Sepsis remains one of the leading causes of death in burn patients who survive the initial insult of injury. Disruption of the intestinal epithelial barrier has been shown after burn injury; this can ...lead to the translocation of bacteria or their products (e.g., endotoxin) from the intestinal lumen to the circulation, thereby increasing the risk for sepsis in immunocompromised individuals. Since the maintenance of the epithelial barrier is largely dependent on the intestinal microbiota, we examined the diversity of the intestinal microbiome of severely burned patients and a controlled mouse model of burn injury. We show that burn injury induces a dramatic dysbiosis of the intestinal microbiome of both humans and mice and allows for similar overgrowths of Gram-negative aerobic bacteria. Furthermore, we show that the bacteria increasing in abundance have the potential to translocate to extra-intestinal sites. This study provides an insight into how the diversity of the intestinal microbiome changes after burn injury and some of the consequences these gut bacteria can have in the host.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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 criteria0–99 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.
Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current ...definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.
OBJECTIVES:To determine whether the graded severity of smoke inhalation is reflected by the acute pulmonary inflammatory response to injury.
DESIGN:In a prospective observational study, we assessed ...the bronchoalveolar lavage fluid for both leukocyte differential and concentration of 28 cytokines, chemokines, and growth factors. Results were then compared to the graded severity of inhalation injury as determined by Abbreviated Injury Score criteria (0, none; 1, mild; 2, moderate; 3, severe; 4, massive).
SETTING:All patients were enrolled at a single tertiary burn center.
PATIENTS:The bronchoalveolar lavage fluid was obtained from 60 patients within 14 hrs of burn injury who underwent bronchoscopy for suspected smoke inhalation.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Those who presented with worse grades of inhalation injury had higher plasma levels of carboxyhemoglobin and enhanced airway neutrophilia. Patients with the most severe inhalation injuries also had a greater requirement for tracheostomy, longer time on the ventilator, and a prolonged stay in the intensive care unit. Of the 28 inflammatory mediators assessed in the bronchoalveolar lavage fluid, 21 were at their highest in those with the worst inhalation injury scores (grades 3 and 4), the greatest of which was interleukin-8 (92,940 pg/mL, grade 4). When compared in terms of low inhalation injury (grades 1–2) vs. high inhalation injury (grades 3–4), we found significant differences between groups for interleukin-4, interleukin-6, interleukin-9, interleukin-15, interferon-γ, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 (p < .05 for all).
CONCLUSIONS:These data reveal that the degree of inhalation injury has basic and profound effects on burn patient morbidity, evokes complex changes of multiple alveolar inflammatory proteins, and is a determinant of the pulmonary inflammatory response to smoke inhalation. Accordingly, future investigations should consider inhalation injury to be a graded phenomenon. (Crit Care Med 2012; 40:–1121)
Apoptotic injury participates in hepatic fibrosis, but the molecular mechanisms are not well understood. The present study aimed to investigate the role of inducible TIMP1 in the pathogenesis of ...hepatic apoptosis-fibrosis. Apoptosis was induced with GCDC, LPS, and alcohol in precision-cut liver slices or bile duct ligation (BDL) in rats, as reflected by caspase-3 activity, TUNEL assay, and apoptosis-related gene profiles. The hepatic fibrosis was detected with Picrosirius staining, hydroxyproline determination, and expression profiling of fibrosis-related genes. Levels of TIMP1 were upregulated by the hepatic apoptosis, but downregulated by caspase inhibitor. The inducible TIMP1 was apoptosis-dependent. Once TIMP1 was inhibited with treatment of TIMP1-siRNA, the fibrotic response was reduced as demonstrated by hydroxyproline assay. In addition, the expression of fibrosis-related genes aSMA, CTGF, and TGFb2r were down-regulated subsequent to the treatment of TIMP1-siRNA. TIMP1 could mediate the expression of fibrosis-related genes. TIMP1 was transcriptionally regulated by nuclear factor c-Jun as demonstrated by EMSA and ChIP assay. The treatment of c-Jun siRNA could significantly decrease the expression of TIMP1 induced by alcohol, GCDC, or LPS treatment. Hepatic apoptosis induces the expression of TIMP1. Inducible TIMP1 can modulate the expression of fibrosis-related genes in liver. TIMP1 pathway is a potential target for therapeutic intervention of fibrotic liver diseases.
Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for ...alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia.
Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells.
Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages.
The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively.
We hypothesized that the number of rib fractures independently impacted patient pulmonary morbidity and mortality.
The National Trauma Data Bank (NTDB, v. 3.0 American College of Surgeons, Chicago, ...IL) was queried for patients sustaining 1 or more rib fractures. Data abstracted included the number of rib fractures by International Classification of Diseases-9 code, Injury Severity Score, the occurrence of pneumonia, acute respiratory distress syndrome, pulmonary embolus, pneumothorax, aspiration pneumonia, empyema, and associated injuries by abbreviated injury score, the need for mechanical ventilation, number of ventilator days, intensive care unit (ICU) length of stay (LOS), hospital LOS, mortality, and use of epidural analgesia. Statistical analysis was performed using the Student t test and linear regression analysis. Statistical significance was defined as a P value of less than .05.
The NTDB included 731,823 patients. Of these, 64,750 (9%) had a diagnosis of 1 or more fractured ribs. Thirteen percent (n = 8,473) of those with rib fractures developed 13,086 complications, of which 6,292 (48%) were related to a chest-wall injury. Mechanical ventilation was required in 60% of patients for an average of 13 days. Hospital LOS averaged 7 days and ICU LOS averaged 4 days. The overall mortality rate for patients with rib fractures was 10%. The mortality rate increased (
P < .02) for each additional rib fracture. The same pattern was seen for the following morbidities: pneumonia (
P < .01), acute respiratory distress syndrome (
P < .01), pneumothorax (
P < .01), aspiration pneumonia (
P < .01), empyema (
P < .04), ICU LOS (
P < .01), and hospital LOS for up to 7 rib fractures (
P < .01). An association between increasing hospital LOS and number of rib fractures was not shown (
P = .19). Pulmonary embolism also was not related to the number of rib fractures (
P = .06). Epidural analgesia was used in 2.2% (n = 1,295) of patients with rib fractures. A reduction in mortality with epidural analgesia was shown at 2, 4, and 6 through 8 rib fractures. The use of epidural analgesia had no impact on the frequency of pulmonary complications. When stratifying data by Injury Severity Score and the presence or absence of rib fractures the mortality rates were similar.
Increasing the number of rib fractures correlated directly with increasing pulmonary morbidity and mortality. Patients sustaining fractures of 6 or more ribs are at significant risk for death from causes unrelated to the rib fractures. Epidural analgesia was associated with a reduction in mortality for all patients sustaining rib fractures, particularly those with more than 4 fractures, but this modality of treatment appears to be underused.
Severely injured burn patients receive multiple blood transfusions for anemia of critical illness despite the adverse consequences. One limiting factor to consider alternate treatment strategies is ...the lack of a reliable test platform to study molecular mechanisms of impaired erythropoiesis. This study illustrates how conditions resulting in a high catecholamine microenvironment such as burns can instigate myelo-erythroid reprioritization influenced by β-adrenergic stimulation leading to anemia. In a mouse model of scald burn injury, we observed, along with a threefold increase in bone marrow LSK cells (lin
Sca1
cKit
), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). β-Blocker administration (propranolol) for 6 days after burn, not only reduced the number of LSKs and MafB
cells in multipotent progenitors, but also influenced myelo-erythroid bifurcation by increasing the MEPs and reducing the granulocyte monocyte progenitors in the bone marrow of burn mice. Furthermore, similar results were observed in burn patients' peripheral blood mononuclear cell-derived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective β1,2-adrenergic blocker) increases MEPs. Also, MafB
cells that were significantly increased following standard burn care could be mitigated when propranolol was administered to burn patients, establishing the mechanistic regulation of erythroid commitment by myeloid regulatory transcription factor MafB. Overall, results demonstrate that β-adrenergic blockers following burn injury can redirect the hematopoietic commitment toward erythroid lineage by lowering MafB expression in multipotent progenitors and be of potential therapeutic value to increase erythropoietin responsiveness in burn patients.
