Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial.

BACKGROUND: Efforts to identify therapies to treat hospitalised patients with COVID-19 are being continued. Alkaline phosphatase (AP) dephosphorylates pro-inflammatory adenosine triphosphate (ATP) into anti-inflammatory adenosine. METHODS: In a randomised controlled trial, we investigated the safety and efficacy of AP in patients with SARS-CoV-2 infection admitted to the ICU. AP or a placebo was administered for four days following admission to the ICU. The primary outcome was the duration of mechanical ventilation. Mortality in 28 days, acute kidney injury, need for reintubation, safety, and inflammatory markers relevant to the described high cytokine release associated with SARS-CoV-2 infection were the secondary outcomes. RESULTS: Between December 2020 and March 2022, 97 patients (of the intended 132) were included, of which 51 were randomised to AP. The trial was terminated prematurely based on meeting the threshold for futility. Compared to the placebo, AP did not affect the duration of mechanical ventilation (9.0 days vs. 9.3 days, p = 1.0). No safety issues were observed. After 28 days, mortality was 9 (18%) in the AP group versus 6 (13%) in the placebo group (p = 0.531). Additionally, no statistically significant differences between the AP and the placebo were observed for the other secondary outcomes. CONCLUSIONS: Alkaline phosphatase (AP) therapy in COVID-19 ICU patients showed no significant benefits in this trial.

An in silico modeling approach to understanding the dynamics of the post-burn immune response.

Introduction: Burns are characterized by a massive and prolonged acute inflammation, which persists for up to months after the initial trauma. Due to the complexity of the inflammatory process, Predicting the dynamics of wound healing process can be challenging for burn injuries. The aim of this study was to develop simulation models for the post-burn immune response based on (pre)clinical data. Methods: The simulation domain was separated into blood and tissue compartments. Each of these compartments contained solutes and cell agents. Solutes comprise pro-inflammatory cytokines, anti-inflammatory cytokines and inflammation triggering factors. The solutes diffuse around the domain based on their concentration profiles. The cells include mast cells, neutrophils, and macrophages, and were modeled as independent agents. The cells are motile and exhibit chemotaxis based on concentrations gradients of the solutes. In addition, the cells secrete various solutes that in turn alter the dynamics and responses of the burn wound system. Results: We developed an Glazier-Graner-Hogeweg method-based model (GGH) to capture the complexities associated with the dynamics of inflammation after burn injuries, including changes in cell counts and cytokine levels. Through simulations from day 0 - 4 post-burn, we successfully identified key factors influencing the acute inflammatory response, i.e., the initial number of endothelial cells, the chemotaxis threshold, and the level of chemoattractants. Conclusion: Our findings highlight the pivotal role of the initial endothelial cell count as a key parameter for intensity of inflammation and progression of acute inflammation, 0 - 4 days post-burn.

Kinetics of Inflammatory Mediators in the Immune Response to Burn Injury: Systematic Review and Meta-Analysis of Animal Studies.

Burns are often accompanied by a dysfunctional immune response, which can lead to systemic inflammation, shock, and excessive scarring. The objective of this study was to provide insight into inflammatory pathways associated with burn-related complications. Because detailed information on the various inflammatory mediators is scattered over individual studies, we systematically reviewed animal experimental data for all reported inflammatory mediators. Meta-analyses of 352 studies revealed a strong increase in cytokines, chemokines, and growth factors, particularly 19 mediators in blood and 12 in burn tissue. Temporal kinetics showed long-lasting surges of proinflammatory cytokines in blood and burn tissue. Significant time-dependent effects were seen for IL-1ß, IL-6, TGF-ß1, and CCL2. The response of anti-inflammatory mediators was limited. Burn technique had a profound impact on systemic response levels. Large burn size and scalds further increased systemic, but not local inflammation. Animal characteristics greatly affected inflammation, for example, IL-1ß, IL-6, and TNF-α levels were highest in young, male rats. Time-dependent effects and dissimilarities in response demonstrate the importance of appropriate study design. Collectively, this review presents a general overview of the burn-induced immune response exposing inflammatory pathways that could be targeted through immunotherapy for burn patients and provides guidance for experimental set-ups to advance burn research.

