Oedema

Oedema (oedema), accumulation of watery fluid (transudate) in tissues (see Dropsy). Oedemas can be local or general, widespread (see Anasarca). The composition of the watery fluid (see Transudate) varies considerably in different cases of O., especially in protein content (min. 0.1, max. up to 4.5-5%); salt content averages about 0.7%; impurities of products of tissue metabolism or cell breakdown (especially in inflammatory oedema) are common—mucin, leucine, cholesterol, hemoglobin, urobilin; specific gravity of oedema fluid 1.007-1.013; pH=7.35-5.9 (Scha&e). The site of predominant accumulation of oedema fluid is connective tissue, the spaces between its structural elements. In addition to the free transudate located in the intertissue spaces, a large amount of oedema fluid is always physically and chemically bound by the tissues, causing them to swell. Signs of O.: increase in tissue volume, pallor, decreased elasticity, doughiness, cooling, increased gloss of the surface (serous membranes, skin, brain substance incision, etc.), exudation of a large amount of watery fluid from the surface of the incision. Microscopically, in O. of connective tissue, the connective tissue fibers are pushed apart by oedema fluid, split into fibrils, often with dilation of lymphatic vessels; in long-lasting O. in addition, swelling of connective tissue fibers, maceration and disappearance of fibrils, swelling and vacuolization of connective tissue cells, as well as epithelial and muscle cells, and various kinds of degenerative and atrophic changes are observed. In long-lasting O., proliferation and sclerosis of connective tissue may occur, but these do not reach a severe degree of development (except in cases partly associated with O. such as elephantiasis and scleroderma). The oedema fluid, like normal tissue lymph, originates from the blood by the passage of plasma components (mainly water and salts—with greater or lesser admixture of protein) through capillary walls into the tissues. The basic mechanism of O. development lies in the disturbance of the normal quantitative relationships between lymph formation (transudation) and lymph outflow, with the predominance of the former over the latter; as a result, lymph fluid (tissue lymph, transudate) accumulates in the tissues. In the vast majority of cases, O. does not result from difficulty in lymph outflow through lymphatic pathways (the latter are always very richly developed, moreover lymph always drains away through veins, being absorbed at their origins), but from increased formation of transudate and its retention in the tissues, which bind water during their swelling. Difficulty in outflow through lymphatic pathways plays a secondary role in the origin of O.; only when very many lymphatic pathways are obstructed (e.g., by tumor cells, in inflammatory changes) can O. arise on this basis. However, it has been experimentally proven that obstruction of lymphatic drainage pathways promotes the development of oedema and prevents the absorption of oedema fluid (Notkin) (see also path.-hist. investigations by Recklinghausen, Klebs, Ziegler, Bauer). The primary importance for the development of O. belongs to the processes of water distribution and retention in tissues (in connection with mechanical factors and the ratio of proteins and electrolytes—see below); therefore O. is also considered from the standpoint of disturbance of water balance in tissues with predominance of water inflow over outflow, i.e., water retention in tissues due to both local and general factors affecting water metabolism. Hence, the immediate factors leading to the development of O. can be purely schematically divided into local (tissue) and general (disorders of water metabolism throughout the body). A. Local (tissue) factors. Disturbance of each of the physical, resp. physical-chemical factors that normally determine the movement of fluid in the direction from capillaries through their walls and through tissues to the draining lymph pathways, or more often simultaneous disturbance of several of these factors can lead to O. The following types of these factors are distinguished: 1. Mechanical factors; their importance was emphasized on the basis of the mechanical (filtration) theory of lymph formation by Ludwig (C. Ludwig), which attributed the main role in the origin of lymph to the mechanical pressure of blood in capillaries. Landerer, Reichel, Korner, Klemensiewicz and others pointed out that along with the pressure in capillaries, the influence of tissue counter-pressure, resp. tissue lymph, must also be taken into account. Sometimes O. arises mainly in connection with a decrease in mechanical tissue pressure, e.g., due to breakdown of tissue elements or their atrophy (O. of the soft meninges in brain atrophy). Such O. are called oedema ex vacuo (by analogy with hydrops ex vacuo). The significance of the difference in mechanical pressures inside and outside capillaries for the origin of O. follows mainly from observations of congestive O. By experiments of Ludwig and Thorns (ligation of plexus pampiniformis), Cohnheim and Lichtheim, Voit and Andrei (clamping of sin. coronar. cordis), the direct connection between venous congestion and O. has been shown very convincingly. The absence of O. after ligation of any vein is explained b. c. by the rapid restoration of blood outflow through collaterals, which the venous system is so rich in. Obstruction of numerous veins in a limb (e.g., introduction of plaster into them—Sotnitsky), application of an elastic tourniquet (after bringing out the main artery) always leads to O. O. development is especially promoted by venous congestion when the vasoconstrictor nerves are excluded, as well as any additional irritating effects on the congested tissues: chemical, thermal, etc. The fact of a sharp increase in lymph outflow from ductus thoracicus in case of obstruction of the right atrium and from the femoral lymph trunk in case of ligation of the femoral vein with certainty speaks for the direct dependence of increased lymph formation on venous congestion. The significance of mechanical factors for increased transudation is also evident from experiments by Hess and Erb, who