General principles of the treatment of edema in adults

INTRODUCTION — Edema is defined as a palpable swelling produced by expansion of the interstitial fluid volume; when massive and generalized, the excess fluid accumulation is called anasarca. A variety of clinical conditions are associated with the development of edema, including heart failure, cirrhosis, and the nephrotic syndrome, as well as local conditions such as venous and lymphatic disease or malignant ascites (table 1). (See "Pathophysiology and etiology of edema in adults".)

The general principles for the treatment of edema in adults, including the use of diuretics to remove the excess fluid, will be reviewed here. The specific effects of diuretics in the three major generalized edema states (heart failure, cirrhosis, and the nephrotic syndrome), the clinical features and diagnosis of the generalized edematous states, and the treatment of refractory edema are discussed separately. (See "Use of diuretics in patients with heart failure" and "Ascites in adults with cirrhosis: Initial therapy", section on 'Diuretic therapy' and "Pathophysiology and treatment of edema in adults with the nephrotic syndrome" and "Clinical manifestations and evaluation of edema in adults" and "Causes and treatment of refractory edema in adults".)

GENERAL PRINCIPLES OF THERAPY — Treatment of edema consists of reversal of the underlying disorder (if possible), dietary sodium restriction (to minimize fluid retention), and, in most patients, diuretic therapy. Before initiating diuretic therapy, it is important to consider the following questions, which apply to all edematous states:

●When must edema be treated?

●What are the consequences of the removal of edema fluid?

●How rapidly should edema fluid be removed?

When must edema be treated? — Pulmonary edema is the only form of edema that is life threatening and requires immediate therapy. (See "Treatment of acute decompensated heart failure: General considerations".)

In most other edematous states, removal of the excess fluid can proceed more slowly since it usually is of no immediate danger to the patient. This is particularly true in patients with cirrhosis in whom hypokalemia, metabolic alkalosis, and rapid fluid shifts induced by diuretics can precipitate hepatic coma or the hepatorenal syndrome. (See "Ascites in adults with cirrhosis: Initial therapy", section on 'Diuretic therapy'.)

What are the consequences of the removal of edema fluid? — The retention of sodium and water by the kidney in heart failure and cirrhosis is compensatory in that it raises the effective arterial blood volume (also called the effective circulating volume) toward normal. By comparison, fluid accumulation is inappropriate with primary renal sodium retention (eg, kidney failure) where both the effective circulating volume and the total extracellular volume are expanded. These issues are discussed in detail elsewhere. (See "Pathophysiology and etiology of edema in adults".)

If the retention of edema fluid is compensatory (eg, heart failure or cirrhosis), then removal of this fluid with diuretics should diminish the effective arterial blood volume (ie, tissue perfusion). To the degree that the fluid lost by diuresis initially comes from the plasma volume, there will be a decrease in venous return to the heart and therefore in the cardiac filling pressures. From the Frank-Starling relationship, the reduction in the left ventricular end-diastolic pressure (LVEDP) should lower the stroke volume in both normal and failing hearts, possibly resulting in a fall in cardiac output and consequently in tissue perfusion (figure 1).

There is a large body of evidence that this sequence is common in edematous patients with heart failure or cirrhosis, as illustrated by the following observations (see "Ascites in adults with cirrhosis: Initial therapy", section on 'Rate of fluid removal' and "Use of diuretics in patients with heart failure", section on 'Hemodynamic effects'):

●The administration of diuretics to patients with either acute or chronic heart failure frequently leads to a reduction in cardiac output [1-3]. A similar sequence can occur in cirrhosis, particularly in patients who are rapidly diuresed [4,5].

●Diuretic-induced fluid removal leads to increased secretion of the three "hypovolemic" hormones (renin, norepinephrine, and antidiuretic hormone) in many patients with heart failure or cirrhosis [6-8].

