A Clinical Study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Efficacy of Treatment in Burn Intensive Care Unit

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1 J Korean Surg Soc 0;: DOI:.414/jkss 원 저 A Clinical Study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Efficacy of Treatment in Burn Intensive Care Unit Departments of Surgery and 1 Plastic Surgery, Burn Center, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea Haejun Yim, M.D., Jin Mo Park, M.D., Yong Suk Cho, M.D., Dohern Kim, M.D., Jun Hur, M.D., Wook Chun, M.D., Jong Hyun Kim, M.D., Dong Kook Seo, M.D. 1 Purpose: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (), potentially life-threatening skin diseases with organ failures caused by drugs, require specialized intensive care. However, SJS and have usually been managed in general wards and intensive care units by most doctors. This study describes the efficacy of treatment in the burn intensive care unit (BICU) compared to previous general treatments. Methods: To investigate the clinical features, outcomes and benefits of patients with SJS and treated in our burn intensive care unit. Data on patients who were treated between January 004 and December 00 were collected via a retrospective chart review. Also, the data were reviewed with previous literatures on SJS and treatments. Results: Patients were classified with overlap SJS/ (n=4, 36.36%) or (n=, 63.64%). Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most common causative agents. Hepatitis was the most common organ involvement in both overlap SJS/ (n=1, 9.1%) and (n=4, 36.36%). Renal dysfunction (n=4, 36.36%) and respiratory disorders (n=3,.%) were seen in some cases. Mean time of total reepithelization was 9 days and mean hospital day was days. Two patients with died from sepsis with multi-organ failure, and the mortality rate was 1.1%. Conclusion: Adequate treatment of SJS and in the BICU supports efficacy with a low mortality rate, short healing time, short hospitalization and fewer complications. (J Korean Surg Soc 0;: ) Key Words: Burn intensive care unit, Stevens-Johnson syndrome, Toxic epidermal necrolysis INTRODUCTION Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis () are characterized by widespread epidermal necrosis and mucosal involvement secondary to keratinocyte apoptosis mostly by drugs with high mortality. Though the pathophysiology has not yet been fully elucidated, both disorders are considered to be within the same spectrum, Correspondence to: Yong Suk Cho, Department of General Surgery, Hangang Sacred Heart Hospital, Hallym University Medical Center, 94-00, Yeongdeungpo-dong -ga, Yeongdeungpo-gu, Seoul , Korea. Tel: , Fax: , maruchigs@hallym.or.kr Received October 5, 009, Accepted December 1, except the involved body areas.(1-4) Several treatments with advanced dressing material and drug therapy were introduced. Some authors not by dermatologist but by surgeons suggested some advantages of burn intensive care unit (BICU) treatment in SJS and. There were some reports of clinical studies of SJS and in Korean dermatologic literature, however, only limited number of reports included treatment in the burn intensive care unit.(5-) However, the BICU supports the patients with proper thermoregulations, intensive fluid replacement with electrolyte balance, enteral nutrition, infection control and wound management with specialized nursing. Those specialized treatments of BICU provide the efficacy with a low mortality rate, short healing time, short hospitalization and