found blood thickening after injection of adrenaline (due to increased transudation under the influence of increased blood pressure). However, the results of these experiments were later interpreted differently: blood thickening occurred due to increased secretion of various glands. More convincing are the experiments of Magnus—increase in the percentage of Hb in the blood after blood transfusion due to increased blood pressure (including in capillaries) and increased transudation of fluid from vessels into tissues. With other effects leading to a sharp increase in blood pressure (clamping of the aorta, strangulation), no blood thickening is observed (Ascher). In general, an increase in the difference in mechanical pressures between capillaries and tissue is only one of the factors leading to O.; it plays the main role only in the origin of the so-called mechanical O., which occur in venous congestion. Against the exclusive significance of the mechanical factor in the origin of O. in general speaks the following: a) an increase in blood pressure in capillaries alone, e.g., in arterial hyperemia, usually does not lead to O., although lymph formation is then increased (Pashutin, Rogovich, Klemensiewicz, Ostroumov); b) no complete parallelism between the amount of transudate and the degree of pressure increase in capillaries is noted (Starling); c) O. are observed in which the pressure in capillaries is not increased (e.g., cachectic O.). 2. The osmotic factor, whose importance was emphasized by Coranyi, Cohnstein, Schade, Burger and Baur and others, consists in an increase in the existing difference in osmotic pressures between blood (Δ=0.56-0.58°) and tissue lymph (Δ≈0.62°). An example of increased transudation with increased difference in osmotic pressures is the experiment with introduction of a hypertonic NaCl solution into the abdominal cavity: first there is an increase in the amount of fluid in the latter and equalization of osmotic concentrations of the introduced fluid and blood, and only then absorption of the fluid. An increase in osmotic concentration of tissue lymph occurs with increased tissue metabolism, when larger (e.g., protein) molecules break down into smaller ones, which occurs especially in toxic and inflammatory O. In the latter case, osmotic pressure in the tissue can reach Δ=1.4° (Schade). Furthermore, an increase in osmotic pressure in tissues occurs with retention of salts in the body, especially chlorides (Wallgren), to which some attribute important significance in the pathogenesis of renal O. An increase in osmotic pressure corresponding to a decrease in freezing point by 0.1° is equivalent to an increase in mechanical pressure by more than 1 atmosphere. However, in the process of transudate formation in O., only a small part of this pressure is significant, because the capillary wall cannot be fully equated to a semipermeable membrane: it is permeable not only for water but also for many substances dissolved in it (Schade).

Some manifestation of osmotic forces (as in the case of a semipermeable membrane) occurs only because, when passing through the vessel wall membrane, many molecules and ions experience delay depending on their size and electrical charge, resp. on the properties and charge of the membrane itself. What significance the particular case of osmotic membrane equilibrium known as Donnan's equilibrium has in the origin of edemas remains unclear; Schade denies the importance of this factor in the genesis of O., attributing to it only some role in the distribution of electrolytes between the blood and tissues. 3. Oncotic factor. The greater part of water in the organism is bound with colloids, both dense and liquid. Of particular importance for water retention is the ability of connective tissue to swell, which in the organism acts as a huge depot of water and substances dissolved in it. In normal conditions, connective tissue never exists in a state of maximum possible swelling for it. This is counteracted by the considerable swellability of colloids of other tissues and especially of the blood, as well as the mechanical tension of the tissues. If the total mass of connective tissue in a lean young subject amounts to about 10 kg, then its swelling by just 10% already gives a water retention equal to 1 liter (Schade). The ability of connective tissue to swell depends on the concentration of H- and OH-ions and on the concentration of electrolytes (the degree of swelling in salt solutions is subject to the distribution of the latter in the Hofmeister series of anions). According to Schade, the ability to swell is different in the cells of connective tissue, its fibers, and the intermediate ground substance. Within certain limits of concentration of H- and OH-ions, even antagonistic fluctuations in the degree of swelling of these constituent elements of connective tissue are observed. The force with which water is bound by the colloids of connective tissue during their swelling is measured by the pressure necessary for squeezing water out of them and is denoted by the term 'oncotic' pressure. Fischer (M. N. Fischer), the first to emphasize the importance of tissue swelling in the pathogenesis of O., explained it by increased tissue acidity. This theory is based on observations of the increased swelling of gelatin and fibrin in acidic media. Similarly, the tissues of the organism (e.g., the eyeball, frog legs) also show particularly marked swelling in acidified isotonic solutions. A marked O. can be obtained on the legs of frogs deprived of circulation by ligation with a ligature, if the frog remains in water. From this Fischer concludes that the phenomenon of O. is not connected with circulation, but depends only on the impregnation of tissues with water. Acid products in the tissues, promoting swelling and leading to O., are formed, according to Fischer, partly due to toxic disintegration and partly on the basis of venous stasis. Fischer's theory has been subjected to sharp criticism and in its main positions proved to be incorrect. From the side of pathologists (Marchand, Dietrich) it was objected that in O. not only tissue swelling occurs, but mainly the accumulation of fluid in the