PEDAL EDEMA

by Glen E Hastings MD September 12, 2005 I Pathophysiology 1 : Fluid Retention: Fluid is transferred from the intravascular to the extravascular compartment through the proximal portion of the capillary next to the arteriolar, because thats where the hydrostatic pressure of the blood within the lumen exceeds the colloid oncotic pressure exerted by the plasma proteins. At the venous end of the capillary the Differential Diagnosis intraluminal oncotic pressure exceeds the hydrostatic pressure, so Heart Failure: fluid moves back into the capillary next to the venule. Opposing this LV Systolic Arteriosclerotic Heart Disease movement are the hydrostatic & colloid oncotic pressures within the Hypertensive CV Disease extracellular compartment. Anything that perturbs either the Cardiomyopathies intravasculture or extravascular hydrostatic or oncotic pressures or LV Diastolic the integrity of the vascular wall will change the balance of these PMH Hypertension RV Cor Pulmonale Starling Forces, producing either tissue edema or dehydration. COPD Circulating Fluid Volume: Anything that lowers the hydrostatic Sleep Apnea o intravascular pressure will be interpreted by the carotid bodies & the 1 Pulmonary Hypertension Biventricular juxtraglomerular apparatus of the kidneys as loss of circulating fluid Longstanding all the above volume. Fluid loss activates the carotid body to activate the adrenal Renal Failure: medulla to increase the secretion of epinephrine & norepinephrine Nephrotic Syndrome while the juxtraglomerular apparatus & epinephrine stimulate Glomerulonephritis Liver Failure: increased renin production, which in turn increases conversion of Cirrhosis angiotensin I to angiotensin II & that increases aldosterone Nutritional: production. This chain of events results in vasoconstriction, salt & Calorie Deficiency water retention, elevated blood pressure & increased fluid & Protein Deficiency Thiamin Deficiency (Beri Beri) electrolyte retention, which may change the balance of Starling Drugs: Forces enough to cause tissue edema. In addition to producing more Vasodilators aldosterone, the half life of aldosterone is prolonged because the drop Minoxidil in perfusion pressure of the liver reduces aldosterones catabolism. Hydrazine Calcium Channel Blockers Antidiuretic hormone (arginine vasopressin, AVP) release is Nifedipine triggered by stimulation of the V3 receptor by an increase in Amlodipine Felodipine extracellular osmolality. It is also stimulated by decreasing perfusion -Blockers all of them pressures. Elevation of AVP increases resorption of free water by the -Blockers all of them distal renal tubule & collecting duct which increases total body water & Thiazolindinediones sometimes causes hyponatremia in the face of edema. Rosiglitazone Piaglitazone Endothelin secretion by endothelial cells is also stimulated by NSAIDs all of them decreased perfusion pressures, increasing systemic vasoconstriction Corticosteroids which further reduces renal perfusion & augments water & sodium Anabolic Steroids retention. Estrogens Progestins When filling pressures rise in the atria of the heart they release Atrial Cyclosporine Naturetic Peptide (ANP) & the ventricular myocardium releases Venous Obstruction Thromboembolism Brain Naturetic Peptide (-NP) into the circulation. ANP & -NP are Budd-Chiari Syndrome counter-regulatory hormones. They augment glomerular filtration, Superior Vena Cava Syndrome increase sodium & water excretion & antagonize the release of rennin, Lymphagitic Obstruction aldosterone & the vasoconstricting effects of ATII, AVP & the Primary Lymphedema Secondary Lymphedema catecholamines. ANP & BNP are elevated in congestive heart failure Other: (CHF) & may be used as diagnostic tests for the presence of CHF. Angioedema Causes Related to Increased Venous Pressures1: Allergic Reactions Bacterial or Viral Infections Congestive Heart Failure (CHF) is the generic term for a group of Myxedema or Hyperthyroidism syndromes produced by impairment of the effectiveness of myocardial Idiopathic Edema Pregnancy & Pre-eclampsia output. If the left ventricles contractility becomes impaired the patient

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has left ventricular systolic failure. If the left ventricles contractility is okay but its too hypertrophic to relax properly during diastole its called left ventricular diastolic failure or diastolic dysfunction. In either case, whether the problem is a weakened heart muscle or a heart that just cant relax, the result is the same: an increase in left atrial pressure which is transmitted backwards resulting in increased pulmonary vascular pressures. When these pressures become high enough that the hydrostatic pressure within the pulmonary capillaries exceeds the intravascular colloid oncotic pressure, fluid moves out into the lungs interstitial space & the patient presents with the syndrome of pulmonary edema. The progressive decrease in perfusion pressure triggers a baroreceptor mediated release of catecholamines along activates the rennin/angiotensin/aldosterone (RAAS) system producing vasoconstriction & sodium & water retention. At