Barriers and co-designed strategies for the implementation of negative pressure wound therapy in acute pediatric burn care in Australia: A mixed method study.

PURPOSE: Pediatric burn injuries are a global clinical issue causing significant morbidity. Early adjunctive negative pressure wound therapy improves re-epithelialization rates in children with burns, yet adoption in acute burn care is inconsistent. This investigation aimed to determine barriers to the implementation of adjunctive negative pressure wound therapy for the acute management of pediatric burns and co-design targeted implementation strategies. METHODS: A sequential mixed methods design was used explore barriers to adjunctive negative pressure wound therapy implementation in acute pediatric burn care. An online questionnaire was disseminated to healthcare professionals within four major Australian pediatric hospitals, each with a dedicated burns service. Barriers were coded according to the Consolidated Framework for Implementation Research (CFIR). Semi-structured interviews with senior clinicians tailored implementation strategies to local contexts. A stakeholder consensus meeting consolidated implementation strategies and local processes. RESULTS: Sixty-three healthcare professionals participated in the questionnaire, and semi-structured interviews involved nine senior burn clinicians. We identified eight implementation barriers across all five CFIR domains then co-designed targeted strategies to address identified barriers. Barriers included lack of available resources, limited access to knowledge and information, individual stage of change, patient needs and resources, limited knowledge and beliefs about the intervention, lack of external policies, intervention complexity, and poor implementation planning. CONCLUSION: Multiple contextual factors affect negative pressure wound therapy uptake in acute pediatric burn settings. Results will inform a multi-state stepped-wedge cluster randomized controlled trial. Additional resources, education, training, updated policies, and guidelines are required for successful implementation. It is anticipated that adjunctive negative pressure wound therapy, in conjunction with tailored implementation strategies, will enhance adoption and sustainability. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12622000166774. Registered 1 February 2022.

Inflammatory proteins and neutrophil extracellular traps increase in burn blister fluid 24h after burn.

Burn wound blister fluid is a valuable matrix for understanding the biological pathways associated with burn injury. In this study, 152 blister fluid samples collected from paediatric burn wounds at three different hospitals were analysed using mass spectrometry proteomic techniques. The protein abundance profile at different days after burn indicated more proteins were associated with cellular damage/repair in the first 24 h, whereas after this point more proteins were associated with antimicrobial defence. The inflammatory proteins persisted at a high level in the blister fluid for more than 7 days. This may indicate that removal of burn blisters prior to two days after burn is optimal to prevent excessive or prolonged inflammation in the wound environment. Additionally, many proteins associated with the neutrophil extracellular trap (NET) pathway were increased after burn, further implicating NETs in the post-burn inflammatory response. NET inhibitors may therefore be a potential treatment to reduce post-burn inflammation and coagulation pathology and enhance burn wound healing outcomes.

Unremitting pro-inflammatory T-cell phenotypes, and macrophage activity, following paediatric burn injury.

Objectives: The aim of this study was to characterise the dynamic immune profile of paediatric burn patients for up to 18 months post-burn. Methods: Flow cytometry was used to measure 25 cell markers, chemokines and cytokines which reflected both pro-inflammatory and anti-inflammatory immune profiles. Peripheral blood mononuclear cells from 6 paediatric burn patients who had returned for repeated burn and scar treatments for > 4 timepoints within 12 months post-burn were compared to four age-matched healthy controls. Results: While overall proportions of T cells, NK cells and macrophages remained relatively constant, over time percentages of these immune cells differentiated into effector and proinflammatory cell phenotypes including Th17 and activated γδ T cells. Circulating proportions of γδ T cells increased their expression of pro-inflammatory mediators throughout the burn recovery, with a 3-6 fold increase of IL-17 at 1-3 weeks, and NFκß 9-18 months post-burn. T-regulatory cell plasticity was also observed, and Treg phenotype proportions changed from systemically reduced skin-homing T-regs (CCR4+) and increased inflammatory (CCR6+) at 1-month post-burn, to double-positive cell types (CCR4+CCR6+) elevated in circulation for 18 months post-burn. Furthermore, Tregs were observed to proportionally express less IL-10 but increased TNF-α over 18 months. Conclusion: Overall, these results indicate the circulating percentages of immune cells do not increase or decrease over time post-burn, instead they become highly specialised, inflammatory and skin-homing. In this patient population, these changes persisted for at least 18 months post-burn, this 'immune distraction' may limit the ability of immune cells to prioritise other threats post-burn, such as respiratory infections.

