Daithi S. Heffernan

Treatment of Complicated Skin and Soft Tissue Infections

BACKGROUND Skin and soft tissue infections (SSTIs) may produce substantial morbidity and mortality rates, particularly those classified as complicated or necrotizing. OBJECTIVE To weigh the strength of recommendations using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology and to provide evidence-based recommendations for diagnosis and management for SSTIs. DATA SOURCES Computerized identification of published research and review of relevant articles. STUDY SELECTION All published reports on the management of complicated and necrotizing SSTIs were evaluated by an expert panel of members of the Surgical Infection Society according to published guidelines for evidence-based medicine. The quality of the evidence was judged by the GRADE methodology and criteria. Practice surveys, pharmacokinetic studies, and reviews or duplicative publications presenting primary data already considered were excluded from analysis. DATA EXTRACTION Information on demographics, study dates, microbiology findings, antibiotic type, surgical interventions, infection-related outcomes, and the methodologic quality of the studies was extracted. Results were submitted to the Therapeutic Agents Committee of the Surgical Infection Society for review prior to creation of the final consensus document. DATA SYNTHESIS Current surgical and antibiotic management of complicated SSTIs is based on a small number of studies that often have insufficient power to draw well-supported conclusions, with the exception of antimicrobial therapy for non-necrotizing soft tissue infections, for which ample data are available.

Sympathetic hyperactivity after traumatic brain injury and the role of beta-blocker therapy.

Head injury remains the leading cause of death among trauma patients and accounts for one-third of all trauma mortalities.1,2 Of these, 75% will die within the first 3 days. In patients who survive beyond this period, however, the underlying causes of death are the result of non-neurologic organ dys

High Levels of Endogenous Estrogens are Associated With Death in the Critically Injured Adult

BACKGROUND Sex hormones exhibit predictable changes in their physiologic patterns during critical illness. Endogenous estrogens are elevated in both genders as a result of the peripheral conversion of androgens to estrogens by the aromatase enzyme. Elevated endogenous estrogens have been associated with death in medical and mixed surgical intensive care unit (ICU) patients. Our objective was to determine the relationship between endogenous estrogens and outcomes in critically injured patients. METHODS A prospective cohort of injured patients remaining in the ICU for at least 48 hours at two trauma centers was enrolled. Sex hormones (estradiol, progesterone, testosterone, prolactin, and dehydroepiandrosterone-sulfate) were assayed and mortality was assessed. A logistic regression model was used to determine the association between estradiol and death. The area under the receiver operating characteristic (AUROC) curve was used to estimate the accuracy of estradiol in predicting death. RESULTS Nine hundred ninety-one patients were enrolled with a 13.4% mortality rate. Despite no detectable difference in mortality among genders, estradiol was significantly elevated in nonsurvivors (16 pg/mL vs. 35 pg/mL, p < 0.001). Estradiol was a marker for injury severity with the most severely injured patients exhibiting the highest levels. The ability of estradiol to predict death (AUROC = 0.65) was comparable with Trauma and Injury Severity Score (AUROC = 0.65) and superior to Injury Severity Score (AUROC = 0.54) in this cohort. CONCLUSIONS Serum estradiol is a marker of injury severity and a predictor of death in the critically injured patient, regardless of gender. Whether or not estradiol plays a causal role in outcomes is unclear, but estrogen modulation represents a potential therapy for improving outcomes in critically ill trauma patients.

B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients

IntroductionSepsis is a deadly inflammatory condition that often leads to an immune suppressed state; however, the events leading to this state remain poorly understood. B and T lymphocyte attenuator (BTLA) is an immune-regulatory receptor shown to effectively inhibit CD4+ T-cell function. Therefore, our objectives were to determine: 1) if lymphocyte BTLA expression was altered in critically ill patients and experimentally induced septic mice, 2) whether augmented CD4+ T-cell BTLA expression was associated with poor septic patient outcomes, and 3) if BTLA expression affected the CD4+ T-cell apoptotic cell loss observed in the lymphoid organs of septic mice.MethodsChanges in CD4+ lymphocyte BTLA expression were compared with morbid event development in critically ill ICU patients (11 septic and 28 systemic inflammatory response syndrome subjects). Wild type and BTLA gene deficient mice were utilized to evaluate the expression and role of BTLA in septic lymphocyte apoptotic cell loss.ResultsThe observed septic ICU patients had a significantly higher percentage of peripheral blood BTLA+ CD4+ lymphocytes compared with critically ill non-septic individuals. Moreover, the non-septic patients with CD4+ T-cells that were greater than 80% BTLA+ were more susceptible to developing nosocomial infections. Additionally, in general, critically ill patients with CD4+ T-cells that were greater than 80% BTLA+ had longer hospital stays. Comparatively, circulating CD4+ T-cell and B-cell BTLA expression increased in septic mice, which associated with the increased septic loss of these cells. Finally, the loss of these cells and cellular apoptosis induction in primary and secondary lymphoid organs were reversed in BTLA deficient mice.ConclusionsAn increased BTLA+ CD4+ lymphocyte frequency in the observed critically ill non-septic patients was associated with a subsequent infection; therefore, BTLA may act as a biomarker to help determine nosocomial infection development. Additionally, BTLA expression contributed to primary and secondary lymphoid organ apoptotic cell loss in experimentally septic mice; thus, BTLA-induced apoptotic lymphocyte loss may be a mechanism for increased nosocomial infection risk in critically ill patients. This study had a relatively small human subject cohort; therefore, we feel these findings warrant future studies evaluating the use of BTLA as a critically ill patient nosocomial infection biomarker.

Gender and acute respiratory distress syndrome in critically injured adults: a prospective study.

