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OBJECTIVE: To describe a case of partial nephrogenic diabetes insipidus in a burned patient after prolonged delivery of low inspired concentrations of sevoflurane via an Anesthetic Conserving Device. DATA SOURCES: Clinical observation. STUDY SELECTION: Case report. DATA EXTRACTION: Relevant clinical information. DATA SYNTHESIS: A 34-year-old man was admitted with burns covering 52% of his total body surface area. Mechanical ventilation was provided during sedation with continuous infusions of sufentanil and midazolam. Sedation became increasingly difficult, and in order to limit administration of IV agents, sevoflurane was added to the inspiratory gas flow. This was provided using an Anesthetic Conserving Device and continued for 8 days. The patient rapidly developed polyuria and hypernatremia with an inappropriate decrease in urinary osmolality. Administration of desmopressin resulted in only a modest effect on renal concentrating ability. After cessation of sevoflurane, all variables returned to normal within 5 days. The results of further investigations (cerebral computed tomographic scan, cerebral magnetic resonance imaging, and serum arginine vasopressin concentration) were compatible with a diagnosis of partial nephrogenic diabetes insipidus. The temporal sequence of clinical findings in relation to sevoflurane administration suggests that the sevoflurane was the probable underlying cause. CONCLUSIONS: Clinicians should be aware of the possibility of sevoflurane-induced diabetes insipidus not only during general anesthesia but also in the intensive care setting of sedation in critically ill patients. This is especially important in patients, such as those with severe burns, in whom preserved renal concentrating ability is important to ensure compensation for extrarenal fluid losses.
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Anestésicos por Inhalación/efectos adversos , Quemaduras/terapia , Sedación Consciente/efectos adversos , Nefropatías Diabéticas/inducido químicamente , Éteres Metílicos/efectos adversos , Adulto , Anestésicos por Inhalación/administración & dosificación , Anestésicos por Inhalación/uso terapéutico , Sedación Consciente/instrumentación , Sedación Consciente/métodos , Humanos , Masculino , Éteres Metílicos/administración & dosificación , Éteres Metílicos/uso terapéutico , Respiración Artificial/métodos , SevofluranoRESUMEN
High-definition optical coherence tomography (HD-OCT) permits real-time 3D imaging of the impact of selected agents on human skin allografts. The real-time 3D HD-OCT assessment of (i) the impact on morphological and cellular characteristics of the processing of human acellular dermal matrices (HADMs) and (ii) repopulation of HADMs in vitro by human fibroblasts and remodelling of the extracellular matrix by these cells. Four different skin decellularization methods, Dispase II/Triton X-100, Dispase II/SDS (sodium dodecyl sulphate), NaCl/Triton X-100 and NaCl/SDS, were analysed by HD-OCT. HD-OCT features of epidermal removal, dermo-epidermal junction (DEJ) integrity, cellularity and dermal architecture were correlated with reflectance confocal microscopy (RCM), histopathology and immunohistochemistry. Human adult dermal fibroblasts were in vitro seeded on the NaCl/Triton X-100 processed HADMs, cultured up to 19 days and evaluated by HD-OCT in comparison with MTT proliferation test and histology. Epidermis was effectively removed by all treatments. DEJ was best preserved after NaCl/Triton X-100 treatment. Dispase II/SDS treatment seemed to remove all cellular debris in comparison with NaCl/Triton X-100 but disturbed the DEJ severely. The dermal micro-architectural structure and vascular spaces of (sub)papillary dermis were best preserved with the NaCl/Triton X-100. The impact on the 3D structure and vascular holes was detrimental with Dispase II/SDS. Elastic fibre fragmentation was only observed after Dispase II incubation. HD-OCT showed that NaCl/Triton X-100 processed matrices permitted in vitro repopulation by human dermal fibroblasts (confirmed by MTT test and histology) and underwent remodelling upon increasing incubation time. Care must be taken in choosing the appropriate processing steps to maintain selected properties of the extracellular matrix in HADMs. Processing HADMs with NaCl/Triton X-100 permits in vitro the proliferation and remodelling activity of human dermal fibroblasts. HD-OCT provides unique real-time and non-invasive 3D imaging of tissue-engineered skin constructs and complementary morphological and cytological information.