MicroRNAs involved in human skin burns, wound healing and scarring.

MicroRNAs are small, non-coding RNAs that regulate gene expression, and consequently protein synthesis. Downregulation and upregulation of miRNAs and their corresponding genes can alter cell apoptosis, proliferation, migration and fibroproliferative responses following a thermal injury. This review summarises the evidence for altered human miRNA expression post-burn, and during wound healing and scarring. In addition, the most relevant miRNA targets and their roles in potential pathways are described. Previous studies using molecular techniques have identified 197 miRNAs associated with human wound healing, burn wound healing and scarring. Five miRNAs alter the expression of fibroproliferative markers, proliferation and migration of fibroblasts and keratinocytes post-burn: hsa-miR-21 and hsa-miR-31 are increased after wounding, and hsa-miR-23b, hsa-miR-200b and hsa-let-7c are decreased. Four of these five miRNAs are associated with the TGF-ß pathway. In the future, large scale, in vivo, longitudinal human studies utilising a range of cell types, ethnicity and clinical healing outcomes are fundamental to identify burn wound healing and scarring specific markers. A comprehensive understanding of the underlying pathways will facilitate the development of clinical diagnostic or prognostic tools for better scar management and the identification of novel treatment targets for improved healing outcomes in burn patients.

Systemic long-term metabolic effects of acute non-severe paediatric burn injury.

A growing body of evidence supports the concept of a systemic response to non-severe thermal trauma. This provokes an immunosuppressed state that predisposes paediatric patients to poor recovery and increased risk of secondary morbidity. In this study, to understand the long-term systemic effects of non-severe burns in children, targeted mass spectrometry assays for biogenic amines and tryptophan metabolites were performed on plasma collected from child burn patients at least three years post injury and compared to age and sex matched non-burn (healthy) controls. A panel of 12 metabolites, including urea cycle intermediates, aromatic amino acids and quinolinic acid were present in significantly higher concentrations in children with previous burn injury. Correlation analysis of metabolite levels to previously measured cytokine levels indicated the presence of multiple cytokine-metabolite associations in the burn injury participants that were absent from the healthy controls. These data suggest that there is a sustained immunometabolic imprint of non-severe burn trauma, potentially linked to long-term immune changes that may contribute to the poor long-term health outcomes observed in children after burn injury.

Chemical burn to the skin: A systematic review of first aid impacts on clinical outcomes.

Chemical burns can cause deep injury and subsequently significant scarring to the skin. The mechanism and pathophysiology of chemical burns is distinct to thermal burns, and recommended first aid approaches are consequently different. Twenty minutes of cool running water is an effective first aid measure to improve outcomes after thermal burn. For chemical burns to the skin, the recommendations are immediate water lavage for 60 min, removal of contaminated clothing if not stuck to the skin and then covering the wound with a sterile dressing. This review assesses the peer-reviewed literature to find the evidence behind the efficacy of cutaneous chemical burn first aid on short term outcomes such as length of hospital stay, depth of burn and longer-term outcomes such as scarring; in particular, the effect of immediate or early water lavage, and the effect of the duration of water lavage. Ocular chemical burns were not included in this review. The review suggests some evidence to support that the early application of cool water irrigation may reduce length of hospital stay and the extent of scarring. Community education should emphasize that water irrigation is recommended and that the earlier this happens, the better.

Management of non-severe burn wounds in children and adolescents: optimising outcomes through all stages of the patient journey.

Paediatric burn injuries are common, especially in children younger than 5 years, and can lead to poor physical and psychosocial outcomes in the long term. In this Review, we aim to summarise the key factors and interventions before hospital admission and following discharge that can improve the long-term outcomes of paediatric burns. Care can be optimised through first aid treatment, correct initial assessment of burn severity, and appropriate patient referral to a burns centre. Scar prevention or treatment and patient follow-up after discharge are also essential. As most burn injuries in children are comparatively small and readily survivable, this Review does not cover the perioperative management associated with severe burns that require fluid resuscitation, or inhalational injury. Burns disproportionately affect children from low socioeconomic backgrounds and those living in low-income and middle-income countries, with ample evidence to suggest that there remains scope for low-cost interventions to improve care for those patients with the greatest burden of burn injury. Current knowledge gaps and future research directions are discussed.

