Burn Resuscitation Practices in North America: Results of the Acute Burn ResUscitation Multicenter Prospective Trial (ABRUPT).

OBJECTIVES: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial. SUMMARY BACKGROUND DATA: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation. METHODS: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols. RESULTS: Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2 ± 2.3 vs 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours), but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone. CONCLUSIONS: Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate.

Uncovering a multitude of human glucocorticoid receptor variants: an expansive survey of a single gene.

BACKGROUND: Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; however, significant variations in response to treatment have been demonstrated. Although the underlying mechanisms have yet to be fully understood, this variable response may be a result of alterations in human glucocorticoid receptor (hGR) expression and function. In addition to hGRα, the biologically active isoform, a screening of current databases and publications revealed five alternative splice isoforms and hundreds of variants that have been reported to date. Many of these changes in the hGR-coding gene, NR3C1, have been linked to pathophysiology. However, many studies focus on evaluating hGR expression in vitro or detecting previously reported variants. RESULTS: In this study, blood from healthy volunteers, burn and asthma patients, as well as from peripheral blood mononuclear cells isolated from leukoreduced donor whole blood, were screened for NR3C1 isoforms. We identified more than 1500 variants, including an additional 21 unique splice isoforms which contain 15 new cryptic exons. A dynamic database, named the Universal hGR (UhGR), was created to annotate and visualize the variants. CONCLUSION: This identification of naturally occurring and stress-induced hGR isoforms, as well as the establishment of an hGR-specific database, may reveal new patterns or suggest areas of interest that will lead to the improved understanding of the human stress response system.

Transfusion Requirement in Burn Care Evaluation (TRIBE): A Multicenter Randomized Prospective Trial of Blood Transfusion in Major Burn Injury.

OBJECTIVE: Our objective was to compare outcomes of a restrictive to a liberal red cell transfusion strategy in 20% or more total body surface area (TBSA) burn patients. We hypothesized that the restrictive group would have less blood stream infection (BSI), organ dysfunction, and mortality. BACKGROUND: Patients with major burns have major (>1 blood volume) transfusion requirements. Studies suggest that a restrictive blood transfusion strategy is equivalent to a liberal strategy. However, major burn injury is precluded from these studies. The optimal transfusion strategy in major burn injury is thus needed but remains unknown. METHODS: This prospective randomized multicenter trial block randomized patients to a restrictive (hemoglobin 7-8 g/dL) or liberal (hemoglobin 10-11 g/dL) transfusion strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes. RESULTS: Eighteen burn centers enrolled 345 patients with 20% or more TBSA burn similar in age, TBSA burn, and inhalation injury. A total of 7054 units blood were transfused. The restrictive group received fewer blood transfusions: mean 20.3 ±â€Š32.7 units, median = 8 (interquartile range: 3, 24) versus mean 31.8 ±â€Š44.3 units, median = 16 (interquartile range: 7, 40) in the liberal group (P < 0.0001, Wilcoxon rank sum). BSI incidence, organ dysfunction, ventilator days, and time to wound healing (P > 0.05) were similar. In addition, there was no 30-day mortality difference: 9.5% restrictive versus 8.5% liberal (P = 0.892, χ test). CONCLUSIONS: A restrictive transfusion strategy halved blood product utilization. Although the restrictive strategy did not decrease BSI, mortality, or organ dysfunction in major burn injury, these outcomes were no worse than the liberal strategy (Clinicaltrials.gov identifier NCT01079247).

Inherently variable responses to glucocorticoid stress among endogenous retroviruses isolated from 23 mouse strains.

