Wound Healing and Scar Patterning After Addition of Autologous Skin Cell Suspension to Meshed Grafts.

INTRODUCTION: A common treatment for large deep-to-full-thickness burns is excision and grafting with a widely meshed split-thickness skin graft (mSTSG). Due to the differential healing of the interstices and adhered split-thickness skin graft, wound patterning and delayed wound healing are common outcomes of this treatment. Delayed healing may increase infection rates and wound care requirements, while wound patterning may be psychologically and aesthetically consequential for patients. Autologous skin cell suspension (ASCS) can be used to "over spray" a meshed autograft. It was hypothesized that the use of ASCS combined with mSTSG would increase the rate of wound healing and decrease patterning in healed burn wounds. METHODS: Full-thickness burns or excisional wounds (n = 8 each) were created in red Duroc pigs and received 4:1 mSTSGs after wound bed preparation. Half of the wounds received ASCS and half did not at the time of grafting. Percent re-epithelialization, patterning, rete ridge ratio, cellularity, dermal and epidermal thickness, immunofluorescent S100ß staining, and melanin index were assessed for each scar. RESULTS: Wounds that received ASCS exhibited increased rates of re-epithelialization (burn +ACSC versus burn-ASCS; day 3 (53.9 ± 3.1 versus 34.3 ± 3.3, P = 0.009): day 5 (68.1 ± 1.6 versus 40.8 ± 3.2, P < 0.001)). Excision +ASCS versus excision-ASCS; day 7 (98.1 ± 1.2 versus 86.4 ± 2.0, day 7 P = 0.022) compared to wounds not treated with ASCS. There was no difference in rete ridge ratio, cellularity, dermal thickness, epidermal thickness, S100ß staining, melanin index, or patterning was measured between wounds that received ASCS and those that did not. CONCLUSIONS: The addition of ASCS to 4:1 mSTSGs leads to increased rate of wound healing but does not impact the degree of patterning in this model, suggesting that ASCS application likely robustly transfers keratinocytes but not functioning melanocytes at acute timepoints.

Fibrinolytic Dysfunction and Endotheliopathy After Major Thermal Injury: Considerations Needed for New Approaches to Burn Shock Resuscitation.

ABSTRACT: In recent years, it has become apparent that fibrinolytic dysfunction and endotheliopathy develop in up to 40% of patients during the first hours following thermal injury and are associated with poor outcomes and increased resuscitation requirements. Rapidly following burn injury, the fibrinolytic system is activated, with activation generally greater with increased severity of injury. Very high plasma concentrations of plasmin-antiplasmin complex (marker of activation), have been associated with mortality. Patients display hyperfibrinolytic, physiologic/normal or hypofibrinolytic/fibrinolytic shutdown phenotypes, as assessed by viscoelastic assay. Phenotypes change in over 50% of patients during the acute burn resuscitation period, with some patterns (maladaptive) associated with increased mortality risk and others (adaptive, trending toward the physiologic phenotype) associated with survival. Endotheliopathy, as reflected in elevated plasma concentrations of syndecan-1 has also been associated with increased mortality. Here we review the incidence and effects of these responses after burn injury and explore mechanisms and potential interactions with the early inflammatory response. Available data from burn and non-burn trauma suggest that the fibrinolytic, endothelial, and inflammatory systems interact extensively and that dysregulation in one may exacerbate dysregulation in the others. This raises the possibility that successful treatment of one may favorably impact the others.

Fighting A New Front On An Old Battlefield: Examining the Development of Topical Antimicrobial Care to Control Burn Wound Sepsis.

Recognition of invasive burn wound sepsis as a major cause of morbidity and mortality in burn injured patients has profoundly changed the management of burn wounds and its associated complications. The development of effective topical antimicrobial therapy is one of the last major developments of modern burn care and has been driven by major world events and scientific breakthroughs. Topical antimicrobial burn care has evolved from the use of anecdotal remedies to scientific breakthroughs such as Moyer's successful dilution of silver nitrate solution, Fox's described benefit of silver sulfadiazine use in animal models, and Pruitt's dramatic improvement in post-burn mortality using topical mafenide acetate in burn wounds. The objective of this manuscript is to review the definition of burn wound sepsis and highlight the major developments and breakthroughs in topical burn wound care throughout history. This includes historical events like major wars or domestic fires that have influenced or impacted the understanding and treatment of burn wounds. Newer advances in topical antimicrobial care such as nanosilvers and dressing technologies that improve the morbidity and mortality associated with burn wound sepsis and novel approaches to management will also be discussed. To improve burn care, it is prudent to look to the past and learn from the experiences of those who contributed to the control of burn wound sepsis.

