New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy.

The therapeutic management of severe radiation burns remains a challenging issue. Conventional surgical treatment (excision and skin autograft or rotation flap) often fails to prevent unpredictable and uncontrolled extension of the radiation necrotic process. We report here an innovative therapeutic strategy applied to the victim of a radiation accident (December 15, 2005) with an iridium gammagraphy radioactive source (192Ir, 3.3 TBq). The approach combined numerical dosimetry-guided surgery with cellular therapy using mesenchymal stem cells. A very severe buttock radiation burn (2000 Gy at the center of the skin surface lesion) of a 27-year-old Chilean victim was widely excised (10 cm in diameter) using a physical and anatomical dose reconstruction in order to better define the limit of the surgical excision in apparently healthy tissues. A secondary extension of the radiation necrosis led to a new excision of fibronecrotic tissues associated with a local cellular therapy using autologous expanded mesenchymal stem cells as a source of trophic factors to promote tissue regeneration. Bone marrow-derived mesenchymal stem cells were expanded according to a clinical-grade technique using closed culture devices and serum-free medium enriched in human platelet lysate. The clinical evolution (radiation pain and healing progression) was favorable and no recurrence of radiation inflammatory waves was observed during the 11 month patient's follow-up. This novel multidisciplinary therapeutic approach combining physical techniques, surgical procedures and cellular therapy with adult stem cells may be of clinical relevance for improving the medical management of severe localized irradiations. It may open new prospects in the field of radiotherapy complications.

Evaluation of serum procalcitonin concentration in the ICU following severe burn.

The goal of the study was to analyse plasma procalcitonin (PCT) concentrations during infectious events of burns in ICU. Clinical and laboratory data were collected at admission and twice a week in burned patients admitted with a total body surface area (TBSA) >20%. Procalcitonin was determined using both a semi-quantitative detection (PCT-Q) and a quantitative immunoluminometric method (PCT-Lumi). A total of 359 time points in 25 consecutive patients with 40+/-17% (20-86%) TBSA burned, defined as a procalcitonin concentration associated with an inflammatory status according to society critical care medicine definition, were made. The principal site of infection was the respiratory tract (84% of patients required mechanical ventilation). PCT-Lumi values corresponded to the four semi-quantitative ranges of PCT-Q and statistically reflected the simultaneously observed inflammatory status (Kruskall-Wallis test). The area under the receiver operating characteristic curve for C-reactive protein (CRP) was higher than those for PCT and white blood cell (WBC) count, but this difference was not significant. The optimum PCT cut-off value was 0.534 ng/ml with sensitivity and specificity of 42.4% and 88.8%, respectively. However, PCT does not appear to be superior to C-reactive protein (CRP) and white blood count (WBC) as diagnosis marker of sepsis in burns. PCT is not sufficient to diagnose and to follow infection in burns admitted in ICU.

[Heparin-induced thrombocytopenia: report of four cases in severely burned patients]. / Thrombopénie induite par l'héparine de type II: description de quatre observations chez le brûlé grave.

Heparin-induced thrombocytopenia (HIT) is a dangerous complication of heparin therapy caused by an antibody against heparin/Platelet Factor 4 (PF4) complex. HIT complicates about 2% of treatment with unfractionated heparin (UFH). The aim of the study was to determine the incidence of HIT in a burn center and to report four cases in severely burned patients. HIT was documented in 2.8% of burns treated with UFH administered for antithrombotic prophylaxis and in none of burns receiving low molecular weight heparin (LMWH). All HIT cases occurred after extensive deep burns (mean total body surface area or TBSA was 60+/-21%) and three cases had above 75% of burn. We suggest that systemic platelet activation after thermal injury and local production of PF4 in the burn wound could participate to development of HIT. The risk is a late diagnosis since thrombosis clinical detection under burned skin is difficult. HIT appears during the first week of UHF treatment at the same time as a unstable period of fluctuating platelets.

[Respiratory dysfunction in burned patients]. / Lésions respiratoires et brûlures.