2 134 J Korean Surg Soc. Vol., No. 3 fewer complications. Therefore, the aim of the present study is to present the efficacy of the burn intensive care unit treatment with necessity in SJS and. Herein, we report our interesting retrospective study in treating SJS and in the burn intensive care unit with literature reviews. METHODS 1) Patients A retrospective review was performed on all patients who visited our hospital burn center for SJS/ from January 004 to December 00. All of them were admitted to the burn intensive care unit. ) Diagnostic criteria Diagnoses were made by dermatologists with histopathological confirmation. The patients were divided into three groups according to the following criteria of Bastuji-Garin et al.(,9). Bullous erythema multiforme (EM): epidermal detachment involving <% of the body surface, coupled with localized typical targets or raised atypical targets. SJS: epidermal detachment of <% of the body surface in association with widespread erythematous or purpuric macules or flat atypical targets. SJS/ overlap: epidermal detachment of % to 30% of the body surface plus widespread purpuric macules or flat atypical targets. with spots: epidermal detachment of >30% of the body surface coupled with wide spread purpuric macules or flat atypical targets. without spots: large sheets of epidermal detachment involving >% of the body surface without purpuric macules or target lesions. 3) Evaluations Data regarding demographics, causative agents, pattern of involvement, underlying diseases, complications, mortality, and morbidity were obtained. As it is difficult to confirm which drugs are responsible for SJS/, we checked all drugs used within 3 weeks of onset.(5) Severity of illness score for toxic epidermal necrolysis (SCOR) was evaluated during the first 4 hours of admission. From the SCOR score, expected mortality and expected death case were calculated. SCOR includes seven clinical variables: 1) age above 40 years, ) presence of malignancy, 3) tachycardia above /min, 4) involvement of >% of body surface area, 5) serum urea > mg/dl, 6) serum glucose >5 mg/dl and ) bicarbonate <0 meq/l.() 4) Treatment All patients received proper fluid and electrolyte resuscitation, pain management, nutritional support, wound care, surgical debridement of dead tissue by intensive care unit specialist. For the wound management, moisture retentive dressings such as Medifoam R (Hydrophilic polyurethane foam dressing; Il Dong & Biopol, Korea), AQUACEL R (ConvaTec, UK) or Acticoat TM (Smith & nephew, Canada) were applied. Sulfonamide-containing topical agents were avoided. Antibiotics were applied only to treat systemic infections depending on the wound, urine, and blood cultures, which were checked twice a week. Steroids were prohibited and any steroid agents used prior to admission were discontinued. Ten patients in the burn intensive care unit were treated with intravenous immunoglobulin (IVIG) at a dose of 1 g/kg/day for 3 to days (mean 4.3 days). RESULTS 1) Demographics A total of patients (9 males and females, mean age 31.1 years, range 5 3 years) were included in this study. According to the criteria of Bastuji-Garin et al.,(,9) four patients were diagnosed with SJS/ (n=4, 36.36%) and seven with (n=, 63.64%). Six (54.55%) of the patients had underlying diseases, including hypertension, congestive heart failure, gout, nephritic syndrome, epilepsy, and glaucoma (Table 1). ) Medication history The most common causative drugs were NSAIDs (6 of patients, 54.55%) for upper respiratory infections. Two patients (1.1%) took allopurinol for gout. Two others had taken prednisolone for nephrotic syndrome. One (9.1%)

3 Haejun Yim, et al:a Clinical Study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Efficacy of Treatment in Burn Intensive Care Unit 135 Table 1. The clinical profiles related with medication of patients with SJS/ overlap and Patient No. Criteria Age/Sex Onset* (days) TBSA (%) Underlying preexisting disease Previous drug allergy Offending drugs 1 SJS/ 41/M 5 1 Upper respiratory infection NSAIDs SJS/ 6/F 5 Acute pharyngeal tonsillitis, mycoplasma pneumonia NSAIDs 3 SJS/ 3/F 3 Upper respiratory infection NSAIDs 4 SJS/ 5/M 3 Acute pharyngeal tonsillitis NSAIDs 5 4/M 1 36 Hypertension, congestive heart failure, gout Allopurinol 6 9/M 5 40 Hypertension, congestive heart failure, gout Allopurinol /M 5 60 Upper respiratory infection NSAIDs /M 9 60 Epilepsy Carbamazepine 9 15/M 3 90 Nephrotic syndrome Prednisolone 45/M 5 95 Upper respiratory infection, glaucoma NSAIDs 13/M 35 0 Nephrotic syndrome Prednisolone *Time of onset clinical disease following the institution of a new drug regimen; TBSA = total body surface area; NSAIDs = nonsteroidal anti-inflammatory drugs. patient had taken the antiepileptic drug carbamazepine for epilepsy. The average period between taking the relevant drug to the appearance of symptoms was 9 days. Both overlap SJS/ (0%) and (1.4%) showed symptoms within weeks. The mean percentage total body surface area (TBSA) of skin involvement was 4.5% (1 30%) in overlap SJS/ and 6.% (31 0%) in (Table 1). 3) Clinical courses The time from appearance of the first skin lesions to the initiation of therapy varied from 1 to days (mean 4. days). The mean period of hospital care to complete skin healing time was 9 days ( 1 days). The mean period of hospitalization was days ( days). All patients showed involvement of the mucous membranes, including the buccal, conjunctival, and genital mucosae. 4) Complications During admission, coagulase negative staphylococcus, P. aeruginosa, A. baumannii, and methicillin-resistant staphylococcus aureus were cultured. On laboratory examination, neutropenia was found in three cases and normocytic anemia in six cases. The most common complication was hepatitis, which was seen in one case in the overlap SJS/ group and four cases in the group. Acute renal failure occurred in four cases in the group. Continuous renal replacement therapy (CRRT) was applied in two patients. Two patients developed sepsis and three patients had disseminated intravascular coagulation (DIC). developed in six patients. 5) Mortality and SCOR evaluation Two of eleven patients died of septic complications with DIC due to, resulting in a mortality rate of 1.1% (Table ). In two patients, acute renal failure and pneumonia were accompanied with a SCOR score of 5. The mean SCOR score were.5 in the overlap SJS/ group and 3.5 in the group. Three patients had a score of 5. One patient had a score of 4. Four patients had as score of 3 and three patients had a score of (Table 3). The number of expected deaths was 5.05, but the actual number of deaths was (Table 4). DISCUSSION Drugs cause adverse reactions to the skin which can occasionally be life threatening, such as SJS and. Although most adverse reactions are transient, SJS and can be persistent and are often accompanied with multi-organ failure.() Cases with skin surface involvement of <% TBSA are diagnosed as SJS, while those showing involvement of >30% TBSA are called. Epidermal detachment between % and 30% is classified

