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Chapter 12

Battle Casualties in Korea: Studies of the Surgical Research Team Volume III

The Pathology of Skeletal Muscle lschemia in Man:

A Description of Early Changes in Extremity Muscles Following Damage to Major
Peripheral Arteries on the Battlefield

Captain Robert. Scully, MC, USAR
Lieutenant Colonel Carl W. Hughes, MC, USA

During time of war, the treatment of vascular trauma becomes a major problem for the surgeon. Most of the progress in this field has related to the perfection of technics for optional restoration of the interrupted blood flow. Relatively scant attention has been paid to the striking changes that take place in the tissues deprived of their nutrition. Since the changes occurring in devascularized skeletal muscle are of considerable significance to the surgeon who must decide whether or not to amputate, and what level of amputation to select, a pathologic study of ischemic skeletal muscle was undertaken in soldiers sustaining vascular trauma during and shortly after the Korean conflict.

Material and Methods

Muscle specimens taken from the extremities of 31 soldiers whose major peripheral arteries were acutely damaged form the basis of this report. The arterial injuries of 22 of the soldiers resulted from fragmenting missiles, those of 7 from bullets. One individual sustained vascular trauma in a vehicular accident. Another, who was not injured but developed spontaneous occlusion of a major extremity artery, is included in the series because of the similarity of the pathologic changes in his muscles to those of the trauma cases. The patients ranged in age from 19 to 40, with an average age of 24.

Skeletal muscle samples were obtained in three ways. (1) Biopsies (25 specimens from 19 patients) were taken during initial débridement of a wound, at the time of fasciotomy, or coincident with revision or closure of a wound. An effort was made to biopsy regions of muscle which had not been directly traumatized. Thus, the changes in most of the specimens were attributable only to deprivation of blood supply. Most of the biopsy samples were placed in saline for a period of 15 to 20 minutes (to prevent the appearance of certain artefactual changes) and were fixed subsequently in a 10 per cent formalin solu-


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tion. (2) Surgical excision of degenerating muscle groups (3 cases).  (3) Amputation (16 cases). In most instances the entire amputated specimen was received by the pathologist. In a few cases the specimen was dissected by the surgeon, and formalin-fixed samples of various muscles were forwarded to the laboratory.

The clinical aspects of the patients' injuries were recorded and analyzed in most cases. The amputated specimens were dissected by the pathologist with a special view to correlation of the gross appearance of individual muscles with their microscopic changes. The various samples of muscle were embedded in paraffin and stained routinely with hematoxylin and eosin. A bacterial stain (Goodpasture's modification of the Gram stain) and connective tissue stains (Masson's trichrome and phosphotungstic acid hematoxylin stains) were done in selected cases. All muscle sections were viewed using polarized light.. Chemical determinations of myoglobin and hemoglobin content were performed on one specimen.

Results

Muscle Changes During the First Two Days After Arterial Injury. Thirteen samples of muscle were taken from 11 soldiers at intervals of 6.5 to 27 hours after arterial injury. In one (Case 11), the specimen was removed from an amputated limb. In all others, it was obtained by biopsy. The salient clinical and pathologic features of these cases are presented in Table 1.

Surgical Appearance of Muscles. Four of the soldiers (see Cases 1, 6, 7, and 11) had muscle contractures resembling rigor mortis. The involved muscles were described as being hard, tight, and fixed. In four soldiers (see Cases 7, 9, 10, and 11), two of whom had contractures, the muscles were considered by the surgeon to be severely ischemic and probably irreversibly damaged. These muscles exhibited one or more of the following abnormalities: a soft or mushy consistency, a pale or bluish-gray color, a failure to bleed or delayed bleeding on incision, and an inability to contract on pinching. The muscles in the remaining five cases appeared normal at operation.

Pathologic Appearance of Muscles. Many of the specimens, irrespective of their appearance at operation, exhibited artefacts or changes attributable to nearby trauma rather than to ischemia. The more common artefacts were irregular transverse cracking of fibers, blurring of cross-striations, separation of fibers from their sarcolemmae and from one another, swelling with loss of structure of sarcoplasm, and nuclear shrinkage. The last three findings were considered of no significance only when they appeared near the edges of the specimens. Changes that were interpreted as being manifestations of nearby trauma were separation of fibers and swelling of muscle and endothelial
nuclei (Fig. 1).


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Table 1.   Summary of Muscle Changes After Arterial Injury


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Table 1.  Summary of Muscle Changes After Arterial Injury


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Changes of questionable etiology, possibly related to ischemia in some of the specimens, were focal congestion of small blood vessels and perivascular petechiae.

Excluding the above changes, the five samples of muscle considered normal by the surgeon (see Cases 2, 3, 4, 5, and 8) were also unremarkable microscopically. Biopsies from the three muscles which were in contracture but which did not appear ischemic at operation (see Cases 1 and 6) were likewise essentially normal under the microscope (Fig. 2).

Of the five specimens of muscle regarded as severely ischemic by the surgeon, two (see Cases 7 and 10, Specimen D) showed a subtle but definite exaggeration of cross-striations as the only significant changes (Fig. 3). The striations, in addition to appearing coarser than usual,

FIGURE 1.Case 3. Focal separation of fibers with prominence of muscle and endothelial nuclei. This is interpreted as being due to proximity to a wound.

were often smoothly curved instead of straight. One "severely ischemic" muscle (see Case 10, Specimen C) was remarkable only for the presence of intense polymorphonuclear leukocytic infiltration in the walls of its veins. Finally, two muscles placed in the severely damaged category by the surgeon (see Cases 9 and 11) showed marked changes histologically. These comprised, in addition to exaggeration and curving of cross-striations, separation and individualization of fibers and striking engorgement (? thrombosis) of small veins and capillaries with erythrocytes (Fig. 4). The specimen of Case 11 further exhibited focal necrosis of several medium-sized arteries. The necrotic lesions were characterized by fibrinoid degeneration, slight


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polymorphonuclear infiltration, marked edema of the vessel walls, and a spread of round cells into the perivascular connective tissue. These changes resembled strongly those seen in periarteritis nodosa.

Loss of wavy arrangement of longitudinal fibrils described by Harman1 as an early manifestation of experimental muscle ischemia, characterized all the "severely ischemic" muscles in the series. However, this change was also observed in several of the muscles which appeared otherwise normal at operation and under the microscope.

Muscle Changes During the First Two Days After Surgical Repair of Arterial Injury. Five specimens were obtained by biopsy from live soldiers at intervals of 24 to 56 hours after arterial injury (and 12 to 48 hours following surgical repair). The salient details of these cases are presented in Table 2.

FIGURE 2.Case 4. Histologically normal muscle. Note close approximation of fibers and wavy character of fibrils.

