Generalized Edema:

August 1, 2004

ABSTRACT: Restriction of fluid and salt intake is essential in patients with edema. Bed rest and supportive stockings are also helpful. However, diuretics are usually the mainstay of therapy. The effect of thiazide diuretics is relatively mild; they may be adequate in patients with cirrhosis but are ineffective in those with congestive heart failure (CHF) or nephrotic syndrome. Loop-acting diuretics can induce massive natriuresis and diuresis. Intravenous loop diuretics are preferred to oral agents for the relief of pulmonary edema. Acetazolamide, a carbonic anhydrase inhibitor, is commonly used in patients with glaucoma and is also recommended for those with CHF accompanied by metabolic alkalosis. Combination therapy is recommended for patients with refractory edema and normal or somewhat impaired renal function. The adverse effects of thiazide and loop-acting diuretics include renal insufficiency, hyponatremia, hypochloremia, hypokalemia, hypomagnesemia, metabolic alkalosis, hyperglycemia, and hyperlipidemia. These effects are typically reversed when the dosage is reduced or therapy is discontinued. Potassium sparing diuretics can cause life-threatening hyperkalemia.

In my article on page 1221, I outlined an approach to the diagnosis of the underlying cause of edema. Here I delineate the treatment options.

A number of different strategies are used to manage edema. In most patients, 2 or more of the following are necessary to achieve optimal results:

Bed rest.

Variable restriction of salt and fluid intake.

Diuretic therapy.

Treatment of the cause.

Adjuvant therapy.

Measures to prevent the development of chronic edema are listed in Table 1.

BED REST

Bed rest alone helps mobilize fluid in the dependent portions of the body and results in mild diuresis. Supportive stockings further enhance the mobilization of fluid. The mechanism of the diuresis induced by bed rest and/or supportive stocking is not clearly understood, but it appears to be associated with an increase in effective circulating blood volume and renal perfusion.

RESTRICTION OF SALT AND FLUID INTAKE

Unrestricted salt and fluid intake allows the sodium and water balance to remain positive. Therefore, restriction of fluid and salt intake is essential in patients with edema.

Salt intake. To determine the salt intake that is appropriate for a particular patient, measure urinary sodium excretion. Obtain at least one 24-hour measurement of urinary sodium excretion after the patient has been on a 2 g-sodium diet (5 g-sodium chloride) for 3 days and another after he or she has been on a 4 g-sodium diet (7 g-sodium chloride) for 3 days. Make sure the patient is not using diuretics when these measurements are made (urinary electrolyte levels cannot be properly interpreted if urine samples are collected during diuretic therapy). If 24-hour urinary sodium excretion is less than 20 mEq on daily sodium intake of 2 g or 4 g, then the patient's daily sodium intake should be reduced to 1 g (23 mEq) or 0.5 g (essentially a salt-free diet).1

However, because a variety of potent diuretics are available, such a severe restriction of salt intake is seldom necessary. Still, some patients become resistant to diuretic therapy (which may in part result from unrestricted salt intake), and in these patients, rigid restriction of salt and fluid intake is the mainstay of therapy.

Fluid intake. Because of an edematous patient's inability to excrete free water-and his concomitant hyponatremia-prescribe fluid intake that is equal to or less than his daily urinary output plus insensible loss (estimate the latter at 500 mL/d). Restrict gross estimated fluid intake to no more than 1200 mL/d (40 oz/d).1This is equal to a maximum of four 10-oz glasses or cups of fluid, which include water, tea, coffee, soda, and juice. However, in situations in which patients lose additional fluid, such as vomiting or diarrhea, increase their fluid intake to make up for the extra loss.

DIURETIC THERAPY

Four classes of diuretics are commonly used to treat edema:

Thiazide diuretics.

Loop-acting diuretics.

Potassium sparing diuretics.

Carbonic anhydrase inhibitors.

Thiazide diuretics. These include hydrochlorothiazide, indapamide, and metolazone. Hydrochlorothiazide is commonly used to treat hypertension, while indapamide and metolazone are more often used to treat edema. All thiazide diuretics are sulfonamide derivatives and cannot be prescribed in patients with an allergy to sulfa drugs.