Scars.

Wound healing occurs as a response to disruption of the epidermis and dermis. It is an intricate and well-orchestrated response with the goal to restore skin integrity and function. However, in hundreds of millions of patients, skin wound healing results in abnormal scarring, including keloid lesions or hypertrophic scarring. Although the underlying mechanisms of hypertrophic scars and keloid lesions are not well defined, evidence suggests that the changes in the extracellular matrix are perpetuated by ongoing inflammation in susceptible individuals, resulting in a fibrotic phenotype. The lesions then become established, with ongoing deposition of excess disordered collagen. Not only can abnormal scarring be debilitating and painful, it can also cause functional impairment and profound changes in appearance, thereby substantially affecting patients' lives. Despite the vast demand on patient health and the medical society, very little progress has been made in the care of patients with abnormal scarring. To improve the outcome of pathological scarring, standardized and innovative approaches are required.

Monocytes and T cells incorporated in full skin equivalents to study innate or adaptive immune reactions after burn injury.

Introduction: Thermal injury often leads to prolonged and excessive inflammation, which hinders the recovery of patients. There is a notable absence of suitable animal-free models for investigating the inflammatory processes following burn injuries, thereby impeding the development of more effective therapies to improve burn wound healing in patients. Methods: In this study, we established a human full skin equivalent (FSE) burn wound model and incorporated human peripheral blood-derived monocytes and T cells. Results: Upon infiltration into the FSEs, the monocytes differentiated into macrophages within a span of 7 days. Burn-injured FSEs exhibited macrophages with increased expression of HLA-DR+ and elevated production of IL-8 (CXCL8), in comparison to uninjured FSEs. Among the T cells that actively migrated into the FSEs, the majority were CD4+ and CD25+. These T cells demonstrated augmented expression of markers associated with regulatory T cell, Th1, or Th17 activity, which coincided with significant heightened cytokine production, including IFN-γ, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IP-10 (CXCL10), and TGF-ß1. Burn injury did not impact the studied effector T cell subsets or cytokine levels. Discussion: Collectively, this study represents a significant advancement in the development of an immunocompetent human skin model, specifically tailored for investigating burn-induced innate or adaptive immune reactions at the site of burn injury.

Short- and Long-term Outcomes of an Acellular Dermal Substitute versus Standard of Care in Burns and Reconstructions: A Phase I/II Intrapatient Randomized Controlled Trial.

OBJECTIVE: Dermal substitutes promote dermal regeneration and improve scar quality, but knowledge gaps remain regarding their efficacy and indications for use. The authors investigated the safety and short- and long-term efficacy of an acellular dermal substitute in patients with full-thickness wounds. METHODS: This intrapatient randomized controlled, open-label, phase I (safety) and phase II (efficacy) study compared treatment with Novomaix (Matricel GmbH), a dermal collagen/elastin-based scaffold, with split-thickness skin graft (STSG) only. The primary safety outcome was graft take at 5 to 7 days postsurgery. Postsurgical scar quality was assessed by measuring elasticity, color, and scores on the Patient and Observer Scar Assessment Scale at 3 months, 12 months, and 6 years. RESULTS: Twenty-five patients were included, of which 24 received treatment allocation. Graft take and wound healing were statistically significantly lower/delayed in the dermal matrix group compared with STSG alone (P < .004). Serious adverse events were delayed epithelialization in four dermal matrix and three STSG study areas. At 12 months postsurgery, skin extension (P = .034) and elasticity (P = .036) were better for the dermal matrix group compared with the group receiving STSG alone. Other scar quality parameters at 12 months and 6 years did not differ between treatment arms. CONCLUSIONS: The dermal substitute was a safe treatment modality for full-thickness wounds. Compared with STSG alone, time to wound healing was slightly increased. Nevertheless, scar quality at 12 months seemed somewhat improved in the wounds treated with the dermal substitute, indicative of enhanced scar maturation. In the long term, final scar quality was similar for both treatment modalities.