OBJECTIVE:To determine whether restrictive fluid resuscitation results in increased rates of acute kidney injury (AKI) or infectious complications.
BACKGROUND:Studies demonstrate that patients often ...receive volumes in excess of those predicted by the Parkland equation, with potentially detrimental sequelae. However, the consequences of under-resuscitation are not well-studied.
METHODS:Data were collected from a multicenter prospective cohort study. Adults with greater than 20% total burned surface area injury were divided into 3 groups on the basis of the pattern of resuscitation in the first 24 hoursvolumes less than (restrictive), equal to, or greater than (excessive) standard resuscitation (4 to 6 cc/kg/% total burned surface area). Multivariable regression analysis was employed to determine the effect of fluid group on AKI, burn wound infections (BWIs), and pneumonia.
RESULTS:Among 330 patients, 33% received restrictive volumes, 39% received standard resuscitation volumes, and 28% received excessive volumes. The standard and excessive groups had higher mean baseline APACHE scores (24.2 vs 16, P < 0.05 and 22.3 vs 16, P < 0.05) than the restrictive group, but were similar in other characteristics. After adjustment for confounders, restrictive resuscitation was associated with greater probability of AKI odds ratio (OR) 3.25, 95% confidence interval (95% CI) 1.18–8.94. No difference in the probability of BWI or pneumonia among groups was found (BWIrestrictive vs standard OR 0.74, 95% CI 0.39–1.40, excessive vs standard OR 1.40, 95% CI 0.75–2.60, pneumoniarestrictive vs standard, OR 0.52, 95% CI 0.26–1.05; excessive vs standard, OR 1.12, 95% CI 0.58–2.14).
CONCLUSIONS:Restrictive resuscitation is associated with increased AKI, without changes in infectious complications.
Burn injury augments monocyte commitment and abrogates DC differentiation through increased MCSF‐receptors and decreased GATA‐1 expressions orchestrated by high MafB in hematopoietic ...granulocyte‐monocyte progenitor cells.
We have previously shown that perturbed bone marrow progenitor development promotes hyporesponsive monocytes following experimental burn sepsis. Clinical and experimental sepsis is associated with monocyte deactivation and depletion of mDCs. Decrease in circulating DCs is reported in burn patients who develop sepsis. In our 15% TBSA scald burn model, we demonstrate a significant reduction in the circulating MHC‐II+ population and mDCs (Gr1negCD11b+CD11c+) with a corresponding decrease in bone marrow MHC‐II+ cells and mDCs for up to 14 days following burn. We explored the underlying mechanism(s) that regulate bone marrow development of monocytes and DCs following burn injury. We found a robust bone marrow response with a significant increase in multipotential HSCs (LSK) and bipotential GMPs following burn injury. GMPs from burn mice exhibit a significant reduction in GATA‐1, which is essential for DC development, but express high levels of MafB and M‐CSFRs, both associated with monocyte production. GMPs obtained from burn mice differentiated 1.7 times more into Mφ and 1.6‐fold less into DCs compared with sham. Monocytes and DCs expressed 50% less MHC‐II in burn versus sham. Increased monocyte commitment in burn GMPs was a result of high MafB and M‐CSFR expressions. Transient silencing of MafB (siRNA) in GMP‐derived monocytes from burn mice partially restored DC differentiation deficits and increased GATA‐1 expression. We provide evidence that high MafB following burn plays an inhibitory role in monocyte‐derived DC differentiation by regulating M‐CSFR and GATA‐1 expressions.
PDF