intertissue spaces. Furthermore, Fischer completely failed to take into account the oncotic (colloid-osmotic) pressure of blood colloids (equal to 2.5 cm of mercury in normal conditions), which has an effect directly opposite to the oncotic pressure of tissues, i.e., preventing transudation. In Fischer's experiments there was actually the imbibition of dead tissues with water, not comparable with the phenomena of O., since the properties of tissue colloids after cessation of circulation are sharply disturbed. In diabetic acidosis, from Fischer's point of view, a marked development of O. should be expected, which in reality does not occur. Finally, direct observations (Schade and colleagues) show that tissue swelling in O. is not connected with the accumulation of acid products in them: determination of pH in edematous fluid did not reveal an increase in its acidity (except in cases of inflammatory O.). According to Schade's data, connective tissue with increased acidity within limits possible for cell life (pH=7.35-5.9) does not show increased swelling, on the contrary, it shows a decrease in swelling. Fischer did not take into account that the collagen fibers of the cell and the intermediate substance of connective tissue have different optimum swelling, lying in different pH ranges. He also did not consider the effect on tissue swelling of the concentration of other ions. Despite these objections, Fischer's merit is very great: he was the first to emphasize the importance of tissue colloids swelling as a factor of enormous importance in the pathogenesis of O. That this property of colloids has great significance also under conditions of the organism is shown, for example, by Engels' experiments: before visible O. develops, the tissues already contain water in much greater quantity than in normal conditions. Every 'manifest' O. is preceded by a stage of 'latent' O., when due to the ability of tissues to swell, water transuding from the vessels is absorbed by the tissues. Since in normal conditions connective tissue does not reach the limit of its swelling (has a 'swelling deficit' - Schade), it greedily absorbs water when the latter passes in increased quantity from vessels to tissues and retains it. This phenomenon occurs especially in the formation of protein-poor transudates: they are at first entirely absorbed by the tissues until the latter reach the limit of their swelling. Therefore, all types of O., according to Schade, in the first stage represent 'oncotic' O. Only when the tissues reach the limit of swelling does, in case of continuing increased transudation, the accumulation of free fluid in the intertissue spaces begin, i.e., latent O. passes into 'manifest' O. All O. of truly oncotic origin can be divided into two groups: a) O. occurring due to increased oncotic pressure in the tissues (e.g., alkaline O.), and b) O. due to decreased oncotic pressure of blood colloids (e.g., renal O.); of course such a division is very schematic, since it does not cover the entire sum of factors having significance in the pathogenesis of O. An increase in the swelling of connective tissue as a primary cause leading to O. is observed mainly in two cases: a) under the influence of certain electrolytes promoting swelling, and b) in the formation or deposition in the tissue of easily swelling substances. Among the O. caused by tissue swelling under the influence of electrolytes, alkaline O., edema from iodine salts, and edema from NaCl (Kochsalzoedeme in children) should be noted. A direct relationship exists between the amount of electrolytes introduced and the degree of O. (Schade). Alkaline O. often gives an increase in tissue volume of 100-200%. It develops especially frequently in diabetics when they are treated with large amounts of soda. Some believe that alkaline, as well as salt, O. arise due to the ability of Na-ions to retain water (E. Pfeiffer). Water retention when soda is introduced (20-30 g Natr. bicarbon. daily) is also observed in healthy individuals, although usually O. does not develop in this case. - To the O. arising due to the formation or deposition in connective tissue of easily swelling substances belong inflammatory O. (see below) and O. in myxedema. The action of the oncotic factor in the form of swelling of tissue colloids in the occurrence of O. is counteracted by the oncotic pressure of blood colloids. The occurrence of truly oncotic O. depends on the disturbance of equilibrium between the oncotic pressures of tissue colloids and blood colloids. 4. Factor of vessel wall damage has been particularly emphasized by Köngheim, Eppinger, Volhard. The significance of this factor is already evident from the experiments of Köngheim and Lichtheim: despite the marked thinning of the blood caused by the introduction of enormous amounts of physiol. solution into the bloodstream, phenomena of O. do not occur (except for a slight edema of certain vascular areas, e.g., retroperitoneal tissue, intestinal walls, where capillary permeability is greater than in other places). Only the addition of local irritation damaging the capillary walls causes O. under these conditions. The introduction of certain toxic substances into the bloodstream directly causes O. due to damage to the capillary walls (e.g., introduction of AgNO3 causes O. of the lungs). The oncotic pressure of blood colloids can prevent transudation from vessels only as long as their wall membrane is impermeable to blood proteins. If it becomes permeable to them ('membrano-genic hypoonkia' - Schade), the equilibrium of oncotic pressures between blood and tissue colloids is disturbed, and increased transudation is established. A sign of membrano-genic hypoonkia is therefore the significant protein content in the edematous fluid (e.g., in glomerulonephritis). Damage to the vessel wall as one of the causes of O. occurs in many types of O. and is caused partly by changes in the physicochemical structure of the vessel wall membrane (in particular its swelling) and partly by its stretching (e.g., in venous stasis). All the factors considered usually act in the origin of O. in a complex combination with each other. There is no single common cause for the occurrence of all O.