Addressing Burn Hypertrophic Scar Symptoms Earlier: Laser Scar Revision May Begin as Early as 3-6 Months After Injury.

OBJECTIVES: Fractional ablative CO2 laser (FLSR) is used to treat hypertrophic scars (HTSs) resulting from burn injuries, which are characterized by factors, such as erythema, contracture, thickness, and symptoms of pain and itch. Traditionally, waiting a year after injury for scar maturation before starting laser treatment has been recommended; however, the potential benefits of earlier intervention have gained popularity. Still, the optimal timing for beginning laser intervention in patients with HTSs remains uncertain. This study aims to evaluate the ideal timing for the initiation of FLSR for HTSs using several qualitative and quantitative assessment measures. It was hypothesized that early intervention would lead to similar improvement trends as later intervention, however, would be more ideal due to the shortened time without symptom relief for patients. METHODS: Patients who received three or more laser treatment sessions and completed both pre- and posttreatment evaluations were included in this analysis (n = 69). FLSR treatment was administered at 4-8-week intervals. Patients starting treatment before 6 months after injury were classified as the early-stage intervention group and those beginning treatment at 6-12 months after injury were classified as the late-stage intervention group. Demographic data, including the age of patients at the time of first treatment, age of scars at the time of first treatment, biological sex, ethnicity, Fitzpatrick skin type, and use of laser-assisted drug delivery, were collected by retrospective chart review. Patients were evaluated on six subjective scales and objectively for scar stiffness with durometry. For all scales, higher scores indicate worse scars. A two-way ANOVA, Student's t-test, and Mann-Whitney U-test were used to compare scores from the pre- to posttreatment evaluations. RESULTS: There were no significant differences between the groups for any of the demographic or scar-specific variables; thus, differences in outcome can be attributed to the timing of intervention. Both groups demonstrated an improvement in scars with treatment over time (p < 0.05). Both early- and middle-stage initiation showed scar symptom improvement in five out of six scales. In the late-stage intervention, the Patient and Observer Scar Assessment Scale-Patient average score did not show improvement. In the early-stage intervention, the Vancouver Scar Scale total did not show improvement. Quantitative evaluation of scar stiffness by durometry did not show symptom improvement in either group. The Scar Comparison Scale demonstrated the greatest improvement across groups. CONCLUSION: Laser treatment led to scar improvement in at least one scale at each stage of initiation. Both intervention timelines resulted in equivalent outcomes, and early intervention should be considered when initiating FLSR treatment in burn scars to alleviate symptoms earlier.

A phase 3b, open-label, single-arm, multicenter, expanded-access study of the safety and clinical outcomes of StrataGraft® treatment in adults with deep partial-thickness thermal burns.

BACKGROUND: A phase 3b, open-label, multicenter, expanded-access study (NCT04123548) evaluated safety and clinical outcomes of StrataGraft treatment in adults with deep partial-thickness thermal burns with intact dermal elements. METHODS: Adult patients with 3 % to < 50 % total body surface area burns were treated with a single application of ≤ 1:1 meshed StrataGraft and followed for 24 weeks. Primary endpoint was count and percentage of patients with treatment-emergent adverse events (TEAEs). Secondary endpoints included confirmed wound closure (WC) at Week 12, durable WC at Week 24, time to WC, scar evaluation, and wound infection-related events. RESULTS: Fifty-two patients with 96 treatment sites were enrolled. Pruritus was the most common TEAE (22 patients [42.3 %]). Twenty serious TEAEs occurred in 10 patients (19.2 %); none were related to StrataGraft. There were 4 (7.7 %) deaths (aspiration, myocardial infarction, self-injury, Gram-negative rod sepsis); none were related to StrataGraft. Confirmed WC was achieved by Week 12 in 33 patients (63.5 %; 95 % CI: 50.4-76.5 %) and 69 treatment sites (71.9 %; 95 % CI: 62.9-80.9 %). Durable WC was achieved by Week 24 in 29 patients (55.8 %; 95 % CI: 42.3-69.3 %) and 58 treatment sites (60.4 %; 95 % CI: 50.6-70.2 %). CONCLUSIONS: StrataGraft demonstrated clinical benefit. Safety data were consistent with previously reported findings.