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Dermis Acelular , Trasplante de Piel , Tomografía de Coherencia Óptica/métodos , Adulto , Proliferación Celular , Células Cultivadas , Sistemas de Computación , Dermis/citología , Fibroblastos/citología , Humanos , Imagenología Tridimensional , Octoxinol , Cloruro de Sodio , Ingeniería de Tejidos , Andamios del Tejido , Trasplante HomólogoRESUMEN
Wound healing following partial thickness thermal burns is commonly hampered by the risk of hypertrophic scarring. Skin myofibroblast (MF) density is commonly increased in postburn healing. The transition between fibroblast-like cells and α-smooth muscle actin (SMA)+ MF possibly begins with CD14+ monocytes, evolving to CD14+ CD34+ fibrocytes, followed by ß-SMA+ protomyofibroblast (PMF) maturation. Skin biopsies from 25 burn patients were collected about 1 and 4 weeks after injury. Immunohistochemistry was performed using monoclonal antibodies to α-SMA, ß-SMA, factor XIIIa, lysozyme, Mac 387, CD14, CD117 and Ulex europaeus agglutinin-1 (UEA-1). The set of Mac 387+ and CD14+ monocytes was accompanied by both CD34+ fibrocytes and factor XIIIa+ dendrocytes. By contrast, ß-SMA+ PMF were rare. Of note, α-SMA+ MF were more abundant at week 4 than at week 1 (p < 0.01). The UEA-1+ endothelial cells showed marked variations in their dermal distribution, irrespective of the densities in the other scrutinized cells. In conclusion, healing of partial thickness thermal burns involves a diversity of cell types including PMF. In the present samples, the PMF density remained low. © 2015 S. Karger AG, Basel.
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Quemaduras/metabolismo , Miofibroblastos/metabolismo , Piel/metabolismo , Cicatrización de Heridas/fisiología , Actinas/metabolismo , Adulto , Biopsia , Quemaduras/patología , Femenino , Fibroblastos/metabolismo , Humanos , Inmunohistoquímica , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Piel/patología , Factores de Tiempo , Adulto JovenRESUMEN
While real-time 3-D evaluation of human skin constructs is needed, only 2-D non-invasive imaging techniques are available. The aim of this paper is to evaluate the potential of high-definition optical coherence tomography (HD-OCT) for real-time 3-D assessment of the epidermal splitting and decellularization. Human skin samples were incubated with four different agents: Dispase II, NaCl 1 M, sodium dodecyl sulphate (SDS) and Triton X-100. Epidermal splitting, dermo-epidermal junction, acellularity and 3-D architecture of dermal matrices were evaluated by High-definition optical coherence tomography before and after incubation. Real-time 3-D HD-OCT assessment was compared with 2-D en face assessment by reflectance confocal microscopy (RCM). (Immuno) histopathology was used as control. HD-OCT imaging allowed real-time 3-D visualization of the impact of selected agents on epidermal splitting, dermo-epidermal junction, dermal architecture, vascular spaces and cellularity. RCM has a better resolution (1 µm) than HD-OCT (3 µm), permitting differentiation of different collagen fibres, but HD-OCT imaging has deeper penetration (570 µm) than RCM imaging (200 µm). Dispase II and NaCl treatments were found to be equally efficient in the removal of the epidermis from human split-thickness skin allografts. However, a different epidermal splitting level at the dermo-epidermal junction could be observed and confirmed by immunolabelling of collagen type IV and type VII. Epidermal splitting occurred at the level of the lamina densa with dispase II and above the lamina densa (in the lamina lucida) with NaCl. The 3-D architecture of dermal papillae and dermis was more affected by Dispase II on HD-OCT which corresponded with histopathologic (orcein staining) fragmentation of elastic fibres. With SDS treatment, the epidermal removal was incomplete as remnants of the epidermal basal cell layer remained attached to the basement membrane on the dermis. With Triton X-100 treatment, the epidermis was not removed. In conclusion, HD-OCT imaging permits real-time 3-D visualization of the impact of selected agents on human skin allografts.
