Cocaine-Induced Full-Thickness Tissue Necrosis

Sir: Cocaine is a commonly abused drug that leads to approximately 500,000 emergency room visits annually in the United States.1 The cocoa plant, Erythroxylum coca, was chewed in the fifteenth century by Peruvians, causing stimulant effects on the central nervous system that curbed the cold, hunger, and monotony of life in the Andes Mountains. As its medicinal properties were discovered, so too was its highly addictive nature. In 1886, Coca-Cola added the powdered form of the drug to its soft drink recipe, and in 1922, the Dangerous Drugs Act made cocaine consumption illegal.2 Today, it is estimated that nearly 2 million Americans abuse cocaine regularly, and each day 1700 individuals try cocaine for the first time.1 Cocaine’s physiologic effects lead abusers to seek medical attention. Cardiopulmonary, psychiatric, and neurologic sequelae are well documented. Fortunately, few patients require hospitalization and mortality remains low, occurring in less than 1 percent of abusers presenting for medical attention.3 Patients with vasculitic skin lesions and life-threatening agranulocytosis secondary to cocaine use have been reported in recent literature.4 We describe our experience with another manifestation of cocaine use, consisting of full-thickness tissue necrosis requiring prompt surgical treatment. Approval was obtained from our institutional review board. We conducted a retrospective review of patients referred to the Southern Illinois University’s Regional Burn Center with vasculitic-appearing skin lesions that evolved into full-thickness tissue necrosis between December of 2010 and June of 2011. Patients’ medical records were reviewed to obtain demographic information and medical history. Incisional biopsy specimens were obtained, and the histologic specimens were reviewed by a single dermatopathologist at our own institution. Serum immunology studies, medical course, and surgical management were compared. With appropriate consent, photography of the skin manifestations and resultant soft-tissue defects was used to document the natural history of the disease process. Drug paraphernalia was obtained from one patient with the approval of our institutional review board for extraction and analysis of the drug. Four patients were identified for inclusion. These patients consisted of one man and three women aged 37 to 50 years. All patients admitted to recent drug use, and urine toxicology confirmed cocaine in all cases. Primary complaints at the time of presentation included fatigue, polyarthralgia, fever, and the development of new skin lesions. Cutaneous involvement resembled a vasculitis, with poorly demarcated purpura located diffusely over the body. Areas of involvement included the upper extremities, torso, breasts, and lower extremities. All four patients had involvement of the upper extremities, hands, and helices of their ears. Patients were candid regarding their drug use and history of substance abuse. Three patients admitted to smoking crack cocaine, and one patient had snorted the drug in powder form. All patients were admitted for observation, and no further cocaine use was detected after admission. Despite abstinence from the drug, their cutaneous lesions continued to progress. All four patients developed thick, black eschars and full-thickness tissue loss of 10 to 20 percent of their total body surface area within the next 2 to 6 weeks. Three of four patients had a documented history of one or more autoimmune diseases. These diagnoses included autoimmune hemolytic anemia, rheumatoid arthritis, antiphospholipid antibody syndrome, and the catastrophic antiphospholipid syndrome variant. The remaining patient had symptoms and serologic evidence of systemic lupus erythematosus but did not carry the formal diagnosis. Vasculitis was suspected in all patients at presentation. Rheumatologic workup consisted of serologic studies to identify an autoimmune cause. Consistent with their medical histories, all patients were found to have positive autoimmune antibodies (Table 1). One patient was found to have anticardiolipin antibodies consistent, with antiphospholipid antibody syndrome, totaling three patients with this diagnosis. Two of our patients demonstrated positive antinuclear antibodies, perinuclear antineutrophil cytoplasmic antibodies, double-stranded DNA, and lupus anticoagulant titers. Other identified antibodies found in a single patient included rheumatoid factor, cyclic citrullinated peptide antibody, anti-Proteus antibody, and antistreptolysin antibody. Despite the many antibodies identified, the specific combinations of titers in conjunction with the clinical presentations were not sufficient to arrive at an autoimmune diagnosis as a causative entity in any patient.Table 1: Autoimmune Antibodies Identified in Patients at the Time of PresentationFull-thickness skin biopsy specimens from the margins of the purpura were obtained at the time of admission and evaluated by a single dermatopathologist at our institution. One biopsy was delayed until the patient’s operative débridement, and this specimen revealed advanced necrosis. The remaining biopsy specimens showed multiple microthrombi within the superficial and deep dermal vessels (Fig. 1). However, distinguishing the process from a true vasculitis, there was an absence of inflammatory cells seen in specimens from all three patients.Fig 1: Hematoxylin and eosin–stained specimen showing microthrombi within the superficial and deep dermal vessels