INTRODUCTION: Smoke inhalation and respiratory complications are still the major causes of mortality in severely burned patients. STATE OF THE ART: The diagnosis is suspected clinically on the basis of history and physical examination and can be confirmed bronchoscopically. Respiratory failure in burned patients occurs through a number of associated mechanisms. Pneumonitis and adult respiratory distress syndrome (ARDS) are common early complications. New pulmonary treatments and advances in ventilation have reduced the incidence of both barotrauma and infectious complications. Tracheal stenosis can occur as a late complication of prolonged mechanical ventilation. PERSPECTIVES: Clinical and experimental studies have shown that damage to the mucosal barrier and the release of inflammatory mediators are the most important pathophysiological events following smoke inhalation. Manipulation of the inflammatory response following inhalation may be a treatment option in the distant future. CONCLUSION: Inhalation injury occurring in burned patients can produce severe respiratory and systemic complications.

PCC-FISH in skin fibroblasts for local dose assessment: biodosimetric analysis of a victim of the Georgian radiological accident.

We propose a new method of biodosimetry that could be applied in cases of localized irradiation. The approach is based on excess chromosome segments determination by the PCC-FISH technique in fibroblasts isolated from skin biopsy. Typically, 0 to 10 Gy ex vivo gamma-irradiated human skin biopsies were dissociated and fibroblasts were isolated and grown for several days. Cells next underwent PCC-FISH painting of whole chromosome 4, and the number of excess chromosome segments per metaphase was determined. An ex vivo reference curve correlating the number of excess chromosome segments per metaphase to the radiation dose was established and used to assess the dose delivered to the skin of one of the victims of the radiological accident that occurred at Lia in Georgia in December 2001. Specifically, the victim suffering from moist desquamation underwent skin excision in Hospital Percy (France). Measurement of excess chromosome segments per metaphase was done in fibroblasts isolated and grown from removed wounded skin and subsequent conversion to radiation doses was performed. The radiation dose map obtained was shown to be in accordance with clinical data and physical dosimetry as well as with conventional biodosimetry. These results demonstrated that PCC-FISH painting applied to skin fibroblasts may be a suitable technique for dose estimation. To assess its worth, this approach needs to be extended to future accidents involving localized radiation exposure.

A silver sulphadiazine-impregnated lipidocolloid wound dressing to treat second-degree burns.

OBJECTIVE: To evaluate the efficacy and tolerance of Urgotul SSD dressing (Laboratoires Urgo) in the treatment of second-degree burns. METHOD: This was a national multicentre phase III non-comparative open-label prospective study involving 10 burns units. The 41 subjects were non-immunosuppressed adults with second-degree thermal burn(s), which were clinically non-infected, less than 24 hours old, had a surface area less than 500 cm2 and warranted the local use of silver sulphadiazine. For four weeks, subjects were followed up weekly with a clinical assessment, bacteriological swabs and photographic recording. RESULTS: Of the 41 patients, 24 healed within a mean of 10.8 days and 13 had a skin graft on the study burn within a mean of 11.5 days. There were four premature study withdrawals. The total number of cumulative treatment days was 445, and 298 treatments were performed (including 257 dressing changes). Mean dressing wear time was 1.73 days. None of the subjects acquired a secondary infection. Researchers took 121 bacteriological samples, and wound colonisation with Staphylococcus aureus was found in only one patient. At follow-up nursing staff reported that dressing acceptability was good. CONCLUSION: Use of Urgotul SSD led to a good wound outcome--wounds healed or were grafted.

Urgotul: a novel non-adherent lipidocolloid dressing.

Urgotul belongs to a new class of non-adherent dressings: the lipidocolloid dressings. It is composed of an open weave polyester mesh impregnated with hydrocolloid polymers dispersed within petrolatum. The first clinical trial data are presented. Efficacy and safety were evaluated in a multicentre non-comparative trial involving 92 patients treated to healing or up to 4 weeks. Adult outpatients with acute wounds (n = 34), leg ulcers (n = 24), other chronic wounds (n = 14) or with second-degree burns (n = 20) were included. Results showed 32.4% (n = 11) of the acute wounds, 12.5% (n = 3) of the leg ulcers and 14.3% (n = 2) of the other chronic wounds completely healed before 4 weeks. Surface areas decreased on average by 76.4%, 63.5% and 44.2% at study endpoint respectively. For burns, 19 patients healed (95%) within 5-19 days. A total of 771 dressing changes were performed during the course of the study. Dressing application was considered as easy or very easy in 90% or more of the changes and there was no difficulty in removing the dressing in about 95% of the cases. Safety was good with five reports of a transitory local adverse event, probably dressing-related, being observed, two patients (2.2%) prematurely stopped treatment because of moderate periwound erythema. Urgotul is a highly promising new dressing which is currently undergoing further comparative clinical evaluation.

