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Chapter IX

Contents

CHAPTER IX
 
Pathogenesis and Pathologic Process
 
PATHOGENESIS

 
    Generally speaking, both the clinical manifestations and the pathologic process in cold injury depend upon two mechanisms: (1) The duration of the exposure to cold or wet cold, and (2) the degree to which the temperature of the tissues is reduced. The comparison has frequently been made and is valid that cold injuries resemble thermal burns with one exception: in cold injury there is no coagulation of the components of the blood serum.
 
    The altered physiologic processes resulting from exposure to cold have been described by a number of observers, notably Ariev,1 Blackwood,2 Burdenko,3 Lange and Boyd,4 Lewis,5 and Kreyberg and his associates.6 Of these descriptions, Lewis' articles and the various contributions of Kreyberg best summarize current concepts of the mechanisms involved in injuries caused by cold. As a matter of convenience, their material will be summarized separately.
 
Theories of Pathogenesis (Lewis)
 
    A discussion of the pathogenesis of cold injury necessarily begins with the mechanism of simple cooling and its effects on the blood flow to the skin.
 
A comfortably warm person, who sits unclothed, at rest, in a room without a source of radiant heat, progressively loses body heat if the room temperature is 61 F. (16.1 C.). In many persons, the cooling process begins at 64 F. (17.8 C.), and in some persons it begins at 68 F. (20.0 C.). Progressive
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1 Ariev, T. V.: Fundamental Outlines of Present Day Knowledge of Frostbite. Medgiz: Moscow, 1943.
2 Blackwood, W.: Injury from Exposure to Low Temperature: Pathology. Brit. M. Bull. 2 (7): 138-141, 1944.
3 Burdenko, N. N.: The Effect of Frostbite on the Sympathetic Nervous System. Am. Rev. Soviet Med. I: 15-22, October 1943.
4 (1) Lange, K., and Boyd, L. I.: Use of Fluorescein Method in Establishment of Diagnosis and Prognosis of Peripheral Vascular Diseases. Arch. Int. Med. 74: 174-184, September 1944. (2) Lange, K., and Boyd, L. J.: The Functional Pathology of Experimental Frostbite and the Prevention of Subsequent Gangrene. Surg., Gynec. & Obst. 80: 346-350, April 1945.
5 (1) Lewis, T.: Observations on Some Normal and Injurious Effects of Cold upon the Skin and Underlying Tissues. I. Reactions to Cold and Injury of Normal Skin. Brit. M. J. 2: 795-797, 6 Dec. 1941. (2) Lewis, T.: Observations on Some Normal and Injurious Effects of Cold upon the Skin and Underlying Tissues. II. Chilblains and Allied Conditions. Brit. M. J. 2: 837-839, 13 Dec. 1941. (3) Lewis, T.: Observations on Some Normal and Injurious Effects of Cold upon the Skin and Underlying Tissues. III. Frost-bite. Brit. M. J. 2: 869-871, 20 Dec. 1941.
6 (1) Kreyberg, L., and Rotnes, L.: La Stase Experimentale. Methode pour la Mettre en Evidence au Moyen de Preparations Speciales. Compt. rend. Soc. de biol. 106: 895-897, 21 Mar. 1931. (2) Kreyberg, L.: Some Notes and Considerations Regarding Injuries from Cold. Report to the Commanding Officer, 108th United States General Hospital, 12 Apr. 1945. (3) Kreyberg, L.: Tissue Damage Due to Cold. Lancet 1: 338-340, 9 Mar. 1946. (4) Kreyberg, L.: Experimental Immersion Foot in Rabbits. Acts path. et microbiol. Scandinav. 27: 296-308 1949.


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cooling becomes apparent chiefly in certain parts of the body, particularly the extremities and even more particularly the digits, in which the temperature eventually approaches that of the surrounding air. The cooling process varies according to the precise circumstances of exposure and also varies from subject to subject. The result is naturally influenced by whether or not clothing is worn, especially if the room air is in motion, since clothing holds a, layer of warm air on the surface of the skin. Cooling occurs very much more rapidly if the part is immersed in water.
 
    Effect of cooling on blood flow.- The first reaction of the skin to cold is vasoconstriction, which is manifested clinically by a sensation of cold and a contraction of the smooth muscle of the skin (gooseflesh). Vasoconstriction resulting from cold, however, is not a simple reaction. It involves three separate components: (1) A direct and persistent response of the superficial vessels, in the form of local constriction; (2) a transient general vasoconstriction brought about by reflex action through the central nervous system; and (3) a persistent general vasoconstriction. This general vasoconstriction is caused by the return of cold venous blood from the cooled skin and the consequent lowering of the temperature of the general circulation. The cooled general circulation acts, in its turn, upon a central nervous mechanism which is extremely sensitive to cold. All surface vessels, including arteries, arterioles, capillaries, venules, and veins, are involved in these mechanisms, and the total response constitutes the general defense of the body against cold.
 