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Epidermis/anatomía & histología , Tomografía de Coherencia Óptica/métodos , Colágeno/metabolismo , Sistemas de Computación , Dermis/anatomía & histología , Dermis/metabolismo , Endopeptidasas , Epidermis/metabolismo , Humanos , Imagenología Tridimensional , Microscopía Confocal , Octoxinol , Cloruro de Sodio , Dodecil Sulfato de Sodio , Ingeniería de Tejidos , Adulto JovenRESUMEN
PURPOSE: On 22 March 2016, the burn unit (BU) of Queen Astrid Military Hospital assessed a surge in severely injured victims from terror attacks at the national airport and Maalbeek subway station according to the damage control resuscitation (DCR) and damage control surgery (DCS) principles. This study delves into its approach to identify a suitable triage scoring system and to determine if a BU can serve as buffer capacity for mass casualty incidents (MCIs). METHODS: The study reviewed retrospectively the origin of explosion, demographic data, sustained injuries, performed surgery, and length of stay of all admitted patients. Trauma scores (Injury Severity Score (ISS) and New Injury Severity Score (NISS)) and triage scores (Revised Trauma Score (RTS), New Trauma Score (NTS), and Trauma Score Injury Severity Score (TRISS)), were compared to burn mortality scores (Osler updated Baux Score and Tobiasen's Abbreviated Burn Severity Index (ABSI)). RESULTS: Of the 23 casualties admitted to the BU, the scores calculated on average 3.5 indications for a level 1 trauma center (ISS 4, NISS 6, RTS 0, T-NTS 4). Nevertheless, no deaths occurred during admission or the 1-year follow-up. CONCLUSION: MCIs create chaos and a high demand for care. Avoiding bottlenecks and adhering to the DCR/DCS principles are necessary to deliver the best care to the largest number of people. This study indicates that a BU can serve as buffer capacity for MCIs. Nevertheless, its integration into the medical resilience plan depends on accurate scoring, comprehensive care availability, and understanding of the DCR/DCS concept. NTS for triage seems the best fit for scoring polytrauma referrals to a BU during MCIs.
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The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.
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Trasplante de Células/economía , Trasplante de Células/legislación & jurisprudencia , Comercio , Atención a la Salud/legislación & jurisprudencia , Unión Europea , Legislación como Asunto , Trasplantes/economía , Trasplante de Células/ética , Atención a la Salud/economía , Atención a la Salud/ética , Industria Farmacéutica/legislación & jurisprudencia , Humanos , Legislación como Asunto/ética , PolíticasRESUMEN
BACKGROUND: A European response plan to burn mass casualty incidents has been jointly developed by the European Commission and the European Burn Association. Upon request for assistance by an affected country, the plan outlines a mechanism for coordinated international assistance, aiming to alleviate the burden of care in the affected country and to offer adequate specialized care to all patients who can benefit from it. To that aim, Burn Assessment Teams are deployed to assess and triage patients. Their transportation priority recommendations are used to distribute outnumbering burn casualties to foreign burn centers. Following an appropriate medical evacuation, these casualties receive specialized care in those facilities. METHODS: The European Burns Association's disaster committee developed medical-organizational guidelines to support this European plan. The experts identified fields of interest, defined questions to be addressed, performed relevant literature searches, and added their expertise in burn disaster preparedness and response. Due to the lack of high-level evidence in the available literature, recommendations and specially designed implementation tools were provided from expert opinion. The European Burns Association officially endorsed the draft recommendations in 2019, and the final full text was approved by the EBA executive committee in 2022. RECOMMENDATIONS: The resulting 46 recommendations address four fields. Field 1 underlines the need for national preparedness plans and the necessary core items within such plans, including coordination and integration with an international response. Field 2 describes Burn Assessment Teams' roles, composition, training requirements, and reporting goals. Field 3 addresses the goals of specialized in-hospital triage, appropriate severity criteria, and their effects on priorities and triage. Finally, field 4 covers medical evacuations, including their timing and organization, the composition of evacuation teams and their assets, preparation, and the principles of en route care.