[Inflammatory reaction and infection in severe burns]. / Réaction inflammatoire et infection chez le brûlé grave.

Major burn injury is a lesion where the inflammatory reaction is exported to the whole body. After a short time of hemodynamic changes, this inflammation is kept by necrotic tissues, persistence of an opened wound, and by the pulmonary and gut reactions. When infection starts, it becomes difficult to distinguish its symptoms among the inflammatory signals. The main point of the care of burn patient consists in trying to control this reaction and the immuno-depression it leads to: early excision and grafts, early enteral nutrition, perfect nursing care. There is no specific medical treatment of this state. The antibiotic use must be well weighed up. Infection is often the trigger of the multiple organ dysfunction which is the way the burn patient dies but is not mandatory.

Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous controls.

OBJECTIVE: To compare the effectiveness on wound healing time in severe burn patients of ornithine alpha-ketoglutarate supplementation of enteral feeding vs. an isonitrogenous control. Previous clinical and experimental studies suggest a beneficial effect of enterally administered ornithine alpha-ketoglutarate supplementation on protein metabolism in burn patients, but few data deal with clinical outcome. DESIGN: Prospective double-blind randomized trial. SETTING: Burn treatment center of an army hospital. PATIENTS: Forty-seven severe burn patients with total burned body surface areas of 25% to 95% and presence of full thickness burn who were prescribed early exclusive enteral nutrition. Either ornithine alpha-ketoglutarate or isonitrogenous control (soy protein mixture, Protil-1) were administered twice a day as a bolus (2 x 10 g) at 9 am and 9 pm for 3 wks. The patients were evaluated for wound healing time (primary end point), antibiotic use, tolerance, duration of enteral nutrition, and nutritional status. INTERVENTIONS: Serial blood samples were collected in each patient for determination of serum transthyretin and plasma phenylalanine, and urine sampling was performed for determination of 3-methylhistidine excretion at day 4 and day 21 after burn injury. MEASUREMENTS AND MAIN RESULTS: Wound healing times in patients receiving ornithine alpha-ketoglutarate or Protil-1 were 60 +/- 7 and 90 +/- 12 days, respectively (p < .05) for similar grafted surfaces. Based on increased serum transthyretin concentrations, both groups showed an improvement of nutritional status at day 21 after burn. Taking a cut-off value of 110 unit burn standard for severity of injury, plasma phenylalanine concentrations, and urinary 3-methylhistidine/creatinine ratio were significantly reduced (p < .05) in the less severe burn patients (<110 unit burn standard) supplemented with ornithine alpha-ketoglutarate. CONCLUSIONS: Ornithine alpha-ketoglutarate supplementation of enteral feeding significantly shortens wound healing time in severe burn patients. In addition, ornithine alpha-ketoglutarate administration was safe and well tolerated and decreased protein hypercatabolism in the less severe burn patients.

Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five year single-center experience with 30 patients.

OBJECTIVE: We report recent five-year experience in a large, single center series of severely burned and otherwise traumatized patients given cultured epithelial autografts (CEA) from a single commercial laboratory. SUMMARY BACKGROUND DATA: Initial optimism over CEA application has been tempered by subsequent reports asserting that this modality is unreliable and expensive. Discussion continues over its clinical role. METHODS: From 1991 to 1996, CEA were applied to a mean 37+/-17% of total body surface area (TBSA) of 30 patients. These patients had 78+/-10% average burn size, 65+/-16% average third-degree burn size, 90% prevalence of endoscopically confirmed inhalation injury and 37% prevalence of other serious conditions. RESULTS: CEA achieved permanent coverage of a mean 26+/-15% of TBSA, an area greater than that covered by conventional autografts (a mean 25+/-10% of TBSA). Survival was 90% in these severely burned and otherwise traumatized patients. Final CEA take was a mean 69+/-23%. In subset analyses, only younger age was significantly associated with better CEA take (p = 0.0001 in univariate analysis, p<0.04 in multivariate analysis, Student's t-test). CONCLUSIONS: Epicel CEA successfully provided extensive, permanent burn coverage in severely traumatized patients, proving an important adjunct to achievement of a high survival rate in a patient population whose prognosis previously had been poor. In our experience CEA appear to have a very high beneficial value in the management of bur ns >60% TBSA. In some cases studied it is very likely that CEA was a life-saving treatment.

Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix.