    In the very act of conserving general body heat, the subcapillary plexuses of the venules, which are so extensively involved in the process, may themselves be sacrificed. As these vessels constrict to safeguard the organism against an excessive fall of temperature, there is, necessarily, a fall in the temperature of the limb. As the limb cools, more and more of the regional vessels constrict, so that eventually a vicious circle is set up by which the temperature of the limb gradually approaches the environmental temperature.
 
    Local defense.-When the temperature has fallen to 50 F. (10 C.) or lower, the clinical effects of cooling become manifest. The skin feels numb. Touch sense and pain sense are lost. There are also certain muscular effects, which Lewis describes as "local defence." This is a process of alternate vasoconstriction and vasodilatation, by means of which the mean temperature of the exposed part is raised several degrees. The mechanism depends upon axon reflexes which are called into play by the cold injury and which are similar to the reflexes called into play by burns, cuts, and other local injuries to the skin.
 
    Lewis' explanation is that all of these injuries cause the release of histaminelike substances from the cells of the skin. He has been able to show that the production of pain is associated with actual damage to the skin. The sensation of pure coldness begins to change to stinging or pain at about 59 F. (15 C.). The defensive mechanisms just described are easily recognized when the temperature is below this level, and in exceptional cases they can be observed up to 64 F. (17.8 C.). The hypothesis of injury to the skin by cold is further supported by the release of a vasodilator substance, as the result


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of cellular damage caused by supercooling, hypersensitivity to cold (in some persons), and the swelling which follows prolonged cooling.  

    The maximum response to cold occurs in the vascular system. Vasodilatation and increased cellular permeability result in inflammation, which is manifested clinically by redness, heat, and swelling. 

    Supercooling.- The supercooling property of the skin is attributable to the protective effect of its dry, horny layers. The dryness of these layers is the important consideration. Wetness tends to destroy the supercooling property, ,which is always more evident in skin that remains unwashed.
 
    Mechanisms of special cold injuries.- The predisposing cause of chilblains, Lewis points out, is almost certainly a habitually defective circulation, associaated with repeated exposure to cold. He also implies that erythrocyanosis, trenchfoot, and immersion foot occur on the same basis. In the early stages, all of these conditions present the common characteristics of itching, tenderness, coldness, and high vascular coloration. In more severe cases, swelling, blistering, and ulceration occur. Except in the extremely severe forms of frostbite, necrosis of tissue occurs more frequently in trenchfoot than in other forms of cold injury. The initial damage in trenchfoot may not appear to be as great as in frostbite, but the injury is of the silent type, which means that trauma continues over a long period of time and anoxia is correspondingly prolonged, while the temperature of the tissue is not sufficiently low to retard metabolic or degenerative activity. The circumstances of the injury also play a part. Iit trenchfoot, it may be some time before the soldier realizes that he is injured, or, if he does realize it, he may be unable to seek care or be unable to do anything for himself, because he is pinned down by enemy fire. Under these circumstances, immobility and dependency begin to exert their influence.  

    Indolence and slow healing are characteristic of all cold injury. According to Lewis' theory, a reduced blood supply permits greater cooling on exposure to cold in chilblains, erythrocyanosis, and trenchfoot alike; and failure to prompt healing, at least in chilblains and erythrocyanosis, is attributable to the same cause. All three conditions may present the same acute inflammatory processes observed in a number of other injuries, such as those caused by heat.  

    In frostbite, in which there is actual freezing of the skin, the deeper tissues may be involved. Although the freezing temperature of the skin lies between 32 F. (0 C.) and 28 F. (-2.2 C.), the supercooling property of the skin may prevent freezing until a temperature of 23 to 14 F (-5 to -10 C.) is reached. Once freezing has begun, however, the process is rapid, and large areas of the skin surface may become involved in a very short time. 

    As freezing increases in severity, Lewis' triple-response phenomenon appears, that is, local reddening, wheal formation over the affected area, and a surrounding bright-red flare. This reaction is the result of reflex vasodilatation, and in Lewis' opinion it depends upon the release of histaminelike substances from skin cells injured by ice crystals. Later, after the wheal disappears, local redness is persistent. Some edema is also persistent, and warming gives rise to both pain and tenderness. Skin which is damaged to this degree shows,


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on microscopic examination, edema of both epidermis and dermis, together, with perivascular infiltration of the superficial dermal layers with lymphocytes, extravasated red cells, and some polymorphonuclear cells.  

Theories of Pathogenesis (Kreyberg)  

    Lewis' observations on the pathogenesis of cold injury, which have just been summarized, were confirmed by the observations of Stray and of Kreyberg, whose work was done independently. Kreyberg's observations are in large degree similar to those of Lewis, but he follows the various physiopathologic processes more nearly to their ultimate conclusions.  

