Arthur R. Hagen, M.D. Joseph G. Matthews, M.D. Joseph J. Nixon, M.D.
Gangrene of the extremities has been reported in newborns and infants as a complication of several disease entities: congenital deformities of the distal extremity complicated by constrictive amniotic bands(1); arterial or venous occlusion associated with dehydration(2); sepsis(3); vascular injuries, venous thrombosis and clotting disorders have been implicated in gangrenous sequelae associated with such disease processes as pneumonia, rubella, and varicella(4).
This paper reports on a case of gangrene of the lower extremities in a three-year-old white female as an aftermath of chickenpox.
On December 27, 1964, W.F., a three-year-old Caucasian female, was admitted with a chief complaint of chickenpox of one week's duration, purpura on the day of admission, and hematuria on the evening of admission. She had had coryza and a nondescript rash approximately seven days prior to her admission, and a day later, the typical lesions of chickenpox had developed. The last new lesions developed three days later and on the day of admission she was noted to have purpura which was most marked on the legs but with several small purpuric areas on the trunk. The evening of her admission she had passed a small amount of smoky urine.
Her initial physical examination revealed an acutely ill child who weighed approximately 30 pounds. Her temperature was 100°, and pulse 90. Recorded blood pressure was 96/0 with a respiration rate of 34. Three huge purpural lesions were evident on the legs and several small ones noted over the remainder of the extremities. Several lesions one-quarter to three-quarters of an inch in diameter were present on the trunk. Numerous healing pox were present over the body. The mucous membranes of the respiratory tract were reddened. She was noted to move all extremities well. No comment was made in the case history as to the peripheral pulses in the extremities on admission.
On admission, a complete laboratory work-up was done. It was noted that the patient's platelet count was 62,000, with a hematocrit of 28 percent and hemoglobin of 10.2 gm. White blood cell count was 9,250, with 10 percent bands, 58 percent lymphocytes, 3 percent monocytes, and 28 percent neutrophils. The red blood cell count was 3.1 million. The urine showed gross blood albuminuria (4-plus), and was strongly positive for acetone. Blood urea nitrogen (BUN) was 34 mg percent. On initial laboratory studies prothrombin time was normal, as well as the partial thromboplastin time (PTT). The patient was placed on intravenous fluids, penicillin, and Kantrex. A lumbar puncture yielded clear fluid and no growth. On December 28, after 200 cc of fresh blood, the platelet count was repeated and it was down to 32,000. The child was given three units of platelet concentrate and placed on Solu-Cortef.
Because of the increasing edema of the left lower extremity, vertical fasciotomies were done. On the medial aspect of the left calf, the incision extended from the medial malleolus to the level of the tibial plateau and penetrated through the subcutaneous tissue and underlying superficial fascia. Extensive old hemorrhage with a considerable amount of port wine stain was noted in the subcutaneous tissues of the wound together with massive edema of the muscles. Several incisions were made on the lateral aspect of the leg also and a third incision was made on the dorsum of the foot. The wound was packed lightly with fresh Furacin gauze.
Transfusions and Chemotherapy
On December 29, 1964, massive hemorrhaging occurred into the soft tissues of the right lower extremity, the toes became cold and cyanotic, and shock ensued. Transfusions with fresh blood were accomplished. Her blood at that time was reported to clot readily, with a good solid clot described. PTT was normal and the prothrombin time was increased slightly. Because of the desperateness of the situation, the patient was placed on fibrinogen and epsilon-aminocaproic acid treatment was initiated. Early on December 30, fasciotomies were done on the right leg which, with the right foot, was deeply cyanotic and cold. The child was given 200 cc of fresh blood. Following the procedure, there appeared to be some improvement in the extremity, while at surgery the muscles had appeared viable. Ecchymosis was noted over the right supraspinatus area.