Surgical Appearance of Muscles. In four of the five soldiers a striking clinical feature was the onset of muscle swelling some hours after vascular repair. When fasciotomies were performed to relieve the tension within the muscle compartments, the swollen muscles bulged through the incisions. In some instances, blood-tinged fluid exuded. In addition to swelling, all four swollen muscles exhibited changes suggestive of severe ischemia. In Case 16, the muscle was not swollen and appeared normal at operation
.
Pathologic Appearance of Muscles. Microscopically, the biopsy sample of Case 16 was essentially normal. The specimens of the four swollen and "ischemic" muscles, on the other hand, exhibited striking


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Table 2.  Summary of Muscle Changes After Arterial Repair


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Table 2.  Summary of Muscle Changes After Arterial Repair


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changes. Because all four cases presented special features of interest, they merit separate brief discussion.

In Case 14, the biopsy specimen showed advanced necrosis characterized by disruption and loss of structure of fibers, and extensive polymorphonuclear leukocytic infiltration. These changes were far out of proportion to and different in kind from those ordinarily observed in ischemic muscle. They were also quite similar to those characterizing directly traumatized muscle. Therefore, thisspecimen was interpreted as having been taken from contused muscle, even though the surgeon was able to find no clinical evidence of this.

FIGURE 3. Case 7. Exaggeration of cross-striations. (For pictorial purposes, filter was used to emphasize the striations.)

FIGURE 4. Case 11.  Separation and individualizatio of fibers; engorgement (?thrombosis)  of small vein

In Case 15, the anterior tibial compartment gradually swelled after repair. A fasciotomy, performed 34 hours following operation, revealed swollen muscle which appeared severely ischemic. Microscopically the biopsy specimen showed changes consistent with early ischemia; exaggeration of cross-striations, prominent capillaries, congested small vessels, and numerous large and small hemorrhages.

In Case 13, pulsations were palpable in the foot following repair; later they disappeared as the calf muscles began to swell. At the time of fasciotomy, the gastrocnemius muscle was swollen and was considered probably nonviable. Microscopically most of the fibers were closely approximated. Over half of them showed degenerative changes. These included waxy swelling characterized by deep staining


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of sarcoplasm, nuclear pyknosis, and focal fiber rupture (Zenker's degeneration or necrosis), vacuolar degeneration (Figs. 5 and 6), exaggeration of cross-striations, and weak staining of fibers with eosin. Many fibers were normal in appearance.

In Case 12, the muscles had been in contracture prior to operation. Although warmth was restored to the arm by vascular repair, the contracture increased thereafter, and the muscles of both flexor and extensor compartments began to swell. The small biopsy specimen showed slight separation of many fibers, exaggeration and slight curving of cross-striations, and small foci of waxy swelling of fibers.

FIGURE 5.Case 13. Focal waxy and vacuolar degeneration of gastrocnemius muscle.  Note that many of the fibers appear normal.

FIGURE 6. Case 13. Gastrocnemius muscle. Focal waxy and vacuolar degeneration.  Most of the fibers appear normal

Later Muscle Changes (Four to Twenty-six Days After Arterial Injury). The pathologic material obtained from 21 soldiers included five biopsy specimens, three specimens composed of fragments from muscle compartment excisions, six samples taken from amputated limbs, twelve entire amputated limbs, and one amputation stump
.
Surgical Appearance of Muscles. Adequately detailed data unfortunately were not available on this aspect of most of the cases. Although the surgeon's observations must have been similar to the gross observations of the pathologist in some instances, it is obvious that such properties as color and consistency may often have differed at operation and at the dissecting table. Therefore, the gross pathologic findings described below cannot be regarded as coinciding in every respect with the findings of the surgeon.


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Pathologic Appearance of Muscle. A wide range of pathologic changes characterized the later stages of muscle ischemia. Essentially four types of muscle were seen. Categorized in order of decreasing damage, these were: (1) more or less completely necrotic muscle with little or nothing in the way of inflammatory or reparative responses, (2) muscle showing patchy, and usually extensive necrosis, but exhibiting inflammatory and reparative responses as well, (3) severely damaged muscle showing small foci of complete necrosis, but notable for widespread survival of stroma and muscle regeneration,
 

FIGURE 7. Case 26. Photograph of portions of muscles of the leg. The soleus muscle (upper left) shows a characteristic pattern of patchy pale brown zones alternating with irregular broad, yellowish-white bands. The flexor hallucis longus muscle (lower left) and extensor hallucis longus muscle (center) are of a normal or at most a slightly pale color. The lateral head of the gastrocnemius (right) is for the greater part the color of fat. At the left is a rim of pale red surrounding blotchy opaque brownish-yellow tissue. See corresponding photomicrographs (Figs. 5, 6, 9, 10, 14, 15).
 

and (4) essentially normal or minimally damaged muscle. Although borderline forms existed between these four categories and although one portion of a given muscle might fit into one category and another portion into a second, by and large an entire muscle or a large part of it was uniform in its pathologic appearance.

1. Completely necrotic muscles were most often exemplified by the long slender muscles of the leg. On dissection of the amputated limb, these muscles appeared to be of normal color or somewhat pale (Fig. 7). Their consistency was normal or slightly flabby. They were at times swollen and bulged slightly when their fasciae were


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FIGURE 8. Case 22. Gastrocnemius muscle. Granular disintegration of muscle fibers.

incised. Microscopically there was extensive necrosis involving both fibers and interstitial tissue. The fibers were closely approximated in some instances (Figs. 8 and 9), widely separated in others (Fig. 10). Although some fibers had structureless sarcoplasm and appeared slightly swollen, the predominant change was one of discoid necrosis.

FIGURE 9. Case 26. Flexor hallucis longus muscle. Fragmentation and granular disintegration of fibers.

FIGURE 10. Case 26. Extensor hallucis longus muscle. Discoid degeneration with curving of discs and cracking between them. Nuclei have disappeared.


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Many of the discs were curved and there was periodic transverse cracking of the fibers between them (Fig. 10). The sarcoplasm often stained feebly with eosin. The nuclei showed increasing degrees of shrinkage and disappeared in time. In the areas of most advanced damage, the fibers were split longitudinally and transversely or were fused into coarsely granular amorphous masses (see Fig. 8). The interstitial tissue showed necrosis as evidenced by its weak staining properties and shrinkage of nuclei. The small vessels were collapsed and their contents were no longer recognizable as blood. There was no congestion; at most, an exceedingly thin band of polymorphonuclear leukocytes was the sole evidence of an inflammatory response. A frequent finding in this type of muscle, if it lay in proximity to a

FIGURE 11. Case 23. Discoid necrosis of muscle of flexor compartment of arm. Many of the fibers fall to show the normal dark blue coloration with phosphotungstic and hematoxylin stain. The fibers are individualized and show curving of and cracking between the discs.

wound or infected incision, was an invasion by bacteria sometimes in massive numbers. Some of these bacteria were morphologically recognizable as Clostridia species. They appeared in the perimysium, endomysium, and within the sarcolemmae. In our small series, gas, edema, or other recognizable lesions attributable to the presence of Clostridia were not seen.

