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Current Drug Safety, 2012, 7, 361-366 361 Deciphering Supportive Treatment Strategies for Toxic Epidermal Necrolysis Serge Jennes1, Gérald E. Piérard*,2 and Philippe Paquet2

1Burn Unit, Queen Astrid Military Hospital, Brussels, Belgium 2Department of Dermatopathology, University Hospital of Liège, Liège, Belgium

Abstract: Toxic epidermal necrolysis (TEN) is a dreadful life-threatening syndrome typically induced by an adverse drug reaction. This condition is characterized by the sudden and extensive destruction of the epidermis. The patient should be promptly addressed to a burn unit where three types of treatment should be administered, namely, (a) specific topical care of the bullous/eroded skin areas, (b) systemic anti-apoptotic/necrotic treatments, and (c) supportive care preventing secondary internal organ failures. This latter aspect is covered by the present review and focuses on (a) early withdrawal of the causative drug, (b) airway management, (c) hydro-electrolytic control, (d) nutritional support, (e) antibiotherapy, (f) prevention of venous thrombosis and gastroduodenal ulcers, and (g) analgesia and anesthesia. Keywords: Drug reaction, toxic epidermal necrolysis, burn, epidermis.

INTRODUCTION sometimes influenced by pharmacogenetics [11-13]. TEN treatment requires an integrated team approach to promote Drug-induced toxic epidermal necrolysis (TEN) is epidermal healing and to secure vital organ functions [4, 14, characterized by the acute epithelial tissue necrosis 15]. Nowadays TEN still remains a life-threatening condition extending over 30% of the total body surface area (TBSA). with an overall mortality ranging from 25 to 40% [2, 16, 17]. Epidermal sloughing off commonly runs for several days Prediction of survival relies on SCORTEN assessment which (usually 10-20 days) after discontinuation of the causative represents a severity-of-illness score [18-21]. The criteria are drug. When skin detachment is limited to less than 10% of : age above 40 years, malignancy, tachycardia above 120 per the TBSA, the condition is considered as the Stevens- min, initial percentage of epidermal detachment above 10%, Johnson syndrome (SJS). When sloughing involves 10 to serum urea above 10 mmol per liter, serum glucose above 14 30% of the TBSA, it is referred to as SJS/TEN overlap [1, mmol per liter, and bicarbonate below 20 mmol per liter. 2]. New treatments are regularly offered to manage TEN [2, 22, 23], but none has been approved in large scale studies. IMPORTANCE OF TEN WOUND HEALING The purpose of this article was to revisit both some In recent years, general wound management and related systemic supportive management of TEN, and the preventive basic research rapidly progressed leading to impressive measures to counter possible secondary complications. In advances. In this field, the TEN incidence remains low, and this era of rapidly developing understanding of the TEN the literature about TEN supportive treatments is scarce. processes developed in elite laboratories of urban center, Currently, there is no established evidence-based medicine there must be anxiety that such up-to-date information is not information about TEN management. The present article readily available in the overall community. In the field of reflects a single center experience. Clearly, the causative TEN, management is still sub-optimal and one must nature of any wound influences the extent in tissue therefore welcome updated publications to help anyone in destruction. Thus, therapy must be adequately adapted. the field to understand the specific problems and advances. Traumatic wounds, burns of different depth involvement, vasculitis-related ulcers, necrotic inflammatory skin lesions, EARLY WITHDRAWAL OF THE CAUSATIVE DRUG ulcerative infections and toxic wounds are clearly distinct conditions that merit some specific management procedures Once the diagnosis of TEN is clinically suspected, the [3, 4]. Among the specific clinical entities, TEN formerly patient management begins with a thorough medical search named under its eponym Lyell’s syndrome, is characterized for disclosing the causative drug [24-26]. The first and most by a widespread apoptotic/necrotic process involving the important aspect of TEN treatment consists of the immediate epidermis and leading to its sloughing off [2, 5-8]. The discontinuation of any suspicious drug and avoidance of any dermis remains apparently intact including its vasculature. A chemically-related drug [2, 27]. If these basic measures are scarce inflammatory cell is commonly present [9, 10]. TEN neglected TEN is subject to aggravation or recurrence typically results from a dramatic drug reaction possibly leading to fatality [28]. In general, the faster the causative drug is discarded, the better the prognosis. The

most frequently disclosed drugs responsible for TEN are *Address correspondence to this author at the Department of Dermatopathology, listed in Table 1. CHU Sart Tilman, BE-4000 Liège, Belgium; Tel: 32 4 3662408; Fax: 32 4 3662976; E-mail: [email protected]