    Immediate reactions.- The immediate reaction of the skin to cold, as Kreyberg describes it, is blanching, caused by contraction of the blood vessels, including the minute vessels (the minute end organs or terminal loops of blood vessels, in which the exchange of fluid and metabolic processes take place). At skin temperatures of 77 to 59 F. (25 to 15 C.), cyanosis appears, as the result of local oxygen deficiency, and the skin is cold to touch. As the temperature of the skin becomes progressively lower, a series of other color changes occurs. After the cyanotic stage, when the temperature is about 59 F. (15 C.), the color of the skin is bluish red. At about 50 F. (10 C.), it is reddish purple or red, and below that level it is bright pink. At this point, pain begins to be felt. From the cyanotic stage onward, an increasing tissue anoxia accentuates tissue damage. Paradoxically, however, the red stage is explained by a surplus of oxygen in the local skin areas, this being the result, according to Kreyberg, of a lack of consumption, and a lowered dissociation, of oxygen. At this stage, as well as at the blue stage, the sensations of touch and of pain are reduced.  

    Once the bright-pink stage is reached, the alternating constriction and dilatation described by Lewis begin to occur, and there is a resultant rise in the skin temperature. The high color is the result of the presence of blood in the minute regional vessels, which remain constantly dilated during this phase. The sensation of cold is lost, and there is further reduction in touch and pressure sense. With exposure to still lower temperatures, however, these minute vessels contract, and there results a second white stage, which must not be confused with the white appearance of frozen tissues containing ice crystals. There is not, incidentally, full agreement with the theory of the formation of ice crystals, and there is also considerable debate over whether or not, if they do occur, they are of great significance. 

    Up to this time, according to Kreyberg's thesis, reactions which have occurred as the result of exposure to cold are chiefly physiologic and are reversible if and when the environmental temperature returns to normal. The position, however, is borderline, and prolonged exposure in any of the stages of cold described may be sufficient for the process to pass over into actual pathologic damage to the tissues. Further loss of body heat from protracted moderate exposure thus may result in trenchfoot or immersion foot, with severe tissue  


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damage, while additional exposure to low temperatures may cause actual freezing of the skin and tissues.
 
    Effects of cold on the vascular supply.- One of the effects of exposure to cold, according to Kreyberg, is greatly increased permeability of the capillary walls, which is most likely to occur during the red or hyperemic stage. As a result, there is a transudation of plasma through the vessel walls, combined with a slowing down of the flow of blood through the minute vessels. When the injury is severe enough, all the plasma passes through the vessel walls, leaving the blood cells tightly packed in the lumen and preventing further blood flow by what amounts to mechanical occlusion of the vessel. Kreyberg regards it as most important that this phenomenon be recognized as true stasis and not be interpreted as intravascular coagulation. By the use of vital dyes, he and Rotnes (one of his associates) were able to demonstrate both capillary permeability and blood cell stasis in the ears of rabbits which had been injured by cold. Their observations were confirmed by Lange and Boyd, who demonstrated transudation into injured tissue spaces by the use of intravenous injections of fluorescein combined with examination by ultraviolet light. Reversibility of the process was observed in frogs, but it remains to be proved that stasis in man is a reversible process.
 
    Although the initial edema in cold injury can be explained as the result of the imbalance between the outpouring and the drainage of tissue fluids, an inflammatory factor enters the picture as capillary permeability increases. Kreyberg, by using vital stains, was also able to demonstrate this phenomenon in experimental animals which had been injured by cold.
 
    From the cyanotic stage onward, as has already been pointed out, tissue damage is accentuated by increasing anoxia of the tissues. In the more severe types of injury, lack of oxygen brought about by the processes described leads to necrosis, which may involve both the tissues and the packed, static blood cells within the vessels. The final intravascular stage is the production of a hyaline mass from degeneration of the blood cells. Necrosis, in Kreyberg's opinion, is primarily the result of vascular stasis and anoxemia and is not influenced by cold per se.
 
    All the reactions thus far described are known to be the result of local tissue damage in frostbite. Whether these same reactions result from long exposure to moderate cold and wet, as in trenchfoot, cannot be so readily demonstrated. Kreyberg, however, is emphatically of the opinion that the end results of exposure, with and without freezing to ice, differ only in degree and not in principle. The reaction to severe or prolonged cold, he believes, is the result of a single factor; namely, acute aseptic inflammation from tissue damage caused by the lowered temperature, the freezing to ice, and the deprivation of oxygen. By the term "acute aseptic inflammation" he means the combined vascular and cellular local reactions which occur after the introduction of an element foreign to the tissues. Dead and damaged tissues and abnormal metabolic products may act as the foreign elements. Either a cellular or a vascular type of reaction may predominate.  