2. Patchy and usually extensive necrosis, inflammation, and repair were observed most often in the soleus muscle (see Fig. 7); other muscles occasionally showed this type of change. Grossly these muscles were brownish-yellow or had such a light yellow color that they were easily mistaken for fat. A common appearance was a geographic pattern of pale brown patches of necrosis separated by yellow


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or white bands of inflammatory exudate (see Fig. 7). Gross areas of hemorrhage were often visible. Although the consistency was generally about normal, it was sometimes mushy or liquid. Microscopically, there was extensive patchy death of both fibers and interstitial tissue. The fibers sometimes showed a more or less pure picture of discoid necrosis (Fig. 11); more often, however, there was a considerable admixture with swollen fibers having blurred or absent striations. It was also not uncommon to find dead fibers which had retained exceedingly delicate cross-striations. The fibers were generally separated from one another, sometimes by empty spaces (Fig. 11), at other times, by edema fluid and disintegrating polymorphonuclear leukocytic exudate. If the muscle was liquefied, fragments of

FIGURE 12. Case 13. Soleus muscle. Swollen homogenous, anuclear, necrotic fibers are separated by dense polymorphonuclear leukocytic exudate. Note thrombosed vein.

FIGURE 13. Case 26. Soleus muscle. Note dead muscle on the right. On the left there is extensive polymorphonuclear infiltration of dead muscle. A large thrombosed vein is visible at the center.

disintegrating fibers penetrated by polymorphonuclear leukocytes might be seen lying in seas of exudate or hemorrhage. The interstitial tissue in this category of muscle stained weakly and exhibited pyknosis of its nuclei. The small vessels were collapsed and necrotic or were distended by closely packed erythrocytes. The larger vessels in and near the zones of necrosis commonly showed inflammation or necrosis of their walls. Often the veins, and less frequently the arteries, were distended by thrombi (Figs. 12 and 13) which eventually underwent organization.

In the muscle peripheral to the areas which had undergone complete necrosis, a variety of changes was seen. Early, bands of disintegra-


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ing polymorphonuclear leukocytes characterized this zone (Figs. 12, 13, and 14). Later, histiocytic invasion of sarcolemmic tubes with digestion of degenerating sarcoplasm, and an addition of chronic inflammatory cells were prominent features. Finally, there appeared a striking proliferation of capillaries and of fibroblasts laying down collagen (Fig. 15), as well as an intense but limited muscle cell regeneration. We have not observed more than minimal penetration of fibroblasts, capillaries, and regenerating muscle nuclei into completely necrotic muscle, a process which has been described as extensive in rabbits with experimental ischemic muscle necrosis.2

FIGURE 14. Case 26. Lateral head of gastrocnemius muscle corresponding to opaque brownish- yellow area. Note discoid necrosis and separation of fibers and broad zone of polymorphonuclear leukocytic infiltration in perimysium.

FIGURE 15. Case 31. Note necrotic, swollen muscle fibers at left, and dense fibrous tissue at right. Near the center are a few regenerating muscle fibers.

In one case (Case 31) the myoglobin content of a pale yellow muscle belonging in this category was analyzed; and it was found to be half its normal value.

3. Severely damaged but live muscle with widespread regenerative activity was exemplified in two cases (see Cases 23 and 26); in the first, by the triceps (8 days after wounding) and, in the second, by the gastrocnemius (10 days after wounding). The soleus muscle of Case 29 and the upper portion of the gastrocnemius muscle of Case 30 appeared to belong in Category 3 from a microscopic viewpoint. However, since no detailed gross descriptions were given, and since the samples taken for microscopic examination possibly may not have been representative of any large portions of the muscles, these were


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not definitely placed in this category. The triceps (Case 23) was cream-colored with focal patches of hemorrhage. The gastrocnemius (Case 26), in large part, presented a color somewhat paler than that of fat (see Fig. 7). Both muscles were of more or less normal consistency. Microscopically these muscles showed severe degenerative changes within the fibers, but a survival of many muscle nuclei and of interstitial tissue. Since complete necrosis occurred, at most, in small foci, there was little stimulation to fibroblastic proliferation, and eventual extensive muscle regeneration and reconstitution seemed possible. The degenerating sarcoplasm was discoid, structureless, or

FIGURE 16.Case 23. Triceps muscle. Fibers show disintegrating sarcoplasm. Some sarcolemmic tubes contain large numbers of histiocytes. Most of the fibers are surrounded by necklaces of elongated cells.

fragmented. The fibers were closely approximated or were separated from one another by an edematous endomysium containing scattered histiocytes and round cells. The perimysium was edematous and contained inflammatory cells in small numbers. Within the sarcolemmic tubes were focal collections of histiocytes in the process of digesting the degenerating sarcoplasm (Fig. 16). Along the edges of the fibers, nuclei were periodically missing. Elsewhere, however, were rows of elongated cells with scant cytoplasm (Figs. 16, 17, and 18). Some of these were recognizable as regenerating muscle cells with basophilic cytoplasm; others as endothelial cells of elongated tubular capillaries (Fig. 18).

What appeared to be later phases of the same process microscopically were observed in Cases 29 and 30 (18 and 12 days after wounding, respectively). These muscles showed large numbers of thin regenerating fibers arrayed in an orderly fashion in a very edematous


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viable connective tissue stroma (Figs. 19 and 20). The degenerated fibers were no longer recognizable and the oniy trace of previous damage was the presence of variable numbers of lymphocytes, plasma cells, and histiocytes in the stroma. The new fibers had longitudinal fibrils; in a few of them cross-striations could be identified.

4. Essentially normal muscle. Of the muscles examined microscopically, the gastrocnemius or large portions of it most commonly fell into this category. This type of muscle sometimes exhibited focal fiber damage in the form of waxy swelling or vacuolar degen-

FIGURE 17. Case 26. Lateral head of gastrocnemius, corresponding to pale yellow area grossly. Note elongated bands of regenerating cells among degenerating fibers.

FIGURE 18. Case 26. Lateral head of gastrocnemius muscle. Note disintegrating sarcoplasm, elongated capillary tubes, and regenerating multinucleated muscle cells at top and midcenter.

eration. Small areas of inflammation, regeneration, and repair were also seen.

A striking finding in the amputated legs was the relatively better condition of the gastrocnemius than the soleus muscle after the major artery of supply to the extremity had been damaged. Thus, of 10 cases in which damage occurred to either the femoral or popliteal artery and in which sections of both gastrocnemius and soleus muscles were available for study, the former showed a lesser degree of ischemic change in nine and a slightly greater degree in only one. In some instances, the gastrocnemius appeared relatively normal when the soleus was either necrotic or regenerating; in others, the former was regenerating when t.he latter was necrotic; while in


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still others the former, though extensively damaged, exhibited a somewhat less complete form of necrosis than the latter.  Because of the nature of the material, it was not possible to relate the pathologic category into which individual muscles fell to lesions in specific arteries or veins or to explain why certain muscles fared better than others. This aspect of the pathology of muscle ischemia will be discussed at greater length below.

The use of special connective tissue staining and of polarizing microscopy afforded additional data on the microscopic characteristics

FIGURE 19.Case 29. Soleus muscle. At the left are some remaining normal fibers. To their right are numerous small regenerating fibers arrayed in an orderly fashion in edematous connective tissue. Small numbers of chronic inflammatory cells lie among the small fibers.