BACKGROUND The acute respiratory distress syndrome (ARDS) is a proinflammatory condition that often complicates trauma and critical illness. Animal studies have shown that both gender and sex hormones play an important role in inflammatory regulation. Human data are scant regarding the role of gender and sex hormones in developing ARDS. Our objective was to describe gender and hormonal differences in patients who develop ARDS in a large cohort of critically injured adults. METHODS A prospective cohort study of adult trauma patients requiring intensive care unit admission for at least 48 hours was performed. Demographic and clinical data were collected prospectively, and sex hormones were assayed at study entry (48 hours). The primary outcome was the development of ARDS. Multivariate logistic regression was used to determine the adjusted odds of death associated with differences in gender. RESULTS Six hundred forty-eight patients met entry criteria, and 180 patients developed ARDS (31%). Women were more likely to develop ARDS (35% vs. 25%, p=0.02). This association remained after adjusting for age, mechanism of injury, injury severity, and blood product transfusion (odds ratio, 1.6; 95% confidence interval: 1.1-2.4; p=0.02). Of patients with ARDS, there was no difference in mortality related to gender (22% mortality in women with ARDS vs. 20% in men; p=not significant). A proinflammatory sex hormone profile (low testosterone and high estradiol) was associated with ARDS in both men and women. CONCLUSION Women are more likely than men to develop ARDS after critical injury. Despite the increased incidence in ARDS, the mortality in patients with ARDS does not differ according to gender. The inflammatory properties of sex hormones may contribute to ARDS, but they do not fully explain observed gender differences.

Programmed death 1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient.

ABSTRACT Programmed death 1 (PD-1) is an inhibitor protein receptor for the immune system and has been shown to be upregulated in animal models of critical illness as well as after trauma and in burn victims in humans. It is believed that PD-1 may play a role in the immune dysfunction seen in surgical critical illness. However, although prior studies have associated changes in PD-1 expression with altered immune cell function, it is not known if a correlation with clinical status exists. We therefore aimed to describe a potential role for PD-1 in the immune dysfunction seen in critically ill trauma and surgical patients. This is an observational cohort study. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on critically ill and injured trauma and surgical intensive care unit patients from a tertiary care/level I trauma center. Blood was drawn within 24 h of establishment of diagnosis and admission to the intensive care unit to measure circulating cytokine levels, as well as PD-1 expression on circulating cells. Main outcome measures included PD-1 expression on leukocytes and the relationship to physiological dysfunction (APACHE II) as well as the correlation of PD-1 expression and interleukin 10 levels among patients with severe physiological dysfunction. Samples were collected from 90 critically ill surgical patients. Among patients with severe physiological dysfunction (APACHE II >20), there were increased numbers of granulocytes (median, 144 vs. 90 cells/&mgr;L; P = 0.037) and monocytes (median, 12 vs. 6 cells/&mgr;L; P = 0.022) with PD-1 expression. In addition, among patients with an APACHE II score of greater than 20, there was a larger percentage of CD3+ cells (44% vs. 29%; P = 0.015) expressing PD-1. When only patients with an APACHE II score greater than 20 were assessed, PD-1 expression on monocytes correlated positively with interleukin levels in the serum (r = 0.525, P = 0.05). Variability in the expression of PD-1 on leukocytes in critical surgical illness correlates with physiological dysfunction and suggests that PD-1 may be a valuable tool in the assessment of immune dysfunction following trauma or severe surgical insult.

Mechanisms of indirect acute lung injury: a novel role for the coinhibitory receptor, programmed death-1.

Objective:To determine the contribution of programmed death receptor (PD)-1 in the morbidity and mortality associated with the development of indirect-acute lung injury. Background:The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, we have recently shown that the murine cell surface coinhibitory receptor, PD-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level. Methods:PD-1 -/- mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 hours after with cecal ligation and puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand—PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality. Results:PD-1 -/- mice showed improved survival compared to wild type controls. In the mouse lung, CD4+, CD11c+, and Gr-1+ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, although the rise in bronchial alveolar lavage fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 -/- and wild type animals subjected to indirect acute lung injury, the PD-1 -/- animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-&agr; levels, MPO activity, and Caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells. Conclusions:PD-1 expression contributes to mortality after the induction of indirect-acute lung injury and this seems to be associated with modifications in the cellular and cytokine profiles in the lung.

Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice.

Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. Although Ang-1/Tie2 has been shown to promote vessel integrity, stimulating downstream prosurvival/antiinflammatory signaling, Ang-2, released from activated ECs, is reported to promote vessel destabilization. This mechanism of regulation, together with recent clinical findings that plasma Ang-2 levels are significantly elevated in patients who develop acute respiratory distress syndrome, has focused our investigation on the contribution of Ang-2 to the development of iALI. A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to EC Ang-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-α. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils.

A case of appendiceal diverticulitis, and a review of the literature

Appendiceal diverticulitis is a rare presentation, often presenting outside of the classical age grouping for appendicitis. We describe a case of appendiceal diverticulitis and issue a cautionary note in the management of patients with atypical features of right lower quadrant pain. In light of its clinical course the finding of a non-inflamed appendiceal diverticulum should prompt one to consider incidental appendicectomy. We also review the literature on appendiceal diverticulitis.

Local tissue expression of the cell death ligand, fas ligand, plays a central role in the development of extrapulmonary acute lung injury.

Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. To examine this, we used a model of indirect ALI in mice (dual insult of hemorrhagic shock followed 24 h later by cecal ligation and puncture, in which animals received FasL small interfering RNA (siRNA) intratracheally (local silencing) or intravenously (systemic/distal delivery) after hemorrhage. After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.