Under normal conditions, the three types of pressure (mechanical, osmotic, oncotic) acting on both sides of the vascular walls balance each other. There may also be mutual balancing between individual types of these pressures (e.g., oncotic pressure with osmotic pressure). Usually, in individual cases of O., the disruption of one of these pressure equilibriums is of primary importance, but all other types of pressure more or less participate in the origin of O. Therefore, all O. can only be schematically divided according to the nearest mechanism of their occurrence into mechanical, osmotic, and oncotic O. (Shade). In recent years, Shade and his colleagues, in experiments with models of capillaries made from colloidal membranes, have studied in more detail the influence of certain combinations of factors on the occurrence of transudate. When an isotonic solution containing no colloids is passed through such capillaries under a certain pressure, fluid exits through the wall along the entire length of the capillary. This "transudation" occurs to the greatest degree at the afferent ("arterial") end of the capillary, i.e., where the lateral mechanical pressure of the fluid being passed is greatest. Other relationships are obtained when a fluid containing colloids is passed through the same capillary. In this case, "transudation" (dialysis) does not occur along the entire length of the capillary, but only in the afferent segment, where the lateral pressure of the fluid being passed is sufficiently high to overcome the reverse influence of the colloids contained in it: the latter, due to the oncotic pressure they develop, attract fluid from the surrounding environment (which contains no colloids) in which the capillary is immersed. As the intracapillary mechanical pressure gradually decreases, the oncotic pressure of the colloids in the fluid being passed takes precedence, and at the efferent end of the capillary, a current of fluid is established not from its lumen into the surrounding environment, but conversely, from the latter into the capillary lumen, i.e., not transudation but reverse absorption of fluid occurs. The higher the mechanical pressure in the capillary lumen, the greater the extent of its length, starting from the afferent end, at which transudation occurs, and the extent at which reverse absorption occurs is correspondingly shortened. Conversely, the greater the oncotic pressure of the fluid being passed at the same mechanical pressure, the greater the extent at which reverse absorption occurs. Similar relationships apparently also exist in the body's capillaries: if an isotonic fluid without colloidal impurities is passed through isolated limbs, after a certain time, a sharp O. of the tissues occurs; if then a fluid containing colloids is passed under the same pressure, the O. not only does not progress further, but the edematous fluid that has already accumulated in the tissues undergoes reverse absorption (Starling's experiments).-As an additional factor in the pathogenesis of edema, gravity sometimes plays a role. For example, the excretion of lymph from the thoracic duct in a dog varies depending on the position of the body, decreasing when the animal is in a vertical position with the head upward and increasing in the opposite position. The development or intensification of O. in the lower extremities is observed under the influence of gravity in humans as well, especially with relative insufficiency of cardiac activity leading to venous congestion. B. General factors influencing the occurrence of O. by disrupting the overall water balance in the body. In this regard, the function of the kidneys as an excretory organ for water and salts stands first (see below). Among the endocrine organs, the thyroid gland has particularly important significance in the pathogenesis of O. The role of its insufficiency is particularly evident in myxedematous O. (see Myxedema), in which there is retention of a large amount of water in the tissues. It has been experimentally proven that the excretion of water sharply increases when thyroid preparations are administered and decreases after thyroidectomy. In various types of O., the administration of thyroidine has a very favorable therapeutic effect (Eppinger). Eppinger explains this influence by an increase in tissue metabolism leading to impoverishment of the tissue fluid in protein, as a result of which the oncotic pressure in the tissues decreases and reverse absorption of fluid into the capillaries occurs.-The significance of the pituitary gland (see) in the pathogenesis of O. is taken into account insofar as its influence on water and salt exchange has been proven. The main importance in these processes probably belongs to the vegetative exchange centers of the gray tubercle area. According to Zondek (H. Zondek), the endocrine function of the ovaries also plays a certain role in regulating water balance and in the origin of O.: thus, in many pregnant women in the last months, water retention in the tissues is observed, sometimes even edema. In general, endocrine influences, as well as neuro-vegetative ones, mostly do not directly cause O., but create a certain tendency of tissues to retain water (Oedem-bereitschaft), acting either on tissue metabolism or on kidney function. From this point of view, the tendency to retain water in tissues in many cases of general obesity should probably also be explained. The factors discussed, which directly lead to the development of O. by disrupting water equilibrium between blood and tissues, in turn arise under the influence of more distant general causes. Accordingly, several clinical forms of O. are distinguished: 1. Mechanical, or congestive, O. arise due to local or general venous congestion (e.g., with weakness of cardiac activity). Among the immediate factors, the main importance here belongs to the increase in blood pressure in the capillaries due to transmission of the increased pressure from the veins. As a result, there is an intensification of fluid filtration from the blood into the tissues. However, this is not the only factor causing increased transudation in venous congestion. At the same time, difficulty in the outflow of transudate from the tissues also always occurs. The latter drains from the tissues not only through lymphatic vessels, but to an even greater extent through veins, being absorbed into the beginnings of veins and venous capillaries (see above). The importance of veins for the outflow of lymph from tissues was experimentally proven by Asher, Starling, and Tubby and others: after cutting all tissues of the hind limb in a dog (including lymphatic pathways), while the limb remains connected to the trunk only via the main artery and vein, subcutaneous injection of dye is accompanied by its rapid appearance in the general bloodstream, hence absorption of the dye through the vein occurs. Besides the mechanical factor, in the origin of congestive O., the increased permeability of capillary walls due to stretching (Krogh) and damage to their walls ("asphyxiant" damage-Shade) is always of importance. In the initial stages of congestive O., mechanical factors are of almost exclusive importance, as the vascular walls are not yet damaged at this time (Klemensevich), which is also evident from the composition of the edematous fluid, which contains almost no protein [0.025-0.062% (Haas)]. In the subsequent stages of congestive edema, damage to the capillary wall always joins to a greater or lesser degree, and the amount of protein in the edematous fluid increases to 0.4-0.8% or more (Beckmann, Haas). General congestive edema can be obtained experimentally by causing chronic pericarditis and thereby hindering the work of the heart (Voigt). In humans, very severe general O. occur especially with weakness of the right heart or with difficulty in blood access to it. Schott (E. Schott) showed that before the development of O. in cardiac patients with insufficient compensation, there is always an increase in venous pressure (by 5-12 cm of water column). Such an increase in venous pressure is quite sufficient to cause transudation of fluid to predominate over absorption in the capillaries. The pressure particularly increases during muscular work, establishing a connection in cardiac patients between the latter and the appearance of O. The connection of congestive O. with mechanical moments is also evident from the distribution of these O. in those areas where mechanical difficulties for blood outflow are greatest (lower extremities). However, there is no complete parallelism between the degree of venous congestion and O. Besides the congestion itself (its degree, duration), the condition of the vascular walls as well as extra-vascular factors (condition of tissues, kidney function, endocrine influences) are obviously of importance here. 2. Hydremic and related cachectic O., as well as O. arising on the basis of reduced or disturbed nutrition, develop mainly due to a decrease in the oncotic pressure of blood colloids (decrease in protein content in plasma). According to Shade, a decrease in oncotic pressure of blood colloids from the normal 2.5 (for blood) to 1.9 cm of mercury is already sufficient to cause transudation to predominate over absorption in artificial capillaries. When it decreases to 1.2 cm, such a sharp transudation is established that up to 10.7% of the fluid being passed exits from the capillary. Experimentally, however, it is not possible to cause general O. in severe hydremia after the introduction of a large amount of physiological solution into the blood, despite a decrease in the dry residue of the blood from 10% to 2% (Cohnheim and Lichtheim).