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Quemaduras , Planificación en Desastres , Incidentes con Víctimas en Masa , Humanos , Triaje , Hospitales , Unidades de QuemadosAsunto(s)
Lesión Renal Aguda/etiología , Bacteriófagos , Colistina/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Colistina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Pseudomonas/complicaciones , Pseudomonas aeruginosa/patogenicidad , Sepsis/complicaciones , Sepsis/tratamiento farmacológicoRESUMEN
Since 1987, keratinocytes have been cultured at the Queen Astrid Military Hospital. These keratinocytes have been used routinely as auto and allografts on more than 1,000 patients, primarily to accelerate the healing of burns and chronic wounds. Initially the method of Rheinwald and Green was used to prepare cultured epithelial autografts, starting from skin samples from burn patients and using animal-derived feeder layers and media containing animal-derived products. More recently we systematically optimised our production system to accommodate scientific advances and legal changes. An important step was the removal of the mouse fibroblast feeder layer from the cell culture system. Thereafter we introduced neonatal foreskin keratinocytes (NFK) as source of cultured epithelial allografts, which significantly increased the consistency and the reliability of our cell production. NFK master and working cell banks were established, which were extensively screened and characterised. An ISO 9001 certified Quality Management System (QMS) governs all aspects of testing, validation and traceability. Finally, as far as possible, animal components were systematically removed from the cell culture environment. Today, quality controlled allograft production batches are routine and, due to efficient cryopreservation, stocks are created for off-the-shelf use. These optimisations have significantly increased the performance, usability, quality and safety of our allografts. This paper describes, in detail, our current cryopreserved allograft production process.
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Técnicas de Cultivo de Célula/métodos , Técnicas de Cultivo de Célula/normas , Células Nutrientes/citología , Prepucio/citología , Queratinocitos/citología , Seguridad , Animales , Biopsia , Proliferación Celular , Separación Celular , Células Cultivadas , Prepucio/trasplante , Humanos , Recién Nacido , Queratinocitos/trasplante , Masculino , Ratones , Bancos de Tejidos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Human donor skin allografts are suitable and much used temporary biological (burn) wound dressings. They prepare the excised wound bed for final autografting and form an excellent substrate for revascularisation and for the formation of granulation tissue. Two preservation methods, glycerol preservation and cryopreservation, are commonly used by tissue banks for the long-term storage of skin grafts. The burn surgeons of the Queen Astrid Military Hospital preferentially use partly viable cryopreserved skin allografts. After mandatory 14-day bacterial and mycological culture, however, approximately 15% of the cryopreserved skin allografts cannot be released from quarantine because of positive culture. To maximize the use of our scarce and precious donor skin, we developed a glycerolisation-based recovery method for these culture positive cryopreserved allografts. The inactivation and preservation method, described in this paper, allowed for an efficient inactivation of the colonising bacteria and fungi, with the exception of spore-formers, and did not influence the structural and functional aspects of the skin allografts.