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Table 1. Drugs Commonly Responsible for TEN However, painful epidermal detachment impedes some physiotherapy procedures such as postural drainage. Antiepileptic Drugs During the initial 3-15 days of disease evolution, it is Phenobarbital occasionally necessary to protect the airways by placing an Phenytoine endotracheal tube in order to guarantee controlled Carbamazepine ventilation. The main reason for this procedure is the risk of Valproic acid combining massive sloughing, swelling and bleeding of the Lamotrigine oropharyngeal, epiglottal and bronchial mucosa, dysphagia, fatigue, weak cough, impaired airway reflexes, confusion, Sulfonamide Antibiotics cachexia and respiratory distress. However, some caregivers Sulfamethoxazole, consider TEN as a contraindication for endotracheal intubation because artificially ventilated TEN patients were co-trimoxazole (trimethoprim-sulfamethoxazole) reported to have a worse prognosis [32, 33]. However, this issue is more likely related to the poor condition of the Allopurinol patients needing ventilation rather than to the ventilation procedure itself. In fact, in some circumstances, airway Antibiotics management and ventilation rather improve the prognosis Aminopenicillins [32, 33]. Hence, when signs of respiratory distress are Cephalosporins present, the decision of airway intubation should not be Quinolones postponed by fear of worsening the prognosis. Systemic or Tetracyclines local corticosteroids are unlikely to offer benefits for airway management in TEN patients [16], except for overcoming NSAIDs bronchospasm refractory to inhaled and systemic beta2– adrenergic receptor agonists. Prevention of respiratory Oxicam distress relies on clearing the tracheo-bronchial tree from Diclofenac epithelial remnants and clots. Therefore, adequate airway management should involve bronchoscopy, incentive Pain Killers spirometry, mobilization, coughing and administration of N- Acetaminophen acetylcysteine-containing aerosols, beta2-adrenergic receptor Tramadol agonists and humidified warmed oxygen. Of note, N- acetylcysteine, a mucolytic and antioxidant agent, should be Antiretroviral Drugs administered at a 300 mg dosing per inhalation aerosol, 3-6 Nevirapine times a day, in association with or after administration of beta2-adrenergic receptor agonists like salbutamol or Others fenoterol. In addition, the administration of anticholinergic drugs like ipratropium might be considered. Sertraline Tetrazepam In our experience, intrapulmonary percussive ventilation (IPV®) using VDR3 and VDR4 ventilators is not recommended for aerosol administrations. Such limitation The patient should be admitted posthaste to a specialized tends to avoid aggravation of the mucosal detachment and medical department, usually a burn unit [4]. It has been subsequent bleeding inside the tracheobronchial airways. If stated that the rapidity of this management step directly airway obstruction persists despite the above-mentioned governs the survival rate [28-30]. However, this opinion is measures, IPV® can ultimately be used in combination with not shared by everyone. At admission, the TEN patient care N-acetylcysteine and heparin (5000 units/4 hours). Such a is similar to that of a patient with extensive partial thickness combination has proven its efficacy in smoke inhalation burns. In our practice, it consists of the implementation of injuries [34, 35]. rules established by the Australian and New Zealand Burn Association [31]. However, there are two main differences in HYDRATION AND FLUID RESUSCITATION the early management of TEN and burns, namely the rare indication for escharotomy in TEN, and the mandatory skin Epidermal sloughing in TEN causes major cumulative biopsy in any TEN-suspect patient in order to rule out any loss of water, heat, electrolytes, proteins and micronutrients. other dermatological disorder. Proper hydration and eventual fluid resuscitation are mandatory to prevent multiple-organ failures. TEN patients AIRWAY MANAGEMENT are usually unable to drink and eat enough to compensate for the wastes from the eroded skin. Intravenous compensation During the early TEN phase, the upper airways are for fluid loss is thus required (Table 2). frequently moderately involved (rhinitis, sore throat and coughing). In a second step, the loss of the bronchial In burn patients, fluid resuscitation volumes are epithelium possibly causes atelectasis, pneumonia and conveniently assessed following the Parkland formula. In respiratory failure. It is therefore crucial to initiate early the TEN patients, no such a formula has been offered so far. administration of humidified oxygen and to promote Clearly, the rate of fluid loss in TEN is considerably less bronchial clearance by specific chest physiotherapy. impressive than in second degree burns with similar area of TEN Supportive Treatments Current Drug Safety, 2012, Vol. 7, No. 5 363