Despite the reduction in the effective arterial blood volume, most patients benefit from the appropriate use of diuretics. As an example, the diminished exercise tolerance and symptoms of pulmonary congestion in patients with heart failure are often improved by diuretic therapy, even though the cardiac output may fall by an average of 20 percent [2]. This observation suggests that small reductions in the cardiac output can be well tolerated. Similarly, relief of symptoms of fatigue and bloating are common in patients with noncardiac causes of edema.

However, in some patients, the decrease in effective arterial blood volume with diuretic therapy is sufficient to significantly impair tissue perfusion. This most often occurs in two settings: when there is very low baseline effective arterial blood volume, as in severe heart failure; and after overly rapid fluid removal in cirrhosis [4].

The adequacy of tissue perfusion following diuretic therapy can be estimated simply by monitoring the blood urea nitrogen (BUN) and serum creatinine concentration. As long as these parameters remain constant, it can be assumed that diuretic therapy has not led to a significant impairment in perfusion to the kidney or therefore to other organs. By comparison, significant and otherwise unexplained elevations in the BUN and serum creatinine concentration indicate that further fluid removal should be avoided if possible (eg, no pulmonary edema) and that other therapeutic measures should be attempted (such as vasodilator or inotropic therapy in heart failure). The decline in tissue perfusion in this setting can also lead to weakness, fatigue, postural dizziness, and lethargy or confusion due to decreased cerebral blood flow. (See "Use of diuretics in patients with heart failure", section on 'Hemodynamic effects'.)

Some patients have an otherwise unexplained rise in BUN (eg, not due to variceal bleeding in cirrhosis) with no change in serum creatinine (often called prerenal azotemia). It is likely that there is a reduction in kidney perfusion that is too small to lead to a reduction in glomerular filtration rate and therefore an elevation in serum creatinine. This finding alone is an indication for more frequent monitoring of the serum creatinine. In some cases, however, an attempt to achieve additional diuresis may be justified if the patient still has symptomatic edema and does not have symptomatic hypovolemia.

In contrast to the adverse hemodynamic changes that may be seen in heart failure, cirrhosis, or some cases of the nephrotic syndrome, impaired kidney perfusion should not occur after the appropriate use of diuretics in patients with primary renal sodium retention (table 1). In these conditions, the effective arterial blood volume is increased by fluid retention. Although diuretic therapy will still reduce the effective arterial blood volume, it will be from an initially high level back toward normal.

How rapidly should edema fluid be removed? — When diuretics are administered, the fluid that is lost initially comes from the intravascular space. This results in a reduction in the venous pressure and consequently in capillary hydraulic pressure, thereby promoting partial restoration of the plasma volume by the mobilization of edema fluid into the vascular space.

The rapidity with which this occurs is variable. In patients with generalized edema due to heart failure, the nephrotic syndrome, or primary sodium retention, the edema fluid can be mobilized rapidly since most capillary beds are involved. Thus, in patients with anasarca, removal of 2 to 3 liters of edema fluid or more in 24 hours can usually be accomplished without a clinically significant reduction in plasma volume.

An important exception occurs in patients with cirrhosis and ascites but no peripheral edema [4,5]. In this setting, the excess ascitic fluid can only be mobilized via the peritoneal capillaries. Direct measurements have indicated that 300 to 500 mL/day is the maximum amount that can be mobilized by most patients with isolated ascites [4,5,8]. If the diuresis proceeds more rapidly, the ascitic fluid will be unable to completely replenish the plasma volume (figure 2), resulting in azotemia and possible precipitation of the hepatorenal syndrome. This limitation does not apply to patients with cirrhosis who also have peripheral edema, due to the rapid mobilization of the edema fluid into the vascular space (figure 2). (See "Ascites in adults with cirrhosis: Initial therapy", section on 'Rate of fluid removal'.)