with a paucity of inflammatory cells.At presentation, all lesions were superficial and treated conservatively using Xeroform petrolatum gauze (Covidien, Mansfield, Mass.) and bacitracin ointment. Despite abstinence from further cocaine use and diligent local wound care and hygiene, the purpura did not resolve. The once patchy areas of purpura evolved into large, confluent, full-thickness eschars in all patients. These full-thickness wounds were dressed with topical silver sulfadiazine cream to enhance eschar penetration (Fig. 2). Surgical débridement of these full-thickness wounds was necessary.Fig. 2: All purpura progressed into eschars and full-thickness tissue necrosis.At the initial débridement, the large eschars were removed with electrocautery. As the eschars were lifted away, pockets of purulence were identified in all patients. After irrigation and débridement, the resultant soft-tissue defects were covered with E-Z Derm Porcine Xenograft (Brennen Medical LLC, Saint Paul, Minn.) (Figs. 3 and 4). Two of the patients demonstrated adherence of the xenograft and formation of healthy granulation tissue and were taken to the operating room within 1 week for definitive split-thickness skin grafting (Fig. 5). The autograft in both patients healed, and the patients had no further skin lesions at the time of discharge. At 1-year follow-up, these patients’ wounds remained closed.Fig. 3: Application of xenograft after initial operative débridement.Fig. 4: Adherence of xenograft to healthy wound bed.Fig. 5: Definitive closure with split-thickness skin grafts.Despite aggressive débridement, one patient continued to have progression of his wounds. He required five staged operative débridements and, after each, continued to demonstrate necrosis of adipose tissue and muscle at the base of the wounds (Fig. 6). In this patient, the necrosis appeared to progress in a vertical fashion as opposed to a radial pattern. His residual wounds were managed with negative-pressure therapy (V.A.C. Therapy; KCI, Inc., San Antonio, Texas) over the ensuing months. All wounds were healed 10 months after initial débridement.Fig. 6: One patient demonstrated continued loss of skin grafts with progressive necrosis. His wounds were eventually closed with the aid of a negative-pressure dressing.One morbidly obese patient had a clinical course that differed from the others. Her lesions first appeared on her upper extremities, breasts, and under her pannus. Despite local wound care and abstinence from cocaine, her lesions progressed to full-thickness necrosis. The necrosis of her pannus included a previous Pfannenstiel incision overlying a known ventral hernia. She spontaneously eviscerated through the necrotic tissue and was taken to the operating room emergently for closure. Acellular dermal matrix was used to bridge the fascial defect, and her redundant skin allowed for primary skin closure. Laboratory evaluation of the drug paraphernalia from one patient was analyzed. An extraction with butylacetate was made from a rinsing of the residual powder drug on a glass pipe. Along with cocaine, the drug levamisole was also found on the pipe. Nearly 25 million Americans have used cocaine, yet very few people have presented with this devastating tissue reaction.2 It appears that there is something different about the autoimmunity of these patients that may makes them more susceptible to the effects of the drug. Given the history of cocaine use spanning more than two centuries, there may also be something different about today’s cocaine that is capable of causing this full-thickness tissue necrosis in a susceptible patient. The cocaine bought on the street on average contains only 69 percent cocaine hydrochloride.5 A variety of substances are added or “cut” into the powder, and cocaine bought in the United States ranges in purity, with some samples containing essentially no cocaine at all. An adulterant is something that is added to cocaine purposefully to potentiate its effects or to increase the bulk and weight of the product. Low-cost items such as talc and baking soda are cut into cocaine by dealers to increase the quantity of the product and thus their profit. Medications and other drugs including lidocaine, caffeine, and methamphetamine may also be added for their stimulant properties. In 2005, a new adulterant, levamisole, was detected in cocaine seized in the United States. Not only was this a new substance never before detected in cocaine, it was peculiar that the product was already cut into the cocaine before it reached the United States because, typically, cocaine is transported into the United States in its pure powder form. Adulterants are added both in metropolitan hubs and by local dealers before distribution of the drug to consumers. In 2008, the U.S. Drug Enforcement Administration estimated that 10 percent of cocaine imported into the United States was laced with levamisole. In 2011, 82 percent of cocaine imported into the United States already contained the chemical. This has been reported not just in the United States, but also in Canada, the United Kingdom, and Italy.2 More recently, heroin samples laced with levamisole have also been identified.6 Historically, levamisole was used for the treatment of metastatic colon cancer. Its use quickly fell out of favor, as it showed no benefit in the treatment of the disease.7 It was then used for its immunomodulating effects in the nephrotic syndrome in children. After prolonged clinical trials in Europe, numerous case reports had evidence