Altering CO2 Laser Pulse Energy Settings Did Not Influence Differential Gene Transcription in Normal Skin in a Red Duroc Pig Model.

OBJECTIVES: Fractional ablative CO2 lasers are used clinically to treat cutaneous burn scars with reported varying degrees of effectiveness. It was hypothesized that different laser pulse energy settings may lead to differential gene transcription in a porcine model. METHODS: Uninjured skin from red Duroc pigs was treated with a fractional ablative CO2 laser set to 70, 100, or 120 mJ across the abdomen (n = 4 areas per treatment). Punch biopsies of both treated and untreated sites were taken before treatment (baseline), at 30 min, and at each hour for 6 h and stored in All-Protect tissue reagent. The biopsies were then used to isolate RNA, which was subsequently used in qRT-PCR for eight genes associated with wound healing and the extracellular matrix: CCL2, IL6, FGF2, TIMP1, TIMP3, COL1A2, MMP2, and DCN. RPL13a was used as a housekeeping gene to normalize the eight genes of interest. One-way ANOVA tests were used to assess for differences among laser pulse energies and two-way ANOVA tests were used to assess the differences between treated and untreated areas. RESULTS: While six of the eight genes were upregulated after treatment (p < 0.05), there were no significant differences in gene expression between the different laser pulse energies for any of the eight genes. CONCLUSION: While laser treatment is correlated with a positive and significant upregulation for six of the eight genes 4 h after intervention, the pulse energy settings of the laser did not lead to a statistically significant difference in gene transcription among the treatment areas. Different laser pulse energies may not be required to induce similar cellular responses in a clinical setting.

A Nude Mouse Model of Xenografted Hypertrophic Scar Cells to Test Therapeutics in the Skin.

BACKGROUND: Existing animal models for testing therapeutics in the skin are limited. Mouse and rat models lack similarity to human skin in structure and wound healing mechanism. Pigs are regarded as the best model with regards to similarity to human skin; however, these studies are expensive, time-consuming, and only small numbers of biologic replicates can be obtained. In addition, local-regional effects of treating wounds that are closely adjacent to one-another with different treatments make assessment of treatment effectiveness difficult in pig models. Therefore, here, a novel nude mouse model of xenografted porcine hypertrophic scar (HTS) cells was developed. This model system was developed to test if supplying hypo-pigmented cells with exogenous alpha melanocyte stimulating hormone (α-MSH) will reverse pigment loss in vivo. METHODS: Dyschromic HTSs were created in red Duroc pigs. Epidermal scar cells (keratinocytes and melanocytes) were derived from regions of hyper-, hypo-, or normally pigmented scar or skin and were cryopreserved. Dermal fibroblasts (DFs) were isolated separately. Excisional wounds were created on nude mice and a grafting dome was placed. DFs were seeded on day 0 and formed a dermis. On day 3, epidermal cells were seeded onto the dermis. The grafting dome was removed on day 7 and hypo-pigmented xenografts were treated with synthetic α-MSH delivered with microneedling. On day 10, the xenografts were excised and saved. Sections were stained using hematoxylin and eosin hematoxylin and eosin (H&E) to assess xenograft structure. RNA was isolated and quantitative real-time polymerase chain reaction (qRT-PCR) was performed for melanogenesis-related genes TYR, TYRP1, and DCT. RESULTS: The seeding of HTSDFs formed a dermis that is similar in structure and cellularity to HTS dermis from the porcine model. When hyper-, hypo-, and normally-pigmented epidermal cells were seeded, a fully stratified epithelium was formed by day 14. H&E staining and measurement of the epidermis showed the average thickness to be 0.11 ± 0.07 µm vs. 0.06 ± 0.03 µm in normal pig skin. Hypo-pigmented xenografts that were treated with synthetic α-MSH showed increases in pigmentation and had increased gene expression of TYR, TYRP1, and DCT compared to untreated controls (TYR: 2.7 ± 1.1 vs. 0.3 ± 1.1; TYRP1: 2.6 ± 0.6 vs. 0.3 ± 0.7; DCT 0.7 ± 0.9 vs. 0.3 ± 1-fold change from control; n = 3). CONCLUSIONS: The developed nude mouse skin xenograft model can be used to study treatments for the skin. The cells that can be xenografted can be derived from patient samples or from pig samples and form a robust dual-skin layer containing epidermis and dermis that is responsive to treatment. Specifically, we found that hypo-pigmented regions of scar can be stimulated to make melanin by synthetic α-MSH in vivo.