Table 2. Supportive Care for TEN Patients

Hydration Dextrose 5% + NaCl + KCl + K2HPO4 + MgSO4

Fluid resuscitation Cristalloids Ringer lactated ; albumin 5% solution Albumin transfusion Albumin 20% solution 0,75g/kg/d Fresh frozen plasma transfusion To correct coagulation disturbances Red packed cells transfusion Keep a Hb level over 9 g/dl Platelets transfusion If platelets count is under 20 000/mm Nutrition Enteral high protein and high energy nutrients (NGT) Antacids Anti-H2 or PPI Antibiotics Only if sepsis is suspected Anticoagulants LMWH enoxaparin Analgesia anesthesia Tramadol, morphine, ketamine, propofol skin involvement. Accordingly, the Parkland resuscitation replacement to quickly compensate for the fluid deficit. formula overestimates the actual fluid need in TEN patients [36, Starch colloids or 4-5% human albumin solutions should be 37]. Evaporative water loss must, however, be considered in used in combination with Ringer’s lactate. It is important to the maintenance fluid calculation, particularly when the maintain a controlled plasma oncotic pressure. Serum patient is placed on an air fluidized bed [38]. Another albumin, a major contributor to the oncotic pressure, must be formula could help managing fluid resuscitation in TEN kept above 2 g/dl, which is conveniently achieved through patients (Table 3). One of the most important goals is to continuous infusion of a 20% albumin solution. Prophylactic maintain a urinary output of at least over 0.3 ml/kg/h. use of 20% albumin solution is possibly initiated during the acute phase of extensive skin detachment and adapted to the Table 3. Calculations of the Total Daily Maintenance Fluid Requirements in TEN Patients serum albumin level. Fresh frozen plasma is recommended when facing coagulation disturbances caused by loss of coagulation factors. Once wound coverage is secured [39], Total daily fluid requirement (TDFR) = Basal Need + Evaporative Water Loss fluid requirement usually decreases. The blood concentrat- ions of major electrolytes including potassium, calcium, 1. Basal Need (BN): 1500ml/m
x TBSA* m
/24 hours magnesium and phosphate should be monitored and kept 2. Evaporative Water Loss (EWL) ( 2 possibilities: a or b) within normal ranges. Formula a (25 + % TBSA denuded m
) x TBSA m
x 24 ml/24 hours NUTRITIONAL SUPPORT Formula b 0,4 ml/cm
of denuded skin Reepithelialization requires increased energy, proteins *: Thumb rule of calculation for TBSA of adults: a 1.60 m tall person weighing 60 kg and micronutrients [40-42]. The enteral route is the best way has a TBSA of 1.60 m2. For each 10 cm over 1.60 m and 10 kg over 60 kg, 0.10 m
is to reach the caloric needs. Enteral nutrition should be started added to 1.60 m2. Example considering a 70 kg and 1m70 patient and 30% eroded skin: on admission because mucosal and pharyngeal ulcerations Formula a commonly hinder oral nutrition. A nasogastric tube place- TBSA : 1.6 + 0.10 + 0.10 = 1.8 m
. ment is required. If the patient remains able to eat, but fails BN : 1500 x 1.80 = 2700 ml/24 h. EWL = (25 + 30) x 1.8 x 24= 2376 ml/24 h. covering the caloric requirement, and/or if the gastro- TDFR = 5076 ml/day or 211.5 ml/h. intestinal function is impaired, parenteral nutrition should be Formula b initiated. Yet, exclusive parenteral feeding should, be BN: 2700 ml/24 h. EWL: 18000 cm
x 0.3 = 5400 cm
of denuded skin. avoided. In general, TEN patients receive the required 5400 cm
x 0.4 = 2160 ml/24h. nutrition by means of a combination of enteral and parenteral TDFR = 4860 ml/day or 202,5 ml/h. administrations.

