Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS): experience with high-dose intravenous immunoglobulins and topical conservative approach. A retrospective analysis

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare, drug-induced, severe acute exfoliative skin and mucosal disorders. Several treatments previously proposed have produced contradictory results in small series; in 1998 the use of intravenous immunoglobulins (IVIG) was introduced with excellent clinical findings. Our experience (1999-2005) using IVIG in the therapy of TEN/SJS, together with a local conservative approach, is reported and related to our previous treatments (1993-1998). The SCORTEN and the standardized mortality ratio (SMR) was used to evaluate the efficacy of our therapeutic modalities. Eight patients were treated before IVIG era and 23 patients have been treated with IVIG. There was no significant difference in SCORTEN between the two groups. Concerning the local approach, a conservative wound management in IVIG series replaced an extensive epidermal debridment and coverage with artificial skin substitutes of the pre-IVIG series. Overall mortality in patients treated before IVIG was 75% (6/8), in the IVIG group it decreased to 26% (6/23) with a cessation of further epidermal detachment after an average of 5 days (3-10 days) from the onset of the therapy. The SMR showed a trend to lower actual mortality (not significative) with IVIG treatment than the predicted mortality (SMR=0.728; 95% CI: 0.327-1.620).     

The optimal timing of outpatient Biobrane™ application for superficial and mid dermal partial thickness burns: Evidence for the ‘12-hour rule’

BackgroundBiobrane? is a skin substitute used for the definitive management of partial thickness burns. No studies have examined the optimal timing of Biobrane? application in this setting. The purpose of this study was to determine whether there was a clinically significant difference in applying Biobrane to a superficial and mid dermal partial thickness burn within 12 h after burn.MethodsFrom August 2016–February 2017, 29 consecutive superficial and mid dermal partial thickness burn injuries were prospectively treated with Biobrane? within 12 h of the injury. This ‘early Biobrane?’ cohort was compared to a historical cohort of 148 patients who were treated with Biobrane? for superficial and mid dermal burns after 12 h after injury during 2015 to 2016. Multivariate regression analysis was used to determine the difference in time to re-epithelialisation and number of outpatient visits between the two cohorts.ResultsIn the ‘early Biobrane?’ group, the mean TBSA was 3.5 ± 2.7%. and the mean time to Biobrane? application was 7.1 ± 2.7 h after burn injury. The mean time to re-epithelialisation in this group was 9.1 ± 3.0 days, and no patients underwent skin grafting. In the ‘delayed Biobrane?’ group, the mean TBSA was 2.6 ± 2.8% and the mean time to Biobrane? application was 35.1 ± 21.4 h. The mean time to re-epithelialisation was 14.8 ± 8.7 days, with 3 patients undergoing skin grafting. Regression analysis demonstrated a statistically significant 63% reduction in time to re-epithelialisation (95% CI = 0.23–0.60; P < 0.0001) with early Biobrane? application.ConclusionPatients treated with application of Biobrane? within 12 h of superficial and mid dermal partial thickness burns have a statistically significant reduction in healing time when compared to patients treated with standard Biobrane? practice.     

The application of new biosynthetic artificial skin for long-term temporary wound coverage

Temporary dressings protect wounds from desiccation and infection. In our previous study, we used meshed acellular porcine dermis (APD) to enhance wound healing and decrease wound contraction; however, the wounds showed meshed scar [Wang HJ, Chen TM, Cheng TY. Use of a porcine dermis template to enhance widely expanded mesh autologous split-thickness skin graft growth: preliminary report. J Trauma 1997;42(2):177–82]. In this study, we produced an artificial skin composed of a cross-linked silicon sheet on the surface of APD which we have called silicone acellular porcine dermis (SAPD). This new artificial skin can protect the wound long enough to promote wound healing either by second intention or covered long enough until cultured epithelium autograft (CEA) or autologous skin graft can be harvested for permanent coverage.

We delivered 4 cm × 5 cm full-thickness wound on the back of 350 g Sprague–Dawley rats. Thirty-six rats were divided into two groups. Eighteen rats had SAPD and the other 18 were covered with Biobrane. The wounds were first examined 2 weeks after grafting and followed weekly for an additional 4 weeks to evaluate the wound and study pathological changes by using H.E. and Masson's stains. Wound size was calculated by ruler and analyzed by Student's t-test.