Full Skin Equivalent Models for Simulation of Burn Wound Healing, Exploring Skin Regeneration and Cytokine Response.

Healing of burn injury is a complex process that often leads to the development of functional and aesthetic complications. To study skin regeneration in more detail, organotypic skin models, such as full skin equivalents (FSEs) generated from dermal matrices, can be used. Here, FSEs were generated using de-epidermalized dermis (DED) and collagen matrices MatriDerm® and Mucomaix®. Our aim was to validate the MatriDerm- and Mucomaix-based FSEs for the use as in vitro models of wound healing. Therefore, we first characterized the FSEs in terms of skin development and cell proliferation. Proper dermal and epidermal morphogenesis was established in all FSEs and was comparable to ex vivo human skin models. Extension of culture time improved the organization of the epidermal layers and the basement membrane in MatriDerm-based FSE but resulted in rapid degradation of the Mucomaix-based FSE. After applying a standardized burn injury to the models, re-epithelization occurred in the DED- and MatriDerm-based FSEs at 2 weeks after injury, similar to ex vivo human skin. High levels of pro-inflammatory cytokines were present in the culture media of all models, but no significant differences were observed between models. We anticipate that these animal-free in vitro models can facilitate research on skin regeneration and can be used to test therapeutic interventions in a preclinical setting to improve wound healing.

The Future of Burn Care From a Complexity Science Perspective.

Health care is undergoing a profound technological and digital transformation and has become increasingly complex. It is important for burns professionals and researchers to adapt to these developments which may require new ways of thinking and subsequent new strategies. As Einstein has put it: "We must learn to see the world anew." The relatively new scientific discipline "Complexity science" can give more direction to this and is the metaphorical open door that should not go unnoticed in view of the burn care of the future. Complexity science studies "why the whole is more than the sum of the parts." It studies how multiple separate components interact with each other and their environment and how these interactions lead to "behavior of the system." Biological systems are always part of smaller and larger systems and exhibit the behavior of adaptivity, hence the name complex adaptive systems. From the perspective of complexity science, a severe burn injury is an extreme disruption of the "human body system." But this disruption also applies to the systems at the organ and cellular levels. All these systems follow the principles of complex systems. Awareness of the scaling process at multilevel helps to understand and manage the complex situation when dealing with severe burn cases. This paper aims to create awareness of the concept of complexity and to demonstrate the value and possibilities of complexity science methods and tools for the future of burn care through examples from preclinical, clinical, and organizational perspectives in burn care.

Hydrosurgical and conventional debridement of burns: randomized clinical trial.

BACKGROUND: Tangential excision of burned tissue followed by skin grafting is the cornerstone of burn surgery. Hydrosurgery has become popular for tangential excision, with the hypothesis that enhanced preservation of vital dermal tissue reduces scarring. The aim of this trial was to compare scar quality after hydrosurgical versus conventional debridement before split-skin grafting. METHODS: A double-blind randomized within-patient multicentre controlled trial was conducted in patients with burns that required split-skin grafting. One wound area was randomized to hydrosurgical debridement and the other to Weck knife debridement. The primary outcome was scar quality at 12 months, assessed with the observer part of the Patient and Observer Scar Assessment Scale (POSAS). Secondary outcomes included complications, scar quality, colour, pliability, and histological dermal preservation. RESULTS: Some 137 patients were randomized. At 12 months, scars of the hydrosurgical debrided wounds had a lower POSAS observer total item score (mean 2.42 (95 per cent c.i. 2.26 to 2.59) versus 2.54 (95 per cent c.i. 2.36 to 2.72; P = 0.023)) and overall opinion score (mean 3.08 (95 per cent c.i. 2.88 to 3.28) versus 3.30 (95 per cent c.i. 3.09-3.51); P = 0.006). Patient-reported scar quality and pliability measurements were significantly better for the hydrosurgically debrided wounds. Complication rates did not differ between both treatments. Histologically, significantly more dermis was preserved with hydrosurgery (P < 0.001). CONCLUSION: One year after surgery scar quality and pliability was better for hydrosurgically debrided burns, probably owing to enhanced histological preservation of dermis. REGISTRATION NUMBER: Trial NL6085 (NTR6232 (http://www.trialregister.nl)).