Active participation of endogenous retroviruses (ERVs) in disease processes has been exemplified by the finding that the HERV (human ERV)-W envelope protein is involved in the pathogenesis of multiple sclerosis, an autoimmune disease. We also demonstrated that injury-elicited stressors alter the expression of murine ERVs (MuERVs), both murine leukemia virus-type and mouse mammary tumor virus (MMTV)-type (MMTV-MuERV). In this study, to evaluate MMTV-MuERVs' responses to stress (e.g., injury, infection)-elicited systemic glucocorticoid (GC) levels, we examined the GC-stress response of 64 MMTV-MuERV promoters isolated from the genomes of 23 mouse strains. All 64 promoters responded to treatment with a synthetic GC, dexamethasone (DEX), at a wide range from a 0.6- to 85.7-fold increase in reporter activity compared to no treatment. An analysis of the 10 lowest and 10 highest DEX responders revealed specific promoter elements exclusively present in either the three lowest or the two highest responders. Each promoter had a unique profile of transcription regulatory elements and the glucocorticoid response element (GRE) was identified in all promoters with the number of GREs ranging from 2 to 7. The three lowest DEX responders were the only promoters with two GREs. The findings from this study suggest that certain MMTV-MuERVs are more responsive to stress-elicited systemic GC elevation compared to the others. The mouse strain-specific genomic MMTV-MuERV profiles and individual MMTV-MuERVs' differential responses to GC-stress might explain, at least in part, the variable inflammatory responses to injury and/or infection, often observed among different mouse strains. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.

Burn center volume makes a difference for burned children.

OBJECTIVES: Determine the relationship between the volume of burn admissions and outcomes for children with burns. DESIGN: Retrospective review of the National Burn Repository from 2000-2009 using mixed effect logistic regression modeling. SETTING: Tertiary burn centers in the United States. PATIENTS: All children <18 years of age admitted with burn injury to a burn center submitting data to the National Burn Repository. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 210,683 records in the NBR from 2000-2009, 33,115 records for children ≤ 18 years of age met criteria for analysis; 26,280 had burn sizes smaller than 10%; only 32 of these children died. Volume of children treated varied greatly among facilities. Age, total body surface area burn, inhalation injury, and burn center volume influenced mortality (p < 0.05) An increase in the median yearly admissions of 100 decreased the odds of mortality by approximately 40%. High volume centers (admitting >200 pediatric patients/year) had the lowest mortality when adjusting for age and injury characteristics (p < 0.05). CONCLUSIONS: Higher volume pediatric burn centers had lower mortality, particularly at larger burn sizes. The lower mortality of children a high volume centers could reflect greater experience, resource, and specialized expertise in treating pediatric patients.

Wound Management of Pediatric Burns.

The goal for treating pediatric burns is to allow the patient to heal with as little scarring as possible. Compared to older children and adults, very small children have anatomic differences that alter their treatment. They have thinner skin that leads to a higher risk for full-thickness burns. Children also tend to freeze when touching a hot item, so that the prolonged contact also leads to deeper burns. Two healing strategies are needed to treat these wounds. One must optimize reepithelialization in superficial burns to reduce scarring. Deeper burns require skin grafting, but there are techniques, such as the use of "sheet" autograft skin that lead to excellent outcomes. Strategies to treat the massive pediatric burn will also be covered. Finally, there are instances where different strategies are needed to cover exposed bone or tendon. The ultimate goal is to return the skin to as normal a state as possible.

Single nucleotide polymorphisms and type of steroid impact the functional response of the human glucocorticoid receptor.

BACKGROUND: Clinical trials evaluating the use of steroids in septic shock have shown variable outcomes. Our previous studies have implicated human glucocorticoid receptor (hGR) polymorphisms as a possible cause of altered steroid response. To further evaluate this variability, we hypothesized that hGR polymorphisms along with type of steroid influence the functional response. METHODS: Total RNA was isolated from healthy human blood samples and surveyed for the hGR gene. The National Center for Biotechnology Information hGRα sequence was used as a reference, and two unique single nucleotide polymorphisms (SNPs) (A214G and T962C) were selected for evaluation. Functional response was measured using a luciferase reporting assay after transfecting hGR isoforms into tsA201 cells and stimulation with graded concentrations of hydrocortisone (HYD), methylprednisolone (MPS), and dexamethasone (DEX). RESULTS: Each isoform had a unique dose-response curve with the optimal activity depending on concentration and type of steroid. The presence of either SNP A214G or T962C resulted in a decreased response when compared with hGRα when stimulated with HYD (P < 0.01). The same decreased response occurred for the SNPs with DEX stimulation, but at a much lower concentration range than HYD (P < 0.01). However, in the presence of MPS, SNP A214G resulted in greater activity when compared with hGRα (P < 0.01), whereas the presence of T962C resulted in activity equivalent to hGRα. CONCLUSIONS: SNPs, type of steroid, and concentration range impact the functional response of the hGR. A greater understanding of hGR polymorphisms and steroid response may further elucidate mechanisms explaining the variable response seen with patient treatment.