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    Two forms of tissue damage, according to Kreyberg's theory, thus progress during prolonged cooling, one caused by the cooling itself and the other by the resultant lack of oxygen in the tissues. One of the first effects of prolonged cooling is increased transudation and the development of edema. The passage of plasma through the blood vessel walls is augmented by the increase in hydrostatic pressure which may result from long standing or immobilization. It is also the result of constriction, which increases venous congestion.
 
    Kreyberg also believes that cardiac disease and poor physical condition, whether from hunger, reduced protein intake, or reduced colloid pressure, may increase transudation. Whatever the various causes may be, a vicious circle is soon set up, consisting of increased local tissue damage and increased permeability of the minute vessels. The shift of body fluid may be sufficient, in some cases, to produce shock.
 
    All of these reactions are retarded as long as the part is cold, partly because of the slowing down of all activities and partly because of the prolonged contraction of the arteries and arterioles. These facts account in large measure for the early clinical appearance of trenchfoot. They are of clinical importance, for they indicate that the tissues are not dead. Therefore, unless the process is of long standing when the patient is first brought under treatment, the chances are that with properly applied treatment it will not go on to necrosis.
 
Theories of Pathogenesis (Ariev)
 
    According to Ariev, the reaction of the tissues to cold is comparable to a chemical reaction in which the speed of the reaction is proportional to the temperature at which it takes place. If the comparison is valid, the injury from frostbite would occur early but would become manifest only when the temperatures of the injured part had been raised. The behavior of cold injury suggests that this hypothesis is sound. The predominant early clinical features are pallor, edema, and numbness. When the part is warmed, the arterial circulation increases rapidly, while in the later stages of hyperemia, which is both reactive and inflammatory, blister formation, necrosis, and actual gangrene appear, according to the severity of the injury. These latter processes, however, remain latent and do not become manifest, because of the retarding effects of cold, until the injured part is warmed. If the injury is superficial and the underlying tissues are not dead, feet which seem to be seriously damaged may go on to recovery. This process is what Kreyberg describes as the "fulminating vascular reaction which precedes tissue necrosis."
 
    As the circulation is reestablished, there may also occur, in addition to gross exudation, rupture of the minute vessels and bleeding into the tissues and the skin, with resultant ecchymotic areas and blister formation.


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PATHOLOGIC PROCESS
 
    The pathologic change in all cold injuries is essentially the same, such differences as exist being explained by differences in the duration and severity of the exposure. The process is essentially inflammatory and degenerative. The skin, subcutaneous tissues, muscles, nerves, and blood vessels are chiefly affected; but degenerative changes in the body structure and joint tissue have also been observed.
 
World War I Studies
 
    The changes which occur in trenchfoot were first adequately described by Smith, Ritchie, and Dawson,7 in 1915. After an intensive clinical study of 51 cases of "trench frost-bite," they carried out a series of experiments on rabbits, in which they were able to reproduce perfectly the edematous swelling characteristic of trenchfoot in man. The development of edema and its degree depended upon the controlled degree of the cold, wet, and constriction by which the condition was reproduced.
 
    Microscopic examination of the affected tissues showed that the blood vessels were chiefly affected. The changes included dilatation of the lumen, which contained a certain amount of fibrin deposit; swelling of the endothelium of the intima; vacuolation of the muscle fibers of the intim.a; and an increase in the number of cells in the perivascular tissue.
 
    The lymph vessels were sometimes normal and sometimes dilated and filled with masses of fibrin, but the walls were usually unaffected. The tissue spaces were filled with a copious deposit of threads and granules of fibrin. The collagen bundles of the fibrous tissue were separated and swollen and were undergoing solution in the exudate in whatever areas it was abundant. When the edema was of long standing, the swollen tissues were diffusely infiltrated with leukocytes. When the foot had been placed in warm water after exposure to cold, the tissues were diffusely infiltrated with red blood corpuscles, the infiltration in some areas amounting to actual hemorrhage.
 
    The nerves of the affected area presented edematous swelling of the axis cylinders, apparently as a part of the general edema. Degenerative changes were not present, as they are in true frostbite. In the voluntary muscles, the staining was modified and there was a loss of striation. In longstanding cases, examination revealed leukocytic infiltration, edema, and deposit of fibrin between the fibers. These changes were in contrast to the definite disintegration and regeneration seen in the muscles in true frostbite.
 
    The sinuses of the regional lymph nodes were dilated and the lymphoid follicles were hypertrophied. The sinuses contained a deposit of fibrin threads and granules, and red corpuscles, polymorphonuclear leukocytes and proliferated endothelial cells were observed in the meshwork of fibrin.
____________
7 Smith, J. L., Ritchie, J., and Dawson, J.: On the Pathology of Trench Frost-Bite. Lancet 2: 595-598, 11 Sept. 1915.