The impact of incisional negative pressure wound therapy on scar quality and patient-reported outcomes: A within-patient-controlled, randomised trial.

Literature provides a moderate level of evidence for the beneficial effects of incisional negative pressure wound therapy (iNPWT) on scar quality. The purpose of this study was to establish if iNPWT results in improved scar outcomes in comparison to the standard of care. Therefore, a within-patient randomised controlled, open-label trial was conducted in transgender men undergoing gender-affirming mastectomies. A unilateral side was randomised to receive iNPWT (PICO™, Smith&Nephew) without suction drains and contrastingly the standard dressing (Steri-Strips™) with suction drain. Scar quality and questionnaires were bilaterally measured by means of objective assessments and patient-reported outcome measures (PROM) at 1, 3 and 12 months. Objective scar outcomes were scar pliability (Cutometer®), colouration (DSM-II) and scar width (3-D imaging). PROM outcomes were related to scars (POSAS and SCAR-Q) and body satisfaction (BODY-Q). From 85 included patients, 80 were included for analyses. No significant difference between treatments was seen in the quantitative outcomes of scar pliability, colour, and width. For qualitative scar outcomes, several significant findings for iNPWT were found for several subscales of the POSAS, SCAR-Q, and BODY-Q. These effects could not be substantiated with linear mixed-model regression, signifying no statically more favourable outcome for either treatment option. In conclusion, this study demonstrated that some PROM outcomes were more favourable for the iNPWT compared to standard treatment. In contrast, the quantitative outcomes showed no beneficial effects of iNPWT on scar outcomes. This suggests that iNPWT is of little benefit as a scar-improving therapy.

Scar formation from the perspective of complexity science: a new look at the biological system as a whole.

A burn wound is a complex systemic disease at multiple levels. Current knowledge of scar formation after burn injury has come from traditional biological and clinical studies. These are normally focused on just a small part of the entire process, which has limited our ability to sufficiently understand the underlying mechanisms and to predict systems behaviour. Scar formation after burn injury is a result of a complex biological system-wound healing. It is a part of a larger whole. In this self-organising system, many components form networks of interactions with each other. These networks of interactions are typically non-linear and change their states dynamically, responding to the environment and showing emergent long-term behaviour. How molecular and cellular data relate to clinical phenomena, especially regarding effective therapies of burn wounds to achieve minimal scarring, is difficult to unravel and comprehend. Complexity science can help bridge this gap by integrating small parts into a larger whole, such that relevant biological mechanisms and data are combined in a computational model to better understand the complexity of the entire biological system. A better understanding of the complex biological system of post-burn scar formation could bring research and treatment regimens to the next level. The aim of this review/position paper is to create more awareness of complexity in scar formation after burn injury by describing the basic principles of complexity science and its potential for burn care professionals.

Review: Lessons Learned From Clinical Trials Using Antimicrobial Peptides (AMPs).

Antimicrobial peptides (AMPs) or host defense peptides protect the host against various pathogens such as yeast, fungi, viruses and bacteria. AMPs also display immunomodulatory properties ranging from the modulation of inflammatory responses to the promotion of wound healing. More interestingly, AMPs cause cell disruption through non-specific interactions with the membrane surface of pathogens. This is most likely responsible for the low or limited emergence of bacterial resistance against many AMPs. Despite the increasing number of antibiotic-resistant bacteria and the potency of novel AMPs to combat such pathogens, only a few AMPs are in clinical use. Therefore, the current review describes (i) the potential of AMPs as alternatives to antibiotics, (ii) the challenges toward clinical implementation of AMPs and (iii) strategies to improve the success rate of AMPs in clinical trials, emphasizing the lessons we could learn from these trials.

Antibacterial and safety tests of a flexible cold atmospheric plasma device for the stimulation of wound healing.