The provision of large doses of Vitamin C was begun, and fibrinogen and SoluCortef were discontinued. High doses of Decadron (4 mg every 6 hours) were started on December 30th. After three days, the dosage of Decadron was gradually reduced and the medication was completely discontinued on February 3rd.
On January 2, 1965, her appetite became poor as was her general intake. Her dressings were changed and the leg photographed (Fig. 1 ). Muscles over the posteromedial aspect of the left leg appeared black and necrotic and the skin was dark blue from the upper thigh to the foot. On the right leg the skin was dark blue from the knee down. Bullous formation was noted to follow on January 3rd, and on January 5th, when the dressings were changed, the left leg appeared necrotic.
Irreversible Gangrene and Amputation
On January 7th, the patient continued to have a poor appetite and a poor intake. Her dressings were changed on January 11, 1965,and irreversible gangrene of both lower limbs was noted. Amputations were then planned.
On January 13, 1965, the 18th day of hospitalization, disarticulation of the right knee and a high amputation of the left thigh were performed. Because of the conservatism of the amputation level, the patient required debridement and a dressing change on January 26, 1965. On February 16th both stumps were skin-grafted;and on February 19th the dressings were changed again. A repeat skin graft to the right thigh and posterior stump was done on March 1, 1965, and a final skin graft to the right stump was necessary on March 8, 1965. On discharge, the left thigh was healed and a small amount of granulation was noted around the skin graft on the posterior portion of the right thigh. On March 29th, the patient was seen at the Florida Crippled Children's Commission and was noted to have a left hip flexion contracture of five to ten degrees with a ten to 15 degree abduction contracture. She was scheduled to attend Forrest Park School for physical therapy to reduce her contractures.
On May 1, 1965, she was seen at the Amputee Clinic for the first time (Fig. 2A/2B ). Due to lack of parental cooperation, her first prosthesis was delayed and she was admitted to Harry Anna Hospital for Crippled Children to receive additional physical therapy.
On June 24, 1965, a standard knee-disarticulation prosthesis for the right limb was prescribed. It incorporated an anterior elastic strap to stabilize the knee and a pelvic band to maintain the leg in a relatively abducted position. On August 26, 1965, the patient had received her right prosthesis and was learning to balance herself using a three-point gait. On September 9, 1965, a Canadian hip-disarticulation prosthesis was ordered for the left side, with an extension strap over the knee for stability. The pelvic band of the right knee-disarticulation prosthesis was attached to the hip-disarticulation socket (Fig. 3 ).
In December of 1966, the patient was walking with a four-point gait and using a walker with wheels. She also demonstrated early four-point gait with crutches and was soon to master this method of ambulation. On June 23, 1966, her permanent plastic socket was ordered for the left amputation and fitted. In February of 1967, she was ambulating satisfactorily with two quadripod canes (Fig. 4 ). She insisted on maintaining the left knee in complete extension as this gave her a little more confidence. At present she is ambulating with a four-point gait and two canes, but she still retains the extended knee (Fig. 5 ).
Pathological sections of the vascular structures of the lower extremities (Fig. 6 A/B , Fig. 7 , Fig. 8 A/B and Fig. 9 ) revealed the presence of organized vascular thrombosis. The small arterioles were occluded partially by hyalin and fine granular eosinophilic material, partially covered by an endothelial lining. A fibrinoid degenerative process was noted in the vascular walls.
Varicella usually is regarded as a trivial condition except for the few and rare complications such as fatal nephritis, septicemia, empyema, inflammatory eye conditions, and the rare occurrence of hemorrhagic forms.
In 1807, Dr. Woodley Stokes of Dublin, Ireland, described this condition which was commonly known as "burnt holes" and "eating hives." Dr. Stokes referred to it as "pemphigus chickenpox."
