Toxic epidermal necrolysis and Stevens-Johnson syndrome at the Prague Burn Centre 1998-2008.

BACKGROUND: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are skin disorders characterized by extensive necrosis of the mucous membranes and the epidermis caused by an autoimmune response. OBJECTIVES: To present experience of treating TEN and SJS at the Prague Burn Centre (PBC) 1998-2008. METHODS: 22 patients with the diagnosis TEN or SJS were enrolled. We collected data including the extent of the skin involvement, the ratio of men:women, the average age, the mortality rate, presence of comorbidities, the length of hospital stay, the period from the first symptoms to the admission to the PBC, corticosteroids administration prior to admission. RESULTS: 82% patients had injuries larger than 30% of body surface area. The ratio of men:women was 1 : 1.5; the average age was 48.4 years; the mortality was 32%. Significant comorbidities were present in 41% of the cases. The average length of hospital stay was 12.9 days. The period from the first symptoms to the admission to the PBC was 9.6 days; corticosteroids were administered to 68% of the cases. CONCLUSION: Treatment strategies at the PBC are based upon a multidisciplinary approach and focus on the general principles of treating patients with extensive skin loss. Corticosteroids must be avoided, antibiotics are not indicated and intravenous immunoglobulins are not justified in the standard therapy. Early diagnosis, prompt transport to a burn center are essential for patients outcomes. The medical community should be informed about these rare but potentially life threatening diseases.

Survival and quality of life in burns.

Advances in medical technology and practices have been associated with increasing medical specialization, but they have developed at a price. This price has included not only enormous financial costs, but the additional cost of dehumanized patient care, diminished confidence in the medical staff and, consequently, human suffering. Burn injuries are catastrophic in scope and require specialized, intensive and prolonged treatment from which ensure ethical and psychological problems often complicated by many individual factors. Some of them arising from the Code of Patients Rights not only in the Czech Republic and contribute to DNR decisions (do-not-resuscitate). Not only "Quantity" of life but also "Quality" of life should be considered, particularly in burns. Critical factor is age. In old patients more sophisticated medical knowledge and practice may actually contribute to suffering. At any age scarring represents a special type of disfigurement. The "burn image" is more likely to evoke public avoidance than sympathy. The non handicapped by their negative attitudes help create and perpetuate the handicap and the consequent burden of suffering in burn patients.

Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma.

BACKGROUND: Tumour-specific expression of matrix metalloproteinase (MMP)-7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVES: To examine the potential role of MMP-7 in shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in RDEB-associated and sporadic SCCs. METHODS: Tissue microarrays of RDEB-associated SCC (n = 20), non-EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP-7, CD44 variant 3 (CD44v3) and HB-EGF. Shedding of HB-EGF was studied in vitro using two cutaneous SCC cell lines. RESULTS: Immunohistochemical analysis showed that HB-EGF was absent in tumour cells when MMP-7 and CD44v3 colocalized, and that the absence of HB-EGF was more pronounced in RDEB-associated SCCs than in non-EB SCCs. The loss of HB-EGF in MMP-7-CD44v3 double-positive areas was interpreted to indicate shedding and activation of HB-EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP-7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB-EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. CONCLUSIONS: These findings provide evidence for the role of MMP-7 in promoting the growth of cutaneous SCCs by shedding HB-EGF, and identify EGFR signalling as a potential therapeutic target in RDEB-associated SCC and unresectable sporadic cutaneous SCC.

Transformation-specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas.

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. OBJECTIVES: To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen's disease. METHODS: Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen's disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. RESULTS: MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen's diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. CONCLUSIONS: These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface.

Nutrition in patients with burn injuries in the intensive care unit.

Authors discuss the choices of nutritional support in patient after severe burn injury during the last three decades. Severe burn injury presents one of the most critical states of starvation under a severe stress to the organism. Timely and appropriate metabolic intervention can positively influence the hypermetabolism, which is a common reaction after an injury. Burn injury causes a long-term reaction with a great risk of multiple organ dysfunction (requirement to perform repeated dressing changes under general anesthesia, repeated surgeries, and infections). Incorporation of a nutritional support is based on the knowledge of pathophysiology and metabolic response to injury, and is influenced by choice of nutrition substrates and by possibility of its administration.

Care for children after burn injury.