Identification of a group of Mus dunni endogenous virus-like endogenous retroviruses from the C57BL/6J mouse genome: proviral genomes, strain distribution, expression characteristics, and genomic integration profile.

About 10 % of the mouse genome is occupied by sequences associated with endogenous retroviruses (ERVs). However, a comprehensive profile of the mouse ERVs and related elements has not been established yet. In this study, we identified a group of ERVs from the mouse genome and characterized their biological properties. Using a custom ERV mining protocol, 191 ERVs (159 loci reported previously and 32 new loci), tentatively named Mus dunni endogenous virus (MDEV)-like ERVs (MDL-ERVs), were mapped on the C57BL/6J mouse genome. Seven of them retained putative full coding potentials for three retroviral polypeptides (gag, pol, and env). Among the 57 mouse strains examined, all but the Mus pahari/Ei strain had PCR amplicons corresponding to a conserved MDL-ERV region. Interestingly, the Mus caroli/EiJ's amplicon was somewhat larger than the others, coinciding with a substantial phylogenetic distance between the MDL-ERV populations of M. caroli/EiJ and C57BL/6J strains. MDL-ERVs were highly expressed in the lung, spleen, and thymus of C57BL/6J mice compared to the brain, heart, kidney, and liver. Seven MDL-ERVs were mapped in the introns of six annotated genes. Of interest, some MDL-ERVs were mapped periodically on three clusters in chromosome X. The finding that these MDL-ERVs were one of several types of retroelements, which form mosaic-repeat units of tandem arrays, suggests that the formation of the mosaic-repeat unit preceded the tandem arrangement event. Further studies are warranted to understand the biological roles of MDL-ERVs in both normal and pathologic conditions.

ERE database: a database of genomic maps and biological properties of endogenous retroviral elements in the C57BL/6J mouse genome.

Endogenous retroviral elements (EREs), a family of transposable elements, constitute a substantial fraction of mammalian genomes. It is expected that profiles of the ERE sequences and their genomic locations are unique for each individual. Comprehensive characterization of the EREs' genomic locations and their biological properties is essential for understanding their roles in the pathophysiology of the host. In this study, we identified and mapped putative EREs (a total of 111 endogenous retroviruses [ERVs] and 488 solo long terminal repeats [sLTRs]) within the C57BL/6J mouse genome. The biological properties of individual ERE isolates (both ERVs and sLTRs) were then characterized in the following aspects: transcription potential, tropism trait, coding potential, recombination event, integration age, and primer binding site for replication. In addition, a suite of database management system programs was developed to organize and update the data acquired from current and future studies and to make the data accessible via internet.

Infections in Burn Patients.

Infections are the leading cause of mortality in burn patients who survive their initial resuscitation. Burn injury leads to immunosuppression and a dysregulated inflammatory response which can have a prolonged impact. Early surgical excision along with support of the multidisciplinary burn team has improved mortality in burn patients. The authors review diagnostic and therapeutic challenges as well as strategies for management of burn related infections.

Modified Frailty Index is an Independent Predictor of Death in the Burn Population: A Secondary Analysis of the Transfusion Requirement in Burn Care Evaluation (TRIBE) Study.