However, with prolonged infusion of physiological solution, general oedemas still occur. Apparently, for the development of oedema in hydremia, additional factors in the form of damage to the capillary walls are necessary. The increased permeability of capillaries during starvation and cachexia is explained in part by the depletion of the body of lipoids, which have important significance for the normal permeability of the capillary endothelium. Others admit the appearance in the blood during cachexia of abnormal protein breakdown products that act toxicologically on the capillaries (Volgard, Timofeev). Finally, for the increased permeability of capillaries, the depletion of the body of salts, especially salts of Ca, observed in cachectic and some nutritional oedemas, apparently also has significance. Thus, the 'oat' oedema, which develops in animals fed exclusively oats, barley, or wheat, can be prevented by the addition of salts to the food, especially salts of Ca. In humans, 'oat' oedema is observed mainly in diabetes, especially in weak patients in old age, with prolonged consumption of oat flour. Noorden (v. Noorden) attributes this type of oedema to toxic oedemas, since he succeeded in isolating toxic substances from oats. When oat flour is excluded from the diet, the oedemas disappear; when its consumption is resumed, they reappear. The addition of large amounts of fat to the food prevents the appearance of 'oat' oedema. Apparently closely related to oat oedemas are the oedemas that develop in children suffering from nutritional disorders due to one-sided carbohydrate feeding (Mehlnahrschaden) with the addition of NaCl. To the group of oedemas arising on the basis of nutritional disorders belong the oedemas observed in some avitaminoses, especially in B-avitaminosis—in the so-called hydro-atrophic form of beriberi, since they do not arise from weakening of cardiac activity; the latter is very often severely disturbed in beriberi. Also in scurvy, oedemas are often observed, especially on the shins and ankles. Based on these data, some authors are inclined to attribute an 'avitaminotic component' in general important significance in the origin of various types of oedemas arising from nutritional deficiency. It is also possible that some influence in the same oedemas and insufficiency of thyroid function (Eppinger, Lichtwitz) plays a role. Oedemas developing on the basis of nutritional deficiency reach particularly severe degrees in the so-called oedematous disease (see) in famine oedemas. 3. Infectious-toxic oedemas arise from the action on tissues of many toxic substances and infectious agents that cause oedemas at the site of their penetration into tissues or also at distant parts of the body. Such substances can be of both exogenous and endogenous origin. The former include, for example, the poisons of many plants and animals, which sometimes cause very rapidly developing oedemas at the site of their application, often with the formation of blisters on the skin. Oedemas of the same character arise from the action on the skin of various irritating substances (mustard oil, some combat gases, etc.), in general poisoning with morphine, etc. Furthermore, in many infections, for example in diphtheria, oedemas often appear, which some authors attribute less to disturbance of cardiac and renal function than to damage of the capillary endothelium (Lyubarsch). Particularly marked infectious oedema occurs locally in anthrax. The often observed admixture of blood to the oedema fluid in infectious-toxic oedemas speaks for severe damage to the vessel walls. An example of oedema on the basis of endogenous intoxications are the oedemas observed in urticaria, in some anaphylactic conditions, resp. idiosyncrasies to certain food substances (crayfish, strawberries, etc.). However, often such oedemas are very difficult to distinguish from nervous oedemas in their origin: both are often characterized by extreme rapidity of onset and equally rapid disappearance. Also, no sharp boundary can be drawn between infectious-toxic and inflammatory oedemas: in the origin of both, the main significance is damage to the vessel walls (membranogenic hypoonkia—Shade); hence the richness of the oedema fluid in protein. Damage to vessels at the site of application of toxic substances can be easily demonstrated by the increased transition of vital dyes from the blood into the tissues here. The oedema observed next to a focus of inflammation and arising mainly due to the toxic influence of substances that caused the inflammation and products of tissue breakdown is also called 'collateral' oedema. In addition to damage to vessels, other factors that have significance in the pathogenesis of oedema in general participate in the origin of infectious-toxic and inflammatory oedemas; these include: osmotic hypertonicity of tissues (due to the accumulation of breakdown products), increased ability of cells and intermediate substance to swell, decrease in tissue counterpressure (due to their decreased elastic properties), partly increased mechanical pressure in the capillaries (due to stasis), compression of lymphatic pathways. Finally, the toxic component apparently participates in the origin of other types of oedemas (mechanical, cachectic, etc.). 4. Nervous (neuropathic) oedemas. Their development is only partly conditioned by neurovascular reactions. The significance of the latter is supported by the following experimental data: irritation of the vasodilating nervi lingualis leads to oedema of the tongue (Ostroumov), irritation of ansa Vieusseni—to oedema of the lip (Rogovich); paralysis of vasoconstrictors rarely causes oedema by itself, but promotes the occurrence of oedema with simultaneous venous hyperemia. It is also necessary to take into account the possibility of direct influence of nervous factors on the permeability of capillaries, as well as neurotrophic factors on the state of the chemical processes of tissues (trophic oedemas). Increased permeability of capillaries after cutting sympathetic fibers has been observed many times, mainly by means of vital staining and the introduction of fluorescein. The occurrence of nervous oedemas in humans is partly apparently analogous to their origin in these experiments: these include oedemas appearing after damage to peripheral nerves, in neuralgias (especially for example trigeminal and sciatic