Thiazide diuretics act solely through inhibition of sodium and chloride reabsorption in the distal convoluted tubule. They partially decrease free water clearance and partially lessen the ability to maximally dilute urine, but they do not interfere with the ability to concentrate urine. Thiazide diuretics induce natriuresis to the extent of 5% to 7% of total filtered sodium; therefore, they are considered relatively mild diuretics. A thiazide diuretic alone may be adequate in patients with cirrhosis but may prove ineffective in those with congestive heart failure (CHF) or nephrotic syndrome.

Loop-acting diuretics. These are of 2 types: sulfonamide derivatives (furosemide, bumetanide, and torsemide) and a phenoxyacetic acid derivative (ethacrynic acid). The only loop diuretic that is safe to use in patients who are allergic to sulfa drugs is ethacrynic acid. Furosemide has been reported to cause severe allergic reactions, including exfoliative dermatitis and acute allergic interstitial nephritis with acute renal failure. If a patient complains of a rash or if dermatitis and impaired renal function develop in a patient who is taking a loop diuretic other than ethacrynic acid, consider hypersensitivity reaction to sulfa drugs as a possible explanation and discontinue the loop diuretic.

Loop-acting diuretics have both a hemodynamic and a tubular mode of action. Hemodynamically, these agents increase renal blood flow and, in some instances, glomerular filtration rate. These effects appear to be mediated by prostaglandins, since the natriuretic and diuretic effects of loop diuretics are blunted by prostaglandin synthesis inhibitors, such as indomethacin.

In the renal tubules, loop diuretics act on the ascending thick limb of the loop of Henle and inhibit transport of sodium chloride. This results in the excretion of 15% to 20% of total filtered sodium and chloride. Also, by inhibiting transport of sodium chloride in the ascending thick limb, they impair the formation of a hypertonic medullary interstitium. Hypertonicity in the medullary interstitium-together with the influence of arginine vasopressin-generates the gradient for final concentration of urine. Therefore, a patient who is treated with a loop diuretic will be unable to maximally concentrate the urine during hydropenia. Loop diuretics also markedly reduce renal diluting capacity during water diuresis. Thus, the natriuresis and diuresis effected by these agents can be quite massive. In a patient with normal or near-normal renal function, 1 bolus intravenous injection of 40 mg of furosemide can result in a urinary output of 5 to 6 L in 4 hours.

Furosemide, the most commonly used loop diuretic, is usually administered by the oral route. However, intravenous administration of loop diuretics is preferred for the relief of pulmonary edema; this effect is not observed with oral therapy. An intravenous bolus of a loop diuretic reduces left ventricular filling pressure and pulmonary vascular resistance, which minimizes pulmonary edema and thereby ameliorates dyspnea. Nonetheless, intravenous administration of a loop diuretic does not always produce as dramatic an effect in chronic CHF as it does in acute CHF with pulmonary edema.

Adverse effects of thiazide and loop-acting diuretics. The adverse effects of thiazide diuretics and loop-acting diuretics are similar; they result from fluid, electrolyte, metabolic, and acid-base disturbances. Renal insufficiency with an elevated blood urea nitrogen/serum creatinine ratio-which suggests volume depletion-is a common complication of diuretic therapy (Box). The electrolyte disturbances seen with diuretic use include hyponatremia, hypochloremia, hypokalemia and hypomagnesemia. Simple metabolic alkalosis often accompanies electrolyte disturbances (see Box).

Two common metabolic disturbances seen with diuretic therapy are hyperglycemia and hyperlipidemia. Hyperglycemia can result from hypokalemia or dehydration, either of which can blunt insulin release. The connection between hyperglycemia and dehydration may be more significant than that between hyperglycemia and hypokalemia. This is deduced from the observation that saline infusion alone generally corrects hyperglycemia, whereas increasing the serum potassium level (with potassium supplements) does not always reduce an elevated glucose level.

Hyperlipidemia-usually an elevated serum cholesterol level-is commonly associated with diuretic therapy. However, in long-term diuretic users, increases in serum cholesterol eventually level off. Although clinicians are sometimes cautioned about the increased cardiovascular risk caused by hyperlipidemia associated with diuretic therapy, this increased risk has not been substantiated.

Also bear in mind that in almost all patients, the adverse effects of diuretic therapy reverse when the therapy is discontinued or the dosage reduced (see Box).