first, the fluid retention may be modest & so long as the patient is up & around on his feet during the day, the excess fluid pools in the extravascular compartment of the legs & feet & the patient may not notice shortness of breath. However, once he lies supine, the excess fluid will redistribute & expand the circulating volume. This increases the glomerular filtration rate, & precipitate nocturia. As more fluid accumulates the hydrostatic pressure in the pulmonary circuit increases enough to push fluid out into the lung tissue when the patient lies flat. At this point he is said to have paroxysmal nocturnal dyspnea (PND) & orthopnea. So, early symptoms of left sided CHF are increased nocturia, orthopnea, & paroxysmal nocturnal dyspnea. The physical signs of early left sided systolic CHF are a third heart sound & terminal crackling rals in the right lung base that do not clear with coughing. A third heart sound is heard best at the apex of the heart with the bell of the stethoscope pressed lightly to the skin. It occurs shortly after the second heart sound. If the patient has diastolic heart failure, there will not be a 3rd heart sound, but a 4th heart sound will occur just before the 1st heart sound. An elevated plasma -naturetic peptide level supports the diagnosis. Chest x-ray findings include engorgement of hilar vasculature, Kerley B lines & later on fluffy infiltrates &/or pleural effusion usually on the right (Because of the location of the thoracic duct on the left side). An echocardiogram will show a diminished left ventricular ejection fraction (<50%). If the problem is diastolic heart failure the ejection fraction is normal or greater than normal, & delayed diastolic filling will be apparent on the cine films. Dilation of the left atrium & elevated left atrial & pulmonary artery pressures are expected in either type of left sided CHF. These elevated pulmonary artery pressures are transmitted back to the right ventricle, which eventually over-expands & fails. The increase in hydrostatic pressure (at this point) is transferred backward to the venous & capillary beds of the body at large, causing engorgement of the liver (hepatomegally), jugulovenous distention (JVD) & pedal edema. At the point the patient has biventricular failure. He may be grossly edematous, but his lungs may be clear & he probably feels better because now the extra cellular fluid is in the peripheral tissues instead of the lung. People with longstanding chronic obstructive pulmonary disease (COPD) or sleep apnea eventually develop secondary pulmonary hypertension because hypoxemia causes pulmonary arteriolar constriction that over time becomes fixed. Hydrostatic pressure increases in the right heart chambers, the right ventricle fails & the patient develops hepatomegally, JVD & pedal edema. This is called cor pulmonal heart disease with right heart failure, because the primary problem is in the lung not the heart. Thromboembolism increases venous hydrostatic pressure in 2 ways: First, the obstruction of the normal intravascular pathway of return increases hydrostatic pressure. In addition, the intravenous clotting sometimes disrupts the fragile flap-valve structures in the superficial venous system that normally would support part of the weight of the column of returning blood. The net result is a dramatic increase in hydrostatic pressure in the involved peripheral venules which alters balance of Starling forces enough to cause fluid to transudate out into the tissue causing in the involved limb, & in severe cases varicose veins &/or stasis dermatitis. Unilateral edema usually means there is some kind obstruction to venous or lymphatic return from the affected limb. Its the doctors responsibility to identify the nature of the obstruction. Lymphedema is swelling of a body part related to obstruction of lymph drainage. There are primary & secondary causes. There are 3 types of primary lymphedema. Congenital lymphedema appears shortly after birth, lymphedema praecox occurs during adolescence & lymphedema tardus occurs

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after age 35. It may be associated with Turner, Klinefelter, Noonan or yellow nail syndrome. Worldwide the most common secondary cause of lymphedema is filariasis, but the most common secondary form in the US is repeated episodes of bacterial lymphangitis. Lymphomas, prostate cancer & breast cancer sometimes infiltrate & obstruct lymphatics. Less common causes include pregnancy, tuberculosis lymphogranuloma venereum, & rheumatoid arthritis. Cirrhosis of the Liver impedes venous return through the portal system which causes blood to pool in the splanchnic bed, increasing portal venous pressures. In addition to the increase in hydrostatic pressure engendered by this resistance, intravascular colloid osmotic pressures are often reduced because of reduced production of plasma proteins by the damaged liver. The increased portal pressure impedes renal blood flow, which is interpreted by the juxtraglomerular cells as volume depletion, so the RAAS becomes activated causing salt & water retention & initiating a vicious cycle of self reinforcing