35 - 43 Edema

43 Edema

Cyanosis can be caused by small quantities of circulating methe­ moglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin (Chap. 103); both of these hemoglobin derivatives impair oxygen delivery to the tissues. Although they are uncommon causes of cya­ nosis, these abnormal hemoglobin species should be sought by spec­ troscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with these conditions. Peripheral Cyanosis  Probably the most common cause of periph­ eral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vaso­ constriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arte­ riolar constriction, as in cold-induced vasospasm (Raynaud’s phenom­ enon) (Chap. 292), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebi­ tis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis. APPROACH TO THE PATIENT Cyanosis Certain features are important in arriving at the cause of cyanosis:

1. It is important to ascertain the time of onset of cyanosis. Cya­ nosis present since birth or infancy is usually due to congenital heart disease.
2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems is help­ ful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis.
3. The presence or absence of clubbing of the digits (see below) should be ascertained. The combination of cyanosis and club­ bing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arte­ riovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits.
4. Pao2 and Sao2 should be determined, and in patients with cya­ nosis in whom the mechanism is obscure, spectroscopic exami­ nation of the blood should be performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis). CLUBBING The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be heredi­ tary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see above), infective endo­ carditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, for example, in jackhammer operators. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperios­ teal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of

hypertrophic osteoarthropathy may be confirmed by bone radiograph or magnetic resonance imaging (MRI). Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from platelet precursors in the digital circulation. In certain circumstances, clubbing is reversible, such as following lung transplantation for cystic fibrosis.

■ ■FURTHER READING Essouma M et al: Epidemiology of digital clubbing and hypertrophic osteoarthropathy: A systematic review and meta-analysis. J Clin Rheumatol 28:104, 2022. Gao H et al: Acquired methemoglobinemia: A systematic review of Edema CHAPTER 43 reported cases. Transfus Apher Sci 61:103299, 2022. MacIntyre NR: Tissue hypoxia: Implications for the respiratory clinician. Respir Care 59:1590, 2014. Joseph Loscalzo

Edema PLASMA AND INTERSTITIAL FLUID EXCHANGE Approximately two-thirds of total body water is intracellular and onethird is extracellular. One-fourth of the latter is in the plasma, and the remainder comprises the interstitial fluid. Edema represents an excess of interstitial fluid that has become evident clinically. There is constant interchange of fluid between the two compart­ ments of the extracellular fluid. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid pro­ mote the movement of water and diffusible solutes from plasma to the interstitium. This movement is most prominent at the arterial origin of the capillary and falls progressively with the decline in intracapillary pressure and the rise in oncotic pressure toward the venular end. Fluid is returned from the interstitial space into the vascular system largely through the lymphatic system. These interchanges of fluids are nor­ mally balanced so that the volumes of the intravascular and interstitial compartments remain constant. However, a net movement of fluid from the intravascular to the interstitial spaces takes place and may be responsible for the development of edema under the following condi­ tions: (1) an increase in intracapillary hydrostatic pressure; (2) inad­ equate lymphatic drainage; (3) reductions in the oncotic pressure of plasma; (4) damage to or dysfunction of the capillary endothelial bar­ rier; and (5) increases in the oncotic pressure of the interstitial space. ■ ■REDUCTION OF EFFECTIVE ARTERIAL VOLUME In many forms of edema, the effective arterial blood volume, a param­ eter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by the pooling of blood in the splanchnic veins (as in cir­ rhosis), and by hypoalbuminemia (Fig. 43-1A). As a consequence of this underfilling, a series of physiological responses designed to restore the effective arterial volume to normal are set into motion. A key ele­ ment of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to the development or intensification of edema. ■ ■RENAL FACTORS AND THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal

Low-output heart failure, Pericardial tamponade Constrictive pericarditis ↓Extracellular fluid volume ↓Cardiac output ↓Effective arterial volume Activation of ventricular and arterial receptors Nonosmotic vasopressin stimulation PART 2 Cardinal Manifestations and Presentation of Diseases SNS stimulation ↑Systemic and renal arterial vascular resistance Renal H2O retention Restoration of effective arterial volume A High-output cardiac failure Sepsis Cirrhosis Arteriovenous fistula Pregnancy Arterial vasodilators ↓Systemic vascular resistance ↓Effective arterial volume Activation of arterial baroreceptors SNS stimulation Nonosmotic AVP stimulation ↑Cardiac output ↑Systemic arterial, vascular, and renal resistance Renal H2O retention Maintenance of arterial circulatory integrity B FIGURE 43-1  Clinical conditions in which a decrease in cardiac output (A) and systemic vascular resistance (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. AVP, arginine vasopressin; RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system. (From Annals of Internal Medicine, RW Schrier: Body fluid volume regulation in health and disease: A unifying hypothesis. 113(2):155-159, 1990. Copyright © 1990, American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.) juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its sub­ strate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties,

particularly on the renal efferent arteri­ oles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration frac­ tion raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle. ↓Oncotic pressure and/or ↑capillary permeability The renin-angiotensin-aldosterone system (RAAS) operates as both a hor­ monal and paracrine system. Its activa­ tion causes sodium and water retention and thereby contributes to edema for­ mation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptors enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomeru­ losa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the col­ lecting tubule, further favoring edema formation. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a mod­ erate diuresis in edematous states. Activation of RAAS Renal Na+ retention ■ ■ARGININE VASOPRESSIN (See also Chap. 393) The secretion of arginine vasopressin (AVP) by the posterior pituitary gland occurs in response to increased intracellular osmolar concentration; by stimulat­ ing V2 receptors, AVP increases the reabsorption of free water in the dis­ tal tubules and collecting ducts of the kidney, thereby increasing total body water. Circulating AVP is elevated in many patients with heart failure sec­ ondary to a nonosmotic stimulus asso­ ciated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia. Activation of RAAS Renal Na+ retention ■ ■ENDOTHELIN-1 This potent peptide vasoconstrictor is released by endothelial cells. Its con­ centration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema. ■ ■NATRIURETIC PEPTIDES Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a 3000-Da polypeptide. A high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. A closely related natriuretic peptide (pre-prohormone brain natriuretic peptide [BNP]) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic receptor-A, which

causes (1) excretion of sodium and water by augmenting glomerular filtration, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arteri­ oles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states. Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, these natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edema­ tous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness. Further discussion of the control of sodium and water balance is found in Chap. S1. ■ ■CLINICAL CAUSES OF EDEMA A weight gain of several kilograms usually precedes overt manifes­ tations of generalized edema. Anasarca refers to gross, generalized edema. Ascites (Chap. 53) and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema. Edema is recognized by the persistence of an indentation of the skin after pressure, known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening when dependent edema is greatest. Edema may also be recognized by puffiness of the face (most prominent upon awakening), which is most readily appar­ ent in the periorbital areas owing to relative tissue laxity. ■ ■GENERALIZED EDEMA The differences among the major causes of generalized edema are shown in Table 43-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a large majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions. Heart Failure  (See also Chap. 264) In heart failure, the impaired systolic emptying of the ventricle(s) and/or the impairment of ven­ tricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, TABLE 43-1  Principal Causes of Generalized Edema: History, Physical Examination, and Laboratory Findings ORGAN SYSTEM HISTORY PHYSICAL EXAMINATION LABORATORY FINDINGS Cardiac Dyspnea with exertion prominent—often associated with orthopnea—or paroxysmal nocturnal dyspnea Elevated jugular venous pressure, ventricular (S3) gallop; occasionally with displaced or dyskinetic apical impulse; peripheral cyanosis, cool extremities, low pulse pressure when severe Hepatic Dyspnea uncommon, except if associated with significant degree of ascites; most often a history of ethanol abuse Frequently associated with ascites; jugular venous pressure normal or low; blood pressure lower than in renal or cardiac disease; one or more additional signs of chronic liver disease (jaundice, palmar erythema, Dupuytren’s contracture, spider angiomata, male gynecomastia; asterixis and other signs of encephalopathy) may be present Renal (CRF) Usually chronic: may be associated with uremic signs and symptoms, including decreased appetite, altered (metallic or fishy) taste, altered sleep pattern, difficulty concentrating, restless legs, or myoclonus; dyspnea can be present, but generally less prominent than in heart failure Elevated blood pressure; hypertensive retinopathy; uremic fetor; pericardial friction rub in advanced cases with uremia Renal (NS) Childhood diabetes mellitus; plasma cell dyscrasias Periorbital edema; hypertension Proteinuria (≥3.5 g/d); hypoalbuminemia; hypercholesterolemia; microscopic hematuria Abbreviations: CRF, chronic renal failure; NS, nephrotic syndrome. Source: Reproduced with permission from GM Chertow, E Braunwald, L Goldman (eds). Approach to the patient with edema, in Primary Cardiology, 2nd ed. Philadelphia, Saunders, 2003.