4 136 J Korean Surg Soc. Vol., No. 3 Table. The clinical course and outcome of patients Outcome Residual complication Organism Sepsis/ growth DIC Other organ involvement Mucosal involvement Length of hospital stay (days) Time to heal (days) Time to treat* (days) Patient No. Criteria Dead Pneumonia Hepatic failure, acute renal failure Acute renal failure, pneumonia Hepatic failure, acute renal failure / / / / / / / / SJS/ SJS/ SJS/ SJS/ / No growth No growth CNS No growth CNS MRSA, CNS MRSA P. aeruginosa, A.baumannii P. aeruginosa, A.baumannii A. baumannii P. aeruginosa, A.baumannii 15 9 Dead Acute renal failure, pneumonia, pleural effusion / / Mean *Time from appearance of first skin lesions to the initiation of therapy; Time from start of hospital treatment to complete skin healing or reepithelization; Organism cultured from blood during treatment; DIC = disseminated intravascular coagulation; CNS = coagulase negative Staphylococcus; MRSA = methicillin-resistant Staphylococcus auresus. as SJS/ overlap. SJS occurs predominantly in children and adolescents, whereas occurs in all ages regardless of sex and race.() The incidence rates of SJS and are approximately 1 cases and cases per 1 million people, respectively, per year.(-15) The incidences of and drug reactions are generally higher among patients with HIV infection, SLE, and bone marrow transplantation.(16) The most frequently implicated drugs are sulfonamide antibiotics, aromatic anticonvulsants such as phenytoin, phenobarbital, and carbamazepine, beta-lactam antibiotics, nevirapine, abacavir, NSAIDs, allopurinol, lamotrigine, tetracyclines, and quinolones.(1) Other causes of SJS and include herpes simplex virus, Mycoplasma pneumoniae, Mycobacterium tuberculosis, group A streptococci, hepatitis B virus, Epstein-Barr virus, Francisella tularensis, Yersinia spp., enterovirus, Histoplasma spp., Coccidioides spp., and HIV.(1) In our series, NSAIDs (6 cases, 54.55%) were the most common causative agents, followed by allopurinol, prednisolone and carbamazepine. One girl was positive for anti-mycoplasma antibodies, suggesting that the disease may have been due to mycoplasma infection. Patients with overlap SJS/ and showed prodromal symptoms with fever, chills, myalgia, and sore throat for several days. The mean period of incubation was 9 days. Careful attention to medical history and clinical suspicion are essential to distinguish prodromal symptoms from symptoms of other diseases.(19) Although many treatment options for have been proposed, no satisfactory treatment guidelines have yet been developed. The mortality rate associated with is known as ranging from 0% to 5%.(-) In the present series, patients had an extensive mean body surface area involvement of 5.3% (1 0%) with mortality rate of 1.1%. Since the first report of clinical studies of SJS and by Kim et al.() in 1991, there were few more reports by some authors in Korean dermatologic literature.(5,6) However, as shown in articles, those studies did not include the burn intensive care unit but in the general ward. Compared to those previous studies, the burn intensive care unit treatment presents some positive points (Table 5).

