Formation of Edema Fluid
Edema formation can be understood by consideration of the Starling forces across the microvessel wall. The mathematical relationship between fluid filtration rate (Jv) and transmural hydrostatic and oncotic pressures is written as
Jv = LPS[(Pc - p)-o(nc -n,)], where s is the osmotic reflection coefficient, S the vessel surface area, Lp the hydraulic conductivity, P the capillary hydrostatic pressure, n the oncotic pressure, and the subscripts c and i, capillary and interstitial compartments. The
Underlying Causes of Edema Fluid Formation: Role of Starling Forces
An elevated net driving pressure without a marked increase in permeability underlies "pressure edema" (i.e., edema resulting from increase in the pulmonary capillary hydrostatic pressure). Hydrostatic edema, when it is not associated with frank barrier breakdown, is generally protein-poor, at least in early stages of the syndrome, because the barrier properties tending to exclude large molecules are preserved. in hydrostatic edema the ratio of plasma to alveolar fluid protein concentration is usually less than 0.6. Critical capillary pressure for formation of edema due strictly to elevated hydrostatic pressure is a Pc above 25 mmHg. Fluid accumulation in the lung is minimized by "safety factors" that are activated below this critical capillary pressure (see later discussion). The pulmonary extravascular water content increases progressively as a result of the inability of these safety factors to reduce fluid filtration rate when capillary hydrostatic pressure increases above the critical value. Most clinical manifestations of pulmonary edema can be understood in terms of changes in Starling forces through pulmonary microvessel walls. A decrease in the plasma protein concentration, such as in hypoalbuminemia, reduces the transmural oncotic pressure difference, thus favoring increased fluid filtration. In this case, the critical capillary pressure at which lungs begin to gain water decreases in direct proportion to the reduction in plasma oncotic pressure.
Causes of Lung Edema: Increased Vascular Permeability
Barrier rupture or breakdown underlies "permeability edema," which creates a protein-rich fluid because of the loss of normal protein-excluding properties of the alveolar-capillary barrier. Some evidence suggests that stimulation of protein transport could make a contribution to formation of protein-rich edema fluid. For example, a vigorous transcellular albumin transport process involving vesicular carriers is well established in pulmonary microvascular endothelial cells . These carriers are predominantly caveolae that occupy a remarkably high percentage (15%) of the endothelial cell volume. An important area of investigation is whether pathologic conditions can substantially stimulate this active transport process leading to secretion of a protein-rich edema fluid.
Lung vascular permeability can increase as a result of a direct injury of endothelial cells, alterations in the dimensions of interendothelial junctions (i.e., paracellular pathways), or a combination of these factors . The increase in lung vascular permeability is operationally defined in the Starling equation by an increased capillary filtration coefficient (KfiC), which is equivalent to the LpS term in the equation. An increase in the Kf c value corresponds to decreased barrier resistance to the movement of liquid across the capillary wall barrier. The albumin reflection coefficient (fAlb), which describes the albumin permeability of the vascular endothelial barrier, provides a widely used measure of the protein permeability of the barrier. In high-permeability pulmonary edema, the alveolar fluid protein concentration approximates the plasma protein concentration. The increase in lung vascular permeability shifts the relationship between left atrial pressure and pulmonary extravascular water content toward lower pressures, indicating that edema will occur at a reduced driving pressure in the face of an increased vascular permeability.
Causes of Pulmonary Edema: Role of the Lymphatic System
Lymphatics are capable of removing excess extravascu-lar fluid because of their effectiveness as a pump. Lymphatic propulsion is determined by the intrinsic contractility of lymphatic vessels, by inspiration and expiration, and by unidirectional lymphatic valves. The extent to which lymphatic insufficiency serves as an important mechanism of fluid accumulation in the lung is not clear. Some studies have indicated that surgical removal of the lymphatics predisposes lung to edema, although the increase in water content is usually transient.
Newly formed edema fluid initially distends the interstitial compartment and then disrupts the interstitial lattice; proteolysis of interstitial structural proteins may occur, leading to increased interstitial compliance . Fluid that cannot be cleared by lymphatics accumulates in the connective tissue surrounding smaller vessels and bronchioles. The fluid then migrates down the interstitial fluid pressure gradient to interstitial spaces around larger vessels and airways. If lymphatics in the connective tissue sheaths are unable to remove the excess fluid, undrained fluid becomes compartmentalized and forms perivascular cuffs. Normally the interstitial hydrostatic pressure in the lung is a negative value (-9mmHg; ). Because of the low interstitial compliance, excess fluid accumulation within the interstitium will rapidly increase tissue pressure to slightly positive values. The alveolar barrier breaks down at a pressure of 2 mmHg, corresponding to an increase in the interstitial fluid volume of 35 to 50 percent; tissue pressure values above this threshold will cause a precipitous alveolar edema during which individual alveoli begin to flood in an all-or-nothing manner. Initially, the distribution of alveolar flooding is patchy, but rapid severe flooding follows this. The exact route by which fluid moves into the alveoli is not known. Fluid movement may involve bulk flow through large epithelial pores or channels or may be the result of increased transport through intercellular pathways in respiratory epithelium of terminal bronchioles. There is also the possibility of epithelial injury involving detachment of epithelial cells from the underlying matrix, resulting in movement of fluid directly into the alveoli.
Resolution of pulmonary edema involves both removal of already accumulated fluid and protein from alveoli and termination of the conditions causing edema. Mechanisms governing edema resolution following lung injury are poorly understood. A restructuring of the dilated pulmonary interstitium following the degradation of matrix proteins appears to be required. Stimulation of transport processes that drive fluid and protein from distal alveolar epithelium including the (Na, K)-ionic pump  and albumin transport  may be critical removal processes.
Role of "Safety Factors" in Lung Fluid Homeostasis
Several safety factors protect the lung against edema; these are the decrease in albumin exclusion volume, the lymphatic system, and the increase in interstitial hydrostatic pressure.
In high-pressure edema, protein-poor fluid begins to accumulate in the pulmonary interstitial space by ultrafiltration. A decrease in the exclusion volume for albumin (or an increase in its actual volume of distribution) becomes important in decreasing the interstitial protein concentration and thereby decreasing pc. Such a decrease in pc, according to the Starling equation, further reduces net fluid filtration and augments fluid reabsorption through pulmonary microvessel walls.
The pulmonary lymph flow is capable of increasing by a large factor in response to increased interstitial fluid volume. Lymph flow is actually dependent on the interstitial pressure, which in turn is a function of interstitial volume and compliance. Beyond a critical fluid volume, pulmonary lymph flow can no longer increase in proportion to the increase in interstitial pressure. Until this saturation value is attained, lymphatic drainage tracks the rate of edema fluid formation and thereby limits fluid accumulation.
An increase in tissue pressure also represents the lung's short-term protective mechanism to limit edema formation. The low interstitial compliance in the lung reflects an unusually low interstitial volume plus a rigid protein infrastructure. This means that pulmonary tissue pressure (P) undergoes a large rise for a relatively small increase in interstitial volume; such an increase in Pt favors fluid reabsorption, according to the Starling equation, and in this sense qualifies as an important safety factor.
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