activation of the sympathetic nervous system and the RAAS (see above) acts in concert to cause renal vasoconstriction and reduction of glomerular filtration and salt and water retention. Sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous and intracapillary pressure and resulting in edema (Fig. 43-1).

The presence of overt cardiac disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with clinical evi­ dence of cardiac failure, such as dyspnea, basilar rales, venous disten­ tion, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as electrocardiography, echocardiogra­ phy, and measurements of BNP (or N-terminal proBNP [NT-proBNP]) are helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body. Edema CHAPTER 43 Edema of Renal Disease  (See also Chap. 326) The edema that occurs during the acute phase of glomerulonephritis is characteristi­ cally associated with hematuria, proteinuria, and hypertension. In most instances, the edema results from primary retention of sodium and water by the kidney owing to renal dysfunction. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water. Nephrotic Syndrome and Other Hypoalbuminemic States  The primary alteration in the nephrotic syndrome is a dimin­ ished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine and hypoalbuminemia (<3.0 g/dL). As a result of the reduced colloid osmotic pressure, the sodium and water that are retained cannot be confined within the vascular compartment, and total and effective arterial blood volumes decline. This process initi­ ates the edema-forming sequence of events described above, including activation of the RAAS. The nephrotic syndrome may occur during the course of a variety of kidney diseases, including glomerulonephritis, diabetic glomerulosclerosis, and hypersensitivity reactions. The edema is diffuse, symmetric, and most prominent in the dependent areas; periorbital edema is most prominent in the morning. Hepatic Cirrhosis  (See also Chap. 355) This condition is char­ acterized, in part, by hepatic venous outflow obstruction, which in turn expands the splanchnic blood volume, and hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal sodium retention Elevated urea nitrogen-to-creatinine ratio common; serum sodium often decreased; elevated natriuretic peptides If severe, reductions in serum albumin, cholesterol, other hepatic proteins (transferrin, fibrinogen); liver enzymes elevated, depending on the cause and acuity of liver injury; tendency toward hypokalemia, respiratory alkalosis; macrocytosis from folate deficiency Elevation of serum creatinine and cystatin C; albuminuria; hyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, anemia (usually normocytic)

and causes a reduction of effective arterial blood volume. These altera­ tions are frequently complicated by hypoalbuminemia secondary to reduced hepatic synthesis, as well as peripheral arterial vasodilation. These effects reduce the effective arterial blood volume, leading to activation of the sodium- and water-retaining mechanisms described above (Fig. 43-1B). The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Ini­ tially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system, causing ascites (Chap. 53). In later stages, particularly when there is severe hypoal­ buminemia, peripheral edema may develop. A sizable accumulation of ascitic fluid may increase intraabdominal pressure and impede venous return from the lower extremities, thereby contributing to the accumu­ lation of the edema.

