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ON THE CAUSATION OFEDEMA: A LYMPHOLOGIC PERSPECTIVE CHARLES L. WITTE and MARLYS H. WITTE* Edema in all conditions represents an imbalance between lymph formation and lymph absorption. —Ernest Starling. In a recent issue of Perspectives in Biology and Medicine, A. R. Micheli addresses one of the most intriguing pathophysiologic problems, namely regulation of sodium balance and the development of edema [I]. He examines the paradoxes and confusion surrounding the terms plasma volume "underfill" and "overflow," as well as the role of the kidney in several perplexing clinical conditions including congestive heart failure, nephrosis , hepatic cirrhosis especially with ascites, and pregnancy, with special emphasis on the utility of the indeterminate term "effective plasma volume." After a lengthy discourse, Micheli concludes that the latter term obfuscates rather than clarifies, inhibits rather than stimulates original ideas, and, because of its nebulous pseudo-scientific overtone, should properly be dropped from medical usage. The Law ofEdema Whereas many of the points presented in the above article are cogent, Micheli, like many other investigators of salt and water balance over the past century, has underestimated or overlooked a fundamental physiologic truth, namely that sodium does not in itself initiate edema/effusion. Instead , sodium retention is an aggravator, albeit the sine qua non ofprogressive expansion of the interstitial fluid compartment. As we shall make clear, * Department ofSurgery, The University ofArizona College ofMedicine, Tucson, AZ 85724.© 1997 by The University of Chicago. All rights reserved. 0031-5982/97/4101-1038$01.00 86 Charles L. Witte and Marlys H. Witte ¦ Causation of Edema physiologie derangements originating in the adrenal gland, brain, heart, or kidney typically are secondary events in the formation and perpetuation of edema or effusion. Exactly 100 years ago, E. H. Starling, after a series ofepochal experiments designed to understand the formation of lymph, proposed a simple formulation usually termed the "Law of Edema," which has withstood repeated scrutiny for over a century [2-4] . Nowadays, this ' 'Law' ' is usually expressed AIFV = /Kr(Pc - P1) - s(p? - p?) - /Q1. where AIFV = change in interstitial fluid volume; Kf = capillary filtration coefficient, incorporating microvessel porosity and surface area for microvascular exchange; Pc = capillary hydrostatic pressure; Pt = tissue hydrostatic pressure; s = solute reflection coefficient; p? = plasma protein osmotic (oncotic) pressure; p, = tissue protein osmotic (oncotic) pressure; and QL = lymph flow [5]. The expression [Kf(Pc — P1) — s(p? — p,)] describes the microcirculatory forces and barrier characteristics that govern net capillary filtration or lymph formation, and Q, represents the volume of lymph exiting from the tissues and returning to the bloodstream per unit time. The nature of the blood capillary exchange barrier both in terms of permeability (P) and surface area (S) or the PS product influences the rate and composition of liquid filtered in each organ system, whereas the "leakage" of macromolecules is regulated in addition by the hydraulic conductivity or pressure in the microvessels (i.e., convection) and the solute concentration gradient (i.e., diffusion) [6] . Nonetheless, edema, or more precisely AIFV, invariably reflects an imbalance between the rate of lymph formation and the rate of lymph absorption. Nowhere in this time-honored formulation is the sodium ion per se specifically mentioned, although it is implicit that AIFV, albeit regulated by the above formulation, represents a shift in the partition of extracellular fluid, the constituency of which is primarily water along with sodium and chloride ions. Edema Safety Factors In enunciating the transcapillary fluid exchange hypothesis, Starling recognized that minor alterations in any one ofthe hydrodynamic forces alone would be unlikely to promote edema. As he expressed it, The organism has various powers of accommodating itself to changing conditions in the lymphatic apparatus so that it is in most situations difficult to upset the normal balance, that is to cause dropsy [edema and effusion] , by altering only one of the factors unless the alteration be of a very extreme degree. In nearly all cases we Perspectives in Biology and Medicine, 41, 1 ¦ Autumn 1997 | 87 shall find that dropsy is due to the simultaneous alteration of two or more of these factors and finally to a failure of the lymph circulation to continue to handle the tremendous volume of fluid. For example, a rise in filtration rate as...

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