FIGURE 20. Case 30. Gastrocnemius muscle. Elongated regenerating fibers with multiple clusters of nuclei are separated by histiocytes, chronic inflammatory cells, and edema fluid.

of ischemic muscle. With phosphotungstic acid hematoxylin and Masson's trichrome stains (using aniline blue for the latter), degenerating and necrotic muscle fibers often failed to show normal staining properties. These damaged cells were weakly colored or exhibited atypical colors, such as blue with Masson's or buff with PTAH stain (see Fig. 7). Waxy fibers, swollen necrotic fibers, discoid fibers, and the degenerating sarcoplasm of the muscles of Category 3 commonly showed weak or atypical staining. Although Mallory's two cases of crush syndrome suggested an association of these abnormal staining properties with myoglobin loss,3 we found them in normally


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pigmented muscles as well as in depigmented ones. Regenerating muscle cells have stained normally with the connective tissue stains in our limited experience.

Using polarized light, it was found that muscle fibers commonly retained their birefringence in advanced stages of necrosis. Indeed, swollen fibers and fibers showing discoid necrosis were often brightly refractile even after their nuclei had completely disappeared. Refractility was lost in some fibers showing advanced discoid or structureless necrosis and in fibers exhibiting granular disintegration. It reappeared in the early regenerating fibers of Cases 29 and 30.

Discussion

Since most of the basic knowledge of muscle ischemia has come as a result of animal experimentation, a comparison of experimental findings with observations on human cases is in order. Such a comparison may suggest which experimental conclusions can be applied justifiably to humans and what type of further experimentation may be expected to yield clinically valuable information.

The first manifestation of muscle ischemia following arterial injury in humans is contracture. Early ischemic contracture is not to be confused with Volkmann's ischemic contracture, a permanent contracture associated with muscle infarction. It is possible, however, that early ischemic contracture represents an early, reversible stage in the development of Volkmann's contracture. In our series, no instances of persistent contracture were encountered. Early ischemic contracture may have its onset as early as 6 or 7 hours after injury. The muscles of the flexor compartment of the forearm and of the anterior tibial compartment of the leg are most prone to be affected. The contracture is reversible, at least in its initial states. It is not an invariable manifestation of muscle ischemia. In the present small series, the nature of the vascular damage did not seem to differ in those soldiers developing contracture and in those free from it. Likewise, the application of tourniquets did not appear to be a factor. No structural counterpart for early ischemic contracture was identified in the human specimens. In the earlier cases in which the muscles involved appeared otherwise normal at operation, microscopic examination of the samples was essentially unremarkable. In later cases in which the muscles exhibited other evidences of ischemia at surgery, the biopsy specimens showed changes similar to those seen in ischemia without accompanying contracture. Early ischemic contracture has been produced experimentally in muscles in which the arterial blood supply has been more or less completely interrupted; however, its nature has not been investigated. Harman, who has furnished de-


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tailed data on the microscopic features of early muscle ischemia in animals,1 has not mentioned contracture as an ischemic phenomenon.

The earliest structural manifestations of muscle ischemia observed in several humans were similar to those described by Harman in experimental animals (i. e., exaggeration of cross-striations and separation and individualization of fibers).1 Loss of wavy arrangement of longitudinal fibrils, however, did not prove to be a reliable sign of early ischemia in humans. Although this change characterized all the "severely ischemic" specimens, it was observed in several samples of otherwise normal muscle as well. The vascular engorgement (? thrombosis) observed in two of the human "severely ischemic" samples may have been the structural counterpart of the physiologic damage to small vessels demonstrated by Harman 6 in experimental muscle ischemia. The usual vascular changes seen in Cases 10 and 11, i. e., the leukocytic infiltration of the vein walls, and the necrotic arterial lesions resembling those of periarteritis, were unique in the series and, to our knowledge, have not been described in experimental ischemia. Interpretation of their relationship to ischemia must remain conjectural at the present time.

The correlation between surgeon's judgment at operation and the pathologist's interpretation based on microscopic examination, as to muscle viability in early ischemia, was unsatisfactory in the present series. In two specimens believed by the surgeon to be "nonviable" (see Cases 9 and 11) the histologic changes were so severe that a pathologist might justifiably question viability. In three other specimens considered severely ischemic at operation (see Cases 7 and 10), the microscopic abnormalities were, in contrast, only slight. In these two cases it is possible that severe or irreversible changes had taken place, but that the structural manifestations were still too subtle to be recognized. However, if Harman's morphologic criteria for muscle viability in experimental ischemia1 can be transferred to human pathology, the muscles with slight changes were definitely viable and capable of recovery despite their striking abnormalities at operation. Unfortunately in the two cases in which the surgeon and pathologist disagreed (see Cases 7 and 10), the final outcome did not permit conclusions as to whether the muscles were actually viable or were dead at the time of biopsy. Although Harman has established microscopic criteria and has demonstrated the invalidity of contractibility as a criterion of muscle viability in animals, the relative values of other surgical criteria (e. g., color, consistency, and ability to bleed) have not been investigated experimentally to our knowledge.

Swelling of ischemic muscles occurs in humans with arterial injury as well as in experimental animals. In humans it may take place in instances of unrelieved ischemia; however, it is more frequent and


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more severe following surgical restoration of circulation. In experiments performed on animals, ischemic swelling may appear as a result of less than complete interruption of arterial blood supply 7 or may follow release of arterial obstruction. 5 7 8   Pathologic examination of human biopsy specimens of swollen muscle has failed to reveal the pathogenesis of the swelling. It seems possible that five factors, alone or in combination, may contribute to ischemic swelling: (1) lymphatic stasis, (2) vascular congestion, (3) enlargement of individual fibers, (4) interfibrillar edema, and (5) edema of the perimysium (connective tissue between bundles of fibers). Our biopsy specimens did not permit evaluation of the first factor. Vascular congestion and focal hemorrhages were observed only in Case 15. Enlargement of individual fibers was prominent in Case 13 and to a much lesser extent in Case 12. Interfibrillar edema, as evidenced by separation of fibers, was present to a slight degree in Case 12. Neither vascular congestion nor enlargement of individual fibers was observed in Case 15.  Studies in experimental animals have shed little light on the nature of ischemic swelling, although edema and hemorrhages have been described in the involved muscles.7 8  It is possible that larger biopsy specimens or micrometric measurement of muscle fiber size may provide an eventual answer to the problem.

The presence of a Zenker's type of muscle degeneration, not seen in early unrelieved ischemia but seen in two specimens of swollen muscle hours after restoration of circulation (see Cases 12 and 13),is most interesting in view of the fact that Harman6 found this change under similar circumstances in his experimental animals. In the small biopsy specimen of Case 12, this waxy type of degeneration was present only in a few foci. In the specimen of Case 13, the change was widespread. Here, however, the soldier had been exposed to cold, and since fiber degeneration similar to Zenker's has been reported in experimental hypothermia9 as well as in relieved ischemia, cold injury cannot be entirely ruled out as the etiologic factor. If the unusual changes of Cases 12 and 13 are due to restoration of circulation, Harman's observations on the increase in muscle fibe damage wrought by a return of circulating blood may have a direct application to vascular repair in humans. The occurrence of muscle swelling and of new microscopic types of muscle damage following resumption of blood flow in an ischemic muscle also calls attention to the two experiments of Brooks 7   which suggested that a gradual or incomplete return of circulation might result in less damage to an ischemic muscle than an abrupt and complete one.