neuralgias), in lesions of different parts of the brain and spinal cord (hemiplegia, sometimes accompanied by oedema of one half of the body, myelitis traumatica, tabes dorsalis, syringomyelia, etc.). However, the occurrence of a whole series of nervous oedemas in humans is very difficult to explain and apparently depends on different factors. In addition to neurovascular reactions and nervous influences on the permeability of capillaries, here also have significance difficulties in the outflow of blood and lymph (with simultaneous muscle paralysis) and various toxic factors. In the occurrence of skin blisters in particularly sensitive persons in connection with phenomena of dermographism under the influence of even very weak, for example toxic irritations, undoubtedly there occurs an increase in porosity of capillaries: into the oedema fluid of such blisters passes in considerable quantity the colloidal dye congo red, introduced previously into the blood and disappearing from it only very slowly. However, the transition of the dye into the oedema fluid of blisters is observed only within 10 minutes after their appearance (Hoff). Simultaneous introduction of adrenaline or tourniquet of the limb, on which the irritation is applied, prevents the appearance of blisters; however, the latter immediately appear on previously irritated places after the tourniquet is removed, even if it lasted longer than 10 min. These data indicate that in the occurrence of nervous oedemas not only nervous influences but also the formation in the tissues of some toxic substances that increase the permeability of capillaries (Gellhorn) have significance. A typical example of nervous oedema is the acute Quincke's oedema, which develops periodically very rapidly on limited places and disappears just as rapidly (periodic oedema). Such oedemas are observed in neurasthenics, hysterics, in Basedow's disease, sometimes in connection with cooling; they can arise not only in the skin and subcutaneous tissue but also in muscles, under the periosteum, on mucous membranes (for example larynx, digestive tract) and in the lungs, which sometimes leads to life-threatening consequences. Close to acute Quincke's oedema are general idiopathic, or essential, oedemas having a more chronic course. In some of these cases, hereditary predisposition transmitted by the dominant type (Philips, Barrows) can be established. Here also belong hysterical oedemas, which sometimes differ in hardness, as well as the dark color of the skin (blue, resp. Charcot's purple oedemas), and the so-called intermittent hydrops of joints (periodic accumulation of transudate in the knee joint without signs of inflammation), occurring in hysterical subjects, especially after physical fatigue and cooling (neuroarthritic oedema). Probably in all these cases, along with nervous influences, toxic factors and endocrine disorders also have great significance. The same applies to urticaria, in which the moment of auto-intoxication probably plays an even greater role. Some special types of oedemas also require separate consideration. Renal oedemas develop mainly in nephroses and acute glomerulonephritis.

In their origin, both renal factors (disturbance of exchange between blood and kidneys) and extrarenal factors (disturbance of exchange between blood and tissues) participate. Renal factors are mainly reduced to insufficiency of the excretory function of the kidneys and lead directly to retention of water and salts in the body. Therefore, in severe insufficiency of the kidneys, the molecular concentration of blood and tissue lymph is increased, as is the concentration of H-ions (Barcroft, Strauss). At this time, chlorides are absorbed by tissues in large quantities, especially by the skin (Valgren), which also causes retention of water; in such cases, the edema fluid contains more NaCl than blood. Hence it is understandable that in kidney patients, O. shows a clear dependence on the administration of NaCl (Widal, Strauss). By excluding NaCl from food, it is possible to weaken O., and by introducing it, to intensify it. Thus, the osmotic factor undoubtedly participates in the pathogenesis of kidney O., however, some authors attribute main importance to the renal factor-retention of H₂O and chlorides by the kidneys, others-to the extrarenal disturbance of osmotic equilibrium between blood and tissues, and still others-to both factors together (Thannhauser).-The second factor, playing an especially important role in the pathogenesis of kidney O., is the decrease of the oncotic pressure of blood-hypo-onkia of blood (Shade) due to hydremia, resp. decrease in protein content in plasma, as well as due to changes in the relationships between its protein fractions. The oncotic pressure of blood in nephritis fluctuates between 1.98 and 1.10 cm of mercury instead of the normal 2.5 cm; this factor is quite sufficient for the appearance of sharp transudation (however, the degree of the latter does not always correspond to the degree of blood hypo-onkia-Schlayer). The oncotic pressure of blood decreases especially in nephroses, as well as in nephritis due to disturbance of the ability of kidneys to excrete water and due to their excretion of protein. Thus, the oncotic pressure of tissue colloids acquires predominant importance, and an increased flow of liquid is established in the direction from blood into tissues. Particularly large amounts of transudate accumulate in those places where the mechanical counterpressure of tissues is less expressed, for example, in the area of the lower eyelid. The third factor leading to O. in insufficient kidney function is damage to the walls of capillaries, their increased permeability to blood proteins ('albuminuria in tissue'-Eppinger). This 'membranogenic hypo-onkia' (Shade) is especially sharply expressed in glomerulonephritis, for which reason the edema fluid in it contains much more protein (1% and more) than in nephroses (mostly less than 0.1%). The cause of capillary damage in glomerulonephritis is apparently toxic factors simultaneously damaging the renal glomeruli. The above-mentioned oncotic factors combine in various ways in individual forms of kidney damage. In nephroses there is hypo-onkia of blood, in glomerulonephritis there is also membranogenic hypo-onkia, in nephroscleroses both are absent and O. is not observed. In addition to the basic factors causing