Potassium sparing diuretics. Theseinclude spironolactone, triamterene, and amiloride. Potassium sparing diuretics are used primarily when it is important to prevent the development of diuretic-induced hypokalemia, in settings (such as cirrhosis) where the induction of mild diuresis is desired, and for the potentiation of other diuretics.

Potassium sparing diuretics inhibit sodium reabsorption through action on the cortical collecting tubules; they may also act on the outer medullary collecting tubules. These agents induce a mild natriuresis to the extent of 2% to 3% of total filtered sodium. Spironolactone acts by competing with aldosterone to bind to receptor sites. Thus, spironolactone has a more pronounced effect in the presence of aldosterone, while both amiloride and triamterene inhibit sodium reabsorption independent of aldosterone.

The most serious adverse effect of potassium sparing diuretics is hyperkalemia. In the following settings, these agents may give rise to life-threatening hyperkalemia and should be avoided or used with extreme caution:

Impaired renal function.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors.1

Concomitant use of NSAIDs.1

Underlying diabetic nephropathy.

Concomitant use of potassium supplements, especially in the presence of impaired renal function.

Additional adverse effects of spironolactone include gynecomastia, impotence, and (in women) painful breasts and decreased libido.1 Adverse effects of triamterene may include folic acid deficiency (which can lead to megaloblastic anemia) and triamterenic renal calculi. With amiloride, hyperchloremic metabolic acidosis may develop.

Carbonic anhydrase inhibitors. The only agent in this class approved for use in generalized edema is acetazolamide. Acetazolamide acts mainly in the proximal tubule and causes bicarbonate diuresis. Bicarbonate excretion leads to sodium and water diuresis. Because it produces primarily a bicarbonate diuresis, acetazolamide is recommended in CHF accompanied by metabolic alkalosis. Other indications for acetazolamide include uric acid and cystine nephrolithiasis. It helps keep urine alkaline, which increases urinary excretion of uric acid and/or cystine.1 Acetazolamide is used most commonly in glaucoma. Adverse effects of acetazolamide include hypokalemia, hyperchloremic non-anion gap metabolic acidosis, nephrocalcinosis, and nephrolithiasis.

ADJUVANT THERAPY

In patients with generalized edema caused by nephrotic syndrome or cirrhosis and whose serum albumin level is less than 2.5 g/dL, albumin infusion followed by intravenous furosemide may help remove a massive accumulation of fluid. The combination of furosemide and albumin can improve diuretic efficacy, especially in patients with hypoalbuminemia.2,3 A 100- to 200-mL infusion is given intermittently, followed immediately by a 40- to 80-mg bolus of furosemide (the furosemide may also be given as a continuous infusion for 72 hours). Daily serum chemistry panels during the infusion and for 2 to 3 days afterward are essential to control sodium, potassium, and magnesium levels. Keep in mind that albumin has a short half-life, which can make this therapy impractical when the goal is to increase serum albumin levels. This therapy is also very expensive.

MANAGEMENT STRATEGIES IN REFRACTORY EDEMA

Normal or somewhat impaired renal function. In patients with refractory edema but normal renal function, use an oral loop diuretic and an oral potassium sparing diuretic to promote diuresis. In those with refractory edema and mild to moderate impairment of renal function (serum creatinine level greater than 1.5 mg/dL but less than 3 mg/dL), use 1 of the following combinations:

An oral loop diuretic and an oral thiazide diuretic.

Acetazolamide (intravenous or oral) and a loop diuretic (intravenous or oral).

Acetazolamide (intravenous or oral) and an oral loop diuretic and an oral thiazide diuretic.

Markedly impaired renal function. When refractory edema is accompanied by a serum creatinine level greater than 3 mg/dL and a creatinine clearance between 20 and 25 mL/ min), use 1 of the following therapeutic modalities:

Intermittent hemodialysis.

Continuous ambulatory peritoneal dialysis (CAPD).

Continuous venovenous hemofiltration (CVVH).

Continuous venovenous hemodiafiltration (CVVHD).

Of these 4 modalities, CAPD appears to be the most effective for the treatment of generalized edema with impaired renal function.4It uses a simple technique and can be performed by patients themselves; however, a support system is helpful. Loss of albumin through CAPD exchanges, especially when peritonitis is present, is a serious drawback of this therapy. In patients with severe proteinuria and hypoalbuminemia, hemodialysis is preferable; in this setting, proteinuria may be controlled with an ACE inhibitor, such as enalapril.

