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Pharmacology and therapeutics Blackwell Oxford, International IJD © 0011-9059 46 2007 The UK Publishing, International Journal of Ltd. Dermatology Society of Dermatology

Practical guidelines for the management of toxic epidermal necrolysis and Stevens–Johnson syndrome ManagementRamos-Caro, Fromowitz, PHARMACOLOGY of TEN and and THERAPEUTICS and SJS Flowers

Jeffrey S. Fromowitz, MD, Francisco A. Ramos-Caro, MD, and Franklin P. Flowers, MD

From the Department of Medicine, Division of Dermatology and Cutaneous Surgery, University of Florida College of Medicine, and Dermatology and Cutaneous Surgery Section, Malcolm Randall Veterans Administration Medical Center, Gainesville, Florida

Abstract Toxic epidermal necrolysis and Stevens–Johnson syndrome are acute life-threatening dermatoses characterized by extensive sloughing and mucositis. At the University of Florida, we use practical guidelines for the management of these gravely ill patients. These can be of help to other practitioners.

Correspondence Francisco A. Ramos-Caro, MD Division of Dermatology and Cutaneous Surgery University of Florida College of Medicine PO Box 100277 Gainesville, FL 32610-0277 E-mail: Ramosfa@medicine.ufl.edu

Introduction Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life-threatening dermatoses characterized by extensive epidermal sloughing and mucositis. This sloughing and mucositis result from extensive keratinocyte apoptosis. The increased morbidity and mortality associated with these conditions require rapid diagnosis and initiation of treatment. In 1991, our group at the University of Florida published a review on TEN which included our management approach at the time.1 Over the years, our residents have used it when they approach these gravely ill patients. We have updated these guidelines for the residents at our institution to reflect current advances, such as the use of intravenous immunoglobulins (IVIGs).2–4 It is our hope that these guidelines (Table 1) will serve to assist other physicians at other institutions. Discussion

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TEN and SJS are characterized by extensive keratinocyte apoptosis that is, at least in part, mediated by the interaction of the fas receptor and fas ligand.2,5 Both laboratory investigation and human studies have shown that IVIG blocks fas ligand binding to the fas receptor, and interferes with the downstream signaling responsible for programmed cell death.2 International Journal of Dermatology 2007, 46, 1092–1094

We manage both TEN and SJS in a similar fashion as, from a practical standpoint, they both behave similarly and both carry significant morbidity and mortality. Our choice of IVIG over other immunosuppressive agents is supported by two recent papers.2,4 IVIG is prepared from pooled plasma, and contains many variable immune antibodies that interfere with the apoptotic pathway by blocking the binding of the fas ligand and receptor.2 If fas ligand and receptor binding has occurred prior to giving IVIG, downstream signaling continues unperturbed and programmed cell death follows. This emphasizes the importance of rapid disease recognition and treatment within 48–72 h from the start of bulla formation; however, we use IVIG in patients outside this window if new lesions continue to develop. We view this clinical observation as indirect evidence of continued fas to fas ligand binding, and these patients may still respond to IVIG. The dosage and infusion time recommended originate from the work of the TEN-IVIG Study Group.2 We use sucrose-depleted IVIG to minimize the risks of renal failure. The use of IVIG in patients with immunoglobulin A (IgA) deficiency is contraindicated because of increased risks of anaphylaxis. Postponing treatment with IVIG whilst awaiting the results of IgA levels may not always be practical because of the different laboratory turnaround times at each institution. In this case, the decision to treat with IVIG may be based on a thorough history, specifically querying the patient with regard to problems with recurrent sinopulmonary and gastrointestinal infections.6 © 2007 The International Society of Dermatology


Fromowitz, Ramos-Caro, and Flowers

Management of TEN and SJS Pharmacology and therapeutics

Table 1 University of Florida management guidelines for toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