BACKGROUND: Extensive third degree burn wounds can be permanently covered by the transplantation of autologous cultured keratinocytes. Many modifications to Green and colleagues' original technique have been suggested, including the use of a fibrin matrix. However, the properties of the cultured cells must be assessed using suitable criteria before a modified method of culture for therapeutic purposes is transferred to clinical use, because changes in culture conditions may reduce keratinocyte lifespan and result in the loss of the transplanted epithelium. METHODS: To evaluate the performances of human keratinocytes grown on a fibrin matrix, we assay for their colony-forming ability, their growth potential and their ability to generate an epidermis when grafted onto athymic mice. The results of these experiments allowed us to compare side by side the performance for third degree burn treatment of autologous cultured epithelium grafts grown according to Rheinwald and Green on fibrin matrices with that of grafts grown directly on plastic surfaces. RESULTS: We found that human keratinocytes cultured on a fibrin matrix had the same growth capacity and transplantability as those cultured on plastic surfaces and that the presence of a fibrin matrix greatly facilitated the preparation, handling, and surgical transplantation of the grafts, which did not need to be detached enzymatically. The rate of take of grafts grown on fibrin matrices was high, and was similar to that of conventionally cultured grafts. The grafted autologous cells are capable of generating a normal epidermis for many years and favor the regeneration of a superficial dermis. CONCLUSION: We have demonstrated that: 1) fibrin matrices have considerable advantages over plastic for the culture of skin cells for grafting and that it is now possible to generate and transplant enough cultured epithelium from a small skin biopsy to restore completely the epidermis of an adult human in 16 days; and 2) the generated epidermis self-renews itself for years. The use of fibrin matrices thus significantly improves the transplantation of cultured epithelium grafts for extensive burns as recently demonstrated in a follow-up work.

[Ambulatory treatment of burns in children]. / Traitement ambulatoire des brûlures de l'enfant.

A majority of burns in children may have an ambulatory management for which the paediatrician has an important role. He must assess the severity of the burn by quoting extent, depth and localization of the burn injuries and then send the most severe to a specialized burn centre. The circumstances and the social situation are important in the decision of either hospitalization or ambulatory care, remembering that the burn may correspond to child abuse. The treatment consists of initially refreshing the burn to limit the extension, then washing the lesions using topical antiseptic soap, finally applying standard silver sulfadiazine cream. Local care is accomplished daily the first few days, then every three days to follow the healing and to keep a watch on possible complications such as infections or failure to heal, which must be treated in burn units. Pain relief treatment is an important part of the management.

[Pharmacokinetics of fusidic acid in patients with seriously infected burns]. / Pharmacocinétique de l'acide fusidique administré au sujet gravement brûlé infecté.

The pharmacokinetics of fusidic acid (FA) were studied in 10 infected severe burns patients (35 +/- 5 yrs, 81 +/- 17 kg) i.e. 43 +/- 10% in 3rd degree. Treatment was given at the dose of 500 mg/8 hours (2-hour infusion). The kinetics of FA were evaluated on D1 (1st infusion) and at steady state on D4 (10th infusion), each sequence involving 9 whole blood samples. Samples were assayed by high-performance liquid chromatography. Data were analysed by a non-compartmental method. Mean duration of treatment, considered effective in all cases, was 5.9 +/- 2.1 days. The systemic safety of FA was felt to be good. Kinetic analysis revealed the existence of significant differences between D1 and D4 concerning the parameters Cmax, Cmin, AUC, Cl and Vss. These events are attributable to the non-linear nature of the human kinetics of FA. Accumulation ratios R1 and R2 did not differ i.e. 1.51 +/- 0.25 and R2 = 2.44 +/- 0.68. Kinetic modelling based upon the experimental tracing obtained on D1 revealed good coincidence of the predictive tracing in relation to data determined on D4. The dosage algorithm of 500 mg/8 hours was microbiologically satisfactory with Cmin measured on D1 and at steady state constantly greater than the MIC of the main organisms concerned (< to 2 micrograms/ml). Reduction in the parameters Cmax and AUC in comparison with a group of healthy subjects ultimately led to shortening of the mean T1/2 of FA. In the absence of impaired liver function, this is attributable to the known increase in hepatic clearances in burns patients and, to a certain extent, to the existence of translesional extra-hepatic clearance, which could contribute to the success of treatment.

Initial general management and surgery of six extensively burned children treated with cultured epidermal autografts.

