Edema refers to the presence of excess fluid in the body tissues. In most instances, edema occurs mainly in the extracellular fluid compartment, but it can involve intracellular fluid as well.
Two conditions are especially prone to cause intracel-lular swelling: (1) depression of the metabolic systems of the tissues, and (2) lack of adequate nutrition to the cells. For example, when blood flow to a tissue is decreased, the delivery of oxygen and nutrients is reduced. If the blood flow becomes too low to maintain normal tissue metabolism, the cell membrane ionic pumps become depressed. When this occurs, sodium ions that normally leak into the interior of the cell can no longer be pumped out of the cells, and the excess sodium ions inside the cells cause osmosis of water into the cells. Sometimes this can increase intra-cellular volume of a tissue area—even of an entire ischemic leg, for example—to two to three times normal. When this occurs, it is usually a prelude to death of the tissue.
Intracellular edema can also occur in inflamed tissues. Inflammation usually has a direct effect on the cell membranes to increase their permeability, allowing sodium and other ions to diffuse into the interior of the cell, with subsequent osmosis of water into the cells.
Extracellular fluid edema occurs when there is excess fluid accumulation in the extracellular spaces. There are two general causes of extracellular edema: (1) abnormal leakage of fluid from the plasma to the interstitial spaces across the capillaries, and (2) failure of the lymphatics to return fluid from the interstitium back into the blood. The most common clinical cause of interstitial fluid accumulation is excessive capillary fluid filtration.
To understand the causes of excessive capillary filtration, it is useful to review the determinants of capillary filtration discussed in Chapter 16. Mathematically, capillary filtration rate can be expressed as
Filtration = Kf x (Pc - Pif - pc + pif), where Kf is the capillary filtration coefficient (the product of the permeability and surface area of the capillaries), Pc is the capillary hydrostatic pressure, Pif is the interstitial fluid hydrostatic pressure, pc is the capillary plasma colloid osmotic pressure, and pif is the interstitial fluid colloid osmotic pressure. From this equation, one can see that any one of the following changes can increase the capillary filtration rate:
• Increased capillary filtration coefficient.
• Increased capillary hydrostatic pressure.
• Decreased plasma colloid osmotic pressure.
When lymphatic blockage occurs, edema can become especially severe because plasma proteins that leak into the interstitium have no other way to be removed. The rise in protein concentration raises the colloid osmotic pressure of the interstitial fluid, which draws even more fluid out of the capillaries.
Blockage of lymph flow can be especially severe with infections of the lymph nodes, such as occurs with infection by filaria nematodes. Blockage of the lymph vessels can occur in certain types of cancer or after surgery in which lymph vessels are removed or obstructed. For example, large numbers of lymph vessels are removed during radical mastectomy, impairing removal of fluid from the breast and arm areas and causing edema and swelling of the tissue spaces. A few lymph vessels eventually regrow after this type of surgery, so that the interstitial edema is usually temporary.
A large number of conditions can cause fluid accumulation in the interstitial spaces by the abnormal leaking of fluid from the capillaries or by preventing the lymphatics from returning fluid from the interstitium back to the circulation. The following is a partial list of conditions that can cause extracellular edema by these two types of abnormalities: I. Increased capillary pressure
A. Excessive kidney retention of salt and water
1. Acute or chronic kidney failure
2. Mineralocorticoid excess
B. High venous pressure and venous constriction
1. Heart failure
2. Venous obstruction
3. Failure of venous pumps
(a) Paralysis of muscles
(b) Immobilization of parts of the body
(c) Failure of venous valves
C. Decreased arteriolar resistance
1. Excessive body heat
2. Insufficiency of sympathetic nervous system
3. Vasodilator drugs II. Decreased plasma proteins
A. Loss of proteins in urine (nephrotic syndrome)
B. Loss of protein from denuded skin areas
C. Failure to produce proteins
1. Liver disease (e.g., cirrhosis)
2. Serious protein or caloric malnutrition
III. Increased capillary permeability
A. Immune reactions that cause release of histamine and other immune products
C. Bacterial infections
D. Vitamin deficiency, especially vitamin C
E. Prolonged ischemia
IV. Blockage of lymph return
B. Infections (e.g., filaria nematodes)
D. Congenital absence or abnormality of lymphatic vessels
Edema Caused by Heart Failure. One of the most serious and most common causes of edema is heart failure. In heart failure, the heart fails to pump blood normally from the veins into the arteries; this raises venous pressure and capillary pressure, causing increased capillary filtration. In addition, the arterial pressure tends to fall, causing decreased excretion of salt and water by the kidneys, which increases blood volume and further raises capillary hydrostatic pressure to cause still more edema. Also, diminished blood flow to the kidneys stimulates secretion of renin, causing increased formation of angiotensin II and increased secretion of aldosterone, both of which cause additional salt and water retention by the kidneys. Thus, in untreated heart failure, all these factors acting together cause serious generalized extracellular edema.
In patients with left-sided heart failure but without significant failure of the right side of the heart, blood is pumped into the lungs normally by the right side of the heart but cannot escape easily from the pulmonary veins to the left side of the heart because this part of the heart has been greatly weakened. Consequently, all the pulmonary vascular pressures, including pulmonary capillary pressure, rise far above normal, causing serious and life-threatening pulmonary edema. When untreated, fluid accumulation in the lungs can rapidly progress, causing death within a few hours.
Edema Caused by Decreased Kidney Excretion of Salt and Water.