Wide varieties of pathologic changes, ranging from minimal damage to massive necrosis, characterize the later stages of muscle ischemia, both clinical and experimental. For the most part, the findings in man and animal have been quite similar. Two aspects of the


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subject in which clinical and experimental observations are somewhat at variance, namely regeneration and depigmentation, deserve special attention.

Clark has described extensive muscle regeneration, and reconstitution in small experimental animals even when the degree of arterial ischemia has been so great that necrosis of the interstitial tissue has taken place.2 The same author, however, is quoted as saying that a similar degree of regeneration would appear unlikely in man because of the bulk of human muscles.10  Although we have seen only abortive attempts at regeneration when severe necrosis involving the interstitial tissue has occurred, several of our human specimens in which the muscle fibers had undergone widespread degenerative changes, but in which the stroma had survived, showed such striking regeneration that a considerable amount of reconstitution seemed likely had the limb remained intact. More extensive experience with human cases are needed to confirm and expand these observations.

Although Montagnani and Simeone have demonstrated liberation of myoglobin from muscles upon release of ischemia,11  visible depigmentation as a phenomenon of experimental muscle ischemia has not, to our knowledge, been described. Our studies have shown that in humans severe and widespread loss of pigment may occur not only in muscles which show large areas of necrosis, but also in those exhibiting regenerative changes. Thus the appearance of fish-flesh, cream, or pale yellow color in a muscle does not necessarily indicate that it is irreversibly degenerated. In our limited experience, muscle which is more or less completely deprived of its blood supply does not undergo depigmentation, perhaps for the reason that no circulatory system exists in the muscle to furnish enzymes necessary for the release of the myoglobin and to provide for transportation of this pigment from the muscle.

Whereas it is difficult to determine in experimental animals what pathogenic factors are responsible for producing the various forms and degrees of ischemic muscle degeneration, this is an even greater problem when dealing with human cases. Here the variables are multiplied many fold and investigative methods are necessarily limited in extent. Thus, in our series, often only a biopsy specimen was available for study. This may not always have been representative of an entire muscle, nor did it afford information about the state of the blood vessels supplying the muscle. In cases where an entire amputated limb was forwarded for examination, usually the obstructed major vessel remained in the patient above the amputation site. Spasm of arteries or veins and the degree of obliteration of collateral vessels were most difficult, if not impossible, to evaluate. Many of the soldiers had had tourniquets applied; although in most cases in-


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formation was given as to the duration and periods of release, it was not possible to determine how effectively the arterial flow had been obstructed. Exposure to excessive cold or heat, the state of fatigue of the muscle at the time of onset of ischemia, and individual variations in vascular supply were some of the other factors which did not lend themselves to accurate determination.  Considering all these unknown and variable factors, plus the relatively small size of our series, we are unable to state the precise roles of arterial, venous, and capillary obstruction in producing the muscle changes observed. In addition to arterial damage, large veins were directly injured or were ligated in many of our cases. Moreover, major and intramuscular veins and capillaries were often extensively thrombosed in the pathologic specimens. In some instances, the thrombi formed in infarcted vessels damaged by ischemia which damaged the muscles in which they lay. It has been suggested that extensive venous thrombosis may produce muscle death in patients whose arterial flow has been adequately re-established. However, in one of our patients, the involved muscle groups with patent arterial supply and thrombosed veins did not show the pathologic picture encountered in ischemia due to experimental venous occlusion.

The early muscle changes observed in the present series are natural forerunners of the later changes, infarcts enclosed by zones of fibrous tissue, reported by previous authors: Bowden and Gutmann (Group 1), Griffith. 12 13   The extensive regeneration seen in our Category 3 muscles, to our knowledge, has not been described in humans.

There is a remarkable similarity between the pathologic changes in muscle ischemia secondary to arterial trauma and in that characterizing the crush syndrome. In the latter condition, muscle swelling, discoid necrosis, atypical staining of fibers with connective tissue stains, and regeneration have all been described. Moreover, gross depigmentation of muscle and even renal failure may be seen in cases of arterial injury without crushing. 14   Pathologically, the striking similarity of the two conditions support other evidence that the muscle changes of the crush syndrome and due to arterial spasm. 14  15

Precipitation of granular material suggesting calcium, such as is seen in the degenerating muscle fibers involved in the crush syndrome, is unusual except in relation to wounds with ischemia following arterial trauma. The disordered metabolism of renal insufficiency may be the factor determining the presence or absence of this change.

A final observation that merits brief discussion is the usually better outcome of the gastrocnemius than the soleus muscle in injuries of the femoral or popliteal arteries. The reason for this finding is not apparent from this study, or from the literature. Blomfield who has investigated the blood supply of the leg muscles by injection technics


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at autopsy has stated that the gastrocnemius is served by a single artery; the soleus, on the other hand, has at. least five arteries of supply. 16   The author further stated that in local wounds of the calf, the gastrocnemius is more apt to undergo necrosis and secondary clostridial infection because of its less rich blood supply. The disparity between the outcome of the two muscles following local vascular damage and following injury to the major artery of the extremity deserves investigation. Possibly the artery supplying the gastrocnemius communicates by collateral channels with vessels arising above the level of obstruction of the femoral or popliteal artery. Again, the comparative tightness of the sheaths or fascial envelopes of the two muscles or a difference in their metabolic requirements may play decisive roles in their responses to ischemia. A practical corollary of the observation regarding the gastrocnemius and soleus is that the condition of the former muscle cannot be used as a guide to that of the other muscles of the leg.

Summary and Conclusions

1. The early pathologic changes in skeletal muscle following damage to major limb arteries were studied in 31 soldiers, most of whom had sustained injuries on the Korean battlefields. The material consisted of biopsy specimens, surgically excised necrotic muscles, and amputated limbs. The specimens were obtained from 6.5 hours to 26 days after injury.

2. The pathologic lesions observed paralleled those described in experimental muscle ischemia and appeared to be the natural forerunners of later changes reported in humans.

3. The earliest ischemic change recognized under the microscope was an exaggeration of cross- striations. Later separation of fibers and capillary and venular engorgement became evident.

4. Swelling of ischemic muscles following restoration of circulation occurred in several cases. The nature and pathogenesis of this swelling was not evident from study of human or experimental data.

5. After the acute phase of ischemia had passed, the muscles studied fell into one of four pathologic categories: (1) more or less complete necrosis, (2) patchy, but extensive necrosis with inflammation and repair, (3) severe damage of fibers, but survival of stroma and widespread muscle regeneration, and (4) normal structure.

6. A pale yellow or cream color probably attributable to loss of myoglobin was an outstanding feature of several muscles in Category 3 as well as in Category 2. Therefore, depigmentation is not a reliable criteria of irreversible damage in ischemic muscle.

7. The pathologic changes of muscle ischemia following arterial injury resembled closely those reported in the crush syndrome, adding


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to the evidence that the muscle lesions of the latter condition are due to arterial spasm.