Endothelial dysfunction is dampened by early administration of fresh frozen plasma in a rodent burn shock model.

BACKGROUND: Endothelial dysfunction has been implicated in the pathogenesis of burn shock affecting patients with large thermal injury. In response to injury, glycocalyx components like Syndecan-1 (SDC-1) are shed into circulation and have been used as markers of endothelial damage. Previous work in our laboratory has shown that plasma inclusive resuscitation (PIR) with fresh frozen plasma (FFP) ameliorates endothelial damage. However, there remains a paucity of information regarding optimal timing and dosing of PIR as well as organ-specific endothelial responses to shock. We aimed to examine the impact of PIR on endothelial dysfunction using clinically translatable timing and dosing. METHODS: Sprague-Dawley rats were used to create thermal burns. Rats were subjected to 40% total body surface area scald burns and were resuscitated with lactated Ringer's (LR) only, LR plus albumin, and LR plus early 1 mL boluses of FFP at 0, 2, 4, and 8 hours postinjury. A late group also received LR plus FFP starting at hour 10 postinjury. Syndecan-1 levels were quantified by enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis characterized transcription of glycocalyx components and inflammatory cytokines in the lung and spleen. Evan's blue dye was used to quantify amount of vascular leakage. RESULTS: Lactated Ringer's plus early FFP reduced Evan's blue dye extravasation when compared with LR only groups, while late FFP did not. When comparing LR only versus LR plus early FFP, SDC-1 levels were reduced in the LR plus early FFP group at hours 8, 12, and 24 (5.23 vs. 2.07, p < 0.001; 4.49 vs. 2.05, p < 0.01; and 3.82 vs. 2.08, p < 0.05, respectively). Lactated Ringer's only groups had upregulation of Exostosin-1 and SDC-1 in the lung compared with LR plus early FFP groups ( p < 0.01 and p < 0.05) and upregulation of cytokines interluekin-10 and interferon γ ( p < 0.001 and p < 0.001). CONCLUSION: Early administration of LR plus FFP reduces the magnitude of SDC-1 shedding and dampens the cytokine response to injury. The upregulation of glycocalyx components as a response to endothelial injury is also decreased in the lung and spleen by LR plus early FFP administration.

Treatment of hypopigmented burn hypertrophic scars with short-term topical tacrolimus does not lead to repigmentation.