Cold atmospheric plasma (CAP) devices generate an ionized gas with highly reactive species and electric fields at ambient air pressure and temperature. A flexible dielectric barrier discharge (DBD) was developed as an alternative antimicrobial treatment for chronic wounds. Treatment of Staphylococcus aureus in collagen-elastin matrices with CAP for 2 min resulted in a 4 log reduction. CAP treatment was less effective on S. aureus on dermal samples. CAP did not affect cellular activity or DNA integrity of human dermal samples when used for up to 2 min. Repeated daily CAP treatments for 2 min lowered cellular activity of dermal samples to 80% after 2 to 4 days, but this was not significant. Repeated treatment of ex vivo human burn wound models with CAP for 2 min did not affect re-epithelialization. Intact skin of 25 healthy volunteers was treated with CAP for 3× 20" to determine safety. Although participants reported moderate pain scores (numerical rating scale 3.3), all volunteers considered the procedure to be acceptable. Severe adverse events did not occur. CAP treatment resulted in a temporarily increased local skin temperature (≈3.4°C) and increased erythema. Lowering the plasma power resulted in a significantly lower erythema increase. Good log reduction (2.9) of bacterial load was reached in 14/15 volunteers artificially contaminated with Pseudomonas aeruginosa. This study demonstrated the in vitro and in vivo safety and efficacy in bacterial reduction of a flexible cold plasma device. Trial registration number NCT03007264, January 2, 2017 KEY POINTS: • CAP strongly reduced bacterial numbers both in vitro and in vivo. • Re-epithelialization of burn wound models was not affected by repeated CAP. • CAP treatment of intact skin was well tolerated in volunteers.

Silver Sulfadiazine Cream Treatment Results in More Wound Contraction and More Itch in a Standardized Porcine Scald Model.

A variety of dressings is available for the treatment of partial-thickness wounds, but none has strong evidence supporting their beneficial effect on healing. This may be due to variation in the type and depth of wounds in clinical studies. The aim of this study was to use a standardized porcine wound model to compare three dressings commonly used in burn centers for partial-thickness burns. Partial-thickness scalds were made on the flanks of pigs. Wounds were treated with silver sulfadiazine (SSD, flammazine), a hydrofiber dressing, or glycerol-preserved allogeneic (pig) skin. The healing process was monitored for 8 weeks. Macroscopic parameters were the itching behavior, the cosmetic appearance of the scars, and contraction. Microscopic parameters were the inflammatory response, myofibroblast influx, and the numbers of nerves. All wounds were closed on day 14 and wound infection did not occur. Treatment with SSD resulted in significantly more wound contraction compared to treatment with glycerol-preserved pig skin. Animals treated with SSD suffered more from itching (scratching) during the first 2 weeks after wounding. The number of nerves in healing wounds of these animals was significantly higher compared to wounds treated with hydrofiber dressing or allogeneic skin. In our standardized porcine partial-thickness wound model, treatment with SSD resulted in less favorable wound healing. Compared to treatment with glycerol-preserved allogeneic skin, SSD resulted in more contraction.

Patient-reported scar quality of donor-sites following split-skin grafting in burn patients: Long-term results of a prospective cohort study.

BACKGROUND: Skin grafting is the current gold standard for treatment of deeper burns. How patients appraise the donor-site scar is poorly investigated. The aim of this study was to evaluate long-term patient-reported quality of donor-site scars after split skin grafting and identify possible predictors. METHODS: A prospective cohort study was conducted. Patients were included in a Dutch burn centre during one year. Patient-reported quality of donor-site scars and their worst burn scar was assessed at 12 months using the Patient and Observer Scar Assessment Scale (POSAS). Mixed model analyses were used to identify predictors of scar quality. RESULTS: This study included 115 donor-site scars of 72 patients with a mean TBSA burned of 11.2%. The vast majority of the donor-site scars (84.4%) were rated as having at least minor differences with normal skin (POSAS item score ≥2) on one or more scar characteristics and the overall opinion on 80.9% of the donor-site scars was that they deviated from normal skin 12 months after surgery. The overall opinion on the donor-site scar was 3.2 ± 2.1 vs. 5.1 ± 2.4 on the burn scar. A younger age, female gender, a darker skin type, and location on the lower leg were predictors of reduced donor-site scar quality. In addition, time to re-epithelization was associated with scar quality. CONCLUSION: This study provided new insights in long-term scar quality of donor-sites. Donor-site scars differed from normal skin in a large part of the population 12 months after surgery. Results of this study can be used to inform patients on the long-term outcomes of their scars and to tailor preventive or therapeutic treatment options.