8. Because of the many imponderable variables in human cases of arterial obstruction, it was not possible to assess the exact role of arterial, venous, and capillary obstruction in producing the muscle changes observed.

9. Surgical criteria for irreversible damage in ischemic skeletal muscle have not been established on a sound basis and deserve further experimental investigation.

10. The gastrocnemius muscle fared better than the soleus in the grea.t majority of cases of obstruction of a major leg artery. This result was the opposite of that reported in local wounds involving the immediate arteries of supply of the muscles. The vascular anatomic background for this was not clear. Because of the difference in outcome of the two muscles it is apparent that the condition of the gastrocnemius cannot be used as a guide to that of the other muscles of the leg.

Illustrative Cases

Case 18.  This 21-year-old soldier sustained a mortar-fragment wound which resulted in thrombosis of his right brachial artery. Four days after injury, the arm was amputated above the elbow because of progressive wet gangrene. Pathologic examination revealed moderate swelling of the forearm and hand, dark green discoloration of the skin and subcutaneous tissue of the forearm, and cyanosis of the finger tips. The muscles of the forearm were slightly pale and flabby, but not discolored or swollen. The brachial artery was thrombosed over a length of 8 cm., beginning at the amputation level; the radial and ulnar arteries were thrombosed for 2 to 3 cm. near their origins. The brachial vein and its tributaries, and several large superficial veins in the region of the elbow, were also thrombosed. There were two sizable avulsive wounds of the upper arm and two small superficial wounds of the forearm and antecubital space. Microscopically, multiple sections of superficial and deep muscles revealed striking ischemic changes. The fibers were universally individualized and separated, moderately so in some muscles, only slightly so in others. Some of the fibers showed exaggeration of cross-striations; in others the sarcoplasm was structureless, and the striations were blurred or absent; a few fibers were swollen. The muscle nuclei were not noticeably altered in some muscles, but were shrunken in others. The interstitial collagenous tissue and its nerves and vessels showed varying degrees of necrosis. They stained weakly with eosin and often their nuclei exhibited marked pyknosis. The small vessels were not congested but, for the most part, were collapsed; their lumens were empty or contained pale staining unidentifiable material upon which


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basophilic debris was sometimes deposited. Here and there small collections of bacilli were found in the endomysium, perimysium, and beneath the sarcolemmae.

Comment.  This type of necrosis, which is accompanied by little swelling of individual fibers and is unassociated with small vessel congestion or inflammatory cell reaction, is a reflection of a more or less complete interruption of arterial blood supply. Separation of fibers, which requires little if any intact circulation for its development in experimental animals,1 was striking here; nevertheless, as in Case 11, it did not result in gross swelling of the muscles.

Case 13.  The salient features of the early history have been presented in Table 2. Following fasciotomy (performed at the time of the original biopsy) the pulses failed to return and the foot remained cold. By the fourth day after wounding, the foot showed early gangrene. The leg was amputated below the knee. At operation it was noted that there was a good blood flow through the posterior tibial artery and its muscular branches, although the muscles appeared nonviable. Samples of both gastrocnemius and soleus muscles were taken from the amputated leg by the surgeon. The formalin-fixed gastrocnemius specimen taken at the fasciotomy site was pale tan with a zone of dark reddish-brown at one margin. Microscopically, one surface of the biopsy showed fascia, another showed granulation tissue containing an abundance of polymorphonuclear leukocytes. The muscle fibers close to the line of surgical incision were widely separated by the edematous granulation tissue. They showed various changes: loss of structure of sarcoplasm, vacuolar degeneration, swelling, rupture, and histiocytic digestion. The muscle at a distance from the granulating surface was essentially normal except for edema and focal hemorrhage of the perimysium, focal edema of the endomysium, swelling of muscle and endothelial nuclei, and spotty Zenker's and vacuolar degeneration (see Fig. 6).

The over-all picture was one of focally damaged muscle showing changes chiefly attributable to proximity to an operative incision. The formalin-fixed soleus specimen was dark brown, mottled with pale yellowish-gray. Microscopically, there was vast necrosis involving not only the muscle fibers, but their supporting tissue as well. The fibers were minimally to markedly separated. Many showed discoid degeneration, others loss of structure and swelling of their sarcoplasm with varying degrees of obscuration of cross-striations (see Fig. 12). The nuclei were absent or severely pyknotic. There was an extensive irregular outpouring of polymorphonuclear leukocytes and edema fluid. A thin zone just beneath the fascia showed a granulation tissue type of response. The larger vessels were often necrotic; many veins and fewer arteries contained thrombi (see Fig. 12). The


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smaller vessels were frequently distended; they appeared dead and showed little affinity for stains.

Comment.  There are several points of interest here: (1) the gastrocnemius which was thought to be nonviable at operation was essentially normal, except for focal fiber damage which might have been. related, at least in part, to proximity to the fasciotomy incision. The amputation specimen exhibited less damage than the fasciotomy specimen which was taken three days before and was also suspected of being nonviable. (2) The soleus showed more extensive damage than the gastrocnemius.

Case26.  This 22-year-old soldier sustained multiple shell-fragment wounds, one of which severed his right superficial femoral artery and vein. On admission to a surgical hospital, the foot was cool and paralyzed and the thigh was swollen and tense. The artery was grafted, the vein ligated, and a calf fasciotomy performed 7.5 hours after injury. Postoperatively there was an adequate distal pulse. The day after the repair, the foot was cool and cyanotic. The next day no pulsation was felt and there was some edema of the foot and calf. Four days after wounding, demarcation was beginning at the mid-foot level, and the calf was tight and edematous. The next day an anteromedial fasciotomy was performed.

Eight days after wounding the leg was amputated above the knee. Pathologically there was considerable swelling of the leg; small areas of patchy bluish-pink discoloration were visible on the skin of the dorsum of the foot. Two long gaping fasciotomy incisions were present, as well as a smaller débrided wound. There was extensive thrombosis of the anterior tibial, posterior tibial, and peroneal veins. The corresponding arteries were free from thrombi. The muscles showed most interesting color changes. The lateral head of the gastrocnemius was pale yellow (not the intense yellow of fat, but a more washed-out color); in the peripheral portion of the muscle was a rim of red or pale red tissue alternating with blotchy opaque brownish-yellow areas (see Fig. 7).

The pale-yellow zone corresponded microscopically to a digestive and regenerative process more advanced than that seen in Case 23 (see Fig. 17). Here, the fibers were universally separated from one another; most of them showed discoid degeneration and a few were swollen and structureless. The sarcoplasm was being digested focally by histiocytes; and there was early regeneration of muscle cells with formation of many thin basophilic fibers (see Fig. 18). The endomysium and perimysium showed marked edema and infiltration with inflammatory cells, particularly histiocytes and round cells. The endomysial capillary network was prominent, often appearing in the form of longitudinal tubes extending between the muscle fibers (see Fig. 18). Corresponding to the blotchy opaque brownish-yellow areas


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with red rims were microscopic zones of massive necrosis of discoid type with rims of granulation tissue. The necrosis involved both fibers and interstitial tissue and was accompanied by an
outpouring of edema fluid and degenerating polymorphonuclear leukocytes (see Fig. 14). The medial head of the gastrocnemius in part resembled the lateral head, being light yellow and in an early regenerative state. Elsewhere, it was pale brown and exhibited extensive discoid necrosis with exudation of polymorphonuclear leukocytes and edema fluid. The soleus, on section, showed patchy opaque pale-brown zones alternating with irregular yellowish-white bands (see Fig. 7).