OBJECTIVES: Dyschromia is an understudied aspect of hypertrophic scar (HTS). The use of topical tacrolimus has successfully shown repigmentation in vitiligo patients through promotion of melanogenesis and melanocyte proliferation. It was hypothesized that HTSs treated with topical tacrolimus would have increased repigmentation compared to controls. METHODOLOGY: Full-thickness burns in red Duroc pigs were either treated with excision and meshed split-thickness skin grafting or excision and no grafting, and these wounds formed hypopigmented HTSs (n = 8). Half of the scars had 0.1% tacrolimus ointment applied to the scar twice a day for 21 days, while controls had no treatment. Further, each scar was bisected with half incurring fractional ablative CO2 laser treatment before topical tacrolimus application to induce laser-assisted drug delivery (LADD). Pigmentation was evaluated using a noninvasive probe to measure melanin index (MI) at Days 0 (pretreatment), 7, 14, and 21. At each timepoint, punch biopsies were obtained and fixed in formalin or were incubated in dispase. The formalin-fixed biopsies were used to evaluate melanin levels by H&E staining. The biopsies incubated in dispase were used to obtain epidermal sheets. The ESs were then flash frozen and RNA was isolated from them and used in quantitative reverse transcription polymerase chain reaction for melanogenesis-related genes: Tyrosinase (TYR), TYR-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Analysis of variance test with Sídák's multiple comparisons test was used to compare groups. RESULTS: Over time, within the grafted HTS and the NS group, there were no significant changes in MI, except for Week 3 in the -Tacro group. (+Tacro HTS= pre = 685.1 ± 42.0, w1 = 741.0 ± 54.16, w2 = 750.8 ± 59.0, w3 = 760.9 ± 49.8) (-Tacro HTS= pre = 700.4 ± 54.3, w1 = 722.3 ± 50.7, w2 = 739.6 ± 53.2, w3 = 722.7 ± 50.5). Over time, within the ungrafted HTS and the NS group, there were no significant changes in MI. (+Tacro HTS= pre = 644.9 ± 6.9, w1 = 661.6 ± 3.3, w2 = 650.3 ± 6.2, w3 = 636.3 ± 7.4) (-Tacro HTS= pre = 696.8 ± 8.0, w1 = 695.8 ± 12.3, w2 = 678.9 ± 14.0, w3 = 731.2 ± 50.3). LADD did not lead to any differential change in pigmentation compared to the non-LADD group. There was no evidence of increased melanogenesis within the tissue punch biopsies at any timepoint. There were no changes in TYR, TYRP1, or DCT gene expression after treatment. CONCLUSION: Hypopigmented HTSs treated with 0.1% tacrolimus ointment with or without LADD did not show significantly increased repigmentation. This study was limited by a shorter treatment interval than what is known to be required in vitiligo patients for repigmentation. The use of noninvasive, topical treatments to promote repigmentation are an appealing strategy to relieve morbidity associated with dyschromic burn scars and requires further investigation.

Cold atmospheric plasma is bactericidal to wound-relevant pathogens and is compatible with burn wound healing.

Burn wound healing can be significantly delayed by infection leading to increased morbidity and hypertrophic scarring. An optimal antimicrobial agent would have the ability to kill bacteria without negatively affecting the host skin cells that are required for healing. Currently available products provide antimicrobial coverage, but may also cause reductions in cell proliferation and migration. Cold atmospheric plasma is a partially ionized gas that can be produced under atmospheric pressure at room temperature. In this study a novel handheld Aceso Plasma Generator was used to produce and test Aceso Cold Plasma (ACP) in vitro and in vivo. ACP showed a potent ability to eliminate bacterial load in vitro for a number of different species. Deep partial-thickness and full-thickness wounds that were treated with ACP after burning, after excision, after autografting, and at days 5, 7, and 9 did not show any negative effects on their wound healing trajectories. On par with in vitro analysis, bioburden was decreased in treated wounds vs. control. In addition, metrics of hypertrophic scar such as dyschromia, elasticity, trans-epidermal water loss (TEWL), and epidermal and dermal thickness were the same between the two treatment groups.It is likely that ACP can be used to mitigate the risk of bacterial infection during the phase of acute burn injury while patients await surgery for definitive closure. It may also be useful in treating wounds with delayed re-epithelialization that are at risk for infection and hypertrophic scarring. A handheld cold plasma device will be useful in treating all manner of wounds and surgical sites in order to decrease bacterial burden in an efficient and highly effective manner without compromising wound healing.

Rete ridges are decreased in dyschromic burn hypertrophic scar: A histological study.