Admit patient directly to the burn intensive care unit (BICU) or an intensive care setting Discontinue corticosteroids if they are being used to treat the eruption Discontinue unnecessary medications and suspect medications Obtain baseline laboratory tests, such as complete blood count, liver function tests, metabolic panel, chest X-ray films, and any other appropriate imaging or serologic tests, including an immediate (stat) immunoglobulin A (IgA) serum level Look carefully for evidence of infection Obtain punch biopsies of skin for diagnosis confirmation. An alternative for rapid diagnosis is removal of a bulla roof for immediate frozen sections to differentiate between TEN and staphylococcal scalded skin syndrome (SSSS) Culture skin, blood, body orifices (as appropriate), and urine daily to monitor for early infection, and keep abreast of changing antibiotic sensitivities Use systemic antibiotics only for documented infections or signs of sepsis Place large-bore intravenous lines or a central venous line in an area of uninvolved skin to ensure adequate intravenous access If within 48–72°h of bulla onset, use intravenous immunoglobulin (IVIG), sucrose depleted, 1 g/kg/day for 3 days infused over 4 h. If 72 h have passed, but the patient is still actively progressing with new lesions, IVIG may still be useful Monitor fluid and electrolytes closely and begin total parenteral nutrition (TPN) in patients unable to take nourishment. Fluid replacement need not be as aggressive as for burns of same extent Debridement of necrotic and desquamating areas may be performed Consult ophthalmology to assess ocular involvement Consult otorhinolaryngology to evaluate extent of upper respiratory tract involvement Further consultations driven by patient condition (i.e. internal medicine to manage comorbidities, pulmonary medicine for airway involvement, gastroenterology for alimentary involvement, and gynecology or urology for genitourinary involvement) Physical therapy daily to preserve limb mobility Pain relief measures, such as patient-controlled analgesia (PCA) pump Hydrotherapy (whirlpool) if needed Nonstick dressings to denuded areas, saturated with 0.5% silver nitrate impregnated every 3–8 h as needed. Pre-impregnated dressings with silver nitrate are an alternative Avoid sulfa-containing topical or systemic preparations Oral care with chlorhexidine rinses and white petrolatum to lips Air-fluidized bed to minimize shearing force Keep room warm to prevent hypothermia Foley catheter and nasogastric tube placement only when necessary Avoid unnecessary manipulation of skin. Adhesive tape should not be applied directly to involved skin when possible Baby shampoo for cleansing hairy areas daily Mineral oil or petrolatum for dry skin Skin substitute grafting (porcine xenografts or artificial skin) based on BICU protocol

The volume of fluid administered with IVIG also provides some degree of volume resuscitation. TEN/SJS patients do not have the same fluid volume requirements as burn patients, and caution must be taken not to cause fluid overload in these patients. Corticosteroids have been used in the management of these conditions; however, their use is controversial and studies have demonstrated increased mortality in corticosteroidtreated groups.7,8 Corticosteroid-induced down-regulation of nuclear factor kappa beta (NFκβ) in the presence of elevated tumor necrosis factor-α levels may be proapoptotic, and may account for these observations.3 Meticulous wound care is fundamental to improving patient outcomes and minimizing the risks of wound infection or sepsis. Wet dressings impregnated with silver nitrate maintain a moist wound environment, speed reepithelialization, minimize pain, and decrease infection rates.9,10 Hypothermia and hyponatremia are risks associated with the use of these dressings to large body surface areas. We © 2007 The International Society of Dermatology

avoid the use of sulfa-containing products because of the risk of systemic sensitization and leukopenia. The use of air-fluidized mattresses helps to reduce the shearing forces of a traditional mattress, as well as the development of pressure ulcers. Attention must also be paid to the mucous membranes and the pain associated with the mucositis seen in TEN and SJS. White petrolatum acts as an appropriate occlusive dressing to speed healing and minimize the pain of chelitis. Chlorhexidine rinses help minimize colonization of the damaged mucous membranes and maintain good oral hygiene. The use of skin substitutes and wound debridement varies amongst burn centers. In our center, mechanical debridement with whirlpool, or sharp debridement in the operating room under anesthesia, is used if large areas of necrotic tissue are present. Debridement removes a potential nidus of infection and speeds wound healing by removing a barrier to reepithelialization. Skin substitutes may be used depending on the degree of debridement and body surface area involvement. International Journal of Dermatology 2007, 46, 1092–1094

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References 1 Avakian R, Flowers FP, Araujo OE, et al. Toxic epidermal necrolysis: a review. J Am Acad Dermatol 1991; 25: 69– 79. 2 Prins C, Kerdel FA, Padilla S, et al. Treatment of toxic epidermal necrolysis with high dose intravenous immunoglobulins. Arch Dermatol 2003; 139: 26–32. 3 Chave TA, Mortimer MJ, Sladden MJ, et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 2005; 153: 241–253. 4 Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens–Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics 2003; 112: 1430–1436. 5 Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a

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mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996; 134: 710 – 714. Cooper MA, Pommring TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician 2003; 68: 2001–2008. Murphy JT, Purdue GF, Hunt JL. Toxic epidermal necrolysis. J Burn Care Rehabil 1997; 18: 417–420. Kelemen JJ III, Cioffi WG, McManus WF, et al. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180: 273–280. Lehrer-Bell KA, Kirsner RS, Tallman PG, et al. Treatment of the cutaneous involvement in Stevens–Johnson syndrome and toxic epidermal necrolysis with silver nitrate impregnated dressings. Arch Dermatol 1998; 134: 877–879. Heimbach DM, Engrav LH, Marvin JA, et al. Toxic epidermal necrolysis: a step forward in treatment. J Am Med Assoc 1987; 257: 2171–2175.

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