As discussed earlier, most sodium chloride added to the blood remains in the extracellular compartment, and only small amounts enter the cells. Therefore, in kidney diseases that compromise urinary excretion of salt and water, large amounts of sodium chloride and water are added to the extracellular fluid. Most of this salt and water leaks from the blood into the interstitial spaces, but some remains in the blood. The main effects of this are to cause (1) widespread increases in interstitial fluid volume (extracellular edema) and (2) hypertension because of the increase in blood volume, as explained in Chapter 19. As an example, children who develop acute glomerulonephritis, in which the renal glomeruli are injured by inflammation and therefore fail to filter adequate amounts of fluid, also develop serious extracellular fluid edema in the entire body; along with the edema, these children usually develop severe hypertension.
Edema Caused by Decreased Plasma Proteins. A reduction in plasma concentration of proteins because of either failure to produce normal amounts of proteins or leakage of proteins from the plasma causes the plasma colloid osmotic pressure to fall. This leads to increased capillary filtration throughout the body as well as extracellular edema.
One of the most important causes of decreased plasma protein concentration is loss of proteins in the urine in certain kidney diseases, a condition referred to as nephrotic syndrome. Multiple types of renal diseases can damage the membranes of the renal glomeruli, causing the membranes to become leaky to the plasma proteins and often allowing large quantities of these proteins to pass into the urine. When this loss exceeds the ability of the body to synthesize proteins, a reduction in plasma protein concentration occurs. Serious generalized edema occurs when the plasma protein concentration falls below 2.5 g/100 ml.
Cirrhosis of the liver is another condition that causes a reduction in plasma protein concentration. Cirrhosis means development of large amounts of fibrous tissue among the liver parenchymal cells. One result is failure of these cells to produce sufficient plasma proteins, leading to decreased plasma colloid osmotic pressure and the generalized edema that goes with this condition.
Another way that liver cirrhosis causes edema is that the liver fibrosis sometimes compresses the abdominal portal venous drainage vessels as they pass through the liver before emptying back into the general circulation. Blockage of this portal venous outflow raises capillary hydrostatic pressure throughout the gastrointestinal area and further increases filtration of fluid out of the plasma into the intra-abdominal areas. When this occurs, the combined effects of decreased plasma protein concentration and high portal capillary pressures cause transudation of large amounts of fluid and protein into the abdominal cavity, a condition referred to as ascites.
tissues with relatively small additional increases in interstitial fluid hydrostatic pressure. Thus, in the positive tissue pressure range, this safety factor against edema is lost because of the large increase in compliance of the tissues.
Even though many disturbances can cause edema, usually the abnormality must be severe before serious edema develops. The reason for this is that three major safety factors prevent excessive fluid accumulation in the interstitial spaces: (1) low compliance of the inter-stitium when interstitial fluid pressure is in the negative pressure range, (2) the ability of lymph flow to increase 10- to 50-fold, and (3) washdown of interstitial fluid protein concentration, which reduces interstitial fluid colloid osmotic pressure as capillary filtration increases.
Safety Factor Caused by Low Compliance of the Interstitium in the Negative Pressure Range
In Chapter 16, we noted that interstitial fluid hydrostatic pressure in most loose subcutaneous tissues of the body is slightly less than atmospheric pressure, averaging about -3 mm Hg. This slight suction in the tissues helps hold the tissues together. Figure 25-7 shows the approximate relations between different levels of interstitial fluid pressure and interstitial fluid volume, as extrapolated to the human being from animal studies. Note in Figure 25-7 that as long as the interstitial fluid pressure is in the negative range, small changes in interstitial fluid volume are associated with relatively large changes in interstitial fluid hydrostatic pressure. Therefore, in the negative pressure range, the compliance of the tissues, defined as the change in volume per millimeter of mercury pressure change, is low.
How does the low compliance of the tissues in the negative pressure range act as a safety factor against edema? To answer this question, recall the determinants of capillary filtration discussed previously. When interstitial fluid hydrostatic pressure increases, this increased pressure tends to oppose further capillary filtration. Therefore, as long as the interstitial fluid hydrostatic pressure is in the negative pressure range, small increases in interstitial fluid volume cause relatively large increases in interstitial fluid hydrostatic pressure, opposing further filtration of fluid into the tissues.
Because the normal interstitial fluid hydrostatic pressure is -3 mm Hg, the interstitial fluid hydrostatic pressure must increase by about 3 mm Hg before large amounts of fluid will begin to accumulate in the tissues. Therefore, the safety factor against edema is a change of interstitial fluid pressure of about 3 mm Hg.
Once interstitial fluid pressure rises above 0 mm Hg, the compliance of the tissues increases markedly, allowing large amounts of fluid to accumulate in the
Importance of Interstitial Gel in Preventing Fluid Accumulation in the Interstitium. Note in Figure 25-7 that in normal tissues with negative interstitial fluid pressure, virtually all the fluid in the interstitium is in gel form. That is, the fluid is bound in a proteoglycan meshwork so that there are virtually no "free" fluid spaces larger than a few hundredths of a micrometer in diameter. The importance of the gel is that it prevents fluid from flowing easily through the tissues because of impediment from the "brush pile" of trillions of proteoglycan filaments. Also, when the interstitial fluid pressure falls to very negative values, the gel does not contract greatly because the meshwork of proteoglycan filaments offers an elastic resistance to compression. In the negative fluid pressure range, the interstitial fluid volume does not change greatly, regardless of whether the degree of suction is only a few millimeters of mercury negative pressure or 10 to 20 mm Hg negative pressure. In other words, the compliance of the tissues is very low in the negative pressure range.
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