Microscopically, there was massive necrosis with broad bands of polymorphonuclear leukocytic infiltration (see Fig. 13). The necrosis was in large part complete, involving the interstitial tissue as well as the fibers. The latter were widely separated; some showed discoid degeneration, however, most were swollen and structureless. There was extensive necrosis and thrombosis of both arteries and veins (see Fig. 13). In a few of the latter, organization was taking place. In some small areas there was viable tissue; here granulation tissue formation and abortive muscle cell regeneration were occurring.

The flexor hallucis longus appeared grossly normal in color (see Fig. 7). Microscopically, it showed extensive necrosis with thin borders of polymorphonuclear leukocytes. The fibers were for the most part minimally to slightly separated from one another. The majority of them showed advanced discoid necrosis; some exhibited variable degrees of swelling and loss of structure. There was considerable fragmentation of fibers (see Fig. 9). The muscle nuclei had completely disappeared except in a few areas where they were pyknotic. No congestion, granulation tissue response, or regeneration was seen. Many bacilli were scattered throughout the muscle. The extensor hallucis longus appeared grossly slightly paler than normal (see Fig 7). Microscopically, it showed a picture of necrosis similar to that of the flexor hallucis longus (see Fig. 10). Gram-positive rods were seen, especially in the outer portion of the muscle.

Comment.  Again, in this case, the gastrocnemius muscle showed less damage than the soleus. The former exhibited a pale-yellow color that corresponded microscopically to extensive early regeneration. Had the limb survived, the amount of regeneration was probably sufficient to have been able to reform a considerable portion of the muscle. The soleus exhibited a characteristic picture of muscle infarction in which pale-brown areas of necrosis alternated with yellowish-white bands of polymorphonuclear exudate. The flexor hallucis longus and extensor hallucis longus showed the most advanced necrosis but the least in the way of color changes. Presumably, the almost complete interruption of blood supply prevented depigmentation of the muscle from occurring.


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Case 29.  This 25-year-old soldier sustained a gunshot wound which partially severed his left popliteal artery. A tourniquet was in place for 11 hours. On admission, the leg was cold and pale. The artery was anastomosed 16.5 hours after injury; there was no venous involvement; several medium-sized collateral vessels were sacrificed. Postoperatively there were good pulses.

Thirteen days after injury, the anterior and lateral muscles of the leg were excised because of necrosis. The muscles were described as being soft and pale. Microscopically there was extensive advanced necrosis, mostly of the discoid type. In some fragments fiber swelling and hyalinization were prominent. In many areas the dead fibers were closely packed; in others they lay in a sea of exudate. There were wide bands of dead muscle containing large numbers of disintegrating polymorphonuclear leukocytes. Several large areas characterized by marked histiocytic digestion of muscle sarcoplasm, and early regenerative activity were seen. There were fibers in these more viable regions which stained deep blue suggesting calcification.

The leg was amputated above the knee 18 days after injury, and was submitted to the laboratory in formalin. The artery was thrombosed in the region of the anastomosis. The gastrocnemius appeared normal grossly.

Microscopically, it was essentially negative except for slight over-prominence of cross-striations and spotty areas of waxy swelling of fibers. Some of the swollen fibers were being engulfed b histiocytes. The soleus was pale yellow-tan and edematous. Microscopically, the one section taken showed large numbers of very thin regenerating fibers arrayed in an orderly fashion in a very edematous connective tissue stroma (see Fig. 19). Between the fibers were small numbers of lymphocytes, plasma cells and histiocytes. The new muscle cells were for the most part elongated and were one-fifth to one-tenth the diameter of normal fibers. Longitudinal fibrils and, in some instances, cross-striations could be identified. The nuclei were oval and were often present in clusters or rows. In a few small areas, groups of intact fibers of normal size remained. The tibialis posterior muscle was very soft and liquefied. Microscopically, fragmented fibers showing discoid necrosis and occasionally loss of structure and swelling were widely separated by blood an disintegrating acute inflammatory exudate. Peripheral to the necrotic areas, the dead muscle had been largely removed so that there remained edematous collagenous tissue containing cavernous blood vessels and acute and chronic inflarnmatory cells. Here and there were foci of muscle cell regeneration, but this was by no means a prominent feature.

Comment.  Again, in this case, there were different degrees of ischemic change in the muscles examined. The anterior and posterior tibial muscles showed the most advanced degrees of necrosis. In the latter, zones of fibrous tissue containing inflammatory cells had


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already appeared peripheral to the areas of complete necrosis. The gastrocnemius showed little or no damage. The slight exaggeration of cross-striations was probably of no significance. The soleus, which was pale yellowish-tan and grossly edematous, showed extensive regeneration. The new fibers were numerous and arrayed in an orderly fashion; likewise, there was a dearth of new collagenous tissue formation here. For these reasons, it appears possible that this muscle could have been reformed to a large extent if the limb had remained intact.

Case 30.  This 32-year-old soldier sustained a shell-fragment wound involving his right lower thigh. The wound was débrided at a front line hospital. Two days later he developed a massive secondary hemorrhage. The wound was explored and the popliteal artery and vein were found to be severely lacerated. Both were ligated. Gangrene of the foot and lower leg developed and the leg was disarticulated at the knee joint 12 days after wounding. Pathologically, the skin of the leg showed reddish-purple discoloration and zones of desquamation and vesicle formation. The foot was edematous and the tips of the toes were black. The popliteal artery contained a thrombus which extended for a short distance into the anterior tibial artery. The peroneal, posterior tibial, and lower anterior tibial arteries were completely patent. The venae comites were distended by clotted blood. The muscles were described as being pale; and the soleus was said to be pale yellow with focal hemorrhages.

Microscopically, several sections were taken from the gastrocnemius muscle. Two from its mid- portion were essentially negative, although several large veins were greatly distended with thrombi which showed early organization. A third section showed a diffuse area of regeneration in which were scattered small patches of necrosis. The regeneration was characterized by the presence of large numbers of newly formed, elongated muscle fibers separated by edema  fluid, large numbers of histiocytes and lymphocytes, and proliferating capillaries and fibroblasts (see Fig. 20). The new fibers varied in width from one-fifth to one-third that of normal fibers. Longitudinal fibrils, as well as occasional cross-striations, were perceptible. Nuclei were numerous and were arranged in tightly packed rows or clusters. here and there were small areas occupied by normal muscle fibers. The patches of necrosis were characterized centrally by complete death of both fibers and interstitial tissue. The former were partly discoid, partly structureless. There were small foci of hemorrhage.

