Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia.

AIM: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. METHODS: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale. RESULTS/CONCLUSION: EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p < 0.001).

Japanese Leigh syndrome case treated with EPI-743.

BACKGROUND: Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of clinical trials for mitochondrial diseases are accumulating. CASE: At 5months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I. RESULTS: At 8months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5years old. Although brain atrophy has progressed, she has still respiratory free time. CONCLUSION: Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4years. There is a possibility that EPI-743 is modifying the natural course of the syndrome.

Propranolol Dosing Practices in Adult Burn Patients: Implications for Safety and Efficacy.

Studies in children with burn injuries have demonstrated that propranolol improves metabolism and reduces muscle protein wasting. However, safety and efficacy in adults are less well established than in children. The purpose of this study was to determine safety of propranolol use in adult patients with burn injuries. Medical records were reviewed for burn-injured adults receiving propranolol. Patients between 18 and 65 years old and with ≥20% TBSA burn were included. Fifty-four patients met the criteria with mean age of 37 years and mean burn size of 38% TBSA. Propranolol dosages ranged from 0.1 to 3.8 mg/kg/day, with an average maximum dosage of 0.61 mg/kg/day. Mean heart rate decreased by 25% during 4 weeks. Seventy-two percent of patients experienced at least one episode of hypotension and 15% experienced bradycardia. Propranolol doses were most frequently held for low blood pressure; 32% of patients had at least one dose held for hypotension. This retrospective analysis suggests that modest dosing of propranolol results in frequent episodes of hypotension or bradycardia. Our data suggest that adults do not tolerate the higher doses reported in a pediatric population. Despite potential beneficial anti-catabolic effects of propranolol, burn care providers must recognize potential iatrogenic hemodynamic effects of this intervention. Our data support the need for prospective multicenter studies to delineate the safety and efficacy of propranolol in adult burn-injured patients.

Morbidity and survival probability in burn patients in modern burn care.

OBJECTIVE: Characterizing burn sizes that are associated with an increased risk of mortality and morbidity is critical because it would allow identifying patients who might derive the greatest benefit from individualized, experimental, or innovative therapies. Although scores have been established to predict mortality, few data addressing other outcomes exist. The objective of this study was to determine burn sizes that are associated with increased mortality and morbidity after burn. DESIGN AND PATIENTS: Burn patients were prospectively enrolled as part of the multicenter prospective cohort study, Inflammation and the Host Response to Injury Glue Grant, with the following inclusion criteria: 0-99 years old, admission within 96 hours after injury, and more than 20% total body surface area burns requiring at least one surgical intervention. SETTING: Six major burn centers in North America. MEASUREMENTS AND MAIN RESULTS: Burn size cutoff values were determined for mortality, burn wound infection (at least two infections), sepsis (as defined by American Burn Association sepsis criteria), pneumonia, acute respiratory distress syndrome, and multiple organ failure (Denver 2 score>3) for both children (<16 yr) and adults (16-65 yr). Five hundred seventy-three patients were enrolled, of which 226 patients were children. Twenty-three patients were older than 65 years and were excluded from the cutoff analysis. In children, the cutoff burn size for mortality, sepsis, infection, and multiple organ failure was approximately 60% total body surface area burned. In adults, the cutoff for these outcomes was lower, at approximately 40% total body surface area burned. CONCLUSIONS: In the modern burn care setting, adults with over 40% total body surface area burned and children with over 60% total body surface area burned are at high risk for morbidity and mortality, even in highly specialized centers.

An expanded delivery model for outpatient burn rehabilitation.