Frailty can increase the risk of dying after suffering a severe injury. The Modified Frailty Index (MFI) was developed by the American College of Surgeons National Surgical Quality Improvement Program to determine the impact of frailty on outcomes. Our aim was to correlate frailty with survival following a burn injury using the 11-item and 5-item MFI. We performed a secondary analysis of the Transfusion Requirement in Burn Care Evaluation (TRIBE) study. Data including, age, gender, medical history, extent and severity of burn injury, inhalation injury and discharge disposition was collected from the TRIBE database. The 11-item MFI (MFI-11) and 5-item MFI (MFI-5) scores were calculated for all patients in the TRIBE database. The TRIBE database included 347 patients. The mean age of subjects was 43 ± 17 years. Mean total body surface area burn (TBSA) was 38 ± 18%, and 23% had inhalation injury. Multivariate logistic regression analysis determined that both MFI-5 (OR 1.86; 95% CI: 1.11-3.11; P-value .02) and MFI-11 (OR 1.83; 95% CI: 1.18-2.8; P-value .007) were independent predictors for mortality. Additionally, MFI-11 scores that are >1 were independently associated with a markedly increased risk of dying after a burn injury (OR 2.91; 95% CI: 1.1-7.7; P-value .03). The MFI can be used to identify vulnerable burn injured patients who are at high risk of dying.

Understanding Factors in Burn Patient Follow-up.

Follow-up rates are concerningly low among burn-injured patients. This study investigates the factors associated with low follow-up rates and missed appointments. We hypothesize that patients who are homeless, use illicit substances, and have psychiatric comorbidities will have lower rates of follow-up and more missed appointments. Data from a discharge-planning survey of 281 burn-injured patients discharged from September 2019 to July 2020 were analyzed and matched with patients' electronic medical records for a retrospective chart review. Data collected included general demographics, burn characteristics, hospitalization details, follow-up visits, missed appointments, homeless status, substance use, major psychiatric illness, and survey responses. Data analysis used chi-square, Fisher's exact test, Student's t-test, Wilcoxon rank sum test, and multivariate regression analysis. Overall, 37% of patients had no follow-up in clinic and 46% had one or more missed appointment. On multivariate regression analysis, homeless patients were more likely to never follow-up, odds ratio (OR) = 0.23 (95% confidence interval [CI] = 0.11-0.49), as were patients who anticipated experiencing transportation difficulties, OR = 0.28 (95% CI = 0.15-0.50). Homeless patients were more likely to have missed appointments, OR = 0.23 (95% CI = 0.1-0.54). On univariate analysis, patients with one or more documented major psychiatric illness had lower follow-up rates, with 50.62% having no follow-up (P < .01). Among patients who responded to the survey that they were current drug users, 52% had no follow-up as compared to 28% of patients who responded that they did not use drugs (P < .01).

Suicide by self-inflicted burns - A persistent psychiatric problem.

Self-inflicted burns are a relatively uncommon but profound attempt at suicide. Twenty years ago, we first reviewed our experience with self-inflicted burns. With this current study, we sought to determine whether there had been any change in the incidence or outcomes of self-inflicted burns. All burn patients admitted between January 1, 2012, and December 31, 2021, with self-inflicted burns were compared with all other admissions. The frequency of self-inflicted burns and confounding risk factors of patients with self-inflicted burns remained unchanged. A large proportion (87.4 %) of the patients had psychiatric disease. They also had larger burns and higher mortality than accidental burns. Unexpectedly, logistic regression analysis that controlled for age, total percent total body surface area (TBSA) burn, sex, and inhalation injury revealed that those patients with self-inflicted burns had 72 % lower odds of dying than the general population. In conclusion, there has been no improvement in the incidence of self-inflicted burns. They result in very severe injuries, but when age, burn size, gender, and inhalation injury are controlled for, they have at least as good a chance for survival as the general burn population.

Surviving Sepsis After Burn Campaign.

INTRODUCTION: The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes. METHODS: The International Society for Burn Injuries (ISBI) reached out to regional or national burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific "patient/population, intervention, comparison and outcome" (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC participants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create "statements" based on the literature. The "summary statements" were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or "no consensus" was reported. RESULTS: The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as "static" comments but should rather be used as guidelines for future testing of the best treatments for sepsis in burn patients. They should be updated on a regular basis. CONCLUSION: Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients.

Age-dependent and tissue-specific structural changes in the C57BL/6J mouse genome.