Venous insufficiency, lymphedema, and malignant ascites — Patients with localized edema due to venous or lymphatic obstruction or malignant ascites represent another setting in which diuretic therapy can lead to volume depletion. As discussed in the preceding section, a reduction in venous and therefore intracapillary pressure with fluid removal in a patient with edema allows the edema fluid to be mobilized and the plasma volume to be maintained. However, this sequence will not occur in patients with venous insufficiency, moderate to severe lymphedema, or ascites due to peritoneal malignancy [9]. As a result, diuretics should be used with caution in such patients with monitoring of the serum creatinine. (See "Clinical staging and conservative management of peripheral lymphedema".)

The mainstays of therapy of lower-extremity edema due to venous insufficiency are leg elevation and well-fitted, knee-high compression stockings. Some medical therapies also may be effective. These modalities are discussed in detail elsewhere.

USE OF DIURETICS — Diuretic therapy in generalized edematous states is generally begun with a loop diuretic, such as furosemide. In addition to monitoring the degree of diuresis, patients should also be monitored for electrolyte complications, such as hypokalemia, metabolic alkalosis, and hyponatremia, and for signs of tissue hypoperfusion, such as an otherwise unexplained rise in serum creatinine.

The approach to diuretic therapy has some unique features in each of the generalized edematous states:

●Cirrhosis – For patients with cirrhosis, spironolactone and a loop diuretic is the preferred initial regimen. Spironolactone contributes to the diuresis but, importantly, tends to raise the plasma potassium. Hypokalemia induced by the loop diuretic can precipitate hepatic coma, and spironolactone provides protection against hypokalemia. The diuresis should proceed slowly in the absence of edema since there is a limited rate at which the ascitic fluid can be mobilized to replenish the plasma volume, and patients with tense ascites are often treated with therapeutic paracentesis. (See 'How rapidly should edema fluid be removed?' above and "Ascites in adults with cirrhosis: Initial therapy", section on 'Diuretic therapy' and "Ascites in adults with cirrhosis: Diuretic-resistant ascites", section on 'Therapeutic paracentesis'.)

●Congestive heart failure – For patients with heart failure, the rate of diuresis is usually not a limiting issue, but careful monitoring for signs of hypoperfusion (eg, rise in serum creatinine) is important. (See "Use of diuretics in patients with heart failure".)

●Nephrotic syndrome – For patients with nephrotic syndrome, higher-than-usual doses of a loop diuretic may be required. A higher dose is also required in patients with kidney failure because transport of the diuretic into the tubular lumen is impaired, and the maximal response to the diuretic is limited by a reduced number of functioning nephrons [10,11]. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome", section on 'Diuretics and sodium restriction'.)

●Persistent/refractory edema – For patients with idiopathic edema who are already on diuretics, the initial approach is to discontinue the diuretic for at least two to three weeks since some and perhaps many cases are diuretic induced. (See "Idiopathic edema".)

For patients with resistant edema from any cause, high-dose intravenous loop diuretics and the use of diuretic combinations acting at different sites in the nephron (usually a loop and thiazide-type diuretic) may be required [12,13]. Although metolazone has been championed as the preferred thiazide in this setting, there is no evidence that it is more effective at equivalent doses than more commonly used thiazides (eg, oral hydrochlorothiazide or, if available, intravenous chlorothiazide) [14,15]. (See "Causes and treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption'.)

Choice of loop diuretic — Furosemide, bumetanide, and torsemide, which are sulfonamides, are the most widely used loop diuretics. Ethacrynic acid, which is not a sulfonamide, is rarely used because it may be more ototoxic than the sulfonamide loop diuretics in high doses, and its relative insolubility makes it difficult to administer intravenously. The main indication for ethacrynic acid is a hypersensitivity reaction to one of the sulfonamide loop diuretics, which is usually manifested as a rash or rarely acute interstitial nephritis (as can be produced by other sulfonamide drugs).