Dyschromic hypertrophic scar (HTS) is a common sequelae of burn injury, however, its mechanism has not been elucidated. This work is a histological study of these scars with a focus on rete ridges. Rete ridges are important for normal skin physiology, and their absence or presence may hold mechanistic significance in post-burn HTS dyschromia. It was posited that hyper-, and hypo-pigmented areas of scars have different numbers of rete ridges. Subjects with dyschromic burn hypertrophic scar were prospectively enrolled (n = 44). Punch biopsies of hyper-, hypo-, and normally pigmented scar and skin were collected. Biopsies were paraffin embedded, sectioned, stained with H&E, and imaged. The number of rete ridges were investigated. Burn hypertrophic scars that healed without autografts were first investigated. The number of rete ridges was higher in normal skin compared to HTS that was either hypo- (p < 0.01) or hyper-pigmented (p < 0.001). This difference was similar despite scar pigmentation phenotype (p = 0.8687). Autografted hyper-pigmented scars had higher rete ridge ratio compared to non-autografted hyper-pigmented HTS (p < 0.0001). Burn hypertrophihc scars have fewer rete ridges than normal skin. This finding may explain the decreased epidermal adherence to underlying dermis associated with hypertrophic scars. Though, contrary to our hypothesis, no direct link between the extent of dyschromia and rete ridge quantity was observed, the differences in normal skin and hypertrophic scar may lead to further understanding of dyschromic scars.

Comparison of Rapid-, Kaolin-, and Native-TEG Parameters in Burn Patient Cohorts With Acute Burn-induced Coagulopathy and Abnormal Fibrinolytic Function.

Although use of thromboelastography (TEG) to diagnose coagulopathy and guide clinical decision-making is increasing, relative performance of different TEG methods has not been well-defined. Rapid-TEG (rTEG), kaolin-TEG (kTEG), and native-TEG (nTEG) were performed on blood samples from burn patients presenting to a regional center from admission to 21 days. Patients were categorized by burn severity, mortality, and fibrinolytic phenotypes (Shutdown [SD], Physiologic [PHYS], and Hyperfibrinolytic [HF]). Manufacturer ranges and published TEG cutoffs were examined. Concordance correlations (Rc) of TEG parameters (R, α-angle, maximum amplitude [MA], LY30) measured agreement and Cohen's Kappa (κ) determined interclass reliability. Patients (n = 121) were mostly male (n = 84; 69.4%), with median age 40 years, median TBSA burn 13%, and mortality 17% (n = 21). Severe burns (≥40% TBSA) were associated with lower admission α-angle for rTEG (P = .03) and lower MA for rTEG (P = .02) and kTEG (P = .01). MA was lower in patients who died (nTEG, P = .04; kTEG, P = .02; rTEG, P = .003). Admission HF was associated with increased mortality (OR, 10.45; 95% CI, 2.54-43.31, P = .001) on rTEG only. Delayed SD was associated with mortality using rTEG and nTEG (OR 9.46; 95% CI, 1.96-45.73; P = .005 and OR, 6.91; 95% CI, 1.35-35.48; P = .02). Admission TEGs showed poor agreement on R-time (Rc, 0.00-0.56) and α-angle (0.40 to 0.55), and moderate agreement on MA (0.67-0.81) and LY30 (0.72-0.93). Interclass reliability was lowest for R-time (κ, -0.07 to 0.01) and α-angle (-0.06 to 0.17) and highest for MA (0.22-0.51) and LY30 (0.29-0.49). Choice of TEG method may impact clinical decision-making. rTEG appeared most sensitive in parameter-specific associations with injury severity, abnormal fibrinolysis, and mortality.

Iterative refinement of a histologic algorithm for burn depth categorization based on 798 consecutive burn wound biopsies.

INTRODUCTION: Our group previously reported a burn biopsy algorithm (BBA-V1) for categorizing burn wound depth. Here, we sought to promulgate a newer, simpler version of the BBA (BBA-V2). METHODS: Burn wounds undergoing excision underwent 4 mm biopsies procured every 25 cm2. Serial still photos were obtained at enrollment and at excision intraoperatively. Burn wounds assessed as likely to heal by 21 days were imaged within 72 h of injury and at 21 days. A sample of 798 burn wound biopsies were classified by both BBAV1 and BBAV2 algorithms. For nonoperative burn wounds, the proportion of healing versus nonhealing pixels at 21 days after injury were compared. RESULTS: The 798 biopsies were classified by BBAV1 as 24% SPT, 47% DPT, 28% FT and by BBAV2 as 3% SPT, 67% DPT, and 30% FT (p < 0.0001). Overall, the proportion of biopsies whose wound reclassification changed from a nonoperative to operative pathway was 21% (95% CI: 18-24%). Nonoperative wounds judged at injury as being SPT contained 12.8 million pixels. Repeat 21-day imaging revealed 11.3 million healed pixels (accuracy = 89.6% (95% CI: 89.59-89.62)). CONCLUSIONS: BBA-V2 was associated with a significantly higher concordance with visual assessment for burn wounds clinically judged as deep partial and full thickness.