A systematic review evaluating the influence of incisional Negative Pressure Wound Therapy on scarring.

Pathological scars can result in functional impairment, disfigurement, a psychological burden, itch, and even chronic pain. We conducted a systematic review to investigate the influence of incisional Negative Pressure Wound Therapy (iNPWT) on scarring. PubMed, EMBASE and CINAHL were searched for preclinical and clinical comparative studies that investigated the influence of iNPWT on scarring-related outcomes. Individual studies were assessed using the OHAT Risk of Bias Rating Tool for Human and Animal studies. The body of evidence was rated using OHAT methodology. Six preclinical studies and nine clinical studies (377 patients) were identified. Preclinical studies suggested that iNPWT reduced lateral tension on incisions, increased wound strength, and reduced scar width upon histological assessment. Two clinical studies reported improved patient-reported scar satisfaction as measured with the PSAS (1 year after surgery), POSAS, and a VAS (both 42, 90, and 180 days after surgery). Five clinical studies reported improved observer-reported scar satisfaction as measured with the VSS, SBSES, OSAS, MSS, VAS, and POSAS (7, 15, 30, 42, 90, 180, and 365 days after surgery). Three clinical studies did not detect significant differences at any point in time (POSAS, VAS, and NRS). Because of imprecision concerns, a moderate level of evidence was identified using OHAT methodology. Preclinical as well as clinical evidence indicates a beneficial influence of iNPWT on scarring. Moderate level evidence indicates that iNPWT decreases scar width and improves patient and observer-reported scar satisfaction.

Variation in platelet-rich plasma compositions used for wound healing indications.

At present, the role of platelet-rich plasma (PRP) in burn and wound management is undefined. We present some of the evidence for PRP in wound healing and other medical fields. Currently, the high variation in product composition, mode and timing of application prevent a clear definition of the position of PRP in wound healing. Perspectives on solving these issues are described.

Burns in the elderly: a nationwide study on management and clinical outcomes.

BACKGROUND: In modern-day burn care, advanced age remains an important predictor for mortality among burn victims. In this study, we compared the complete treatment trajectory (including pre-hospital and surgical treatment) and the outcomes between an elderly burn population and a younger adult burn population. METHODS: In this nationwide study, data from the Dutch Burn Repository were used. This is a uniform national registration for Dutch specialized burn care. All adult patients that were admitted to one of the three Dutch burn centres from the period 2009 to 2015 were included in the analysis. Burn patients were considered as elderly when ≥65 years of age, and were then further subdivided into three age categories: 65-74, 75-85 and 85+ years. Younger adults in the age category 18-64 years were used as the reference group.Surgical management was studied comprehensively and included timing of surgery, the number of procedures and details on the surgical technique, especially the technique used for debridement and the grafting technique that was applied.For the comparison of clinical outcome, the following parameters were included: mortality, wound infections, length of stay/TBSA (total body surface area) burned, discharge disposition and secondary reconstructions. RESULTS: During the study period, 3155 adult patients were included (elderly, n = 505). Burn severity, reflected by the median TBSA, varied between 3.2-4.0% and was comparable, but aetiology and pre-hospital care were different between elderly and the younger adult reference group.Surgical treatment was initiated significantly faster in elderly burn patients (p < 0.001). Less selective techniques for surgical debridement were used in the elderly burns patients (hydrosurgery, 42.0% vs 23.5-22.6%), and on the other hand more avulsion (5.3% vs 7.3-17.6%) and primary wound closure (6.7% vs 24.5%). The most frequently used grafting technique was meshed skin grafts (79.2-88.6%); this was not related to age.Mortality increased rapidly with a higher age and showed a high peak in the 85+ category (23.8%). Furthermore, considerable differences were found in hospital discharge disposition between the elderly and the reference group. CONCLUSIONS: In conclusion, elderly burn patients who require specialized burn care are vulnerable and medically challenging. Differences in aetiology, comorbidity, physiology and the management prior to admission possibly affect the initial surgical management and result in significantly worse outcomes in elderly. Elderly patients need optimal, timely and specialized burn care to enhance survival after burn injuries.