At the periphery was a variable amount of penetration of dead muscle by proliferating capillaries and histiocytes and, to a lesser extent, by fibroblasts and regenerating muscle cells. The medium- sized vessels were congested throughout the section. A large vein was distended with an early organizing thrombus. The corresponding artery was not remarkable. The soleus muscle showed extensive


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necrosis. The fibers were mostly swollen and structureless and were slightly to markedly separated by disintegrating polymorphonuclear exudate and edema fluid. The nuclei had disappeared. Histiocytic digestion of dead sarcoplasm and capillary penetration were proceeding to a slight degree at the periphery. The tibialis anterior showed advanced, complete necrosis without congestion or inflammatory cell infiltration. The fibers were minimally to moderately separated; many were structureless; others showed discoid necrosis. Nuclei were severely degenerated. The interstitial tissue was obviously necrotic.

Comment.  This case illustrates again the several types of reaction patterns occurring in the muscles of ischemic limbs, ranging from complete necrosis to maintenance of normal structure. There was marked muscle cell activity and only slight fibroblastic proliferation. Had the limb remained intact, it would appear that the end result of such a process might have been an extensively regenerated muscle with at most focal necrosis and slight, diffuse fibrosis.

Case 31.  This 23-year-old soldier sustained an accidental gunshot wound which lacerated his left bracial artery. An anastomosis was performed. On arrival at another hospital 6 days later the hand and, to a lesser extent, the forearm were cyanotic. By the 12th day, a line of demarcation appeared 3 inches below the elbow.

An amputation was performed slightly below this level in an attempt to save the joint. On pathologic examination, the hand, wrist, and lower forearm were covered by dry, darkened skin. A short distance distal to the amputation level, the subcutaneous tissue became edematous. The superficial veins were extensively thrombosed. Here and there, the arterial system was filled with blood clots which may have been antemortem in time of formation. Sections taken through both deep and superficial muscles revealed advanced necrosis involving both fibers and interstitial tissue. The fibers were minimally to slightly separated; their cross-striations were exaggerated often to the point of disc formation. In some fibers, the striations were blurred. The nuclei were severely pyknotic. In some areas, the fibers had undergone granular disintegration. There was neither congestion nor inflammatory cell reaction. A sample of muscle taken at the level of amputation showed advanced necrosis.

Thirteen days later, on the 25th day after injury, the limb was re-amputated above the elbow joint. Pathologic examination revealed that the bracial artery was thrombosed at the level of the joint. The muscle in the specimen varied in appearance. In the upper portion, most of it seemed grossly unremarkable. Two types of muscle appeared, especially in the lower regions; one had a buff color and somewhat pasty consistency, the other had a waxy pale-yellow hue (the color of fat) and a normal consistency. Under the microscope, the grossly normal muscle showed focal fiber damage, infiltration of chronic inflammatory cells, and fibrosis, as well as small areas of in-


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farction and regeneration. However, the great bulk of the muscle was essentially normal. The pale- yellow, waxy muscle showed massive necrosis of fibers and interstitial tissue. The fibers were slightly to moderately separated from one another.

In the outer areas, exudate composed of fluid, polymorphonuclear leukocytes, and nuclear debris lay between them. Many of them showed advanced discoid necrosis; others exhibited swelling and hyalinization (see Fig. 15). The nuclei had almost entirely disappeared. At the periphery, there was marked fibroblastic proliferation and collagen formation (see Fig. 15), chronic inflammatory cell reaction, some phagocytosis of dead fibers, and regeneration of muscle nuclei. The latter, though extensive, was limited in its progress by the abundant collagen formation and was, therefore, functionally ineffectual. The section taken from the buff-colored pasty muscle showed the most advanced necrosis. Here many 'of the fibers had disintegrated to form a fusing granular mass. Most of the fibers were swollen and hya line; and discoid degeneration was not as prominent as in the previous type of muscle. In several fragments, there was a very thin layer of necrotic exudate at the periphery.

Myoglobin and hemoglobin assays of the normal appearing muscle and the pale-yellow, waxy muscle were performed according to the method of Biorck.17 The results are presented in Table 3.

Table 3. Pigment Content of Muscle*

Comments.  In this case, the muscles of the original amputated specimen exhibited changes indicating an almost complete interruption of arterial blood supply. The presence of extensive necrosis at the level of the amputation presaged the need for further surgery. The muscles in the second specimen obviously had received a better supply of blood than those in the lower forearm. Some of the former muscles were normal; others showed necrosis, but depigmentation and marked inflammatory and reparative phenomena had also occurred. The yellow waxy muscle was of great interest in that gross depigmentation was accompanied by a marked decrease of myoglobin content.


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References

1. Harman, J. H.: A Histological Study of Skeletal Muscle in Acute Ischemia. Am. J. Path. 23: 551, 1947.
2. Clark, W. E. LeG.: An Experimental Study of the Regeneration of Mammalian Striped Muscle. J. Anat. 80: 24, 1946.
3. Mallory, T. B.: Pathology of the Crush Syndrome in Battle Casualties, p.272,  The Physiologic Effects of Wounds. Office of The Surgeon General, Department of the Army, Washington, D. C.,1952.
4. Wilson, W. C.: Occlusion of the Main Artery and Main Vein of a Limb. Brit. J. Surg. 20: 393, 1932.
5. Miller, H. H., and Welch, C. S.: Quantative Studies on the Time Factor in Arterial Injuries. Ann. Surg. 130: 428, 1949.
6. Harman, J. W.: The Significance of Local Vascular Phenomena in the Production of Ischemic Necrosis in Skeletal Muscle. Am. J. Path. 24: 625, 1948.
7. Brooks, B.: Pathologic Changes in Muscle as a Result of Disturbances In Circulation. An Experimental Study of Volkman's Ischemic Paralysis. Arch. Surg. 5: 188, 1922.
8. Barnes, J. M., and Trueta, J.: Arterial Spasm. An Experimental Study. Brit. J. Surg.,30: 74, 1942.
9. Lewis, R. B.: Pathogenesis of Muscle Necrosis Due to Experimental Local Cold Injury. Am. J. Med. Sci. 222: 300, 1951.
10. Clark, W. E. LeG.: Quoted by J. R. Hughes, Ischemic Necrosis of the Anterior Tibial Muscles Due to Fatigue. J. Bone and Joint Surg. 30B: 581, 1948.
11. Montagnani, C. A., and Simeone, F. A.: Observations on the Liberation and Elimination of Myohemoglobin and of Hemoglobin After Release of Muscle Ischemia. Surgery, 34: 169, 1953.
12. Bowden, R. E. M., and Gutmann, E.: The Fate of Voluntary Muscle After Vascular Injury in Man. J. Bone and Joint Surg. 31B: 356, 1949.
13. Griffiths, D. L.: Volkmann's Ischaemic Contracture. Brit. J. Surg. 28: 239, 1940-1941.
14. Bywaters, E. G. L.: Ischemic Muscle Necrosis. J. A. M. A. 124: 1103, 1944.
15. Belsey, B.: Discussion on the Effects on the Kidney of Trauma to Parts Other Than the Urinary Tract, Including Crush Syndrome. Proc. Roy. Soc. Med. 35: 321, 1941.
16. Blomfield, L. B.,: Intramuscular Vascular Patterns in Man. Proc. Roy. Soc. Med. 38: 617, 1945.