PART 2 Cardinal Manifestations and Presentation of Diseases Drug-Induced Edema  A large number of widely used drugs can cause edema (Table 43-2). Mechanisms include renal vasoconstriction (nonsteroidal anti-inflammatory drugs and cyclosporine), arteriolar dilation (vasodilators), augmented renal sodium reabsorption (steroid hormones), and capillary damage. Edema of Nutritional Origin  A diet grossly deficient in calo­ ries and particularly in protein over a prolonged period may produce hypoproteinemia and edema. The latter may be intensified by the development of beriberi heart disease, which also is of nutritional origin, in which multiple peripheral arteriovenous fistulae result in reduced effective systemic perfusion and effective arterial blood vol­ ume, thereby enhancing edema formation (Chap. 344) (Fig. 43-1B). Edema develops or becomes intensified when famished subjects are first provided with an adequate diet. The ingestion of more food may increase the quantity of sodium ingested, which is then retained along with water. So-called refeeding edema also may be linked to increased release of insulin, which directly increases tubular sodium reabsorp­ tion. In addition to hypoalbuminemia, hypokalemia and caloric defi­ cits may be involved in the edema of starvation. ■ ■LOCALIZED EDEMA In thrombophlebitis, varicose veins, and primary venous valve failure, the hydrostatic pressure in the capillary bed upstream (proximal) of TABLE 43-2  Drugs Associated with Edema Formation Nonsteroidal anti-inflammatory drugs Antihypertensive agents   Direct arterial/arteriolar vasodilators   Hydralazine   Clonidine   Methyldopa   Guanethidine   Minoxidil   Calcium channel antagonists α-Adrenergic antagonists Thiazolidinediones Steroid hormones   Glucocorticoids   Anabolic steroids   Estrogens   Progestins Cyclosporine Growth hormone Immunotherapies   Interleukin 2   OKT3 monoclonal antibody Source: Reproduced with permission from GM Chertow, in E Braunwald, L Goldman (eds): Approach to the patient with edema, in Primary Cardiology, 2nd ed. Philadelphia, Saunders, 2003.

the obstruction increases so that an abnormal quantity of fluid is trans­ ferred from the vascular to the interstitial space, which may give rise to localized edema. The latter may also occur in lymphatic obstruction caused by chronic lymphangitis, resection of regional lymph nodes, filariasis, and genetic (frequently called primary) lymphedema. The latter is particularly intractable because restriction of lymphatic flow results in both an increase in intracapillary pressure and increased protein concentration in the interstitial fluid, which act in concert to aggravate fluid retention. Other Causes of Edema  These causes include hypothyroidism (myxedema) due to tissue deposition of hyaluronic acid; hyper­ thyroidism (pretibial myxedema secondary to Graves’ disease), in which edema is typically nonpitting; hypercortisolism; pregnancy; and administration of estrogens and vasodilators, particularly calcium channel blockers. ■ ■DISTRIBUTION OF EDEMA The distribution of edema is an important guide to its cause. Edema associated with heart failure tends to be more extensive in the legs and to be accentuated in the evening, a feature also determined largely by posture. When patients with heart failure are confined to bed, edema may be most prominent in the presacral region. Edema resulting from hypoproteinemia, as occurs in the nephrotic syndrome, characteristically is generalized, but it is especially evi­ dent in the very soft tissues of the eyelids and face and tends to be most pronounced in the morning owing to the recumbent posture assumed during the night. Less common causes of facial edema include trichinosis, allergic reactions, and myxedema. Edema limited to one leg or to one or both arms is usually the result of venous and/ or lymphatic obstruction. Unilateral paralysis reduces lymphatic and venous drainage on the affected side and may also be responsible for unilateral edema. In patients with obstruction of the superior vena cava, edema is confined to the face, neck, and upper extremities in which the venous pressure is elevated compared with that in the lower extremities. APPROACH TO THE PATIENT Edema An important first question is whether the edema is localized or generalized. If it is localized, the local phenomena that may be responsible should be identified. If the edema is generalized, one should determine if there is serious hypoalbuminemia, e.g., serum albumin <3.0 g/dL. If so, the history, physical examination, uri­ nalysis, and other laboratory data will help evaluate the question of cirrhosis, severe malnutrition, or the nephrotic syndrome as the underlying disorder. If hypoalbuminemia is not present, one should determine if there is evidence of heart failure severe enough to promote generalized edema. Finally, it should be ascertained as to whether or not the patient has an adequate urine output or if there is significant oliguria or anuria. These abnormalities are discussed in Chaps. 55, 321, and 322. ■ ■FURTHER READING Clark AL, Cleland JG: Causes and treatment of oedema in patients with heart failure. Nature Rev Cardiol 10:156, 2013. Frison S et al: Omitting edema measurement: How much acute malnutrition are we missing? Am J Clin Nutr 102:1176, 2015. Koirala A et al: Etiology and management of edema: A review. Adv Kidney Dis Health 30:110, 2023. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle. Cardiovascular Res 87:198, 2010. Telinius N, Hjortdal VE: Role of the lymphatic vasculature in cardiovascular medicine. Heart 105:1777, 2019.