At the 2-week inspection, both SAPD and Biobrane showed tight adherence to the wound with no change of wound size. Both the SAPD and Biobrane dermal templates were pink. In the Biobrane-covered group, the wounds contracted soon after the tie-over dressing was removed. Its dermal layer is a layer of thin porcine dermal substance, which was promptly digested by tissue hyaluronidase and provides no real dermal template. In the SAPD-covered group however, the wound size was maintained significantly from third to sixth week after grafting (p < 0.001). SAPD was designed with thick epidermal silicone and a well-organized porcine dermis so that it incorporates into the recipient wound. Clinically the silicone layer of SAPD dislodged from APD about 6–7 weeks after grafting and was followed by dermal matrix exposure and infection. In pathological examination, much like a human skin graft, new vessels were found in APD about 1 week after grafting with minimal inflammatory cells infiltrated in the graft and wound. Six weeks after grafting, the collagen of APD incorporated into the wound, showing palisade arrangement and no sign of rejection. In the Biobrane group however, the wounds showed severe inflammation, the porcine dermal matrix was digested and disappeared 3 weeks after coverage.

In conclusion, SAPD is a thick biosynthetic artificial skin, which protects the rat wound significantly longer than Biobrane and prevents contraction. We expect that using of SAPD for temporary wound coverage will provide enough time to grow autologous-cultured epithelium or to reharvest skin grafts.     

Treatment of partial-thickness burns: a prospective, randomized trial using Transcyte

BACKGROUND: The purpose of the present study was to compare the effectiveness of three burns dressings (TransCyte, a bio-engineered skin substitute; Biobrane; and Silvazine cream (silver sulphadiazine and 0.2% chlorhexidine)), in treating children with partial-thickness burns. The primary objective was to determine the days until > or =90% re-epithelialization. The secondary objectives were to evaluate the number of wounds requiring autografting and the number of dressing changes/local wound care required. METHODS: Study wounds were identified on each patient and the patients were randomized to receive TransCyte or Biobrane or Silvazine. Assessment of study wound closure began at 2 days after treatment and continued at least every other day thereafter until the wounds re-epithelialized or were autografted. A laser Doppler imaging system was used as an adjunct to assessing the depth of the burn. RESULTS: Thirty-three patients with 58 wound sites enrolled in the study (TransCyte, n = 20, Biobrane, n = 17; Silvazine, n = 21). Mean time to re-epithelialization was 7.5 days for TransCyte, 9.5 days for Biobrane, and 11.2 days for Silvazine. The number of wounds requiring autografting were 5/21 (24%) for Silvazine, 3/17 (17%) for Biobrane, and 1/20 (5%) for TransCyte. CONCLUSIONS: When used in partial-thickness burns in children, TransCyte promotes fastest re-epithelialization and required less overall dressings then Biobrane or Silvazine. Patients who received Silvazine or Biobrane require more autografting than those treated with TransCyte.     

Treatment of toxic epidermal necrolysis and a review of six cases

Six cases of drug-induced toxic epidermal necrolysis treated in a burns unit are presented. The mean skin loss was 67.3 per cent of the total body surface area. Two patients developed renal failure and two had ocular symptoms. The mortality rate was 50 per cent, with two patients dying from septicaemia and one from respiratory and renal failure. The diagnosis of toxic epidermal necrolysis can be confirmed by skin biopsy. We recommend that this disease is treated in a burns unit so that both adequate wound care and essential intensive supportive treatment can be given. Antibiotics are indicated only for specific infections such as septicaemia or pneumonia. Steroids have been shown to increase greatly the mortality from septic complications and are not recommended. The mortality ranges from 10 per cent to 70 per cent and bad prognostic factors include increasing age, greater than 50 per cent of body surface skin loss and neutropenia.     

Aquacel Ag with Vaseline gauze in the management of toxic epidermal necrolysis (TEN)

Toxic epidermal necrolysis (TEN) is a rare condition with potentially high mortality and involves severe exfoliative disease of the skin and mucous membranes induced by drugs. The reported fatality of TEN varies widely from 20% to 60%. The technique for TEN wound coverage described in this article involves the use of various dressings.     