Safety and bactericidal efficacy of cold atmospheric plasma generated by a flexible surface Dielectric Barrier Discharge device against Pseudomonas aeruginosa in vitro and in vivo.

BACKGROUND: Cold atmospheric plasma (CAP), which is ionized gas produced at atmospheric pressure, could be a novel and potent antimicrobial therapy for the treatment of infected wounds. Previously we have shown that CAP generated with a flexible surface Dielectric Barrier Discharge (sDBD) is highly effective against bacteria in vitro and in ex vivo burn wound models. In the current paper, we determined the in vitro and in vivo safety and efficacy of CAP generated by this sDBD device. METHODS: The effect of CAP on DNA mutations of V79 fibroblasts was measured using a hypoxanthine-guanine-phosphoribosyltransferase (HPRT) assay. Furthermore, effects on cell proliferation, apoptosis and DNA damage in ex vivo burn wound models (BWMs) were assessed using immunohistochemistry. Next, 105 colony forming units (CFU) P. aeruginosa strain PAO1 were exposed to CAP in a 3D collagen-elastin matrix environment to determine the number of surviving bacteria in vitro. Finally, rat excision wounds were inoculated with 107 CFU PAO1 for 24 h. The wounds received a single CAP treatment, repeated treatments on 4 consecutive days with CAP, 100 µL of 1% (wt/wt) silver sulfadiazine or no treatment. Wound swabs and punch biopsies were taken to determine the number of surviving bacteria. RESULTS: Exposure of V79 fibroblasts to CAP did not increase the numbers of mutated colonies. Additionally, the number of proliferative, apoptotic and DNA damaged cells in the BWMs was comparable to that of the unexposed control. Exposure of PAO1 to CAP for 2 min resulted in the complete elimination of bacteria in vitro. Contrarily, CAP treatment for 6 min of rat wounds colonized with PAO1 did not effectively reduce the in vivo bacterial count. CONCLUSIONS: CAP treatment was safe but showed limited efficacy against PAO1 in our rat wound infection model.

Topical treatment for facial burns.