Despite the numerous multidisciplinary services burn centers provide, a number of challenges to obtaining optimal outcomes exist. The goal of this study was to overcome the barriers to effective burn rehabilitation by utilizing an expanded care coordinator (ECC) to supplement the existing outpatient services. In this between-group, single-blind, randomized, controlled trial, the control group (n = 41) received standard outpatient care and the experimental group (n = 40) received additional services provided by the ECC, including telephone calls at set intervals (24 hours postdischarge, 2, 4, 8, 12 weeks postdischarge and 5, 7, 9 months postdischarge). The ECC was trained in motivational interviewing, crisis intervention, and solution-focused counseling. He assisted patients before and after each clinic visit, coordinated outpatient services in their geographic area (physical and occupational therapy, counseling, primary care provider referrals, etc.), and helped develop problem-solving approaches to accomplish individualized goals. Outcome measures included patient identified goals utilizing the goal attainment scale, the urn-specific health scale-brief, the Short Form 12, a patient satisfaction survey, and a return to work survey. The average subject age was 43 years (SD = 16.9) with a mean TBSA of 19% (SD = 18.8). The average length of hospitalization was 36 days (SD = 42.9). The patient and injury characteristics were similar between the study groups. For the experimental group, 33% completed seven calls, with 23% completing all the eight calls. All were assessed using general linear models and were adjusted for sex, age, length of hospitalization, urban vs rural area of residence, %TBSA burn, and ethnicity. There was no difference between the control and experimental groups for any of the outcome measures at either 6 or 12 months postburn. No differences in outcomes between the groups were found. All participants appreciated the individualized goal setting process that was used as an outcome measure and this may have accounted for the similar outcomes in both the groups. (The measure may have been more of an intervention, thus contributing to the strength of the control group.) Although most patients with burn injuries may not need an intervention that is this intensive, a subset of patients at higher risk or with more severe injuries may benefit from more intensive and personalized services. Future research should examine the benefits of individual goal setting processes for all the patients and also attempt to identify those patients most at risk for poorer outcomes and therefore, likely to benefit of more intensive personalized services.

Benchmarking outcomes in the critically injured burn patient.

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers. BACKGROUND: Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries. METHODS: We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care. RESULTS: Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant. CONCLUSIONS: This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Terahertz spectroscopy for the assessment of burn injuries in vivo.

A diagnosis criterion is proposed for noninvasive grading of burn injuries using terahertz radiation. Experimental results are presented from in vivo terahertz time-domain spectroscopy of second- and third-degree wounds, which are obtained in a 72-hour animal study. During this period, the change in the spectroscopic response of the burned tissue is studied. It is shown that terahertz waves are sensitive not only to the postburn formation of interstitial edema, but also to the density of skin structures derived from image processing analysis of histological sections. Based on these preliminary results, it is suggested that the combination of these two effects, as probed by terahertz spectroscopy of the tissue, may ultimately be used to differentiate partial-thickness burns that will naturally heal from those that will require surgical intervention.

Mild obesity is protective after severe burn injury.

OBJECTIVE: To assess the impact of obesity on morbidity and mortality in severely burned patients. BACKGROUND: Despite the increasing number of people with obesity, little is known about the impact of obesity on postburn outcomes. METHODS: A total of 405 patients were prospectively enrolled as part of the multicenter trial Inflammation and the Host Response to Injury Glue Grant with the following inclusion criteria: 0 to 89 years of age, admitted within 96 hours after injury, and more than 20% total body surface area burn requiring at least 1 surgical intervention. Body mass index was used in adult patients to stratify according to World Health Organization definitions: less than 18.5 (underweight), 18.5 to 29.9 (normal weight), 30 to 34.9 (obese I), 35 to 39.9 (obese II), and body mass index more than 40 (obese III). Pediatric patients (2 to ≤18 years of age) were stratified by using the Centers for Disease Control and Prevention and World Health Organization body mass index-for-age growth charts to obtain a percentile ranking and then grouped as underweight (<5th percentile), normal weight (5th percentile to <95th percentile), and obese (≥95th percentile). The primary outcome was mortality and secondary outcomes were clinical markers of patient recovery, for example, multiorgan function, infections, sepsis, and length of stay. RESULTS: A total of 273 patients had normal weight, 116 were obese, and 16 were underweight; underweight patients were excluded from the analyses because of insufficient patient numbers. There were no differences in primary and secondary outcomes when normal weight patients were compared with obese patients. Further stratification in pediatric and adult patients showed similar results. However, when adult patients were stratified in obesity categories, log-rank analysis showed improved survival in the obese I group and higher mortality in the obese III group compared with obese I group (P < 0.05). CONCLUSIONS: Overall, obesity was not associated with increased morbidity and mortality. Subgroup analysis revealed that patients with mild obesity have the best survival, whereas morbidly obese patients have the highest mortality. (NCT00257244).

Glutathione: a redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies.