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    It was concluded by Smith, Ritchie, and Dawson that these changes duplicated the changes of trenchfoot in man and that they were inflammatory in origin, resulting directly from the action of cold on the tissues. The most important pathologic change, in their opinion, was in the blood vessels, the walls of which were so damaged that they could no longer function, with the result that an excessive amount of fluid was poured out and accumulated in the tissues. The deposition of fibrin followed, and the fibrous elements of the tissues underwent more or less disintegration. Congestion of the damaged vessels, such as would occur from the application of warmth, caused rupture of their walls, allowing the passage of red blood corpuscles into the tissues. Recovery from such a process, Smith and his associates pointed out, would naturally be slow, because the swelling had to subside and the damaged blood vessel walls had to be repaired sufficiently to withstand the strain of normal circulation.
 
    Excellent correlation was possible between these experimental observations and the clinical phenomena observed in human patients, and a sound regimen of therapy was therefore outlined on the basis of the investigation. Two of the most important therapeutic observations were that the feet should not be warmed in any manner that would cause congestion and that the return of normal circulation in the part should be delayed and not hastened.

World War II Studies
 
    During the early months of World. War II, considerable attention was devoted to immersion foot, and extensive studies were published by Blackwood, Ungley, White, and Warren, and others (p.10). Later in the war, the chief attention was centered on high-altitude frostbite (p. 13) and, still later, on the ground type of cold injury.
 
    Observations from the Aleutians.- Patterson,8 who treated wet-cold casualties from Attu (p.95), reported that pathologic studies of amputated parts revealed diffuse, spotty fibrosis, thrombosis, and recanalization of blood vessels. There was total demyelinization of nerves at the demarcating zone, with regression to normal 10 cm. above this area. These changes were all observed in specimens obtained by amputation about 6 weeks, on the average, after injury and were what might have been expected, Patterson concluded, in casualties who had presented edema of the tissues, necrosis, and arterial and venous thrombosis soon after injury. No tissues were available for study immediately after exposure.
 
    Observations from the Mediterranean theater.- In the Mediterranean theater (p.101), only limited opportunities occurred for histologic study of the lesions of trenchfoot, but from the few specimens which could be examined
____________ 
8 Patterson, R. H.: Effect of Prolonged Wet and Cold on the Extremities. Bull. U. S. Army M. Dept. No. 75, pp. 62-70, April 1944. 


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Simeone 9 was able to reconstruct the following composite changes, which were essentially inflammatory and degenerative: <> 

    Edema was observed in all the subcutaneous tissues and in the nerves and muscles. Round-cell infiltration was noted in scattered areas throughout the dermis and around the arterioles and capillaries. Acute inflammatory changes were observed in one specimen, a bursa thought to be from the proximal metatarsophalangeal joint of the great toe.  

    Degenerative changes included atrophy of the epidermis, with decreased thickness of this layer, smoothing of the rete pegs, and atrophy of the sweat glands. Fat tended to disappear from the subcutaneous tissues. Fibrous tissue (collagen) was deposited subcutaneously about the nerves and blood vessels. Elastic tissue was apparently not affected.  

    Small blood vessels showed a similar deposition of fibrous tissue, which sometimes was almost sufficient to occlude the lumen. Fibrosis was also noted in the walls of the large vessels, in which the patency of the lumen was less affected. 

    Wallerian degeneration was noted in the nerves and was most marked peripherally. Regeneration of axis cylinders could be detected in specimens obtained some months after injury. Nerve endings were found still noninnervated as long as a year after injury. Fibrosis was observed in and about the nerves.
 
    Muscle fibers showed early degeneration of the Zenker type. Later, atrophy and fibrosis of the muscles were found. Irregular areas of osteoporosis and new bone formation were observed in bones of the affected parts.
 
Studies at the Army Institute of Pathology 10  

    As previous descriptions indicate, little material was available anywhere for the histologic study of trenchfoot, which would be expected in a condition not in itself lethal and seldom requiring radical surgery. Friedman, working at the Army Institute of Pathology in Washington, D. C., was able to overcome this difficulty and to reconstruct the pathogenesis of trenchfoot from an intensive study of 14 specimens representing various stages of the disease. Three of the specimens were secured at autopsy from patients who died 7 to 10 days after exposure, from conditions other than trenchfoot. In the other 11 cases, gangrene ensued and amputation of portions of the foot and leg was necessary from 1 to 5 months after injury. In 6 of the 14 cases, the injury had been sustained during the Attu invasion.  

    The findings in all 14 specimens permitted the conclusion that all injuries resulting from exposure to low temperatures exhibit a common pattern and result from a similar train of events. Friedman's conclusions concerning
________ 
9 Report, Lt. Col. Fiorindo A. Simeone, to the Surgeon, Fifth V. S. Army, subject: Trenchfoot in the Italian Campaign, 1943-45.
10 Friedman, N. B.: The Pathology of Trench Foot. Am. J. Path. 21: 387-433, May 1945.   