Effect of Rho-Associated Protein Kinase Inhibitors on Epidermal Keratinocytes: A Proposed Application for Burn Wound Healing.

Rho-associated protein kinases (ROCKs) affect a variety of cellular functions, including cell attachment, migration, and proliferation. ROCK inhibitors therefore have potential as tools for optimizing cell behavior in tissue engineering applications, including the manufacturing of cultivated epithelial autografts (CEAs) used in the treatment of burn patients. For example, ROCK inhibitors may facilitate earlier engraftment of CEA sheets by increasing the proliferation of skin keratinocytes ex vivo. Nevertheless, the current understanding of ROCK inhibitor action on epidermal keratinocytes is unclear owing to multiple drug formulations, drug concentrations, and cellular function assays having been used. The aim of this review article therefore is to identify consistent patterns of ROCK inhibitor action on human keratinocytes, as well as revealing key knowledge gaps. In doing so, we propose a clearer course of action for pursuing the potential benefits of ROCK inhibitors for the future treatment of burn patients. Impact statement The properties of Rho-associated protein kinase (ROCK) inhibitors are already used clinically within the fields of cardiology, neurology, and ophthalmology. These results encourage the broadening of ROCK inhibitor uses for other clinical applications. With respect to burn patients, ROCK inhibitors may facilitate improvements in patient survival and healing by reducing the time required for generating cultivated epithelial autograft (CEA) sheets from patient biopsies. Nevertheless, varying approaches to studying the effects of ROCK inhibitors on skin cells in vitro have complicated the development of improved protocols. Our review aims to clarify a diverse and growing body of literature as to the potential benefits for burn patients.

The lethal heat dose for 50% primary human fibroblast cell death is 48 °C.

Understanding the effect of heat on skin cells is important for the prevention of burn injury. Knowledge of the heat dose required to kill cells can be used to study the cellular mechanisms involved in thermal injury cell death, to assist with the development of novel burn treatments. In this study, primary human skin dermal fibroblasts were exposed to temperatures from 37 to 54 °C for 1 h and the relative cell viability of heat-treated and control cells was assessed. Cell damage and viability were assessed by light microscopy, MTT assay and live/dead staining. The LD50 for 1 h of heat exposure was 48 °C for primary fibroblasts; and there was evidence that thermal damage to cells begins to occur at 43 °C. This study presents a reproducible method for examining the effect of heat on primary human cells grown in culture on a cellular level and can be used in the future to study the mechanisms behind heat-induced cell death, to inform burn injury prevention efforts and effective post-burn treatment.

An Exploratory Study Demonstrating That Salivary Cytokine Profiles Are Altered in Children With Small Area Thermal Injury.

Serum can be used to investigate changes in cytokine concentration following burn injury in children; however, for children receiving treatment in an outpatient setting, blood is not routinely collected and therefore cannot be used for monitoring. The aim of this study was to investigate the use of saliva as a noninvasive tool for predicting burn outcomes by measuring the concentration of salivary cytokines in children with small area burns. A multiplex cytokine assay was used to measure 17 cytokines in the saliva of pediatric patients with burns (n = 20) and healthy controls (n = 20). After the removal of cytokines that had >30% of samples below the assay lower detection limit, six cytokines including IL-1ß, IL-4, IL-7, IL-8, MCP-1, and TNFα were analyzed for association with burns. IL-1ß and IL-4 were found to be significantly elevated in the pediatric burn patients compared to healthy controls. Interestingly, IL-1ß was also significantly elevated in scald burns, compared to contact burns. In addition, biologically meaningful differences in cytokine concentration were identified in patients with different burn characteristics, which warrant further investigation. This exploratory study provides evidence that cytokines can be detected in the saliva of children and that salivary cytokine profiles differ between healthy controls and children with burns. Overall, this study demonstrates the value of saliva for the investigation of cytokines and its potential application in pediatric diagnostics, specifically in situations where blood collection is not appropriate.