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Bacterias/efectos de los fármacos , Criopreservación/métodos , Hongos/efectos de los fármacos , Glicerol/farmacología , Trasplante de Piel , Piel/efectos de los fármacos , Piel/microbiología , Humanos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Viable donor skin is still considered the gold standard for the temporary covering of burns. Since 1985, the Brussels military skin bank supplies cryopreserved viable cadaveric skin for therapeutic use. Unfortunately, viable skin can not be sterilised, which increases the risk of disease transmission. On the other hand, every effort should be made to ensure that the largest possible part of the donated skin is processed into high-performance grafts. Cryopreserved skin allografts that fail bacterial or fungal screening are reworked into 'sterile' non-viable glycerolised skin allografts. The transposition of the European Human Cell and Tissue Directives into Belgian Law has prompted us to install a pragmatic microbiological screening and acceptance procedure, which is based on 14 day enrichment broth cultures of finished product samples and treats the complex issues of 'acceptable bioburden' and 'absence of objectionable organisms'. In this paper we evaluate this procedure applied on 148 skin donations. An incubation time of 14 days allowed for the detection of an additional 16.9% (25/148) of contaminated skin compared to our classic 3 day incubation protocol and consequently increased the share of non-viable glycerolised skin with 8.4%. Importantly, 24% of these slow-growing microorganisms were considered to be potentially pathogenic. In addition, we raise the issue of 'representative sampling' of heterogeneously contaminated skin. In summary, we feel that our present microbiological testing and acceptance procedure assures adequate patient safety and skin availability. The question remains, however, whether the supposed increased safety of our skin grafts outweighs the reduced overall clinical performance and the increase in work load and costs.
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Criopreservación/métodos , Tamizaje Masivo/métodos , Técnicas Microbiológicas/métodos , Trasplante de Piel/métodos , Piel/microbiología , Técnicas de Cultivo de Tejidos/métodos , Medios de Cultivo , Árboles de Decisión , Humanos , Trasplante Homólogo , TransportesRESUMEN
With this analysis we would like to raise some issues that emerge as a result of recent evolutions in the burgeoning field of human cells, tissues, and cellular and tissue-based product (HCT/P) transplantation, and this in the light of the current EU regulatory framework. This paper is intended as an open letter addressed to the EU policy makers, who will be charged with the review and revision of the current legislation. We propose some urgent corrections or additions to cope with the rapid advances in biomedical science, an extensive commercialization of HCT/Ps, and the growing expectation of the general public regarding the ethical use of altruistically donated cells and tissues. Without a sound wake-up call, the diverging interests of this newly established 'healthcare' industry and the wellbeing of humanity will likely lead to totally unacceptable situations, like some of which we are reporting here.
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Preparaciones Farmacéuticas/economía , Bancos de Tejidos/economía , Trasplante Homólogo/economía , Unión Europea , Humanos , Internacionalidad , Transferencia de TecnologíaRESUMEN
BACKGROUND: Burn care is centralized in highly specialized burn centers in Europe. These centers are of limited capacity and may be overwhelmed by a sudden surge in case of a burn mass casualty incident. Prior incidents in Europe and abroad have sustained high standards of care through well-orchestrated responses to share the burden of care in several burn centers. A burn mass casualty incident in Romania in 2015 sparked an initiative to strengthen the existing EU mechanisms. This paper aims to provide insight into developing a response plan for burn mass casualties within the EU Civil Protection Mechanism. METHODS: The European Burns Association drafted medical guidelines for burn mass casualty incidents based on a literature review and an in-depth analysis of the Romanian incident. An online questionnaire surveyed European burn centers and EU States for burn mass casualty preparedness. RESULTS: The Romanian burn mass casualty in 2015 highlighted the lack of a burn-specific mechanism, leading to the late onset of international transfers. In Europe, 71% of respondents had existing mass casualty response plans, though only 35% reported having a burn-specific plan. A burns response plan for burn mass casualties was developed and adopted as a Commission staff working document in preparation for further implementation. The plan builds on the existing Union Civil Protection Mechanism framework and the standards of the WHO Emergency Medical Teams initiative to provide 1) burn assessment teams for specialized in-hospital triage of patients, 2) specialized burn care across European burn centers, and 3) medevac capacities from participating states. CONCLUSION: The European burn mass casualty response plan could enable the delivery of high-level burn care in the face of an overwhelming incident in an affected European country. Further steps for integration and implementation of the plan within the Union Civil Protection Mechanism framework are needed.