PURPOSE: The aim of this study was to document the surgical and intensive care methods used in six extensively burned children (EBC), ie, total body surface area (TBSA) burned over 70% or TBSA with deep burns over 60%, treated with cultured epidermal autografts (CEA). METHODS: Six EBC, with a mean age of 7.5 years (range, 2.5 to 12) received CEA. Their mean TBSA burned was 82% (range, 70-94) with 74% (range, 60-90) of TBSA with deep burns. All sustained flame burns and inhalation injuries. RESULTS: The survival rate was six of six. The average initial and final engraftment rates of CEA were, respectively, 79% (range, 70 to 95) and 84% (range, 72 to 100). CEA definitively covered 45% (range, 18 to 57) of TBSA for a mean cost per child of $80,000 (range, 55,000 to 110,000). CONCLUSION: Even if CEA are expensive, such engraftment rates and survival ratio results make them an excellent alternative wound covering method for EBC when donor sites for widely meshed autografts are exhausted.

Evolution and significance of circulating procalcitonin levels compared with IL-6, TNF alpha and endotoxin levels early after thermal injury.

To determine the evolution and significance of circulating procalcitonin (ProCT), IL-6 TNF alpha and endotoxin levels early after thermal injury, we performed a prospective, single unit, longitudinal study. Forty burn patients with total body surface area (TBSA) > 30 per cent were studied, of whom 33 suffered an inhalation injury. Blood samples were taken on the day of admission, every 4 h during the first day and daily during the first week. All patients had increased ProCT and IL-6 levels without any proven infection. Endotoxin and TNF alpha levels remained very low or undetectable. ProCT and IL-levels correlated well with the severity of skin burn injury (respectively, p < 0.006 and p < 0.028, using the non-parametric Kruskal-Wallis test). ProCT levels are not associated with smoke inhalation. ProCT and IL6 are prognostic factors of mortality at the time of admission but less reliable than the clinical UBS (unit burn standard) score. Endotoxin and TNF alpha were undetectable, suggesting that the problem of the early gut bacterial translocation remains to be proven.

[Human albumin solutions in the treatment of burned patients. Current indications]. / Solutions d'albumine humaine dans le traitement des brûlés. Indications actuelles.

A KEY ROLE: Albumin is a large molecule which plays an essential role in generating colloido-osmotic pressure which facilitates fluid retention in the intravascular space. HYPOALBUMINEMIA IN BURNED PATIENTS: Excessive loss is followed by deficient synthesis in the liver (preferential production of inflammatory proteins, insufficient protein intake). HUMAN ALBUMIN IN BURNED PATIENTS: By maintaining fluid in the vascular sector and favoring inflow from the interstitial space, human albumin maintains blood volume. Despite its value as the reference substance, reasonable use as become necessary because of cost-containment. Human albumin should be reserved for severely burned patients whose albuminemia falls to approximately 20 g/l (or proteinemia to 35 g/l).

[Therapeutic monitoring of teicoplanin in a severely burned patient]. / Suivi thérapeutique de la teicoplanine chez un sujet gravement brûlé.

The authors report the study of the kinetics in serum and urine and the clinical safety of a high dose of teicoplanin administered in a 19 year-old patient with major burns (60% of body surface area, the half of which consisting of third-degree burns and UBS at 150) and S aureus meticillin-resistant infection. At day 1, he was given two loading infusions of 12 mg.kg-1 teicoplanin followed by 12 mg.kg-1 per day of treatment. At all times, Cmin concentrations were below the limit value of 8 mg.mL-1. Therefore the therapeutic regimen was increased on several occasions. On days 5, 8 and 15, Cmin were measured by FPIA. Pharmacokinetic analysis was performed at day 16, (i.e., 20 mg.kg-1) and urine was also collected over at least 12 hours. At day 16, serum and urine samples were assayed by HPLC. Data were analyzed with a noncompartmental method. The duration of treatment was 20 days and no adverse events were noted. Bacteriological tests performed at the end of treatment demonstrated the elimination of the agent responsible over the infection. While pharmacokinetics were not assessed at plateau, Cmin remained very low. Vss was similar to values obtained in healthy subjects while total clearance was increased. This phenomenon was explained by the increase of total clearance and a nonrenal translesional diffusion suggested by the body surface area affected by third-degree burns. Finally, the cost of increasing doses of teicoplanin must be taken in account.