Local burn wound environment versus systemic response: Comparison of proteins and metabolites.

In this study, paired blood plasma (BP) and blister fluid (BF) samples from five paediatric burn patients were analysed using mass spectrometry to compare their protein and metabolite composition. The relative quantification of proteins was achieved through a label-free data independent acquisition mode. The relative quantification of metabolites was achieved using a Shimadzu Smart Metabolite Database gas chromatography mass spectrometry (GCMS) targeted assay. In total, 562 proteins and 141 individual metabolites were identified in the samples. There was 81% similarity in the proteins present in the BP and BF, with 50 and 54 unique proteins found in each sample type respectively. BF contained keratinocyte proliferation-related proteins and blood plasma contained abundant blood clotting proteins and apolipoproteins. BF contained more carbohydrates and less alpha-hydroxy acid metabolites than the BP. In this study, there were unique proteins and metabolites in BF and BP which were reflective of the local wound environment and systemic environments respectively. The results from this study demonstrate that the biomolecule content of BF is mostly the same as blood, but it also contains information specific to the local wound environment.

Cost-effectiveness of adjunctive negative pressure wound therapy in paediatric burn care: evidence from the SONATA in C randomised controlled trial.

Negative pressure wound therapy (NPWT) has been shown to improve clinical outcomes for children with burns by accelerating wound re-epithelialisation. Its effects on healthcare costs, however, remain poorly understood. The aim of this study was to evaluate the cost-effectiveness of NPWT from a healthcare provider perspective using evidence from the SONATA in C randomised controlled trial, in which 101 children with small-area burns were allocated to either standard care (silver-impregnated dressings) or standard care in combination with adjunctive NPWT. The primary outcome, time to re-epithelialisation, was assessed through a blinded photographic review. Resource usage and costs were prospectively recorded for each participant for up to 6 months. Incremental cost-effectiveness ratios and dominance probabilities were estimated and uncertainty quantified using bootstrap resampling. Mean costs per participant-including dressings, labour, medication, scar management, and theatre operations-were lower in the NPWT group (AUD $903.69) relative to the control group (AUD $1669.01). There was an 89% probability that NPWT was dominant, yielding both faster re-epithelialisation and lower overall costs. Findings remained robust to sensitivity analyses employing alternative theatre costs and time-to-re-epithelialisation estimates for grafted patients. In conclusion, adjunctive NPWT is likely to be a cost-effective and dominant treatment for small-area paediatric burns (ANZCTR.org.au:ACTRN12618000256279).

The morbidity associated with paediatric burn wound escharotomies.

INTRODUCTION: An escharotomy is an effective surgical procedure for the rapid decompression of a constricting and unyielding eschar, to permit restoration of blood flow. However, an escharotomy is also a full-thickness incision, which adds additional scarring to the burn injury area. The cosmetic and functional morbidity of escharotomy scarring in children is poorly characterised. METHODS: Children who required a burn wound escharotomy at the Queensland Children's Hospital (QCH) between May 2011 and May 2020 were included. Demographics of these children were described. In addition, the number of operations for revision of escharotomy scars was recorded as an indicator of functional or cosmetic concern. RESULTS: A total of 19 patients required an escharotomy after a burn injury. Children with 1% to 96% TBSA burns required an escharotomy, with a median of 28% (IQR 10-39%) TBSA. Two patients (81% and 96% TBSA) died. Seventy-one percent (12/17) of survivors had operative revisions of their escharotomy scars. The median time from burn to first scar intervention was 35 weeks (IQR 19-70 weeks). CONCLUSION: There is substantial morbidity associated with escharotomies in children. Further investigation of the current methods of decompression after burn injury, and the long-term morbidity of escharotomy, is required.

A Rapid Review of Burns First Aid Guidelines: Is There Consistency Across International Guidelines?