A separate issue arises for patients with a history of allergy to sulfonamide antimicrobial drugs. Although patients who have a documented allergic reaction to a sulfonamide antimicrobial have a higher risk of allergic reaction when treated with a sulfonamide nonantimicrobial, most will not react (90 percent). Thus, patients with a history of allergy to sulfonamide antimicrobial drugs would be expected to tolerate nonantimicrobial sulfonamides, such as loop diuretics. Allergic reactions that do occur appear to be related to a predisposition to allergic reactions rather than to sulfonamide cross-reactivity [16]. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Between sulfonamide antimicrobials and nonantimicrobials'.)

Diuretic dose — There is no evidence that there are significant differences in efficacy among the different loop diuretics if given at equipotent doses. All diuretics have a dose-response curve characterized by a minimum rate of drug excretion that is required to induce a diuresis, an ascending portion of the curve in which increased diuretic excretion is associated with increases in sodium excretion, and a plateau at which further elevations in diuretic excretion do not add to the diuresis (figure 3) [13].

Studies in subjects with normal kidney function indicate that a diuresis begins with as little as 10 mg of furosemide, with the maximal effect being seen with 40 mg given intravenously [17]. Going above this maximum will produce little or no further diuresis but may increase the risk of side effects.

The effective diuretic dose is higher in patients with heart failure, advanced cirrhosis, or kidney failure (table 2). In these settings, decreased kidney perfusion (and therefore decreased drug delivery to the kidney), diminished drug secretion into the lumen (due to the retention of competing anions in kidney failure), and enhanced activity of sodium-retaining forces (such as the renin-angiotensin-aldosterone system) combine to diminish the diuretic effect (figure 3).

The initial aim is to find the effective single dose. Most patients with generalized edema are begun on a loop diuretic. Depending upon the circumstance, the drug can be given orally or intravenously. The onset of diuresis is earlier, and the peak diuresis is greater with intravenous therapy because of more rapid excretion in the urine. This difference is not likely to be important in stable patients who are typically treated with oral therapy.

The intravenous equivalent for furosemide, but not the other loop diuretics, is one-half the oral dose because of decreased oral availability. A typical oral dose of furosemide is 20 to 40 mg. Selected hospitalized patients may benefit from a continuous intravenous infusion of a loop diuretic, which can produce a greater diuresis than intravenous boluses (figure 4). (See "Loop diuretics: Dosing and major side effects", section on 'Dosing'.)

As described below, the maximum diuretic response at a given dose in stable patients is generally seen with the first dose (figure 5) [18]. Lack of significant net fluid removal may be due in part to an insufficient rate of diuretic excretion [19]. In this setting, it is important to ask the patient if there is a diuresis in the few hours following diuretic ingestion:

●If the answer is yes, then the dose is effective but short lived. The appropriate response is to give the same dose twice daily.

●If the answer is no, then giving the same dose twice a day will also be ineffective since adequate urinary levels are never achieved. The appropriate regimen is to double the individual dose until a diuresis is obtained or the maximum dose is reached (table 2) [19-21]. Additional measures are required in patients who do not respond to this regimen. (See "Loop diuretics: Dosing and major side effects" and "Causes and treatment of refractory edema in adults".)

Time course of diuretic response — When treating patients with edema, it is important to appreciate the time course of the diuretic response. Assuming that the patient is stable, the diuretic dose is not changed, and dietary solute and water intake are relatively constant, the diuresis of water and electrolytes is maximum with the first dose (figure 5), gradually declines over one to two weeks, and reaches a new steady state in which solute and water excretion are again equal to intake [18,19,22,23]. (See "Time course of loop and thiazide diuretic-induced electrolyte complications".)

The reason for this time limitation is that the initial solute or water loss leads to compensatory changes that limit further losses. Fluid loss eventually leads to increases in a variety of sodium-retaining factors, such as angiotensin II, aldosterone, norepinephrine, and a possible reduction in systemic blood pressure [19,22]. These sodium-retaining forces eventually equal the sodium-losing activity of the diuretic; the net effect is a new steady state in which the extracellular fluid volume is reduced by the amount of sodium lost during the first few days of therapy, but sodium intake and excretion are equal. If the patient remains edematous when the steady state has been achieved, then a higher diuretic dose or combination therapy is required.