BACKGROUND: Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6 months of treatment with EPI-743, a novel redox therapeutic. METHODS: Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays. RESULTS: A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG+GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio. CONCLUSIONS: The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.

Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Repeat hospitalization and mortality in older adult burn patients.

The aim of this study was to examine 2-year postdischarge outcomes-including hospital readmissions, complications, and mortality-for a cohort of older adults with burn injury. In a statewide hospital discharge database, we identified all patients ≥ 45 years of age admitted for acute burn injury from 1996 to 2005 and followed each patient for any hospital admissions 2 years following discharge. We then linked the state database to the National Death Index to identify patients who died within the 2-year period. Kaplan-Meier survival functions estimated proportion of patients who died or were readmitted. Logistic regression was used to estimate mortality risk at 2 years for each age group. A total of 2573 patients were admitted with burn injuries, and 2388 (93%) survived to discharge. Of all index patients, 1077 (45%) had at least one rehospitalization, with those in the older age groups having more rehospitalizations. Of patients rehospitalized within 30 days, 25% were admitted for wound coverage or burn infection, 14% for rehabilitation, 10% for sepsis, and 9% for psychiatric reasons. Compared to those discharged home, more patients discharged to nursing facilities had ≥ 1 rehospitalization (71.5 vs 31.5%, P < .001). Survival progressively decreased by age category throughout the follow-up period. Compared with patients aged 45 to 54 years, the older age groups had increased mortality risk at 2 years: odds ratio (OR) 1.53 (95% confidence interval, 1.22-1.88) for the 55 to 64 years group, OR 2.51 (95% confidence interval, 2.03-3.09) for the 65 to 74 years group, and OR 2.90 (95% confidence interval, 2.36-3.55) for the ≥ 75 years group. This population-based study indicates that older patients have a high likelihood of rehospitalization and increased long-term mortality.

Trajectories to death in patients with burn injury.

BACKGROUND: With unprecedented survival rates in modern burn care, there is increasing focus on optimizing long-term functional outcomes. However, 3% to 8% of patients admitted to burn centers still die of injury. Patterns in which these patients progress to death remain poorly characterized. We hypothesized that burn nonsurvivors will follow distinct temporal distributions and patterns of decline, parallel to the trimodality of deaths previously described for trauma. METHODS: We retrospectively identified all adult deaths from 1995 to 2007 in the National Burn Repository database (n = 5,975) and at our regional burn center (n = 237). We stratified patients by age and analyzed injury and death characteristics. We used objective criteria to allocate nonsurvivors to one of four trajectories: early rapid decline, early organ failure, late sudden death, or late-onset decline. RESULTS: The greatest concentration of deaths in both samples and age groups occurred within 72 hours of injury and decreased subsequently with no later mortality peak. Death was most often caused by burn shock within the first week of injury, cardiogenic shock or lung injury in Weeks 1 to 2, and sepsis/multiorgan failure after Week 2. In decreasing frequency, trajectories to death fit the pattern of early rapid decline (58%), early organ failure (20%), late-onset decline (16%), and late sudden death (6%). CONCLUSION: Most burn deaths follow a pattern of early rapid decline or early organ failure manifested by death or critical illness within several days of the burn. These findings indicate that more than three quarters of burn deaths are attributable to failure or significant decompensation beginning in the resuscitation phase. Sporadic deaths later in hospitalization are uncommon. Despite significant advances in burn resuscitation, our data indicate that ongoing efforts to mitigate deaths in modern burn care should still focus on care improvements in the resuscitation phase. LEVEL OF EVIDENCE: Epidemiologic study, level III.

EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome.

BACKGROUND: Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases. In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. To confirm these initial findings, a phase 2A open label trial of EPI-743 for children with genetically-confirmed Leigh syndrome was conducted and herein we report the results. METHODS: A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6 months with EPI-743 three times daily and all were eligible for a treatment extension phase. The primary objective of the trial was to arrest disease progression as assessed by neuromuscular and quality of life metrics. Results were compared to the reported natural history of the disease. RESULTS: Ten consecutive children, ages 1-13 years, were enrolled; they possessed seven different genetic defects. All children exhibited reversal of disease progression regardless of genetic determinant or disease severity. The primary endpoints--Newcastle Pediatric Mitochondrial Disease Scale, the Gross Motor Function Measure, and PedsQL Neuromuscular Module--demonstrated statistically significant improvement (p<0.05). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale. No significant drug-related adverse events were recorded. CONCLUSIONS: In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome.