We conducted a rapid review of current international and Australian/New Zealand guidelines on first aid for burns to identify any critical variation and any recent major changes in the literature that would warrant a significant change to current recommendations. A search was conducted to identify Australian/New Zealand and international first aid guidelines for burn care using guideline databases, and we compared key recommendations from each guideline relating to burns first aid. A literature search of relevant databases (Medline, Embase, Cochrane Database of Systematic Reviews, PROSPERO international register of systematic reviews, and ClinicalTrials.gov databases) was conducted to identify existing and in-progress research published on the topic of first aid for burn injuries. Seven guidelines were identified from the Australia/New Zealand region, and 11 international guidelines were identified from the United States of America and Europe. All Australian and New Zealand guidelines recommended a cooling duration of 20 minutes and made some mention of when to refer a burn for medical evaluation, while international guidelines saw cooling duration variation, a number of guidelines failed to mention referral criteria. The review of published systematic reviews and clinical trials revealed a lack of new evidence in the last six years. Our rapid review identified key variation between first aid guidelines for burns that would benefit from the development of an international consensus on management. We identified no new significant evidence that would alter guideline recommendations and did not identify any upcoming reviews or clinical trials on this subject.

A Scoping Review of the Methodology Used in Studies of Genetic Influences on the Development of Keloid or Hypertrophic Scarring in Adults and Children After Acute Wounding.

Significance: Keloid and hypertrophic scarring are common following acute wounds. However, the variability in scarring outcomes between individuals and in particular, the association between genetic factors and scarring, is not well understood. This scoping review aims to summarize the methodology used in studies of genetic influences on the development of keloid or hypertrophic scarring in adults and children after acute wounding. The objectives were to determine the study designs used, the characteristics of participants included, the tools used to assess scarring and the length of follow-up after wounding. Recent Advances: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Excerpta Medica Database (EMBASE), Web of Science, Biosciences Information Service (BIOSIS), Prospective Register of Systematic Reviews (PROSPERO), The Human Genetic Epidemiology (HuGE) Navigator (database of genetic association studies), and the genome-wide association study Catalog were searched from January 2008 to April 2020. Cohort studies and case-control studies that examined the association between one or more genetic variations and the development of keloid or hypertrophic scarring were eligible for inclusion. A narrative synthesis that grouped studies by wound type was conducted. Critical Issues: Nine studies met the inclusion criteria (five in burns, four surgical wounds, and none in other types of acute wounds). Seven assessed hypertrophic scarring, one keloid scarring, and one both scar types. Seven studies used a prospective cohort design. All studies used subjective methods (clinician or patient observation) to assess scarring. There was considerable variation in how scar scales were operationalized. Future Directions: This review identified a small body of evidence on genetic susceptibility to scarring after acute wounding. Further studies are needed, and in a wide range of populations, including patients with wounds caused by trauma.

A review of potential biomarkers for assessing physical and psychological trauma in paediatric burns.

Biological markers that evaluate physical healing as well as psychological impact of a burn are essential for effective treatment of paediatric burns. The objective of this review is to summarize the evidence supporting the use of biomarkers in children with burns. An extensive review of the literature was performed using PubMed. A total of 59 biomarkers were identified relating to burn presence, specifically relating to processes involved in inflammation, wound healing, growth and metabolism. In addition, biomarkers involved in the stress response cascade following a burn trauma were also identified. Although many biomarkers have been identified that are potentially associated with burn-related physical and psychological trauma, an understanding of burn biology is still lacking in children. We propose that future research in the field of children's burns should be conducted using broad screening methods for identifying potential biomarkers, examine the biological interactions of different biomarkers, utilize child-appropriate biological fluids such as urine or saliva, and include a range of different severity burns. Through further research, the biological response to burn injury may be fully realized and clinically relevant diagnostic tests and treatment therapies utilizing these biomarkers could be developed, for the improvement of healing outcomes in paediatric burn patients.

The modulation of the burn wound environment by negative pressure wound therapy: Insights from the proteome.