kidney O., additional factors also participate in its origin. This includes primarily disturbance of blood circulation: weakening of cardiac function extremely favors the development of O. in kidney insufficiency, in the same sense affects the change of peripheral blood circulation due to capillary damage. Even nervous and hormonal influences apparently also have significance in the development of kidney O. (favorable effect of thyroidin in them-Eppinger). The tissues themselves apparently retain water and salts more greedily in kidney damage than in normal: absorption of liquid introduced into subcutaneous tissue occurs very slowly (Reichel), excretion of water by skin is decreased. All these factors, along with the main factors, create in kidney damage a sharply expressed 'tendency to O.', so that even insignificant additional influences (administration of NaCl, soda, iodine salts, cooling) already lead to the development of O. Pulmonary edema manifests in various forms of different origin, difficult to distinguish morphologically from each other. The edematous parts of the lungs (most often the posterior lower sections) are voluminous, heavy, of doughy or denser consistency, and from a surface incision they separate much watery liquid with air bubbles. Microscopically, the alveoli are filled with a protein-rich, coagulating upon boiling liquid with an admixture of swollen desquamated cells of alveolar epithelium and leukocytes (in inflammatory O.). The accumulation of edema fluid can actually occur either in the alveoli or in the interstitial tissue of the lungs. Both of these forms constantly combine with each other, so that it is impossible to differentiate them, and they are usually considered together. Furthermore, from proper O. of the lungs, one should distinguish the state of hypersecretion of the bronchial mucosa, arising from inhalation of various gases and vapors (CO₂, HCN, ether, chloroform, some combat O. V. and others) or from the action of some poisons from blood, for example, chloral hydrate-morphine, muscarine. The secretion of bronchi is sometimes in these cases very liquid, and its accumulation, spreading also to the alveoli, can simulate proper O. of the lungs. States of hypersecretion of the bronchial mucosa are possible on a purely nervous basis. The factor of hypersecretion of the bronchial mucosa is often mixed with the phenomena of proper O. of the lungs, intensifying them, especially in toxic forms of O. Administration of 0.5-1.0 mg of atropine quickly stops such phenomena of bronchial hypersecretion. Proper O. of the lungs arises in some acute poisonings, in diseases of lungs and pleura, in acute closure of respiratory passages, in disturbances of blood circulation in lungs, in kidney diseases, in some nervous diseases (neuropathic O., see above).-Pulmonary edema can be temporary, sometimes occurring periodically (nervous O.), or is observed as an atonal phenomenon. The main factors causing O. of the lungs are stagnation in the small circle of blood circulation (mechanical O.) and damage to the walls of pulmonary capillaries (toxic O.). Difficulty in outflow of blood from the lungs leads under experimental conditions to pulmonary edema, however only in cases of sharp obstacle to outflow of blood. According to Modrakowski's data, with artificial passage of blood through the vessels of the lungs (in a cat), stagnation of blood does not lead to O., as long as its pressure does not exceed 35 mm of mercury. However, these data refer only to normal lungs; with pathological changes of pulmonary tissue, O. can occur at much lower pressure. Pulmonary edema can also be caused experimentally by clamping the aorta near the heart or by extensive destruction of the valves of the left heart. From this the idea was created that pulmonary edema generally arises with weakening of the activity of the left heart. However, there is no direct connection between the degree of stagnation of blood in the lungs and the development of pulmonary edema. This fact especially emphasizes the importance of another factor-damage to pulmonary capillaries. It is interesting that the endothelium of pulmonary capillaries and the epithelium of alveoli, not changing for a long time with stagnation in the small circle, are very sensitive to changes in blood composition and to the action of toxic agents both from the respiratory passages and from the vessel lumen. Thus, rapid development of O. is observed on isolated lungs, if some toxic substances are added to the blood passing through them (for example, ammonia-Modrakowski). Sharp pulmonary edema can be obtained in animals by slowly introducing into the blood solutions of iodine or silver nitrate in weak concentrations. How sensitive pulmonary capillaries are to changes in blood is shown by experiments with artificial heart-lung blood circulation: passage of fresh blood serum does not cause O., but passage of serum that has stood for some time gives sharp pulmonary edema. Passage of isotonic salt solutions through pulmonary vessels quickly leads to pulmonary edema. In all these experiments there was no increase in pressure in the small circle, so that pulmonary edema arose exclusively due to the great permeability of pulmonary capillaries. Finally, sharp pulmonary edema on the basis of damage to pulmonary capillaries can be caused by temporary compression of pulmonary vessels (Klemenevich). Toxic pulmonary edema is difficult to distinguish from inflammatory O. and often only precedes inflammatory changes of pulmonary tissue or develops around them (collateral edema). In different cases of pulmonary edema, both factors-mechanical and toxic-usually combine with each other, and now one now the other comes to the forefront. Toxic pulmonary edema has especially important significance in the action of combat O. V. This includes mainly the action of chlorine, chloropicrin, and especially phosgene and diphosgene. Pulmonary edema from the action of phosgene develops 2-6 hours after poisoning and is so sharply expressed that the dry residue of pulmonary tissue decreases to 11% instead of the normal 21%. The transudate in the alveoli is very rich in protein, which indicates sharp damage to capillaries. The latter is also manifested by the fact that in perfusion of lungs poisoned with phosgene, O. develops especially quickly, even with normal pressure of the blood passing through.