Pressure ulcers and risk assessment in severe burns.

Risk and incidence of pressure ulcers (PUs) in the burn population remain poorly understood. The purpose of this study was to determine the timing and incidence of PUs at our regional burn center and to identify early risk factors for PU development in burn patients. A retrospective review of 40 charts was performed from among the 1489 patients admitted to our regional burn center between January 2008 and December 2009. Twenty patients acquired PUs during their admission and were identified on the basis of International Classification of Diseases, ninth revision, designation, hospital stay >7 days, and thermal injury (excluding toxic epidermal necrolysis and purpura fulminans). The remaining 20 patients were matched controls based on ±5 years in age and ±8% TBSA. Patient, injury, and outcome characteristics were compared among patient groups using χ for categorical variables and Mann-Whitney for continuous variables. The incidence of PU was 1.3% of all admissions. PU most commonly occurred at the sacrum/coccyx (eight), lower extremity (seven), and occiput (six). A majority of PU presented at stage 2 (33%), stage 3 (26%), and unstageable (30%). Thirteen were splint or device related and reportable. Ninety percent of patients with PUs presented with a Braden score of 16 or less (P = .03), although 60% of controls also had admission Braden scores less than 16. On an average, PUs were acquired within 17 days of admission. Data suggest burn patients are particularly at risk of developing PU based on admission Braden scores. However, low Braden scores do not necessarily correlate with eventual development of PU. Therefore, early and aggressive PU prevention and risk assessment tools must be used to diagnose PUs at an early and reversible stage.

Characteristics, therapies, and outcome of children with necrotizing soft tissue infections.

OBJECTIVES: Necrotizing soft tissue infections (NSTIs) are uncommon but potentially lethal infections that are well described in adults. Little is known about pediatric patients with NSTI. We sought to examine patients' characteristics, infection characteristics, treatment patterns, and outcomes of children with NSTIs using a large multicenter pediatric database. STUDY DESIGN: The Pediatric Health Information System database was used to examine demographics, diagnoses, procedures, medications, hospital charges, and outcomes of pediatric patients with NSTI during a 5-year period. RESULTS: A total of 334 patients with NSTI were identified. Times from admission to initial amputations and reconstructive surgeries were similar between the 2 groups, but nonsurvivors had a longer time from admission to their first debridement (median, 2 vs. 1 day, P = 0.03). On multivariate analysis, no other significant risk factors for increased mortality were identified, although increased age (P = 0.10), noncommercial insurance (P = 0.12), and use of corticosteroid therapy (P = 0.06) showed trends toward increased mortality. Diagnoses of streptococcal (P = 0.03) or staphylococcal infection (P = 0.03) were associated with a lower mortality on multivariate analysis. CONCLUSIONS: NSTIs are a rare but significant diseases in children. It seems that, as in the adult population, prompt surgical debridement is the most important intervention. Corticosteroid therapy may be associated with a worse prognosis.

Early withdrawal of life support in severe burn injury.

Despite many advances in modern burn care, deaths still occur in the burn intensive care unit. For patients with severe burns, providers may advocate to withdraw life support early during hospitalization when the extent of injury makes survival highly unlikely or when the patient's condition deteriorates during resuscitation. Our regional burn center has implemented a stepwise withdrawal protocol since 2001 in an effort to standardize symptoms palliation at the end of life. In this study, the authors evaluated the frequency of early withdrawal and the protocol impact on end-of-life processes of care in burn patients who died within 72 hours of hospitalization. A 13-year review of all burn patients aged ≥18 years admitted to our burn center to identify all patients who died within 72 hours of hospitalization was performed. Patients were dichotomized to the periods before (1995 to mid-2001) and after implementation of standardized withdrawal protocol (mid-2001 to 2007). Descriptive analyses were performed to compare end-of-life care processes between the two periods. A total of 4374 adult patients with acute burns were admitted during the 13-year study period, of which 252 (6%) died during hospitalization. Of the patients who died within 72 hours, 106 (84%) had withdrawal of life support compared with 20 (16%) who died with ongoing life support. Higher mean TBSA distinguished patients who died by withdrawal (61 vs 48%, P = .06). Since mid-2001, all 61 patients who had life support withdrawn were by protocol. Implementation of the protocol has led to more frequent use of opioid infusion (98 vs 87%, P = .07) and benzodiazepine infusion (95 vs 49%, P < .01), without hastening time to death (median 5.0 vs 5.5 hours, P = .70). The large majority of early burn deaths at our regional center occur via withdrawal of life support. Implementation of a protocolized withdrawal has resulted in more consistent provision of analgesia and sedation without hastening death. Burn centers should consider using a protocol for withdrawal of life support to improve consistency in end-of-life symptoms palliation.