Negative pressure wound therapy has been used to promote wound healing in a variety of settings, including as an adjunct to silver-impregnated dressings in the acute management of paediatric burns. Fluid aspirated by the negative pressure wound therapy system represents a potentially insightful research matrix for understanding the burn wound microenvironment and the intervention's biochemical mechanisms of action. The aim of this study was to characterize the proteome of wound fluid collected using negative pressure wound therapy from children with small-area thermal burns. Samples were obtained as part of a randomized controlled trial investigating the clinical efficacy of adjunctive negative pressure wound therapy. They were compared with blister fluid specimens from paediatric burn patients matched according to demographic and injury characteristics. Protein identification and quantification were performed via liquid chromatography tandem mass spectrometry and sequential window acquisition of all theoretical mass spectra data-independent acquisition. Proteins and biological pathways that were unique to or enriched in negative pressure wound therapy fluid samples were evaluated using principal components, partial least squares-discriminant, and gene ontology enrichment analyses. Eight viable samples of negative pressure wound therapy fluid were collected and analyzed with eight matched blister fluid samples. A total of 502 proteins were quantitatively profiled in the negative pressure wound therapy fluid, of which 444 (88.4%) were shared with blister fluid. Several proteins exhibited significant abundance differences between fluid types, with negative pressure wound therapy fluid showing a higher abundance of matrix metalloproteinase-9, arginase-1, low affinity immunoglobulin gamma Fc region receptor III-A, filamin-A, alpha-2-macroglobulin, and hemoglobin subunit alpha. The results lend support to the hypothesis that negative pressure wound therapy augments wound healing through the modulation of factors involved in the inflammatory response, granulation tissue synthesis, and extracellular matrix maintenance. Data are available via ProteomeXchange with identifier PXD023168.

Coming to Consensus: What Defines Deep Partial Thickness Burn Injuries in Porcine Models?

Deep partial thickness burns are clinically prevalent and difficult to diagnose. In order to develop methods to assess burn depth and therapies to treat deep partial thickness burns, reliable, accurate animal models are needed. The variety of animal models in the literature and the lack of precise details reported for the experimental procedures make comparison of research between investigators challenging and ultimately affect translation to patients. They sought to compare deep partial thickness porcine burn models from five well-established laboratories. In doing so, they uncovered a lack of consistency in approaches to the evaluation of burn injury depth that was present within and among various models. They then used an iterative process to develop a scoring rubric with an educational component to facilitate burn injury depth evaluation that improved reliability of the scoring. Using the developed rubric to re-score the five burn models, they found that all models created a deep partial thickness injury and that agreement about specific characteristics identified on histological staining was improved. Finally, they present consensus statements on the evaluation and interpretation of the microanatomy of deep partial thickness burns in pigs.

Study of negative pressure wound therapy as an adjunct treatment for acute burns in children (SONATA in C): protocol for a randomised controlled trial.

BACKGROUND: Although negative pressure wound therapy (NPWT) is widely used in the management of several wound types, its efficacy as a primary therapy for acute burns has not yet been adequately investigated, with research in the paediatric population particularly lacking. There is limited evidence, however, that NPWT might benefit children with burns, amongst whom scar formation, wound progression and pain continue to present major management challenges. The purpose of this trial is to determine whether NPWT in conjunction with standard therapy accelerates healing, reduces wound progression and decreases pain more effectively than standard treatment alone. METHODS/DESIGN: A total of 104 children will be recruited for this trial. To be eligible, candidates must be under 17 years of age and present to the participating children's hospital within 7 days of their injury with a thermal burn covering <5% of their total body surface area. Facial and trivial burns will be excluded. Following a randomised controlled parallel design, participants will be allocated to either an active control or intervention group. The former will receive standard therapy consisting of Acticoat™ and Mepitel™. The intervention arm will be treated with silver-impregnated dressings in addition to NPWT via the RENASYS TOUCH™ vacuum pump. Participants' dressings will be changed every 3 to 5 days until their wounds are fully re-epithelialised. Time to re-epithelialisation will be studied as the primary outcome. Secondary outcomes will include pain, pruritus, wound progression, health-care-resource use (and costs), ease of management, treatment satisfaction and adverse events. Wound fluid collected during NPWT will also be analysed to generate a proteomic profile of the burn microenvironment. DISCUSSION: The study will be the first randomised controlled trial to explore the clinical effects of NPWT on paediatric burns, with the aim of determining whether the therapy warrants implementation as an adjunct to standard burns management. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618000256279 . Registered on 16 February 2018.