Biobrane™ and skin staples: beware of necrotic ulceration

Biobrane? is a product used for temporary wound coverage post major paediatric burn wound debridement. We report two cases of necrotic ulceration associated with the use of Biobrane? with skin staples. We suggest securing Biobrane? with alternatives such as adhesive tapes and glue to prevent the occurrence of this adverse outcome.     

Therapeutic efficacy of Biobrane in partial- and full-thickness thermal injury

Cadaver allograft skin, porcine xenograft skin, and amniotic membranes have been proved to be adequate temporary thermal wound coverings in four clinical situations: coverage of shallow wounds while awaiting epithelialization (SW), coverage of deep wounds after eschar excision (DEW), coverage of widely meshed autograft while awaiting closure of interstices (AC), and coverage of massive donor sites (DS). This study was undertaken to evaluate the therapeutic efficacy of a new biosynthetic bilaminate dressing, Biobrane. Two hundred one applications of Biobrane were studied in 82 SW, 46 DEW, 19 AC, 54 DS. A total of 124 applications were left in place until healing occurred, with a mean healing time of 12.8 days. Sixty of SW, 10/46 DEW, 10/19 AC, and 44/54 DS remained intact until complete healing. Only four DEW, two SW, and 0 AC applications had to be removed because of suppuration. Twenty five of the applications (SW and DEW) with the Biobrane glove had rare complications.     

Improving mortality outcomes of Stevens Johnson syndrome/toxic epidermal necrolysis: A regional burns centre experience

Introduction

Stevens Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) are rare, potentially fatal desquamative disorders characterised by large areas of partial thickness skin and mucosal loss. The degree of epidermal detachment that occurs has led to SJS/TEN being described as a burn-like condition. These patients benefit from judicious critical care, early debridement and meticulous wound care. This is best undertaken within a multidisciplinary setting led by clinicians experienced in the management of massive skin loss and its sequelae. In this study, we examined the clinical outcomes of SJS/TEN overlap & TEN patients managed by our regional burns service over a 12-year period. We present our treatment model for other burn centres treating SJS/TEN patients.

Decrease in rate of wound contraction with the temporary skin substitute biobrane

In burn patients normal wound healing contraction may lead to contracture deformity requiring secondary reconstruction. Full-thickness skin grafts are observed to inhibit both contraction and myofibroblasts by an unknown mechanism. The temporary synthetic skin substitute Biobrane has become an acceptable alternative to cadaver allografts for many burn and reconstruction wounds. We have postulated that this synthetic membrane might also share the ability to inhibit wound contraction. By comparing open and Biobrane closed wounds in 20 rats, we have demonstrated a significant (p less than 0.005) difference in wound size during the time that the Biobrane is adherent to the wound. Linear regression curves are used to express the rate of contraction and demonstrate a threefold decrease. Alternative mechanisms for this inhibition are postulated, including mechanical stenting versus direct inhibition of contractile myofibroblasts.     

Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report.

Toxic epidermal necrolysis (TEN) is an acute drug-induced life-threatening disorder characterised by extensive epidermal exfoliation and high rate of mortality. Between October 2000 and April 2003, five severe TEN patients were evaluated using a specific TEN severity-of-illness scale (SCORTEN) and treated for the first time, with a combined therapy using Intravenous Human Immunoglobulins (IVIG) and plasmapheresis. The standardised mortality ratio (SMR) analysis ([Sigma observed deaths/Sigma expected deaths]x100) was applied to establish how IVIG and plasmapheresis treatment could reduce TEN patient mortality. The observed mortality was one out of five patients corresponding to 20%. The expected mortality based on SCORTEN was 3.319 corresponding to 66%. The SMR analysis revealed a 70% reduction in mortality (SMR=0.30; 95% confidence interval, 0.0-0.96). Our series show a low mortality rate (20%) related to the severity of the patients (66% expected mortality). The use of IVIG in association with plasmapheresis has a rational basis and may be effective in severe TEN patients.     

Microskin grafting of rabbit skin wounds with Biobrane overlay.