linking levamisole to autoimmune vasculitis in many of the children. The resultant vasculitis consisted of diffuse purpura, agranulocytosis, hepatosplenomegaly, and circulating autoimmune antibodies. In one clinical trial, five of the 150 enrolled children developed a severe vasculitis, leading to premature termination of the study.8 Levamisole was removed from the U.S. market in 2000 and the Canadian market in 2003. Levamisole is now used solely in veterinary medicine as an antihelminthic to deworm cattle, pigs, sheep, and other livestock. The drug has a half-life of just 4 hours, making its detection difficult. In August of 2010, the New York State Department of Health issued a public advisory, warning of the dangers of cocaine cut with levamisole. Symptoms included agranulocytosis and purpura of the ears and face, which were reportedly self-resolving with cessation of the contaminated cocaine.9 Numerous case reports began to surface. Two patients in Rochester, New York, were identified as having agranulocytosis and pruritic plaques of the cheeks and auricles. Both resolved completely with abstinence from cocaine.10 Emergency medicine physicians recommended screening drug abusers for both cocaine and levamisole metabolites if their presentation was unusual or their symptoms unexplained by cocaine ingestion alone.11 In Alberta and British Columbia, mandatory reporting of neutropenia associated with levamisole-tainted cocaine was instituted, and 42 cases of confirmed or probable agranulocytosis were identified. There was no mention of associated cutaneous manifestations in their report.12 Multiple other cases of neutropenia and purpura have since been reported. All but one case demonstrated complete resolution of skin lesions with nonoperative management.13–15 One patient was reported to have involvement of 15 percent total body surface area and required grafting and treatment in a local burn unit, but the details of her surgical management were not described further.15 The presentation of our patients strongly parallels others in the literature. However, in all but one case reported, complete resolution of the skin lesions occurred with abstinence from cocaine. In startling contrast, our patients’ clinical courses were much more aggressive, and each went on to develop devastating full-thickness tissue necrosis. Surgical débridement and reconstruction were necessary in all of our patients. Levamisole was not suspected at the initial presentation of our patients and therefore all patients were outside the window of detection. However, we were able to detect the adulterant in the cocaine itself. With the legal approval of our institution, permission from our institutional review board, and the cooperation of one of our patients, we were able to obtain his drug paraphernalia. In the laboratory, an extraction with butylacetate was made from a rinsing of the residual drug on a glass pipe. As anticipated, the adulterant levamisole and cocaine were identified on the pipe. Although we were able to identify levamisole on one patient’s drug paraphernalia, we were unable to quantify the amount of adulterant in the sample or calculate the purity of the cocaine. Because of the more severe cutaneous manifestations in our patients, it is possible that a more contaminated batch of cocaine was responsible for this reaction. Levamisole may have caused an irreversible thrombus formation, tissue hypoxia, and full-thickness loss that was not seen with smaller quantities of ingestion. The significance of the autoimmune profile of our patients remains unclear. The immunomodulating effects of levamisole have been studied extensively, yet its method of action remains elusive. Levamisole has been found to alter the delicate balance of cytokines and shift the immune response from a type 2 response (predominantly interleukin-4) to a type 1 response (interferon-gamma) in a rat model.16 Patients with certain autoimmune diseases also display a similar imbalance, with an overactive type 1 response and high levels of interferon-gamma. A significant increase in levels of serum interferon-gamma correlates with active clinical disease in both systemic lupus erythematosus and mixed connective tissue diseases.17 In patients with known autoimmune diseases, the administration of interferon-gamma results in a fulminant and aggressive form of systemic lupus erythematosus.18 Therefore, in patients with a predilection for autoimmunity and an innate overexpression of a type 1 immune response, the addition of levamisole may further augment this imbalance and lead to clinical disease. This would suggest that certain individuals are at higher risk of the effects of levamisole because of their underlying disease processes, whereas others without a predisposition for autoimmunity consume the contaminated cocaine without consequence. Although the reason for the sudden appearance of levamisole in cocaine and its mechanism of action have yet to be elucidated, its medical sequelae have hastily demanded the attention of our specialty. As reconstructive surgeons, we must be aware of this new disease process, which is no longer simply a dermatologic phenomenon but a surgical one. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article. Ashley N. Amalfi, M.D. Michael W. Neumeister, M.D. Reuben A. Bueno, Jr., M.D. Nicole Zook Sommer, M.D. Erika A. Henkelman, M.D. Southern Illinois University School of Medicine Institute for Plastic Surgery Springfield, Ill.

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