Shari Honari

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., R2 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.

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

Complex wound management utilizing an artificial dermal matrix.

The benefits of the Integra Dermal Regeneration Template in the management of extensive burn injuries have been well documented. Integra can reduce donor- and graft-site scarring and has been reported to be capable of vascularizing over small areas of exposed bone and tendon. Given these potential advantages, we have used Integra for a variety of other reconstruction applications. We performed a retrospective review of patients with complex wounds treated with Integra at our burn center. Integra was used in the management of a variety of wounds, including necrotizing fasciitis, extremity degloving injury, meningococcemia, Marjolin ulcer, postburn lip reconstruction, and fourth-degree burns with exposed bone or tendon. Engraftment rates of Integra and autograft were 98% ± 4% and 97% ± 4%, respectively. All areas of graft loss healed without need for regrafting. The benefits of Integra in the management of acute burn wounds can be extended to other traumatic and complex wounds.

SCORTEN overestimates mortality in the setting of a standardized treatment protocol

Toxic epidermal necrolysis (TEN) is a rare, severe, exfoliative disorder with a high mortality rate. SCORTEN is a recently developed scoring system that estimates severity and predicts mortality in patients with TEN based on seven independent clinical risk factors recorded within the first 24 hours of admission. An increasing SCORTEN level predicts a higher mortality rate. For more than 20 years, the treatment of TEN at our institution has involved the use of a standardized clinical pathway that includes removal of sloughed epidermis, dermal protection with porcine xenograft, early enteral nutrition, and critical care monitoring. We hypothesize that this standardized clinical approach will result in a lower mortality rate than predicted by SCORTEN. A retrospective review was performed on all patients treated for TEN using the standardized pathway from February 1987 to March 2004. SCORTEN was calculated in each patient. One hundred nine patients were treated for TEN during the study period. Overall observed mortality was 20% compared with a SCORTEN predicted mortality of 30%, resulting in a relative reduction in mortality of 33% (P = .011). In addition, observed probability of death was lower than predicted at all levels, except at SCORTEN score of 6 or greater. In conclusion, TEN remains a life-threatening disease with a high mortality rate. Our standardized treatment protocol results in significantly improved outcomes compared to those predicted by SCORTEN.

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.

Self-reports of anxiety in burn-injured hospitalized adults during routine wound care.

The purpose of this investigation was to examine the amount of anxiety patients believed tolerable and the amount of anxiety experienced during routine burn wound care. Participants included 47 hospitalized adults who provided data for four consecutive assessment periods. Patients (mean TBSA, 16%; range, 2–70%) were primarily Caucasian (87%) and had an average hospital stays of 23 days (range, 11–130). Reports of what level of anxiety they would be able to tolerate and what level of anxiety had been experienced were assessed using 10-point Graphic Rating Scales. The use of anxiolytic was recorded, and patient suggestions for reducing anxiety were obtained. The single most commonly endorsed anxiety treatment goal was 0, although 53% consistently chose a treatment goal other than 0 (range, 1–6). Two repeated-measure analyses of variance indicated that the amount of anxiety patients could tolerate and the amount they reported experiencing did not change over the course of time. Paired t-tests revealed that patients routinely reported more anxiety than they considered tolerable. Analyses of anxiety reports of patients treated with anxiolytics (n = 6) vs patients receiving no anxiolytics (n = 41) revealed inconsistent differences in actual anxiety and treatment goals across time. In general, patient suggestions for lessening anxiety included requests for education, communication, additional medications, and manipulation of the hospital environment. Anxiety for burn-injured, hospitalized adults remains a concern. Our findings are consistent with the literature indicating that adult patients hospitalized for burn wound care report appreciable anxiety, over and above what they consider “tolerable.” Continued research is needed and should include investigations into the relationship between pain and anxiety during routine wound care.

Comparison of pain control medication in three age groups of elderly patients

There are no published reports of burn pain management in the elderly population. To assess the range of requirement and use of opioids among elderly patients with burns of different age categories, a retrospective review of 89 consecutive admissions of patients over 55 years of age (January 1995 through July 1996) was conducted. Complete data were available on 44 patients with a burn mean total body surface area of 17.2%. Patient ages ranged from 55 to 92 years. Individuals were divided into three age categories: Group I (55 to 65) n = 20; Group II (66 to 75) n = 14; and Group III (76 to 92) n = 10. Use of commonly prescribed opioids for procedural pain and breakthrough pain were evaluated. We compared the opioid equivalents of medications prescribed versus the actual amount administered. Paired t tests comparing minimum amount of medication ordered with that given revealed Group I patients received significantly more procedural medication than the minimum prescribed (t = 3.88, p = 0.001), and that Group III patients were given significantly less as needed medication than the minimum prescribed (t = 2.58, p < 0.05).