5 Haejun Yim, et al:a Clinical Study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Efficacy of Treatment in Burn Intensive Care Unit 13 Table 3. SCOR* data in SJS/ overlap and patients Patient No. Criteria Age (>40 yr) Malignancy BSA (>%) Serum bicarbonate (<0 meq/l) Serum glucose (>5 mg/dl) BUN (> mg/dl) Heart rate (>/min) 1 SJS/ 3 SJS/ 3 SJS/ 3 4 SJS/ Mean 3. *SCOR = score for toxic epidermal necrolysis; BSA = body surface area; BUN = blood urea nitrogen. Score Table 4. Mortality assessed by SCOR data in SJS/ overlap and patients SCOR* score No. of patients Expected mortality rate (%) No. of expected death case No. of actual death case > Total *SCOR = score for toxic epidermal necrolysis. First, the burn intensive care unit treatment shortened the time of complete reepithelization. By Kim et al.(5), they studied 5 patients of SJS and patients of, mean time to total reepithelization time was 14.1 days. However, our study showed 9 days for total reepithelization. Second, the burn intensive care unit treatment shortened the length of hospital days. In our study the mean length of hospitalization was days, but in other studies it was much longer as 16.9 days by Kim et al.(6), 19. days by Kim et al.() and 0.6 days by Kim et al.(5). Third, the patients received treatment in the burn intensive care unit showed relatively well controlled vital signs without fluctuation hemodynamic changes also reduced the chance of eye complications (54.54%) and respiratory distress (. %). The mortality rate (n=, 1.1%) in our study is relatively lower than other studies.(-) In 00 reported by Kim et al.,() patients of received IVIG and 4 of them died of sepsis and complications. In case of mortality, both of them died of sepsis and those patients had poor underlying conditions which easily enable to develop into sepsis. One patient was 9 years-old man with past history of hypertension, congestive heart failure and gout involving 40% of TBSA and the other patient was 45 years-old man with involving 95% of TBSA. There are a few suggestive reasons for strong points of the burn intensive care unit treatments. First, similar to other burn centers, treatment at our burn unit focused on providing thermoregulation, fluids and electrolyte therapy, enteral nutrition (if possible), wound management, and infection control. Such supportive treatments could shorten both the reepithelization and hospitalization period. Also with proper antibiotics, respiratory distress including pneumonia was reduced. Second, we did not administer steroids to any patients. Instead of using steroids, intravenous immunoglobulin (IVIG, 1 g/kg/day) was administered in cases for a mean of 4.3 days. The therapeutic effects of immunoglobulin are likely to involve inhibition of Fas-mediated keratinocyte death by naturally occurring Fas-blocking antibodies contained within human immunoglobulin preparations acting directly on the Fas-Fas ligand system at the keratinocyte surface.(0,1) Using oral

6 13 J Korean Surg Soc. Vol., No. 3 Table 5. A comparison of the previous studies on SJS and treatment in general wards to BICU treatment Re-epithelization time (days) Length of hospital stays (days) Mortality rate (%) Involvement of skin area (TBSA*, %) SCOR (mean) No. of patients Report SJS Overlap SJS Overlap SJS Overlap Mean SJS Overlap Mean SJS Overlap Mean Kim et al.(5) Kim et al.(6) Kim et al.() Our case *TBSA = total body surface area; SCOR = score for toxic epidermal necrolysis. steroids in SJS and is still in debate. Kim et al.() and Halebian et al.(3) reported 60% and 30% higher mortality rates, respectively, in patients treated with medium-to high-dose steroids. Also we did not apply any topical antimicrobial agents such as sulfa-containing products, as they might be causative agents and have the risk of systemic sensitization.(1) Third, we used aseptic and highly qualified materials. As occurs at the dermal-epidermal junction, wounds are essentially the same as superficial partial-thickness burn wounds. Therefore, if these wounds can be kept clean without any complications, they can heal within to 14 days. Based on this principle, after cleaning with normal saline and removing all loose skin and blisters, the wounds were dressed with moisture-retentive dressing, such as Medifoam R, AQUACEL R or Acticoat TM. These moisture retentive dressings are effective in the management of partial-thickness burns because they provide an environment suitable for wound healing, minimize evaporative water loss, and reduce pain. Since these products also require relatively few changes, they are convenient for nursing care, including hydrotherapy, and reduction of overall cost.(3,4) In conclusion, no specific treatment regimen has been unequivocally shown to be effective in treating SJS and, and palliative care remains the cornerstone of treatments. Therefore, burn units are considered ideal for the management of patients because of their wide experience in managing burn wounds and their ability to provide infection control and basic life support. We expect the collaborate therapy with a burn intensive care unit in treating severe and SJS patients will reduce the morbidity and mortality rates. REFERENCES 1) Lee JY, Oh MJ, Lee BJ, Choi DC. Comparison of clinical characteristics according to infection in Stevens-Johnson syndrome and toxic epidermal necrolysis. J Asthma Allergy Clin Immunol 006;6:-1. ) Revuz J, Penso D, Roujeau JC, Guillaume JC, Payne CR, Wechsler J, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in patients. Arch Dermatol 19;

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