Biobrane was used to overlay micrografts and the wound using the microskin grafting technique with an expansion ratio of 10:1 in 16 rabbits. The rabbits were divided randomly into four groups, with four rabbits in each group, for evaluating the wound conditions on days 7, 10, 12 and 14. Histological examination of the removed Biobrane showed a variable degree of entrapment of inflammatory cells within the nylon fabric. Biobrane adhered well to the wounds although many wrinkles containing fluid accumulations were noted on day 7. By 10, 12 and 14 days all the wounds become dry and their Biobrane adhered completely. Histological examination of the grafted wound on day 7 showed active proliferation and spread of micrografts. In the later groups, the neoepidermis increased in thickness and differentiated into skin with a normal texture. On day 10, the wounds were almost completely resurfaced with neoepithelium. The growth of these grafts progressed smoothly as the adherent Biobrane was kept on the wound for 12 or 14 days. In these animal studies, the overlain Biobrane provided favourable conditions for the successful growth of micrografts.     

Cultured autologous keratinocytes on a cell-free dermis in the treatment of full-thickness wounds.

The purpose of this study was to establish a method for transplantation of autologous keratinocytes on an allogenic cell-free dermis. From four healthy volunteers two full thickness skin grafts, 1 x 1 cm, were taken. The epidermis was separated from the dermis enzymatically and the cells of the dermal part were removed by incubation in Triton X-100. Keratinocytes were seeded on a cell-free dermis and the combined graft transplanted back to one of the wounds of the donor of the keratinocytes. The other wound was covered with cell-free dermis without keratinocytes. After 2, 3, 4 and 6 weeks, respectively, the grafted wounds were removed from the subjects and investigated histologically and immunohistochemically regarding re-epithelialisation, fibroblast ingrowth and angiogenesis. The wounds covered with cell-free dermis and keratinocytes showed a complete epidermal coverage 2 weeks after transplantation, in contrast to the wounds covered with un-seeded dermis which only showed epidermal coverage at the wound edges. There was also a marked difference concerning fibroblast ingrowth and angiogenesis. In this study we have shown that autologous keratinocytes can be seeded on a cell-free dermis and transplanted as a kerato-dermal graft which stimulate re-epithelialisation as well as fibroblast ingrowth and angiogenesis in the wound.     

Experimental model for local application of growth factors in skin re-epithelialisation.

We did an experimental study to assess the effects of different growth factors on re-epithelialisation of skin wounds by creating a partial-thickness defect in rats with a handle dermatome. Three different growth factors that are particularly involved in the re-epithelialisation phase of wound repair (epidermal growth factor (EGF), keratinocyte growth factor (KGF), and basic fibroblast growth factor (FGF-b) n = 10 in each group) were applied locally in a hydrocolloid dressing containing solutions of the different factors (EGF 10 micrograms/ml, KGF 3.3 ng/ml, bFGF 1 microgram/ml). The dressings were changed daily. The thickness of the epithelium, the percentage of re-epithelialisation, and the maturity of the epithelium were quantified and measured morphometrically. The results showed that: the experimental model allowed us to apply the growth factors, while continuously maintaining the dose within the maximum activity of the growth factor; when EGF, KGF, and bFGF were given according to the protocol there was significant thickening of the new epidermis (p < 0.01) and acceleration of the re-epithelialisation (p < 0.05) rate compared with controls, and significantly more mature epithelium grew (p < 0.05) all of which were evident on both the third and the fifth days; and EGF and KGF cause a more epidermal thickening than bFGF.     

Both dermal matrix and epidermis contribute to an inhibition of wound contraction

Contracture is a major detriment to functional recovery from large wounds. To determine the relative value of dermal replacement and epidermal coverage in inhibiting wound contraction, five full-thickness wounds (all 5 x 5 cm2) were placed on the back of 8 swine and treated in the following manner: (1) open wound, (2) porcine acellular dermis (analogous to AlloDerm for human use), (3) porcine acellular dermis with epidermal autograft placed 7 days postwounding, (4) porcine acellular dermis with immediate epidermal autograft, and (5) conventional-thickness autograft. Scar dimensions and punch biopsies were taken at days 14 and 30 postwounding. The planimetry results demonstrated that wound contraction was significantly greater with the open wounds (group 1) than all other wounds with a dermal substitute. Furthermore, wounds with initial epidermal coverage had significantly less contraction than unepithelialized wounds (14.8 +/- 1.1 cm2 at day 14 in wound group 2 vs. 20.4 +/- 0.6 cm2 in wound group 4; p < 0.05). Biopsy results revealed that wounds with initial epithelial coverage had the least amount of inflammation. These findings suggest that both dermal matrix and epidermal coverage contribute to an inhibition of wound contraction and that prompt epithelial coverage appears to impede contraction by reducing inflammation.     