Unlike burn patients who experience a significantly Fluid maintenance and resuscitation have to be governed elevated metabolic rate, TEN patients exhibit metabolic rates by clinical and biological parameters including the central only slightly raised above basal requirements. Therefore, the venous pressure, the heart rate, the blood pressure, the parenteral feeding should be restricted to 25-30 kcal/kg of respiratory rate as well as blood values including the pH, ideal body weight. The feeding solutions must contain 1.0 to paO2, base excess, natremia, lactate levels, blood urea 1.5 kcal/ml and 8 to 9 g proteins/100 ml. In addition, nitrogen (BUN) and creatinine levels. Any fluid intake, vitamins and trace elements are required (Table 4). During including oral and intravenous medications, as well as infectious/septic episodes caloric needs are increased. Any enteral and parenteral nutrition, must be considered in the underfeeding in turn slows down the healing process and calculation of the total fluid supplemantation. Half-saline in facilitate the occurrence of infectious episodes. Similarly, dextrose 5% (HS-D5%) with electrolytes (KCl, K2HPO4, overfeeding proves to be deleterious. Adequate nutrition MgSO4) is commonly used for the maintenance procedure, prevents excessive catabolism and should facilitate wound as well as Ringer’s lactate for resuscitation. The management healing. of a possible hypovolemic shock requires continuous colloid