Sepsis in surgical patients: Burn sepsis.

Patients with large burn injuries remain a challenge. The loss of skin barrier integrity and induced immunosuppression after injury increases their vulnerability to infection. Sepsis remains the primary cause of death for burn-injured patients who survive their acute injury and resuscitation. The objective of this work is to describe the current understanding and management of sepsis in the burn-injured patient and newer strategies to approach its management. Current understanding of the systemic inflammatory response to burn injury and sepsis, preventative strategies, and novel research will be discussed. Understanding the origin of burn sepsis from wounds themselves is key to understanding current paradigms. Infection control and management begins from the time of injury and continues throughout the patient's hospital course. The use of personal protective equipment, burn unit design considerations, and optimization of prevention protocols and catheter care all play a role in burn sepsis prevention and management. The emergence of drug-resistant pathogens poses a particular challenge for burn patients due to the chronicity with which their wounds are sometimes open. The difficulty of systemic antibiotics to reach wounds has underscored the need to anticipate resistant organisms moving forward. Antibiotic strategies and newer approaches, such as phage therapy, will be discussed. Multi-omics approaches to understanding burn sepsis have developed in hopes of identifying patients more susceptible or at risk of developing burn sepsis. As with many aspects of burn care, a multidisciplinary, proactive approach to the management of burn sepsis is key to minimizing the morbidity and mortality associated with this complication.

Neutrophil Extracellular Traps Are Induced by Coronavirus 2019 Disease-Positive Patient Plasma and Persist Longitudinally: A Possible Link to Endothelial Dysfunction as Measured by Syndecan-1.

Background: Neutrophil extracellular trap (NET) formation is a mechanism that neutrophils possess to respond to host infection or inflammation. However, dysregulation of NETosis has been implicated in many disease processes. Although the exact mechanisms of their involvement remain largely unknown, this study aimed to elucidate NET formation over the time course of coronavirus disease 2019 (COVID-19) infection and their possible role in endothelial injury. Patients and Methods: Plasma samples from COVID-19-positive patients were obtained at six timepoints during hospitalization. Neutrophils were extracted from healthy donors and treated with COVID-19-positive patient plasma. Myeloperoxidase (MPO) assay was used to assess for NETosis. Syndecan-1 (SDC-1) enzyme-linked immunosorbent assay (ELISA) was run using the same samples. Immunocytochemistry allowed for further quantification of NETosis byproducts MPO and citrullinated histone 3 (CitH3). The receiver operating characteristic (ROC) curve discriminated between admission levels of SDC-1 and MPO in predicting 30-day mortality and need for ventilator support. Results: Sixty-three patients with COVID-19 were analyzed. Myeloperoxidase was upregulated at day 3, 7, and 14 (p = 0.0087, p = 0.0144, p = 0.0421). Syndecan-1 levels were elevated at day 7 and 14 (p = 0.0188, p = 0.0026). Neutrophils treated with day 3, 7, and 14 plasma expressed increased levels of MPO (p < 0.001). Immunocytochemistry showed neutrophils treated with day 3, 7, and 14 plasma expressed higher levels of MPO (p < 0.001) and higher levels of CitH3 when treated with day 7 and 14 plasma (p < 0.01 and p < 0.05). Admission SDC-1 and MPO levels were found to be independent predictors of 30-day mortality and need for ventilator support. Conclusions: Neutrophil dysregulation can be detrimental to the host. Our study shows that COVID-19 plasma induces substantial amounts of NET formation that persists over the course of the disease. Patients also exhibit increased SDC-1 levels that implicate endothelial injury in the pathogenesis of COVID-19 infection. Furthermore, MPO and SDC-1 plasma levels are predictive of poor outcomes.

Meta-Analysis of Publicly Available Clinical and Preclinical Microbiome Data From Studies of Burn Injury.