Genetic risk factors for hypertrophic scar development.

Hypertrophic scars (HTSs) occur in 30 to 72% patients after thermal injury. Risk factors include skin color, female sex, young age, burn site, and burn severity. Recent correlations between genetic variations and clinical conditions suggest that single-nucleotide polymorphisms (SNPs) may be associated with HTS formation. The authors hypothesized that an SNP in the p27kip1 gene (rs36228499) previously associated with decreased restenosis after coronary stenting would be associated with lower Vancouver Scar Scale (VSS) measurements and decreased itching. Patient and injury characteristics were collected from adults with thermal burns. VSS scores were calculated at 4 to 9 months after injury. Genotyping was performed using real-time polymerase chain reaction. Logistic regression was used to determine risk factors for HTS as measured by a VSS score >7. Three hundred subjects had a median age of 39 years (range, 18–91); 69% were male and median burn size was 7% TBSA (range, 0.25–80). Consistent with literature, the p27kip1 variant SNP had an allele frequency of 40%, but was not associated with reduced HTS formation or lower itch scores in any genetic model. HTS formation was associated with American Indian/Alaskan Native race (odds ratio [OR], 12.2; P = .02), facial burns (OR, 9.4; P = .04), and burn size ≥20% TBSA (OR, 1.99; P = .03). Although the p27kip1 SNP may protect against vascular fibroproliferation, the effect cannot be generalized to cutaneous scars. This study suggests that American Indian/Alaskan Native race, facial burns, and higher %TBSA are independent risk factors for HTS. The American Indian/Alaskan Native association suggests that there are potentially yet-to-be-identified genetic variants.

Social support correlates with survival in patients with massive burn injury.

Large burn size, inhalation injury, age, and associated trauma increase the rate of mortality after burns. However, not all patients with large burns and significant risk factors die. In this study, we wanted to determine other presenting factors that might indicate a survival benefit for burn patients with large burns. We reviewed charts of 36 patients with burns > or =60% TBSA that were aggressively resuscitated at the University of Washington Burn Center from 1990 to 2000 to determine whether survivors of large burns exhibit presenting variables that predict survival. Patients who had comfort care measures initiated at admission were excluded from this analysis. Survivors (n = 16) and nonsurvivors (n = 20) had no significant differences in age, total burn size, inhalation injury, or need for escharotomy. Full-thickness burn size was significantly smaller for survivors (58%) than for nonsurvivors (73%; P = .02). Survivors (81%) were more likely than nonsurvivors to have social support (35%; P = .007). A full-thickness burn > or =80 % TBSA was the only variable uniformly associated with mortality, suggesting that patients who survive large burns have a partial-thickness component that heals without surgery. The difference in degree of social support was one unique distinction that may impact patient survival and is worth further investigation.

Harborview Burns – 1974 to 2009

Background Burn demographics, prevention and care have changed considerably since the 1970s. The objectives were to 1) identify new and confirm previously described changes, 2) make comparisons to the American Burn Association National Burn Repository, 3) determine when the administration of fluids in excess of the Baxter formula began and to identify potential causes, and 4) model mortality over time, during a 36-year period (1974–2009) at the Harborview Burn Center in Seattle, WA, USA. Methods and Findings 14,266 consecutive admissions were analyzed in five-year periods and many parameters compared to the National Burn Repository. Fluid resuscitation was compared in five-year periods from 1974 to 2009. Mortality was modeled with the rBaux model. Many changes are highlighted at the end of the manuscript including 1) the large increase in numbers of total and short-stay admissions, 2) the decline in numbers of large burn injuries, 3) that unadjusted case fatality declined to the mid-1980s but has changed little during the past two decades, 4) that race/ethnicity and payer status disparity exists, and 5) that the trajectory to death changed with fewer deaths occurring after seven days post-injury. Administration of fluids in excess of the Baxter formula during resuscitation of uncomplicated injuries was evident at least by the early 1990s and has continued to the present; the cause is likely multifactorial but pre-hospital fluids, prophylactic tracheal intubation and opioids may be involved. Conclusions 1) The dramatic changes include the rise in short-stay admissions; as a result, the model of burn care practiced since the 1970s is still required but is no longer sufficient. 2) Fluid administration in excess of the Baxter formula with uncomplicated injuries began at least two decades ago. 3) Unadjusted case fatality declined to ∼6% in the mid-1980s and changed little since then. The rBaux mortality model is quite accurate.