364 Current Drug Safety, 2012, Vol. 7, No. 5 Jennes et al.

Table 4. Daily Needs of Trace Elements and Vitamins Systemic antibiotics are only required in case of invasive systemic infections. To minimize the risk of infection and Vitamins subsequent sepsis, arterial lines and central venous catheters A 10000 IU should ideally be introduced in areas covered by intact skin. B1 250 mg Invasive devices are to be removed as soon as possible, and B6 250 mg replaced by oral and nasogastric routes at earliest convenience. C 2000 mg K 10 mg Folic acid 0.5 mg PREVENTION OF DEEP VENOUS THROMBOSIS Adult multivitamins Measures preventing thromboembolism, such as administration of low-molecular-weight heparin, should be Trace elements initiated as soon as possible. Enoxaparin 0.5 – 1.0 mg/kg Cu 1.5 mg once daily should ideally be started on admission. Zn 10 mg Se 150
g PREVENTION OF GASTRODUODENAL ULCERS Stress ulceration prophylaxis is advisable. Intravenous PREVENTION OF INFECTION administration of proton pump inhibitors or histamine H2-receptor antagonists, such as ranitidine, is recommended. Infections in TEN patients remain a significant source of morbidity and mortality. Pharmacological options call for specific systemic antibiotics and the use of topically applied ANALGESIA AND ANESTHESIA antimicrobials to hinder bacterial growth at the skin surface. Analgesia and anesthesia are worthwhile procedures Some of these topical agents are potentially toxic for the because TEN is a painful condition. Opioids, tramadol, local healing epithelium. anesthetics, anticonvulsants, alpha-2 adrenergic agonists and Most TEN lesions are colonized with varied bacterial antidepressants are possibly used for pain control. species, similarly to any other open wound. A TEN Temperature monitoring is of importance. Patients are often infection, defined as invasion of viable tissue with too ill and weak to use a patient-controlled analgesia (PCA) microorganisms, is typically diagnosed by physical pump delivering morphine or some of its derivatives. Later deterioration in the wound. Quantitative bacteriology and on, during the recovery period, this device becomes a histopathology of a skin biopsy represent the most accurate desirable option. When patients are not intubated, a microbiological methods, followed by semi-quantitative continuous intravenous infusion of tramadol 5-10 mg/kg/24h swab cultures of the wound. with or without lidocaine 0.5-1 mg/kg/h, readily control the pain. Several days later, some patients commonly experience The prevalence of both hospital- and community- drug tolerance and require increased opioid administration to acquired methicillin resistant Staphylococcus aureus maintain a sustained analgesic effect. The administration of (MRSA), vancomyin-resistant enterococcus (VRE) and an alpha-2 adrenergic agonist, like clonidine 5
g/kg/day, resistant Gram-negative bacteria in increasing in burn and/or an anticonvulsivant like gabapentin, 900-1800 centers, sometimes in an epidemic outbreak. There is mg/day, or pregabalin, 150-300 mg/day, is indicated. These growing worldwide evidence of the more frequent two latter drugs are mainly used for the treatment of involvement of these organisms, especially MRSA. neuropathic pain. Regarding analgesia, multimodal strategies Improved antimicrobial control measures are employed to are often welcome. limit the spread of the microorganisms. Systemic antibiotics need to be used only in the case of infection to avoid the For controling any procedural pain (dressing changes, development of more resistant strains. wound debridement), anesthesia should be performed without airway handling (excluding endotracheal intubation Introducing prophylactic antibiotics are ultimately at risk and mask ventilation). Additional mask oxygen is required. for yielding more problems than benefits [16, 36]. Spontaneous ventilation and airway protection must be Nonetheless TEN patients are highly susceptible to septic preserved. Therefore the following protocol is suggested. In complications and a high level of watchfulness is thus a first step starting about 15 minutes before the procedure, required. Frequent and skill monitoring must be focused on premedication is initiated with midazolam 0.1 mg/kg, orally of the urinary tract, respiratory tract, wounds, nose, throat, or through a nasogastric tube. In a second step, intravenous perineum, sputum and catheters. Swabbing all these propofol, 0.5-2 mg/kg is administered in order to reach loss mentioned sites should be performed at least twice a week. of consciousness. The third step, just before the painful In addition, blood examination is recommended at least debridement requires 0.25-0.5 mg/kg ketamine intravenous twice a week and whenever sepsis is suspected. These administration. Pulsed small doses of propofol and/or procedures allow early detection and identification of ketamine are required to maintain the patient unconscious colonizing or infecting multidrug resistant (MDR) bacterial and pain free during the whole procedure. This method and fungal pathogens. Such sustained search, combined with requires close monitoring for avoiding respiratory antimicrobial sensibility testing and eventually molecular depression. At completion of the procedure, intravenous typing procedures help selecting appropriate antimicrobial morphine must be initiated in order to provide a painless treatments. The empiric use of broad-spectrum antibiotics is recovery. The whole procedure is often time consuming in at times necessary in neutropenic TEN patients [28-30]. the range of one to two hours, and the patient must be TEN Supportive Treatments Current Drug Safety, 2012, Vol. 7, No. 5 365 monitored with invasive blood pressure assessment and [13] Wu K, Reynolds NJ. Pharamcogenetic screening to prevent pulse oximetry. carbamazepine-induced toxic epidermal necrolysis and Stevens- Johnson syndrome : a critical appraisal. Br J Dermatol 2012; 166: 7-11. CONCLUSION [14] Piérard GE, Paquet P. Facing up to toxic epidermal necrolysis. Expert Opin Pharmacother 2010; 11: 2443-6. TEN is a difficult-to-treat syndrome that requires medical [15] Daniel BS, Skowronski G, Myburgh J, et al. Concurrent and nursing expertise. There are three main facets to the management of toxic epidermal necrolysis with thermal water treatment of TEN. First, topical treatments should garantee spray and non-stick dressings. Acta Dermatovenereol Croat 2012; 20: 210-2. adequate care of the bullous and eroded skin areas. Eye care [16] Palmieri TL, Greenbach DG, Saffle JR, et al. A multicenter review is of major importance. Control of the ambient temperature of toxic epidermal necrolysis treated in U.S. burn centers at the end is mandatory. Second, systemic treatments aim at limiting of the twentieth century. J Burn Care Rehabil 2002; 23: 87-96. the pathologic process leading to epidermal apoptosis and [17] Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrosis. Third, the systemic supportive management helps necrolysis: a retrospective study on patients included in the preserving the vital functions of the TEN patient. This aspect prospective EuroSCAR Study. J Am Acad Dermatol 2008; 58: 33- is of paramount importance and closely resembles the 40. procedures designed for burn patients. Yet, some specific [18] Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a features are applicable to TEN patients only. severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149-53. [19] Trent J, Kirsner RS, Romanelli P, Kerdel FA. Use of SCORTEN to CONFLICT OF INTEREST accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol 2004; 140: 890-2. The authors confirm that this article content has no conflicts [20] Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis: of interest. analysis of clinical course and SCORTEN-base comparison of mortality rate and treatment modalities in Korean patients. Acta Dermato-Venereol 2005; 85: 497-502. ACKNOWLEDGEMENTS [21] Guegan S, Bastuji-Garin S, Poszepczynska-Guigné E, et al. Performance of the SCORTEN during the first five days of Declared none. hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006; 126: 272-6. 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Received: February 6, 2012 Revised: November 19, 2012 Accepted: November 27, 2012