Even a slight slowing of the venous outflow from such lungs is sufficient to cause O. In the pathogenesis of O. of the lungs in phosgene poisoning, the accumulation of acids in the lung tissue due to the decomposition of phosgene is also significant. As an auxiliary factor, there is also a disturbance of blood circulation in the lung due to thickening of the blood. In the pathogenesis of O. of the lungs, osmotic factors may also play a role. Thus, O. of the lungs can be caused by introducing 1 cm³ of a 56% sugar solution into the lungs (Laquer). Apparently, the osmotic factor, as in other cases, comes to the fore mainly in inflammatory O. of the lungs. Finally, in rare cases, O. of the lungs develops very gradually due to obstruction of the draining lymphatic pathways of the lungs (in inflammatory processes, tumors). Such O. develops slowly, persists for a long time, and gives a somewhat peculiar anatomical picture (a dense, sometimes gelatinous transudate with an admixture of yellowish particles due to fatty degeneration of desquamated alveolar epithelial cells). O. of the brain and its membranes [see separate table (pp. 239-240), Figure 4] develops on the basis of inflammatory hyperemia, stagnation (e.g., in sinus thrombosis) or collaterally around the nodes of tumors, abscesses, hemorrhages, foci of softening; it is also often observed in acute infections, in nephritis. The soft meninges appear tense and swollen in O., with a large amount of clear or slightly turbid fluid in the subarachnoid spaces. O. of the meninges is not always clearly distinguishable from the so-called serous meningitis (e.g., in typhus - Anichkov). The surface of a brain section in O. is succulent, and the blood points protruding on it easily spread and merge. On the basis of O. in the brain, swelling of nerve cells and fibers and secondary degenerative changes are often observed (especially in inflammatory O.). O. of the liver is quite common, especially in brown atrophy, stagnation, although it is rarely recognized. The edematous fluid accumulates in the tissue of Glisson's capsule and in the lymphatic spaces between the liver cell cords and capillaries. Limited edematous areas of liver tissue are the cause of the formation of pale anemic spots on the surface of the liver in septic infections. O. of the larynx, mostly of an inflammatory nature, develops on the epiglottis, plicae ary-epiglotticae, and the inner wall of the larynx, extending to the false vocal cords; it can lead to severe respiratory disorders and suffocation. O. of the larynx is most often caused by acute inflammatory processes (abscesses, phlegmons) of the larynx itself or surrounding tissues. Less commonly, O. of the larynx occurs on a nervous basis or in anaphylactoid states (idiosyncrasy). In general venous stagnation, as well as in kidney diseases, the accompanying O. of the larynx can hasten the exitus. Congenital general edema represents a special form of general fetal O., distinguished by Schridde, not associated with impaired kidney function and blood circulation. In some cases, diseases of the placenta and umbilical vessels were found, in others - developmental defects and diseases of the heart, kidneys, peritoneum, cirrhotic changes in the liver or compression of the portal vein. However, in many cases, no changes explaining the development of O. were found. These latter cases actually represent a special form of congenital general edema. Usually with this form, the child is born prematurely and soon dies. Along with general O. and edema of cavities, there is a marked development of hematopoietic tissue in the liver and spleen, with a predominance of erythroblasts. Foci of the same tissue are found in the kidneys. In the blood, there are many (50-75%) nucleated red blood cells and a few myeloid forms. Additionally, sometimes myeloid tissue is found in the lymph nodes and adrenal glands, sometimes cyanosis, in other cases - fetal anemia, hemosiderosis of the liver and spleen, enlargement of the kidneys and deposition of wear pigment in them, hypertrophy of the heart. From the mother's side, there are either no changes or there is nephritis, which usually passes after childbirth. To explain the pathogenesis of congenital general edema, a number of theories have been proposed (toxic influences causing anemia - Schridde, toxic influences from the mother in connection with nephritis - Fischer, Rautmann). According to Abricosov, the picture of the blood and extramedullary hematopoiesis in congenital O. is an expression of the general underdevelopment of the fetus (delay in the normal reduction of embryonic hematopoiesis); at the basis of the entire process lies intrauterine cachexia of the fetus, expressed in delayed development. Thus, this type of O. can be classified in the group of cachectic O. The absence of O. of internal organs and tissues in congenital general O. or its slight development in some cases, and the accumulation of fluid in cavities, suggest that the edema of the fetus may occur by soaking from the amniotic fluid (Abricosov). The causes of fetal cachexia can be various harmful influences originating from the mother's body. The general significance of O. for the body. In essence, O. is based on the normal process of formation of transudative lymph, but it is so intensified and qualitatively perverted that it becomes harmful to the body. Edematous tissues are nourished and function worse than normal ones. O. of some organs is sometimes the immediate cause of death (O. of the larynx, lungs, brain). However, increased transudation frees the blood from excess water and substances dissolved in it. This is the highest tension of regulation leading to the maintenance of isotonicity and isoionia of the blood, as a result of which excess substances (including toxic ones) are transferred to the relatively worthless and stable connective tissue. The attraction of a large amount of transudate into tissues, in local, e.g., inflammatory O., may also be important in the process of neutralizing harmful substances that have entered the tissues and delaying their absorption. From these points of view, O. is not a process absolutely harmful to the body, and only upon reaching a certain stage of development or involving vital organs, it can itself cause adverse consequences. Angioneurotic edema - see Quincke's edema.