events. The excess fluid pools first in the abdomen causing ascites. Later with increased hypoalbuminurea, pedal edema occurs. Cirrhosis increases renal prostaglandin production which preserves glomerular filtration (GFR). When our patients take NSAIDs, they block renal prostaglandins reducing GFR & causing vasoconstriction that increases sodium & water retention. The damaged liver metabolizes aldosterone more slowly, so secondary hyperaldosteronism further complicates the process. Thats why loop diuretics, used alone have limited value in diuresing patients with ascites. A better plan is to start spironolactone first & watch the urine sodium & potassium. To begin with the sodium will be low & the potassium high. As the spironolactone effect increases (spironolactone is a competitive inhibitor of the aldosterone receptor so it takes several days to reach peak effect) the sodium excretion will increase & potassium loss decreases. Only when this occurs does the clinician add the loop diuretic. III Causes Related to Decreased Intravascular Colloid Oncotic Pressure: Nephrotic Syndrome is present when the 24 hour urinary protein excretion > 3.5gm/24hours. Most cases that occur in children are caused by minimal change disease (MCD) that responds to empirical steroid treatment. In adults 20% are related to MCD. Other adult causes include diabetic glomerulosclerosis, glomerulonephritis, hypersensitivity reactions & amyloidosis. The massive loss of protein results in diminished intravascular colloid oncotic pressure, which in turn allows more fluid to stay in the extravascular space producing edema. Lower perfusion pressures trigger the activation of RAAS & the catecholamines & initiate the self perpetuating cycle of sodium & water retention already described. Other features of the nephrotic syndrome include hyperlipidemia secondary to increased lipoprotein synthesis with accelerated atherosclerosis & hypercoagulation due in part to loss of antithrombin III, with increased risk of renal vein thrombosis, DVT & pulmonary embolism. Renal sodium excretion is also impaired in nephrotic syndrome, further augmenting water retention & edema formation. As with other causes of hypoalbuminemic edema, the edema of nephrotic syndrome tends to be more evenly distributed in the body, making for swollen eyelids & hands as well as pedal edema. Nutritional Edema is usually multifactorial in origin whether the nutritional deficit is total calorie deficiency (Marasmus) or protein deficiency (Kwashiokor) but the first defect is the deficiency of plasma proteins that provide the oncotic pressure that keeps fluids in the vascular compartment. Without them the hydrostatic pressures, unopposed, force increased amounts of water into the extravascular compartment producing generalized edema. The same compensatory mechanisms are triggered (i.e. activation of the RAAS & stimulation of catecholamine secretion).which compounds the problem. In addition however there is many times also a component of thiamin deficiency. Thiamin deficiency produces diffuse vasomotor depression resulting in vasodilatation & increased transudation of fluid into the interstitial space. The massive decrease in afterload causes a dramatic but ineffective increase in cardiac output ending in high output cardiac failure with a large dilated heart & generalized edema & the other physical signs of heart failure already described. This is called beriberi heart disease & Yes!. It does happen here.usually in alcoholics with heart failure taking high doses of loop diuretics & living on a protein deficient diet. They may not be calorie deficient so may not appear malnourished. They usually do have glossitis, chelosis, peripheral neuropathy &/or anemia, tachycardia, a wide pulse pressure, S3 gallop & sometimes a systolic flow murmur. The reasons for the thiamin deficiency are that ethanol inhibits thiamin uptake from the gut & loop diuretic

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accelerate its renal excretion. In the face of inadequate intake of thiamin the combination produces thiamin deficiency in 20% to 90% of class III-IV CHF patients. The response to thiamin in these cases is dramatic. Refeeding Edema is a benign condition that causes pedal edema because of poor skin turgor & vascular tone upon refeeding a patient who has experienced severe protein or calorie starvation. Protein Losing Enteropathy secondary to celiac sprue, inflammatory bowel disease, lymphoma or other causes of mucosal protein loss may also result in sufficient loss of plasma protein to cause edema by the same chain of events already discussed.. IV Causes Related to Vasodilatation or Diminished GFR: Beri-Beri Heart Disease impairs vasoconstriction & causes high output heart failure as described above. It is not uncommon & it often complicates CHF caused by other coronary or hypertensive disease. Vasodilating Drugs such as minoxidil, hydralazine, -blockers & especially the dihydropyridine calcium channel blockers such as nifedipine & amlodipine very commonly cause edema through the capillary engorgement that follows arteriolar relaxation & dilatation. Idiopathic Edema 2,3 