Predictive value of bronchoscopy in assessing the severity of inhalation injury.

Inhalation injury is associated with severe pulmonary complications as inhaled products of combustion cause lung inflammation and loss of natural defenses. A bronchoscopic grading for inhalation injury has been proposed but has not yet been validated in burn patients. In this study, the authors evaluated whether bronchoscopic grading of injury clinically correlated with indices of gas exchange over the first 72 hours or predicted differences in hospitalization outcomes. They conducted a single-center retrospective review of all mechanically ventilated adults with suspected inhalation injury and thermal injury over an 18-month period. All recorded bronchoscopy examinations were reviewed and categorized injury according to the published abbreviated injury score (AIS 0: no injury, 1: mild, 2: moderate, 3: severe, and 4: massive injury). They also compared changes in oxygenation, airway pressures, chest radiograph findings, fluid administration, and early development of pneumonia and organ failure, by severity of inhalation injury according to the AIS. Thirty-two adult patients met inclusion criteria over the study period. This cohort was 69% male with a mean age of 44.5 ± 14 years and a mean % TBSA burn of 33.9 ± 17%. Of these 32 patients, 11 patients (34%) were classified as grade 0, 9 patients (28%) were classified as grade 1, 7 patients (22%) were classified as grade 2, and 5 patients (16%) were classified as grade 3. Measured carboxyhemoglobin levels increased significantly with higher AIS grade. Oxygenation indices were worse as grade worsened by 24, 48, and 72 hours. The incidence of acute respiratory distress syndrome increased by grade of injury: 0, 22, 57, and 80%, respectively, at 24 hours (P < .01), and remained statistically different at 48 and 72 hours. After adjustment for age, % TBSA burn, and full-thickness component, severe inhalation injury (grades 2 and 3) was associated with an increased risk of acute respiratory distress syndrome at 24 and 72 hours, as well as ventilator days >21 days, and a trend toward multiple organ dysfunction syndrome and mortality. Better understanding of the relationship between inhalation injury and lung physiologic sequelae is a burn research priority. The bronchoscopic grading of inhalation injury moderately correlates with early indices of impaired gas exchange in this cohort and may be a promising tool for staging lower airway injury. Prospective studies should definitively answer whether AIS bronchoscopy staging predicts hospitalization outcomes in inhalation injury.

Epidemiology and impact of scarring after burn injury: a systematic review of the literature.

The purpose of this study was to perform a systematic review of the existing literature on the incidence of hypertrophic scarring and the psychosocial impact of burn scars. In a comprehensive literature review, the authors identified 48 articles published since 1965 and written in English which reported the incidence and risk factors for hypertrophic scarring or assessed outcomes related to scarring. Most studies had important methodological limitations limiting the generalizability of the findings. In particular, the absence of standardized valid measures of scarring and other outcome variables was a major barrier to drawing strong conclusions. Among studies on hypertrophic scarring, the prevalence rate varied between 32 and 72%. Identified risk factors included dark skin, female gender, young age, burn site on neck and upper limb, multiple surgical procedures, meshed skin graph, time to healing, and burn severity. With regard to psychosocial outcomes, two studies compared pediatric burn survivors with a nonburn comparison group on a body image measure; neither study found differences between groups. Across studies, burn severity and location had a modest relationship with psychosocial outcome variables. Psychosocial variables such as social comfort and perceived stigmatization were more highly associated with body image than burn characteristics. To advance our knowledge of the epidemiology of scars and the burden of scars, future studies need to implement more rigorous methodologies. In particular, standardized valid measures of scarring and other outcomes should be developed. This process could be facilitated by an international collaboration among burn centers.