Authors are summing up basic approach in the treatment of severe burn injury in children. Thorough evaluation of severity of the injury is essential and determines further therapy. In this phase connection between care prior to hospitalization and in hospital is important. During the course of therapy in hospital, interdisciplinary teamwork is essential for the solution of various complications after burn injury. Important part of the care is cooperation with family of the child.

The role of skin bank in the treatment of severely burnt patients.

The accessibility of suitable temporary covers plays the key role in the treatment of severe skin losses. Biological covers have got the longest tradition in the wound healing. Skin banks are engaged in their production and distribution. Already in 1973 J. Moserová developed the methodology of harvesting pig xenografts. Later on, the short-term and the long-term method of storage were verified (Böhm, Konícková, Vogtová). In 1986, the Skin Bank in the Prague Burn Centre was established. In Prague Burn Centre the allografts are used very rarely, usually from the living donors, family members of the patients. Therefore, in our bank, we specialized in harvesting porcine xenografts. They are produced in three different forms--fresh, deep frozen in vapours of liquid nitrogen, and glycerolized. Porcine xenografts serve as a biological cover; they make barrier against infection and evaporation and protect the wound against desiccation. They are used namely for the treatment of superficial burn wounds, as a temporary coverage of excised wounds and as a dressing on release incision. Every year more than 10,000 strips have been used in our Burn Centre, it represents the area 200 m2. Since 1991 cultivation laboratory has been a part of our Skin Bank. We are interested in cultivation of human epidermal cells--keratinocytes. Cultured epidermal grafts became the first human in vitro prepared tissue, which was successfully transplanted to the patient. For the treatment of deep dermal skin losses we use either autologous keratinocytes, which can create permanent cover, or allogeneic cells, which stimulate spontaneous healing. Cultured keratinocytes are used in the treatment of burnt patients as well as in the trophic defects.

Early and late fatal complications of inhalation injury.

Severe inhalation injury causes a substantial deterioration in the prognosis and increases the general mortality of patients with extensive burns. Recently, in particular due to the development of invasive monitoring of patients and effective treatment of acute burn shock, we encounter with increasing frequency patients who survive the acute stage, including complications such as ARDS, and reach the stage of late complications. The latter include tracheooesophageal fistulas that develop on the basis of pressure ulcers and chondromalacia, usually at the site of the balloon of the tracheostomic cannula, and the overproduction of fibrous tissue in the area of the airways which leads to the development of stenosis, pulmonary fibrosis and bronchiectasia. Frequently, different early and late complications combine.

Burns of the perineum and anus.

One of the critical sites of the thermal injuries is the region of the perineum. Burns of the perineum are relatively frequent, while affections of the anus and sphincters are rare. At the Prague Burns Centre, University Hospital Královské Vinohrady, two patients were treated with this kind of injury. The site of the burns proved in both instances decisive for treatment and for subsequent prognosis. The surgical procedures (necrectomy and autotransplantation) had to be prepared with regard to the case-histories: in the 11-year-old boy by colostomy and in the adult man suffering from muscular dystrophy by a synthetic low-residue diet.

Quality of life in burn victims: a holistic approach.

The prognosis of burn patients is dependent--apart from adequate treatment--upon health care system and health care professionals, regarding not only survival, but also life-long quality of life. The protection of patients' rights is spelled out in the European Countries' constitutions, charters or basic laws. The Code of Patients' Rights in the Czech Republic in 1992 entitles the patients to respectful and professional treatment, to be able to make decisions, ev. to refuse treatment, to the presence of their own families, to continuity of treatment after discharge, to withhold consent to students' participation in the curative process, to die with dignity. The increasing interest in economic justification of any treatment in the EU calls for considering the ethical aspects. There has been differentiated intuitive ethics, ethics based on principles of Hippocrates, ethics defined by duties, ethics defined by consequences, influencing the quality of life (Grant, 1998). The age of patients should not play any role in decision--making concerning diagnostic or curative procedures. However, in geriatric burn patients the "aggressive" therapy should not deteriorate their last days. From the ethical point of view there should be applied "palliative care". The age is a significant factor in the permanent sequels in children and youngsters, in whom scar deformities cause the loss of "body image" and severe psychological problems when the Patients Rights (comprehended in the Code of Czech Republic) are not respected.