BACKGROUND: Burn injuries are an important health problem. They occur frequently in the head and neck region. The face is the area central to a person's identity that provides our most expressive means of communication. Topical interventions are currently the cornerstone of treatment of burns to the face. OBJECTIVES: To assess the effects of topical interventions on wound healing in people with facial burns of any depth. SEARCH METHODS: In December 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the effects of topical treatment for facial burns were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, risk of bias assessment and GRADE assessment of the certainty of the evidence. MAIN RESULTS: In this first update, we included 12 RCTs, comprising 507 participants. Most trials included adults admitted to specialised burn centres after recent burn injuries. Topical agents included antimicrobial agents (silver sulphadiazine (SSD), Aquacel-Ag, cerium-sulphadiazine, gentamicin cream, mafenide acetate cream, bacitracin), non-antimicrobial agents (Moist Exposed Burn Ointment (MEBO), saline-soaked dressings, skin substitutes (including bioengineered skin substitute (TransCyte), allograft, and xenograft (porcine Xenoderm), and miscellaneous treatments (growth hormone therapy, recombinant human granulocyte-macrophage colony-stimulating factor hydrogel (rhGMCS)), enzymatic debridement, and cream with Helix Aspersa extract). Almost all the evidence included in this review was assessed as low or very low-certainty, often because of high risk of bias due to unclear randomisation procedures (i.e. sequence generation and allocation concealment); lack of blinding of participants, providers and sometimes outcome assessors; and imprecision resulting from few participants, low event rates or both, often in single studies. Topical antimicrobial agents versus topical non-antimicrobial agents There is moderate-certainty evidence that there is probably little or no difference between antimicrobial agents and non-antimicrobial agents (SSD and MEBO) in time to complete wound healing (hazard ratio (HR) 0.84 (95% confidence interval (CI) 0.78 to 1.85, 1 study, 39 participants). Topical antimicrobial agents may make little or no difference to the proportion of wounds completely healed compared with topical non-antimicrobial agents (comparison SSD and MEBO, risk ratio (RR) 0.94, 95% CI 0.68 to 1.29; 1 study, 39 participants; low-certainty evidence). We are uncertain whether there is a difference in wound infection (comparison topical antimicrobial agent (Aquacel-Ag) and MEBO; RR 0.38, 95% CI 0.12 to 1.21; 1 study, 40 participants; very low-certainty evidence). No trials reported change in wound surface area over time or partial wound healing. There is low-certainty evidence for the secondary outcomes scar quality and patient satisfaction. Two studies assessed pain but it was incompletely reported. Topical antimicrobial agents versus other topical antimicrobial agents It is uncertain whether topical antimicrobial agents make any difference in effects as the evidence is low to very low-certainty. For primary outcomes, there is low-certainty evidence for time to partial (i.e. greater than 90%) wound healing (comparison SSD versus cerium SSD: mean difference (MD) -7.10 days, 95% CI -16.43 to 2.23; 1 study, 142 participants). There is very low-certainty evidence regarding whether topical antimicrobial agents make a difference to wound infection (RR 0.73, 95% CI 0.46 to 1.17; 1 study, 15 participants). There is low to very low-certainty evidence for the proportion of facial burns requiring surgery, pain, scar quality, adverse effects and length of hospital stay. Skin substitutes versus topical antimicrobial agents There is low-certainty evidence that a skin substitute may slightly reduce time to partial (i.e. greater than 90%) wound healing, compared with a non-specified antibacterial agent (MD -6.00 days, 95% CI -8.69 to -3.31; 1 study, 34 participants). We are uncertain whether skin substitutes in general make any other difference in effects as the evidence is very low certainty. Outcomes included wound infection, pain, scar quality, adverse effects of treatment and length of hospital stay. Single studies showed contrasting low-certainty evidence. A bioengineered skin substitute may slightly reduce procedural pain (MD -4.00, 95% CI -5.05 to -2.95; 34 participants) and background pain (MD -2.00, 95% CI -3.05 to -0.95; 34 participants) compared with an unspecified antimicrobial agent. In contrast, a biological dressing (porcine Xenoderm) might slightly increase pain in superficial burns (MD 1.20, 95% CI 0.65 to 1.75; 15 participants (30 wounds)) as well as deep partial thickness burns (MD 3.00, 95% CI 2.34 to 3.66; 10 participants (20 wounds)), compared with antimicrobial agents (Physiotulle Ag (Coloplast)). Miscellaneous treatments versus miscellaneous treatments Single studies show low to very low-certainty effects of interventions. Low-certainty evidence shows that MEBO may slightly reduce time to complete wound healing compared with saline soaked dressing (MD -1.7 days, 95% CI -3.32 to -0.08; 40 participants). In addition, a cream containing Helix Aspersa may slightly increase the proportion of wounds completely healed at 14 days compared with MEBO (RR 4.77, 95% CI 1.87 to 12.15; 43 participants). We are uncertain whether any miscellaneous treatment in the included studies makes a difference in effects for the outcomes wound infection, scar quality, pain and patient satisfaction as the evidence is low to very low-certainty. AUTHORS' CONCLUSIONS: There is mainly low to very low-certainty evidence on the effects of any topical intervention on wound healing in people with facial burns. The number of RCTs in burn care is growing, but the body of evidence is still hampered due to an insufficient number of studies that follow appropriate evidence-based standards of conducting and reporting RCTs.