental heart failure. Circ Res 1972; 31:881.
INTRODUCTION 49. Ring-Larsen H, Henriksen JH, Wilken C, et al. Diuretic treatment in
PATHOPHYSIOLOGY OF EDEMA decompensated cirrhosis and congestive heart failure: effect of
FORMATION posture. Br Med J (Clin Res Ed) 1986; 292:1351.
Capillary hemodynamics 50. Schwinger RH, Böhm M, Koch A, et al. The failing human heart is
Edema formation unable to use the Frank-Starling mechanism. Circ Res 1994; 74:959.
- Increased capillary hydraulic pressure 51. Gault JH, Covell JW, Braunwald E, Ross J Jr. Left ventricular
- Hypoalbuminemia performance following correction of free aortic regurgitation.
- Increased capillary permeability Circulation 1970; 42:773.
- Lymphatic obstruction or myxedema 52. Komamura K, Shannon RP, Ihara T, et al. Exhaustion of Frank-Starling
Pathophysiology
Safety factors and etiology of edema in adults mechanism in conscious dogs with heart failure.
FindAm J Physiol
Patient 1993;
Print
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The compensated state 53. Markham RV Jr, Gilmore A, Pettinger WA, et al. Central and regional
ETIOLOGY hemodynamic effects and neurohumoral consequences of minoxidil
in severe congestive heart failure and comparison to hydralazine and
Heart failure
nitroprusside. Am J Cardiol 1983; 52:774.
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Clin Sci 1972; 42:145.
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55:236.
FIGURES
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Frank Starling curves in HF
TABLES 5 . Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal
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Actions of angiotensin II on the heart electrolyte metabolism. II. Hepatic disease. J Clin Invest 1956;
35:430.
Chapter 7B: Exchange of water between
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Clinical features of primary peripheral edema. Arch Neurol 2000; 57:729.
aldosteronism 2. Hudis CA, Seidman AD, Crown JP, et al. Phase II and pharmacologic
Clinical features, diagnosis, and long- study of docetaxel as initial chemotherapy for metastatic breast
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4. Piccart MJ, Klijn J, Paridaens R, et al. Corticosteroids significantly
General principles of the treatment of
delay the onset of docetaxel-induced fluid retention: final results of a
edema in adults
randomized study of the European Organization for Research and
Hyponatremia in patients with cirrhosis Treatment of Cancer Investigational Drug Branch for Breast Cancer. J
Idiopathic edema Clin Oncol 1997; 15:3149.
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fluid intake. J Clin Endocrinol Metab 1969; 29:55.
Lymphedema: Etiology, clinical
manifestations, and diagnosis . Saudek CD, Boulter PR, Knopp RH, Arky RA. Sodium retention
Major side effects and safety of calcium accompanying
Help improve insulin
UpToDate. treatment
Did UpToDate of diabetes
answer mellitus. Yes
your question? Diabetes
No1974;
 23:240.
19.3 7. Hopkins DF, Cotton SJ, Williams G. Effective treatment of insulin-
induced edema using ephedrine. Diabetes Care 1993; 16:1026.
. DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal
handling of sodium, potassium, calcium, and phosphate in man. J
Clin Invest 1975; 55:845.
9. Baum M. Insulin stimulates volume absorption in the rabbit proximal
TOPIC OUTLINE
convoluted tubule. J Clin Invest 1987; 79:1104.
INTRODUCTION 70. Nakamura R, Emmanouel DS, Katz AI. Insulin binding sites in various
PATHOPHYSIOLOGY OF EDEMA segments of the rabbit nephron. J Clin Invest 1983; 72:388.
FORMATION
Capillary hemodynamics
Edema formation
- Increased capillary hydraulic pressure
- Hypoalbuminemia
- Increased capillary permeability
- Lymphatic obstruction or myxedema
Safety factors
Renal sodium retention
The compensated state
ETIOLOGY
Heart failure
Drug-induced edema
Refeeding edema
INFORMATION FOR PATIENTS
REFERENCES

GRAPHICSView All
FIGURES
Renin in HF
Frank Starling curves in HF
TABLES
Major causes of edema
Different Starlings forces

RELATED TOPICS
Actions of angiotensin II on the heart
Chapter 7B: Exchange of water between
plasma and interstitial fluid
Clinical features of primary
aldosteronism
Clinical features, diagnosis, and long-
term prognosis of preeclampsia
Clinical manifestations and diagnosis of
edema in adults
Excitation-contraction coupling in
myocardium
General principles of the treatment of
edema in adults
Hyponatremia in patients with cirrhosis
Idiopathic edema
Idiopathic systemic capillary leak
syndrome
Lymphedema: Etiology, clinical
manifestations, and diagnosis
Major side effects and safety of calcium Help improve UpToDate. Did UpToDate answer your question? Yes No