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Quemaduras , Planificación en Desastres , Incidentes con Víctimas en Masa , Humanos , Unión Europea , Quemaduras/epidemiología , Quemaduras/terapia , TriajeRESUMEN
Since 1991, the skin bank of the Queen Astrid Military Hospital uses food-grade aluminum foil as a primary support for storing cryo preserved human donor skin (511 donors). The possible release of heavy metals into the cryo preservation media (30% (v/v) glycerol in physiological water) and the possible impact this release could have on the quality of the cryo preserved donor skin was evaluated. Aluminum was the principal detection target. Possible contaminants of the aluminum foil as such (arsenic, cadmium, chromium and lead) were also investigated. The evaluation was set up after a Belgian Competent Authority inspection remark. Aluminum was detected at a concentration of 1.4 mg/l, arsenic and lead were not detected, while cadmium and chromium were detected in trace element quantities. An histological analysis revealed no differences between cryo preserved and fresh donor skin. No adverse reactions in patients, related to the presence of aluminum or heavy metal traces, were reported since the introduction of the cryo preserved donor skin in our burn wound centre.
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Aluminio/aislamiento & purificación , Criopreservación/métodos , Metales Pesados/aislamiento & purificación , Piel/química , Bancos de Tejidos , Humanos , Piel/ultraestructura , Trasplante de Piel/efectos adversos , Trasplante HomólogoRESUMEN
INTRODUCTION: Burn disasters represent a real challenge to burn centers worldwide. Several burn disasters with a considerable number of casualties happened in Belgium in the past. The positioning of burn centers is a significant issue to account for in a burn disaster preparedness and response. The objectives of this study are to identify the geographic coverage and accessibility of the burn centers in Belgium in the realm of a burn disaster scenario. METHOD: Cross-sectional secondary analysis was performed using data from the Belgian Burn Association and Belgian Department of the Statistic. Data were analyzed using ArcGIS, a geographic information system tool to identify the coverage of burn centers within half an hour driving time, and access time of both populations in the districts and the disaster-prone areas to the individual burn centers. RESULTS: Around 7.3 million (65%) people are covered by a half an hour driving time window from the burn centers. However, the accessibility to the individual burn centers is varied across different regions and provinces. CONCLUSION: There is a slightly over-supply of burn centers in the mid part of the country, contrasted by an under-supply and poor accessibility for the population living near the borders, particularly in the south part of the country. This study would provide a benchmark for stakeholders in Belgium and other industrial countries to consider the coverage and accessibility of the burn centers as part of preparation and planning for burn disasters in the future.
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Unidades de Quemados , Planificación en Desastres , Desastres , Bélgica , Estudios Transversales , HumanosRESUMEN
Burn disaster is defined as a massive influx of patients that exceeds a burn center's capacity and capability. This study investigates the capacity and capability of burn centers to respond to burn disasters in the Belgian ground. Quantitative survey and qualitative semistructured interview questionnaires were administered directly to key informants of burn centers. The data collected from both methods were compared to get a more in-depth overview of the issue. Quantitative data were converted into a narrative to enrich the qualitative data and included in the thematic analysis. Finally, data from both methods were analyzed and organized into five themes. The Belgian Association of Burn Injury (BABI) has a specific prehospital plan for burn disaster management. Once the BABI Plan is activated, all burn centers respond as one entity. Burn Team (B-Team) is a professional team that is formed in case of urgent need and it is deployed to a scene or to nonburn specialized hospitals to help in disaster relief. The challenges for burn disasters response occur particularly in the area of triage, transfer, communication, funding, and training. We conclude that there is a variation in the capacity and capability of burn centers. Overall, the system of burn disaster management is advanced and it is comparable to other high-income countries. Nevertheless, further improvement in the areas of preparation, triage, communication, and finally training would make disaster response more resilient in the future. Therefore, there is still space for further improvement of the management of burn disasters in Belgium.