Uses and abuses of a biosynthetic dressing for partial skin thickness burns

The following report reviews 851 applications of Biobrane on partial skin thickness burn wounds awaiting epithelialization. After the patients had been evaluated and resuscitated as needed, the burn wounds were cleansed and debrided. Those evaluated as shallow were treated with Biobrane application. Joint surfaces were splinted for immobilization. The wound was inspected at 24 and 48 h and if any fluid had accumulated it was aspirated and the wound was redressed. When the Biobrane was adherent, the wound was covered with a light dressing and joint immobilization was discontinued. Treatment with Biobrane dressing provided certain advantages over other topical wound care. As the dressing changes were performed less frequently outpatient care was possible, with a resultant decrease in both the length of hospital stay and the ultimate cost of burn care. Wound desiccation is prevented and pain is decreased. Accurate diagnosis of wound depth is crucial if Biobrane is to be used. Very deep wounds will not allow Biobrane adherence, neither will it occur if the wound has a high bacterial count. If joint surfaces are not splinted, the Biobrane will shear and not adhere to the wound. Convex and concave surfaces can be treated with Biobrane, which may need to be meshed.     

Management of partial thickness facial burns (comparison of topical antibiotics and bio-engineered skin substitutes).

This study compared the effect of standard topical antibiotic management versus a biological skin substitute wound closure for mid-partial thickness burns of the face. Adult patients with mid-dermal facial burns produced by flash flames or flame exposure were studied using a randomized prospective study design. Total daily burn care time, pain (0-10 scale) and healing time were monitored. Immediately after partial thickness debridement, the entire face burn, including ears, was closed with a bioengineered skin substitute coated with fibronectin (TransCyte) or treated by the open technique using bacitracin ointment applied 2-3 times daily. 21 patients were studied, with 10 patients in the skin substitute group. We found a significant decrease in wound care time 0.35 +/- 0.1 versus 1.9 +/- 0.5 h, decrease in pain of 2 +/- 1 versus 4 +/- 2 and re-epithelialization time 7 +/- 2 versus 13 +/- 4 days in the skin substitute group compared to topical antibiotics. We can conclude that a bioengineered skin substitute significantly improves the management and healing rate of partial thickness facial burns, compared to the standard open topical ointment technique.     

Survival after a second episode of toxic epidermal necrolysis

Toxic epidermal necrolysis resulting from severe hypersensitivity to medication has a reported mortality of up to 66%. A patient surviving two episodes with more than a 50% skin loss is unprecedented in the medical literature. Mortality has been associated with many factors, including delayed reepithelialization, persistent skin slough, coagulopathy, severe hypoproteinemia, and sepsis. It may be possible to decrease morbidity and mortality by preventing the shearing of epidermis, thereby limiting the denuded areas. This case report describes the successful management of our patient's second episode of toxic epidermal necrolysis. The treatment of this patient in our specialized burn center consisted of careful fluid and electrolyte management, nutritional support, standard topical antimicrobials, and new modalities of local wound management.     

Microskin grafting with Biobrane: a new application

A new grafting technique involving the combination of skin micrografts and Biobrane is reported. This is a modification of a method originally reported from China, utilising cadaveric allograft and skin micrografts. Experiments to verify the technique were carried out in a pig model. Small split-thickness skin autografts were finely minced into tiny particles and evenly spread on Biobrane. The micrografts with Biobrane were transplanted to controlled wounds in pigs. The expansion ratios of the micrografts were 10:1, they took well and the healing time of the wound was from 35–46 days. Based on successful animal experiments, we have used this technique successfully to treat severely burned patients.