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the pathologic changes in trenchfoot are practically the same as Kreyberg's (p.238), the only real point of difference being the occurrence of thrombosis in the damaged blood vessels. Kreyberg believes that thrombosis does not occur. Friedman's view is that the masses of red blood cells seen in the minute vessels are true agglutinative thrombi which are poor in fibrin.  

    The pathologic changes can be most conveniently summarized under the heading of the areas in which they occur. It must be remembered that the observations listed are composite and that all of the changes listed were not found in all the specimens. 

    Skin and subcutaneous tissues.- The edema in trenchfoot involved the skin and subcutaneous tissues as well as the nerves and muscles. Cellular exudates appeared in the dermis and subcutaneous tissues but were less notable than in the immediate vicinity of congested vessels. There was smoothing of the rete pegs, and the sweat glands showed atrophy, degeneration, cystic dilatation, and vacuolation.

    Changes in fatty tissue in early cases of trenchfoot consisted of infiltration by leukocytes in the deeper subcutaneous tissue and in the tissue around the appendages, even when the overlying layers were not involved; proliferation of the adventitial cells of the prominent capillaries and smaller vessels in the fat lobules; edema and leukocytic infiltration of the interlobular fibrous septa; and fibrinous exudation in the deeper tissues.
 
    Changes in the fat were marked in late cases. Fat lobules were diffusely infiltrated with foam cells laden with finely divided fat (fig.35). Occasional accumulations of giant cells of the foreign body and Touton types were observed in otherwise unaltered fat. In this study, actual fat necrosis with soap formation was observed only in areas of gangrene in a single specimen, which was secured 143 days after injury. Oil cysts (fig. 36), most of which were minute and which were lined by layers of foam cells, contained scattered, free fat globules. Fibrous replacement of adipose tissue was notable and seemed to occur in two ways:

    1. In some regions, serous atrophy or actual replacement by loose areolar or mucinous connective tissue (fig.37) ]eft a collapsed, atrophic structure in which the original outline of the fat lobule was still preserved.
 
    2. In other areas, thickening of the interlobular fibrous septa (fig.38) resulted in conspicuous depletion of the adipose tissue component in the subcutaneous layer. 

    Blood vessels.- Marked engorgement of the vascular tree was characteristically present in the early stages of trenchfoot. Extravasations of red blood cells typically surrounded the engorged plexuses. Numerous vessels contained agglutinative erythrocytic thrombi (fig.39) of the type found in stagnant blood rather than in a freely moving blood stream. The thrombi usually filled the lumen of the involved vessels completely, though some plugs were incomplete, and occasionally mural deposits of hyaline material or fibrin encircled a patent central lumen. Endothelial damage was not striking. Mural hemorrhage


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FIGURE 35.- A. Phagocytosis of fat in subcutaneous adipose tissue in late case of trenchfoot. Foam cells are present throughout the lobule. Hematocylin and eosin stain. (X145) B. High-power view of the lipoid phagocytes shown in A. Masson's trichrome stain. (X1360)
       
FIGURE 36.- Oil cyst, lined by foam cells in subcutaneous fat in late case of trenchfoot.Hematoxylin and eosin stain. (X205) 


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FIGURE 37.- Connective tissue elements replacing cells of subcutaneous fat lobule in late case of trenchfoot. Hematoxylin and eosin stain. (X145) 

FIGURE 38.- Atrophy and inflammation of subcutaneous fat lobules in late case of trenchfoot. The interlobular fibrous septa are thickened. Hematoxylin and eosin stain. (X 30)


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FIGURE 39.- Thrombosis of posterior tibial vein in early case of trenchfoot. The thrombus consists almost entirely of agglutinated red cells. Hematoxylin and eosin stain. (X65)

FIGURE 40.- Thrombosis of artery from gangrenous foot in late case of trenchfoot. Organization of the thrombus and hemorrhage into the vessel wall are shown. Hematoxylin and eosin stain. (X 50)

(fig.40) and inflammation (fig. 41) could be observed in both patent and plugged vessels. There was no instance of periangiitis in any of the 14 specimens.
 
    While many vessels, especially if they were thrombosed or inflamed, were dilated, marked vasoconstriction (fig. 42) was also observed. This was true even of the main trunks, well above the line of demarcation, though it was


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FIGURE 41.- Mural angiitis in early case of trenchfoot. The wall contains chromatin debris and is infiltrated by leukocytes. The muscular elements are degenerated, and the media contain eosinophilic granular material. Hematoxylin and eosin stain. (X 500)

FIGURE 42.- Construction of posterior tibial artery in early case of trenchfoot. Weigert's elastica and van Gieson's stains. (X 32)

not possible to say with certainty that the constriction was characteristically present during life.