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Unidades de Quemados/organización & administración , Planificación en Desastres/organización & administración , Incidentes con Víctimas en Masa , Bélgica , Comunicación , Estudios Transversales , Equipos y Suministros de Hospitales , Humanos , Capacitación en Servicio , Transferencia de Pacientes/organización & administración , Capacidad de Reacción , Triaje/organización & administraciónRESUMEN
BACKGROUND: Wound infections are the main cause of sepsis in patients with burns and increase burn-related morbidity and mortality. Bacteriophages, natural bacterial viruses, are being considered as an alternative therapy to treat infections caused by multidrug-resistant bacteria. We aimed to compare the efficacy and tolerability of a cocktail of lytic anti-Pseudomonas aeruginosa bacteriophages with standard of care for patients with burns. METHODS: In this randomised phase 1/2 trial, patients with a confirmed burn wound infection were recruited from nine burn centres in hospitals in France and Belgium. Patients were eligible if they were aged 18 years or older and had a burn wound clinically infected with P aeruginosa. Eligible participants were randomly assigned (1:1) by use of an interactive web response system to a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages (PP1131; 1â×â106 plaque-forming units [PFU] per mL) or standard of care (1% sulfadiazine silver emulsion cream), both given as a daily topical treatment for 7 days, with 14 days of follow-up. Masking of treatment from clinicians was not possible because of the appearance of the two treatments (standard of care a thick cream, PP1131 a clear liquid applied via a dressing), but assignments were masked from microbiologists who analysed the samples and patients (treatment applied while patients were under general anaesthetic). The primary endpoint was median time to sustained reduction in bacterial burden by at least two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants with a microbiologically documented infection at day 0 who were given at least one sulfadiazine silver or phage dressing (modified intention-to-treat population). Safety was assessed in all participants who received at least one dressing according to protocol. Ancillary studies were done in the per-protocol population (all PP1131 participants who completed 7 days of treatment) to assess the reasons for success or failure of phage therapy. This trial is registered with the European Clinical Trials database, number 2014-000714-65, and ClinicalTrials.gov, number NCT02116010, and is now closed. FINDINGS: Between July 22, 2015, and Jan 2, 2017, across two recruitment periods spanning 13 months, 27 patients were recruited and randomly assigned to receive phage therapy (n=13) or standard of care (n=14). One patient in the standard of care group was not exposed to treatment, giving a safety population of 26 patients (PP1131 n=13, standard of care n=13), and one patient in the PP1131 group did not have an infection at day 0, giving an efficacy population of 25 patients (PP1131 n=12, standard of care n=13). The trial was stopped on Jan 2, 2017, because of the insufficient efficacy of PP1131. The primary endpoint was reached in a median of 144 h (95% CI 48-not reached) in the PP1131 group versus a median of 47 h (23-122) in the standard of care group (hazard ratio 0·29, 95% CI 0·10-0·79; p=0·018). In the PP1131 group, six (50%) of 12 analysable participants had a maximal bacterial burden versus two (15%) of 13 in the standard of care group. PP1131 titre decreased after manufacturing and participants were given a lower concentration of phages than expected (1â×â102 PFU/mL per daily dose). In the PP1131 group, three (23%) of 13 analysable participants had adverse events versus seven (54%) of 13 in the standard of care group. One participant in each group died after follow-up and the deaths were determined to not be related to treatment. The ancillary study showed that the bacteria isolated from patients with failed PP1131 treatment were resistant to low phage doses. INTERPRETATION: At very low concentrations, PP1131 decreased bacterial burden in burn wounds at a slower pace than standard of care. Further studies using increased phage concentrations and phagograms in a larger sample of participants are warranted. FUNDING: European Commission: Framework Programme 7.