We tested the hypothesis that structural changes in the genome parallel age- and organ-specific phenotypes in conjunction with the differential transposition activities of retroelements. The genomes of the liver from C57BL/6J mice were larger than other organs, coinciding with an increase in genomic copies of certain retroelements. In addition, there were differential increments in the genome size of the liver with increasing age, which peaked at 5 weeks. The findings that the genome structure of an individual is variable depending on age and organ type in association with the transposition of retroelements may have broad implications in understanding biologic phenomena.

BACTERIAL PATHOGEN-ASSOCIATED MOLECULAR PATTERNS UPREGULATE HUMAN GLUCOCORTICOID RECEPTOR EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS.

ABSTRACT: It is well known that bacterial components (pathogen-associated molecular patterns [PAMPs]) induce a proinflammatory response through pattern recognition receptor signaling. What is not known, however, is how the inflammatory response is downregulated. We hypothesize that bacterial products initiate compensatory anti-inflammatory responses by inducing expression of the human glucocorticoid receptor (hGR). Peripheral blood mononuclear cells (PBMCs) were isolated from leukocytes concentrated from single human donors (Leukopaks). PBMCs were treated with a gram-negative bacterial component, LPS, or gram-positive bacterial components, lipoteichoic acid (LTA) or peptidoglycan (PGN), for 1, 3, or 13 h. Protein expression of hGR was evaluated by Western blot analysis. RNA was extracted from similarly treated cells for reverse transcription-polymerase chain reaction analysis of hGR and cytokine expression. At 13 h after LPS treatment, there was an increase in the reference hGR protein (hGRα) expressed within some but not all PBMCs isolated from Leukopaks. There was also a dose-dependent increase in hGRα expression with increasing concentrations of PGN (10 and 50 µg/mL). LTA, however, did not affect hGRα expression. PGN also increased the mRNA expression of an hGR splice variant, hGR-B(54). The mRNA expression changes for the inflammatory cytokines were Leukopak specific. We found that cell wall components of both gram-positive and gram-negative bacteria can increase the expression of hGRα. Although these PAMPs augment the inflammatory response, it seems that there is a simultaneous upregulation of hGRα expression. Because binding of cortisol to hGRα typically induces anti-inflammatory proteins, the same PAMPs that induce an inflammatory response seem to also initiate a negative feedback system by inducing hGRα expression in PBMCs.

Cerebellum-specific and age-dependent expression of an endogenous retrovirus with intact coding potential.

BACKGROUND: Endogenous retroviruses (ERVs), including murine leukemia virus (MuLV) type-ERVs (MuLV-ERVs), are presumed to occupy ~10% of the mouse genome. In this study, following the identification of a full-length MuLV-ERV by in silico survey of the C57BL/6J mouse genome, its distribution in different mouse strains and expression characteristics were investigated. RESULTS: Application of a set of ERV mining protocols identified a MuLV-ERV locus with full coding potential on chromosome 8 (named ERVmch8). It appears that ERVmch8 shares the same genomic locus with a replication-incompetent MuLV-ERV, called Emv2; however, it was not confirmed due to a lack of relevant annotation and Emv2 sequence information. The ERVmch8 sequence was more prevalent in laboratory strains compared to wild-derived strains. Among 16 different tissues of ~12 week-old female C57BL/6J mice, brain homogenate was the only tissue with evident expression of ERVmch8. Further ERVmch8 expression analysis in six different brain compartments and four peripheral neuronal tissues of C57BL/6J mice revealed no significant expression except for the cerebellum in which the ERVmch8 locus' low methylation status was unique compared to the other brain compartments. The ERVmch8 locus was found to be surrounded by genes associated with neuronal development and/or inflammation. Interestingly, cerebellum-specific ERVmch8 expression was age-dependent with almost no expression at 2 weeks and a plateau at 6 weeks. CONCLUSIONS: The ecotropic ERVmch8 locus on the C57BL/6J mouse genome was relatively undermethylated in the cerebellum, and its expression was cerebellum-specific and age-dependent.