is a condition of diurnal weight gain that afflicts post-pubertal women exclusively caused by an excessive degree of orthostatic water & sodium retention when the patient remains in the erect position for prolonged periods. There may be discomfort in the areas of fluid accumulation. One pathogenetic feature is thought to be some type of failure of the arteriolar vasoconstriction response to orthostatic change. The proximal cause for this failure of vasoconstriction is unknown. Idiopathic edema is a diagnosis of exclusion. It is not to be confused with cyclic edema which occurs synchronistically with menses & is not secondary to cardiac, nutritional, gastrointestinal, hepatic or renal dysfunction. Eating disorders, laxative & diuretic abuse must be excluded. Premenstrual Edema 4 is a very common complaint that is one component of the premenstrual syndrome (PMS). A recent study shows that retention of sodium & water peaked at days 1 to3 before menses & lagged 3 to 6 days following the peak plasma levels of progesterone. Spironolactone has been shown to be helpful in relieving both fluid retention & other PMS symptoms. Nonsteroidal Anti-inflammatory Drugs & Cyclosporine diminish GFR causing increased downstream reabsorption of water & sodium with consequential edema. Causes Related to Water & Sodium Retention: Acute Glomerulonephritis causes extravascular fluid expansion because of diminished glomerular filtration (GFR) & enhanced tubular reabsorption of water & sodium. The urine shows dysmorphic red blood cells (RBCs), RBC casts & subnephrotic (ie. <3gm/24hr) proteinurea. Renal failure manifested clinically by expanded total body water & sodium with consequential hypertension & edema along with renal failure that occurs acutely or progressively depending on the etiologic agent. Since cardiac function is not impaired pulmonary edema usually doesnt occur. Early diagnosis & appropriate early management are essential for best outcomes. Exogenous Corticosteroid administration is a very common cause of edema related to their direct effect on renal sodium & water resorption anabolic steroids, progestins & estrogens have similar but weaker effects. Heat Edema 5 is a self limited non-life threatening accumulation of excess sodium & water that occurs because of elevated aldosterone production among post pubertal women who are exposed to high environmental temperatures without time for heat acclimation to have occurred. Diuretic Withdrawal Edema is an unusual event that may occur in a patient abruptly withdrawn from long-term diuretic therapy, presumably because the patient has had a longstanding mildly depleted circulating fluid volume, so after the diuretic is discontinued, the hypertrophic RAAS needs some time to readjust. In the interim, rennin, ATII & aldosterone remain elevated unopposed for a short time. Hypothyroidism when severe produces a non-pitting edematous swelling of the subcutaneous tissue (myxedema) caused by the subcutaneous deposition of glycosaminoglycans that increase extracellular oncotic pressure which attracts water into the extravascular compartment.

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VI Causes Related to Capillary Endothelial Damage cause localized swelling along with other clinical signs of inflammation, heat, erythema & tenderness. Trauma, bacterial or viral infections or allergic or immune responses are common causes. The proximate cause is arteriolar endothelial damage with secondary leakage of fluid proteins & electrolytes into the extravascular compartment. Similarly, interleukin-2 & several chimeric human/murine monoclonal antibodies occasionally have a similar effect on the glomerular capillary endothelial cells. The edema found in the preeclampsia syndromes may in part be due to endothelial damage but it is principally secondary to hormonal imbalances. VII Unknown: Thiazolindinedione drugs such as rosiglitazone & piaglitazone regularly cause edema & weight gain & have been known to precipitate pulmonary edema that was refractory to diuretic therapy 6 . This effect is cancelled by deletion of the P-PAR- receptor on the collecting tubule 7 . VIII References:
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Braunwald E, Edema. Chapter 32 in Harrisons Principles of Internal Medicine 16thEdition. Editors: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. McGraw-Hill NY,NY 2005 pages 212-6. Kay A, Davis CL Idiopathic edema. Am J Kidney Dis. 1999;34(3):405-23. Streeten DH. Idiopathic edema. Pathogenesis, clinical features, and treatment. Endocrinol Metab Clin North Am. 1995;24(3):531-47. Seippel L, Eriksson O, Grankvist K, et al Physical symptoms in premenstrual syndrome are related to plasma progesterone and desoxycorticosterone. Gynecol Endocrinol. 2000;14(3):173-81. Wexler RK. Evaluation and treatment of heat-related illnesses. Am Fam Physician. 2002;65(11):2307-14. Singh N. Rosiglitazone and heart failure: long-term vigilance. J Cardiovasc Pharmacol Ther. 2004;9(1):21-5. Zhang H, Zhang A, Kohan DE, et al. Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci USA. 2005;102(26):9406-11.

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