Refractory edema — Some patients with generalized edema do not respond adequately to therapy with loop diuretics. The therapeutic approach to such patients is discussed separately. (See "Causes and treatment of refractory edema in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th 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 patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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 also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Edema (swelling) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Edema is defined as a palpable swelling produced by expansion of the interstitial fluid volume; when massive and generalized, the excess fluid accumulation is called anasarca. A variety of clinical conditions are associated with the development of edema, including heart failure, cirrhosis, and the nephrotic syndrome, as well as local conditions such as venous and lymphatic disease or malignant ascites (table 1).

●Principles of therapy – Pulmonary edema is the only form of generalized edema that is life threatening and requires immediate therapy. In all other edematous states, removal of the excess fluid can proceed more slowly since it is of no danger to the patient. (See 'When must edema be treated?' above.)

•Consequences of fluid removal – If the retention of edema fluid is compensatory (eg, heart failure or cirrhosis), then removal of this fluid with diuretics should diminish the effective arterial blood volume (ie, tissue perfusion). To the degree that the fluid lost by diuresis initially comes from the plasma volume, there will be a decrease in venous return to the heart and therefore in the cardiac filling pressures. From the Frank-Starling relationship, the reduction in the left ventricular end-diastolic pressure (LVEDP) should lower the stroke volume in both normal and failing hearts, possibly resulting in a fall in cardiac output and consequently in tissue perfusion (figure 1). (See 'What are the consequences of the removal of edema fluid?' above.)

•Parameters for daily fluid removal – In patients with generalized edema due to heart failure, the nephrotic syndrome, or primary sodium retention, the edema fluid can be mobilized rapidly since most capillary beds are involved. Thus, in patients with anasarca, removal of 2 to 3 liters of edema fluid or more in 24 hours can usually be accomplished without a clinically significant reduction in plasma volume. (See 'How rapidly should edema fluid be removed?' above.)

There are important exceptions:

-In patients with cirrhosis and ascites but no peripheral edema, the excess ascitic fluid can only be mobilized via the peritoneal capillaries. Direct measurements have indicated that 300 to 500 mL/day is the maximum amount that can be mobilized by most patients. If the diuresis proceeds more rapidly, the ascitic fluid will be unable to completely replenish the plasma volume (figure 2), resulting in azotemia and possible precipitation of the hepatorenal syndrome. (See 'How rapidly should edema fluid be removed?' above.)

-Patients with localized edema due to venous or lymphatic obstruction or malignant ascites represent another setting in which diuretic therapy can lead to volume depletion. A reduction in venous and therefore intracapillary pressure with fluid removal in a patient with edema allows the edema fluid to be mobilized and the plasma volume to be maintained. However, this sequence will not occur in patients with venous insufficiency, moderate to severe lymphedema, or ascites due to peritoneal malignancy. (See 'Venous insufficiency, lymphedema, and malignant ascites' above.)

●Use of diuretics – Diuretic therapy in generalized edematous states is usually begun with a loop diuretic, such as furosemide. In patients with cirrhosis, the combination of spironolactone and a loop diuretic is the preferred initial diuretic regimen. For other causes of generalized edema, loop diuretics are usually preferred, and higher doses may be required in patients with nephrotic syndrome (table 2). (See 'Use of diuretics' above.)

Some cases of idiopathic edema are diuretic induced, and the initial approach in patients with idiopathic edema who are already on diuretics is to stop the diuretics for at least two to three weeks. (See "Idiopathic edema".)

Patients with resistant generalized edema from any cause may require high-dose loop diuretics in combination with a diuretic acting at a different site in the nephron, typically a thiazide diuretic. There is no evidence that metolazone is more effective at equivalent doses than more commonly used thiazides (eg, oral hydrochlorothiazide or, if available, intravenous chlorothiazide). (See "Causes and treatment of refractory edema in adults", section on 'Enhanced tubular sodium reabsorption'.)