    In one specimen (fig.43), secured 32 days after exposure, transitions were observed from the stage of thrombosis seen in early stages to a stage of endarteritis obliterans. Connective tissue and capillaries exhibited proliferation, and the development of a mucinous stroma seemed related to the presumably original thrombi, in which predominance of red blood cells and platelet agglutinations, together with a lack of fibrin, was still evident.


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FIGURE 43.- Longitudinal section of plantar artery in 32-day case of trench-foot. Organization is underway at the head of a thrombus. Hematoxylin and eosin stain. (X 75)
 
    Almost all thrombi observed within 40 days after exposure were organized. Endangiitis obliterans was present in both arteries and veins, even in practically normal tissue above the line of demarcation. The degree varied from slight thickening of the intima to obliteration of the lumen. Arteries which were slightly involved showed subintimal proliferation of cells, often in a mucinous and edematous matrix (fig.44). The intimal thickening was frequently eccentric but sometimes involved the entire circumference. In extreme cases, it produced a marked narrowing of the lumen. When the arteries were obliterated (fig.45), the lumen was filled with fibroblasts, round cells, and hemosiderinladen phagocytes. The central mass usually contained a number of discrete channels with definite muscular walls, which resembled arterioles (fig.46). Similar recanalization was noted even in small arteries and arterioles. The proliferative reaction was central to the inner elastic membrane, which occasionally was destroyed (fig.47) but which usually was intact and not reduplicated.
 
    The veins, although they were less regularly involved than the arteries, sometimes showed nodular intimal thickening caused by edema, mucinous degeneration, and increase in cells, collagen, and elastica. The veins were sometimes obliterated.  


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FIGURE 44.- Proliferation of intima and mucinous degeneration in a small artery. Hematoxylin and eosin stain. (X175)
 
    Muscles.- In early cases, muscle tissues exhibited degeneration, necrosis, and cellulitis, but atrophy was not observed. In later cases (40 days or more after exposure), atrophy (fig. 48) was extensive in all of the specimens. Fibrils could be identified, but the cytoplasm was usually shrunken and homogenized. Cells laden with yellow pigment lay between atrophic fibers, which were occasionally separated from the endomysial network by spaces containing edema fluid.

    The interstitial connective tissue of the muscle was the site of mucinous degeneration. A few true giant cells were identified in areas which had undergone less marked atrophy. Necrosis and inflammation were observed in areas of gangrene and cellulitis. In the zone of demarcation, and above, were circumscribed foci of necrosis, like infarcts. Hyaline degeneration and proliferation of sarcolemmal nuclei were occasionally encountered in isolated fibers. Numerous tendon sheaths exhibited severe exudative and proliferative lesions in which masses of fibrin were more prominent than in the regions of inflammation present elsewhere in the soft tissues.
 


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FIGURE 45.- Obliteration of lumen of artery in late case of trenchfoot. The inner elastic membrane is ruptured, and the media and adventitia are scarred. Hematoxylin and eosin stain. (X 175)
 
FIGURE 46.- Recanalization of small, obliterated artery. Many new channels, some with muscular walls, have formed. Hematoxylin and eosin stain. (X 280)
 


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FIGURE 47.- Organization and recanalization of artery in late case of trenchfoot. The elastica is ruptured, frayed, and distorted. Weigert's elastica and van Gieson's stains. (X 145).
 
FIGURE 48.- Atrophy of muscle in late case of trenchfoot. The shrunken fibers are widely separated. Hematoxylin and eosin stain. (X 145)


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FIGURE 49.- Cross section of portion of posterior tibial nerve in early case of trenchfoot. The groups of small fibers are undamaged. Bielschowsky's stain. (X 500)

FIGURE 50.- Slight demyelinization of nerve above region of gangrene in late case of trenchfoot. Frozen section. Spielmeyer's stain. (X 125)

Nerves.- In specimens secured soon after exposure, nerves which traversed regions of inflammation were swollen and edematous, and, even at a distance from such areas, degeneration of both axis cylinders and myelin was observed. Demyelinization was especially marked in the distal portions of the nerves. The pronounced lipoid phagoeytosis characteristic of late cases was not observed in early cases. Only large myelinated fibers which presumably represented the sympathetic components of the nerves were not significantly altered either in the main trunks or the small branches (fig. 49), and small intraneural vessels showed no essential abnormality.
 
    In late cases, nerves in areas of gangrene and cellulitis were usually badly damaged. Demyelinization (fig.50) was observed at all levels but was more


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FIGURE 51.- Marked segmentation, beading, and loss of myelin in nerve from region of gangrene. This section is of the same nerve as is illustrated in figure 50 but was taken at a different level. Frozen section. Spielmeyer's stain. ( X 220).