In 1881, Jonathan Hutchinson5 also described the condition, for which he coined the term VARICELLA GANGRENOSA. He reported on 15 patients, nine of whom were debilitated. Six of the debilitated patients had tuberculosis and three others had other chronic lung diseases. Six, however, were otherwise healthy children, an important finding, as tuberculosis had been considered to be a primary etiological factor. Hutchinson, therefore, proposed that an individual susceptibility to varicella was the cause of the disease.
The incidence of this condition is not known. Barenberg and Lewis6 reported one case of varicella in 2,000 admissions. Wishik and Bullowa7 studied 2,554 patients over a five-year-period and found four patients who had developed this complication. In three of these instances varicella was associated with streptococcal cellulitis.
No sex predominance has been detected. Two cases have been reported in Negroes 8. The ages of the reported cases ranged from four and one-half months to 11 years. The onset of gangrene occurs between four to eight days after the onset of chickenpox and has been reported as late as the eleventh day. There is no known relationship between the occurrence of gangrene and the severity of the varicella.
The clinical picture usually presents the child as fretful and febrile. Erythema is first noted over the extremity, followed by edema and ecchymosis with an increase in size of the affected area. The scrotum or vulva is frequently edematous and ecchymotic
due to retroperitoneal hemorrhage (Fig. 10 ). Blister formation ensues, followed by tissue necrosis. The trunk will frequently be involved as well as the internal organs, with massive microthrombi which accounts for the severity of the systemic symptoms. The gangrenous lesions of the extremity are more common, however, probably the result of trauma from handling which aggravates the underlying disease process. Prior to antibiotics, death occurred in more than 50 percent of the reported cases. Autopsy specimens have shown intravascular clots, venous or arterial. An abnormal fibroblastic proliferation occluding the vessel lumen has been reported as the cause of the interruption of the vascular supply in at least one case9.
With the first description of this entity in 1807, tuberculosis was regarded as the causative factor because of the frequency of its association with varicella gangrenosa. In 1881 Hutchinson 5 postulated an individual susceptibility to chickenpox virus; but in 1903, Edwards10 again associated the secondary infection of varicella vesicles with tuberculosis. In 1914, Storie11 described two forms-one hemorrhagic, and the other a gangrenous form, but still thought them to be related to tuberculosis.
In 1951, the individual susceptibility theory was again discussed and was thought to have the same etiological background as the Schwartzman phenomenon. Several clotting defects were noted in association with the disease, namely factors 5 and 7, prothrombin, platelets, fibrinogen, and the appearance of excessive amounts of antithrombin 3.
The Schwartzman phenomenon has been described by Bouhasin12 as occurring in three stages: the first stage as a response to a specific antigen is characterized by polymorphonuclear leucocytes migrating into a prepared skin site to form cuffs about the smaller veins. Secondly, following an intravenous challenging dose of this antigen, a rapid clumping of the circulatory platelets and polymorphonuclear leucocytes occurs. At the prepared skin sites, capillaries and small veins exhibit a marked vulnerability to occlusion by the clumping platelets and polymorphonuclear leucocytes which produces intravascular clotting. With this interruption of the blood supply, death and disintegration of the walls of the involved vessels ensue with bleeding into the tissues through the necrotic vessel walls, characterizing the third stage of the phenomenon.
Ratnoff and Conley13 demonstrated that a slow intravenous infusion of thromboplastin in dogs resulted in hypofibrinogenemia, and a prolonged clotting time disproportionate to the hypofibrinogenemia was produced. If rapid infusions were used, death occurred as a result of massive thrombosis.
Granulocytopenia14 and thrombocytopenia are common in varicella gangrenosa. Perivascular cuffing by the polymorphonuclear leucocytes has been demonstrated in the early vesicles of chickenpox as is also noted in the Schwartzman phenomenon12. The thrombocytopenia and granulocytopenia may result from the cuffing to produce a progressive intravascular clumping of platelets and clot formation followed by vessel wall necrosis, circulatory embarrassment, hemorrhage and edema. These events then lead to further circulatory embarrassment with tissue necrosis and gangrene. The widespread coagulating process seen late in the second stage of the Schwartzman phenomenon may result in depletion of the fibrinogen. The rapidity of this process may be compared to the results obtained in the experiments of Ratnoff and Conley13 and, if progression is rapid, it may produce extensive intravascular clot formation rather than microthrombi depletion of the fibrinogen.