Refractory CHF. A number of therapeutic strategies may be beneficial to patients with refractory CHF who have ejection fractions of 10% to 15%, must remain upright in order to breathe, and are almost completely incapacitated. A nitroprusside infusion may be helpful because of its preload and afterload effects. Digoxin, an inotropic agent, increases cardiac output; this results in increased renal blood flow-and hence in diuresis.

An infusion offurosemide and dopamine can be used to promote natriuresis and diuresis.Add 480 mg of furosemide to a liter bag of 5% dextrose solution and infuse at a rate of 42 mL/h; this will deliver 20 mg of furosemide/h. Infuse dopamine separately at a rate of 1 to 3 µg/kg/min. Furosemide administered in this manner reduces left ventricular filling pressure and diminishes pulmonary venous pressure. Dopamine increases renal blood flow. The net result of the dual infusion is decreased pulmonary venous congestion and relief of dyspnea.

An infusion ofdobutamine can help improve a patient's ejection fraction. The recommended dosage is 2.5 to 15 µg/kg/min. Dobutamine is considered a selective β1-adrenergic agonist. In therapeutic doses, dobutamine also has mild β2- and α-adrenergic receptor agonist effects. However, unlike dopamine, dobutamine does not cause release of norepinephrine. The main effect of therapeutic doses of dobutamine is cardiac stimulation. It is used to increase cardiac output in the short-term treatment of patients with cardiac decompensation caused by depressed contractility from organic heart disease. Adverse effects include increases in heart rate and systolic blood pressure.

Although ACE inhibitors improve heart function, their use in refractory CHF tends to cause further deterioration in renal function, which results in aggravated sodium and water retention, a marked decrease in renal response to diuretics, and worsening of CHF. Hence, fluid and electrolyte imbalances worsen, and survival is impaired. Therefore, use ACE inhibitors in this setting only after fluid and electrolyte control has been achieved by some form of dialysis.5 n

References:

REFERENCES:

1. Ellison DH. Edema and the clinical use of diuretics. In: Primer on Kidney Diseases. 2nd ed. New York: National Kidney Foundation; 1998:114-123.

2. Inoue M, Okajima K, Itoh K, et al. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. 1987;32:198-203.

3. Elwell RJ, Spencer AP, Eisele G. Combined furosemide and human albumin treatment for diuretic- resistant edema. Ann Pharmacother. 2003;378:695-700.

4. Konig P, Geissler D, Lechleitner P, et al. Improved management of congestive heart failure: use of continuous ambulatory peritoneal dialysis. Arch Intern Med. 1987;147:1031-1034.

5. Stegmayr BG, Banga R, Lundberg L, et al. PD treatment for severe congestive heart failure. Perit Dial Int. 1996;16(suppl 1):S231-S235.

FOR MORE INFORMATION:

m Bichet DG, Anderson RJ, Schrier RW. Renal sodium excretion, edematous disorders and diuretic use. In: Schrier RW, ed. Renal and Electrolyte Disorders. Boston: Little, Brown and Company; 1992:89-159.

m Ciocon JO, Galindo-Ciocon D, Galindo DJ. Raised leg exercises for leg edema in the elderly. Angiology. 1995;46:19-25.

m de Jonge JW, Knottnerus JA, VanZutphen WM, et al. Short-term effect of withdrawal of diuretic drugs prescribed for ankle edema. BMJ. 1994;308:511-513.

m Karnad DR. Temtulkar P, Abraham P, et al. Head-down as a physiologic diuretic in normal controls and in patients with fluid-retaining states. Lancet. 1987;2:525-528.

m Pockros PJ, Reynolds TB. Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema. Gastroenterology. 1986;90:1827-1833.

m Ritz E, Fliser D, Wiecek A, et al. Pathophysiology and treatment of hypertension and edema due to renal failure. Cardiology. 1994;84(suppl 2):143-154.

m The body fluid compartments: extracellular and intracellular fluids; interstitial fluid and edema. In: Guyton AC, ed. Textbook of Medical Physiology. Philadelphia: WB Saunders Company; 1991:274-285.

m Warner LC, Campbell JC, Morali GA, et al. The response of atrial natriuretic factor and sodium excretion to dietary sodium challenges in patients with chronic liver disease. Hepatology. 1990;12:460-466.