FIGURE 52.- Lipoid phagocytosis in a degenerated nerve in late case of trenchfoot. Foam cells are scattered between the damaged fibers. Weigert's stain. (X 230).
 
extensive below the zone of demarcation (fig. 51). Between the nerve fibers were many foam cells (fig. 52) containing sudanophilic material in fine droplets, presumably fat from broken-down myelin. Many axis cylinders had disappeared and those still present were irregular and ballooned (fig. 53). Damage was usually spotty. Some nerve bundles showed edema and separation of the fibers,


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FIGURE 53.- Degeneration of nerve in late ease of trenchfoot. Many axis cylinders have been lost, and those which remain are ballooned. Bielschowsky's stain. (X 550).

and in a few instances it was thought that actual increase of the endoneural connective tissue elements might be present. Perineural fibrosis (fig. 54) was noted, with exaggeration of the epineurium and perineurium, and occasional nerve bundles were partially or completely hyalinized. Many small blood vessels in the nerves were thickened. The degeneration and phagocytosis observed in the subcutaneous adipose tissue were also observed in the perineural fat.
 
    Panchenko 11 described characteristic changes in the perineural nervous system, nerve trunks, and spinal cord of 12 patients with frostbite who died of intercurrent disease. Tlie changes included typical ischemic neuritis and signs of intensive fibroblastic hyperplasia and hypertrophy. Some of the nerve fibers were in a state of wallerian degeneration, while evidences of regeneration could be seen at the same time. Small axial islands of degenerative necrosis were usually found close to blood vessels. Changes in the cells of the anterior horn of the spinal cord and of the intervertebral ganglia varied from slight chromatophilic granular degeneration of the central area to complete degeneration of the cellular structure. These changes were found only at the levels of the spinal cord which corresponded to the innervation of the injured part. The extent of the damage was related to the intensity of the exposure to cold.

    Bruneau and Heinbecktr 12 also showed that the nerve degeneration occurs in dogs after prolonged chilling of an extremity.
________
11
Panchenko, D. I.: Retrograde Changes in the Spinal Cord in Frostbite of the Extremities. Am. Rev. Soviet Med. 1: 440-443, June 1944.

12 Bruneau, J., and Heinbecker, P.: Effects of Cooling on Experimentally Infected Tissues. Ann. Surg. 120: 716-726, November 1944.


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FIGURE 54.-Sclerosis of nerves in late case of trenchfoot. The nerve bundles are embedded in dense fibrous tissue. Hematoxylin and eosin stain. (X 175)
 
    Bones.- The single specimen of bone, a section of the middle phalanx of a toe, available for study soon after exposure revealed no significant abnormality. In specimens from late cases, areas of osteomyelitis were observed adjacent to areas of cellulitis. The inflammatory exudate had occasionally undermined and eroded articular cartilages, but, except in these areas, there was little evidence of resorption or of osteoclastic activity. There was also no evidence of sequestration. Necrosis of bone had occurred near the zone of demarcation, and osteocytes had disappeared from the lacunae. A sharply defined layer of viable bone surrounded the dead lamellae. In some areas adjacent to necrotic trabeculae, numerous osteoblasts were actively laying down new bone (fig.55). In some of these areas, the bone marrow was necrotic or was involved in the osteomyelitic process. In other areas, serous atrophy was present, with fibrosis, hemorrhage, and infiltration of inflammatory cells. Occasional small oil cysts were noted, and there were many foci of lipoid phagocytosis comparable to those observed in the subcutaneous panniculus. The altered bone marrow contained an increased number of thin-walled, dilated blood vessels.
 
    Summary.-The essential early change in trenchfoot which Friedman's studies revealed was thus a disturbance in the circulatory mechanism; namely, the consequent stagnation of blood leading to thrombosis and, subsequently, to gangrene. In many ways, the gangrene resembled ordinary peripheral ischemic necrosis complicated by secondary infection. There were, however,


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FIGURE 55.- Necrosis of bone. Dead trabeculae with empty lacunae have been sheathed by viable bone. Osteoblasts line the newly formed trabeculae. The marrow is fibrotic. Hematoxvlin and eosin stain. (X 145)
 
certain unusual features. Particularly notable were the agglutinative thirombosis, the profound changes in the fatty tissues, and the interesting neuromuscular and osseous alterations. While Friedman regarded most of the changes, whether superficial or deep, as secondary to vascular occlusion, he called attention to a possible direct thermal effect on structures rich in lipoids, especially adipose tissue and myelinated nerve fibers. The nerve fibers, he thought, might have a special susceptibility to cold.
 
    Friedman suggested two essential lines of future morphologic investigation to clarify the pathogenesis of trenchfoot: (1) Investigation of the early changes in the myelin sheaths and the fat of the subcutaneous panniculus to determine whether tissues rich in lipoid are especially sensitive to cold and (2) detailed examination of the sympathetic fibers which supply blood vessels and of the arteriovenous anastomoses to determine whether the initial lesion of cold injury is vascular or neural.