In reviewing the clotting mechanism, Leavell and Thorup15 proposed that the extrinsic or tissue factors combined with the intrinsic, or blood factors, to produce the thromboplastin activity. This substance acts upon the prothrombin to give thrombin, which in turn acts upon fibrinogen to produce the fibrin clot. The intrinsic factor includes the platelets which, on rupture, release an active substance from their granules which is thought to be ethanolamine phosphatide and serotonin, which produce vasoconstriction. Other factors present in the plasma are anti-hemophiliac factor (AHF), plasma thromboplastin component (PTC), plasma thromboplastin antecedent (PTA) and the Hageman factor; and these substances play a role in the thromboplastin activity. When combined with the extrinsic tissue factors, as might occur following the intravascular clumping of the platelets and polymorphonuclear leucocytes as seen in varicella, a fibrin clot develops. The rapid and widespread perivascular clumping and clot formation associated with viremia may determine the clinical form which will occur, such as one of primary gangrene associated with thrombus formation or secondary gangrene following an initial hemorrhagic form as suggested by Storie11.
In addition to the general supportive care of the patient, treatment should be undertaken with several essential points in mind: (1) the injured parts should be protected from further trauma; (2) infection should be prevented; (3) correction of the clotting disorder should be undertaken; and (4) amputation should be delayed whenever possible until clear demarcation has occurred.
To prevent further trauma, scratching should be prevented by gloving the hands, and by dressing the extremity with soft bulky dressings. Infrequent dressing changes are advised and, whenever performed, sterile technique should be followed.
Appropriate antibiotics should be used to treat secondary infections. Staphylococcus aureus coagulase positive and streptococcal infections are the two most common contaminants cultured in the gangrenous stumps. According to Clauson et al16, penicillin and ampicillin (Polycillin) in four equally divided doses are recommended until the results of culture and sensitivity tests are obtained. Gamma globulin has been given in the face of overwhelming infections. The correction of the clotting disorder is the most difficult. Fresh whole blood should be given to maintain blood volume and the intrinsic clotting factors but will probably be insufficient in severe cases and platelet concentrate and fibrinogen may be needed. Dextran has been advocated for the prevention of thrombosis.
Heparin has been advocated also in the treatment of this condition17 because it: (1) has the ability to block the clotting process and hence, allow the platelets and fibrinogen to be replenished; (2) inhibits Schwartzman's phenomenon; and (3) acts as an anticoagulant. Experimental results indicate that, if given before the onset of viral infection, it would be very effective. Less effect is noted if heparin is given after the viremia and initiation of the Schwartzman phenomenon and it should not be given if the third stage of vessel necrosis and hemorrhage has occurred11.
The use of steroids has proven to be of value in initiating a striking clinical improvement in cases of varicella gangrenosa. This effect is not surprising as cortisone and ACTH have long been known for their ability to block hypersensitivity.
Surgical treatment should consist of fasciotomies to relieve the tight compartments of the extremity and thus prevent further circulatory embarrassment. Conservative amputation should be performed only after demarcation has become clear, unless sepsis and general toxicity necessitates emergency amputation. Multiple skin grafts may be necessary to cover the granulating stumps.
A case of varicella gangrenosa which tends to exhibit a relationship to the Schwartzman phenomenon has been reported. A modest review of the literature has been done and suggestions made regarding management of the disease process.
Arthur R. Hagen, M.D.,Joseph G. Matthews, M.D. and Joseph J. Nixon, M.D. is associated with the Child Amputee Clinic Florida Crippled Children's Commission Orlando, Florida
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