Following burn injury, alterations in host commensal microbiota across body spaces may leave patients susceptible to opportunistic pathogens and serious sequelae such as sepsis. Generally, studies examining the microbiome postburn have had a limited sample size and lack of longitudinal data, which coupled with experimental and analytic variation, impacts overall interpretation. We performed a meta-analysis of publicly available sequencing data from preclinical and clinical burn studies to determine if there were consistent alterations in the microbiome across various anatomical sites and hosts. Ten human and animal 16S rRNA sequencing studies spanning respiratory, urinary, cutaneous, and gastrointestinal microbiomes were included. Taxonomic classification and alpha and beta diversity metrics were analyzed using QIIME2 v2021.8. Alpha diversity was consistently higher in control samples compared to burn-injured samples which were also different based on host and anatomical location; however, phylogenetic evaluation (ie, Faith PD) elucidated more significant differences compared to taxonomic metrics (ie, Shannon entropy). Beta diversity analysis based on weighted UniFrac showed that rodent specimens clustered less closely to humans than pig samples for both rectal and skin sources. Host species and performing institute were found to have a significant impact on community structure. In rectal samples, bacterial composition in pig and human burn samples included Bacteroidetes, Firmicutes, and Proteobacteria, while rodent samples were dominated by Firmicutes. Proteobacteria and Firmicutes increased on burned skin in each host species. Our results suggest that host species and the performing institute strongly influence microbiome structure. Burn-induced alterations in microbiome diversity and taxa exist across hosts, with phylogenetic metrics more valuable than others. Coordinated, multicenter studies, both clinical and preclinical, within the burn community are needed to more completely realize the diagnostic and therapeutic potential of the microbiome for improving outcomes postburn.

Examining Obesity and Its Association With Burn Injury: A Secondary Analysis of the Transfusion Requirement in Burn Care Evaluation Study.

INTRODUCTION: Literature examining the connection between obesity and burn injuries is limited. This study is a secondary analysis of a multicenter trial data set to investigate the association between burn outcomes and obesity following severe burn injury. MATERIALS AND METHODS: Body mass index (BMI) was used to stratify patients as normal weight (NW; BMI 18.5-25), all obese (AO; any BMI>30), obese I (OI; BMI 30-34.9), obese II (OII; BMI 35-39.9), or obese III (OIII; BMI>40). The primary outcome examined was mortality. Secondary outcomes included hospital length of stay (LOS), number of transfusions, injury scores, infection occurrences, number of operations, ventilator days, intensive care unit LOS, and days to wound healing. RESULTS: Of 335 patients included for study, 130 were obese. Median total body surface area (TBSA) was 31%, 77 patients (23%) had inhalation injury and 41 patients died. Inhalation injury was higher in OIII than NW (42.1% versus 20%, P = 0.03). Blood stream infections (BSI) were higher in OI versus NW (0.72 versus 0.33, P = 0.03). Total operations, ventilator days, days to wound healing, multiorgan dysfunction score, Acute Physiology and Chronic Health Evaluationscore, hospital LOS, and intensive care unit LOS were not significantly affected by BMI classification. Mortality was not significantly different between obesity groups. Kaplan-Meier survival curves did not significantly differ between the groups (χ2 = 0.025, P = 0.87). Multiple logistic regression identified age, TBSA, and full thickness burn as significant independent predictors (P < 0.05) of mortality; however, BMI classification itself was not predictive of mortality. CONCLUSIONS: No significant association between obesity and mortality was seen after burn injury. Age, TBSA, and percent full- thickness burn were independent predictors of mortality after burn injury, while BMI classification was not.

The First 24 Hours: Burn Shock Resuscitation and Early Complications.

Resuscitation is required for the management of patients with severe thermal injury. Some of the initial pathophysiologic events following burn injury include an exaggerated inflammatory state, injury to the endothelium, and increased capillary permeability, which all culminate in shock. Understanding these processes is critical to the effective management of patients with burn injuries. Formulas predicting fluid requirements during burn resuscitation have evolved over the past century in response to clinical experience and research efforts. Modern resuscitation features individualized fluid titration and monitoring along with colloid-based adjuncts. Despite these developments, complications from over-resuscitation still occur.