Necrobiotic process causing burn wound conversion may be prevented by allogeneic keratinocytes delivered by the recombined human/pig skin.

The spontaneous necrobiotic process frequently causes conversion of DDB (deep 2nd degree wounds) into full-thickness skin loss (3rd degree wounds). We found that this process may be positively influenced by the activity of living human allogeneic keratinocytes cultured on acellular pig dermis. This RHPS, if applied 'upside-down' with the epidermal layer facing the wound, provides an opportunity for keratinocytes to influence the healing. The aim of the present study was to find conditions, in terms of timing and wound-bed preparation, for optimum healing activity of RHPS. The wound beds were prepared either with tangential excision, surface dermabrasion or deep dermabrasion. Out of 17 wounds grafted with RHPS after tangential excision, 15 (88%) healed in 4-10 days; early excised wounds (up to day 5) healed within less than 10 days after the injury. Out of 8 wounds grafted after surface dermabrasion, only 2 (25%) healed. Out of 6 wounds grafted with RHPS after deep dermabrasion, 4 (67%) healed. The optimum healing effect of RHPS and prevention of conversion was achieved in early tangentially excised wounds.

Marjolin's ulcer.

In 1828 John Nicolas Marjolini characterized ulcer with malignant degeneration which developed in scars after burns, but it occurs under varying clinical conditions. Typical feature is the latent period (on average 30 years). It is encountered in 2 forms: a shallow ulcer or exophytic tumour, most frequently on the lower extremities. At the Prague Burn Centre 11 patients were treated since 1978 till 1998. A unique case was a man suffering from congenital form of epidermolysis bullosa who developed Marjolin's ulcer on his foot (histological examination confirmed well differentiated squamous cell carcinoma). After 4 years he died with extreme cachexia and metastatic spread of the tumour, because he refused repeatedly amputation and lymph nodes dissection. To prevent Marjolin's ulcer several recommendations are presented.

Burn wound coverage and burn wound closure.

Early excision and grafting changed dramatically topical wound treatment, but are restricted by difficulty in diagnosing burn depth, by limited donor sites and by technical skills to excise special areas (perineum, face). In addition to the extent of burn and the age of the patient the depth is determinant of mortality, morbidity and of patient's quality of life. It results from the time-temperature relation and is further influenced by local and systemic causes of conversion: dehydration, edema, infection and shock hypoxia, metabolic derangements, peripheral vessels diseases may contribute do deepening of burn wound. Superficial burn on day one appears deep dermal by day three, where spontaneous epithelization lasts much longer than 21 days and results in hypertrophic scarring. To prevent this sequelae deep dermal burn may be treated like full-thickness injury with excision and autografting. Another way is removal of dead layers of corium and using biological or synthetic cover. We have found a more effective way to reach wound closure (not only cover) in the method of "upside-down" application of recombined human/pig skin (RHPS), composed of allogeneic human keratinocytes cultured on cell-free pig dermis. The allogeneic epidermal cells temporarily "take", "close" the excised wound and simultaneously encourage epithelization from adnexa remnants in the wound bed. Thus definitive closure is achieved.

Experience with banked skin in the Prague Burn Center.

Despite progress in materials science, the use of human allografts and xenografts of pig origin is in the Prague Burn Center among the preferred means of temporary burn wound cover since 1973. True closure is achieved only with living autografts or isografts (identical twins). The method for preparing fresh porcine grafts was introduced in Prague 25 years ago: dermoepidermal sheets are retrieved in strips, are treated with a lavage of chemotherapeutics and antibiotics, are spread onto sterile wet gauze and stored in Pétri dishes at 4 degrees centigrade in a refrigerator. Cellular viability is maintained for 10-14 days when transferred to patients. The Prague Skin Bank commenced its activity in 1986. The Protocol for the cryopreservation of skin was established: the pretreated skin is kept in aluminium vessels in containers with vapours of liquid nitrogen. Cryoprotective Medium is used with 15% glycerol. The skin viability has been verified by investigation of glucose metabolism. The production of fresh and long-term stored viable skin grafts has been increasing continuously and at present, the production represents 2 million square centimeters per year. About 15% of the harvest is distributed to other surgical and trauma departments. Any burn wound dressing may fail due to a failure to use them properly-lack of attention to the details in burn wound care can lead to disappointment.