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Sepsis is a global health challenge marked by limited clinical options and high mortality rates. AMP-activated protein kinase (AMPK) is a cellular energy sensor that mediates multiple crucial metabolic pathways that may be an attractive therapeutic target in sepsis. Pre-clinical experimental studies have demonstrated that pharmacological activation of AMPK can offer multiple potential benefits during sepsis, including anti-inflammatory effects, induction of autophagy, promotion of mitochondrial biogenesis, enhanced phagocytosis, antimicrobial properties, and regulation of tight junction assembly. This review aims to discuss the existing evidence supporting the therapeutic potential of AMPK activation in sepsis management.

IntroductionA hallmark of T cell dysregulation during sepsis is the downregulation of costimulatory molecules. CD28 is one of T cell costimulatory molecules significantly altered on memory T cells during sepsis. We recently showed that treatment with a αCD28 agonist in septic immunologically experienced mice led to improved survival. Therefore, here we aimed to identify the cell subset(s) necessary for the survival benefit observed in the context of CD28 agonism, and to further investigate the mechanism by which CD28 agonism improves sepsis survival in immunologically experienced mice. Methods: Mice received specific pathogen inoculation to generate memory T cell populations similar in frequency to that of adult humans. Once these infections were cleared and the T cell response had transitioned to the memory phase, animals were rendered septic via cecal ligation and puncture in the presence or absence of an agonistic anti-CD28 mAb.ResultsResults demonstrated that CD8+ T cells, and not bulk CD4+ T cells or CD25+ regulatory T cells, were necessary for the survival benefit observed in CD28 agonist-treated septic immunologically experienced mice. Upon examination of these CD8+ T cells, we found that CD28 agonism in septic immunologically experienced mice was associated with an increase in Foxp3+ CD8+ T cells as compared to vehicle-treated controls. When CD8+ T cells were depleted in septic immunologically experienced mice in the setting of CD28 agonism, a significant increase in levels of inflammatory cytokines in the blood was observed.DiscussionTaken together, these results indicate that CD28 agonism in immunologically experienced mice effectively suppresses inflammation via a CD8+-dependent mechanism to decrease mortality during sepsis.

Cell death proteins play a central role in host immune signaling during sepsis. These interconnected mechanisms trigger cell demise via apoptosis, necroptosis, and pyroptosis while also driving inflammatory signaling. Targeting cell death mediators with novel therapies may correct the dysregulated inflammation seen during sepsis and improve outcomes for septic patients.

Abstract The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

IntroductionChronic alcohol use poses significant negative consequences to public health and, among its many biologic effects, is associated with significant T cell dysregulation within the adaptive immune system that has yet to be fully characterized. Novel, automated strategies for high dimensional flow cytometric analysis of the immune system are rapidly improving researchers’ ability to detect and characterize rare cell types.MethodsUsing a murine model of chronic alcohol ingestion in conjunction with viSNE and CITRUS analysis tools, we performed a machine-driven, exploratory analysis comparing rare splenic subpopulations within the conventional CD4+, regulatory CD4+ and CD8+ T cell compartments between alcohol- and water-fed animals.ResultsWhile there were no differences in the absolute numbers of bulk CD3+ T cells, bulk CD4+ T cells, bulk CD8+ T cells, Foxp3- CD4+ conventional T cells (Tconv) or Foxp3+ CD4+ regulatory T cells (Treg), we identified populations of naïve Helios+ CD4+Tconv and naïve CD103+ CD8+ splenic T cells that were decreased in chronically alcohol exposed mice versus water-fed controls. In addition, we identified increased CD69+ Treg and decreased CD103+ effector regulatory T cell (eTreg) subsets in conjunction with increased frequency of a population that may represent a transitional phenotype between central regulatory T cell (cTreg) and eTreg.DiscussionThese data provide further resolution into the character of decreased naïve T cell populations known to be present in alcohol exposed mice, as well as describe alterations in effector regulatory T cell phenotypes associated with the pathogenesis of chronic alcohol-induced immune dysfunction.

OBJECTIVES:. To investigate the relationship between ICU-acquired weakness (ICUAW) signatures and sepsis-related mortality using gene expression from the blood within 24 hours of sepsis onset. DESIGN:. Observational study using differential gene expression analysis. SETTING:. Publicly available gene expression profile GSE54514, single-center medical and surgical ICU. PATIENTS:. Patients with primary bacteremia- and respiratory-triggered sepsis including 8 nonsurvivors and 13 survivors who were 18 years old and older and admitted to ICU. MEASUREMENTS AND MAIN RESULTS:. Among validated 526 ICUAW gene signatures, differential gene expression analysis controlling for age identified 38 significantly expressed genes between nonsurvivors and survivors. Functional enrichment analysis of differentially expressed ICUAW genes identified impaired cadherin binding, sarcomere formation, and energy metabolism among nonsurvivors. CONCLUSIONS:. Our findings demonstrated a biological association between sepsis-related mortality and ICUAW signatures in the early phase of sepsis. Defects in energy metabolism and muscle fiber formation were associated with sepsis-related mortality.

OBJECTIVES:. The optimal staffing model for physicians in the ICU is unknown. Patient-to-intensivist ratios may offer a simple measure of workload and be associated with patient mortality and physician burnout. To evaluate the association of physician workload, as measured by the patient-to-intensivist ratio, with physician burnout and patient mortality. DESIGN:. Cross-sectional observational study. SETTING:. Fourteen academic centers in the United States from August 2020 to July 2021. SUBJECTS:. We enrolled ICU physicians and collected data on adult ICU patients under the physician’s care on the single physician-selected study day for each physician. MEASUREMENTS and MAIN RESULTS:. The primary exposure was workload (self-reported number of patients’ physician was responsible for) modeled as high (>14 patients) and low (≤14 patients). The primary outcome was burnout, measured by the Well-Being Index. The secondary outcome measure was 28-day patient mortality. We calculated odds ratio for burnout and patient outcomes using a multivariable logistic regression model and a binomial mixed effects model, respectively. We enrolled 122 physicians from 62 ICUs. The median patient-to-intensivist ratio was 12 (interquartile range, 10–14), and the overall prevalence of burnout was 26.4% (n = 32). Intensivist workload was not independently associated with burnout (adjusted odds ratio, 0.74; 95% CI, 0.24–2.23). Of 1,322 patients, 679 (52%) were discharged alive from the hospital, 257 (19%) remained hospitalized, and 347 (26%) were deceased by day 28; 28-day outcomes were unknown for 39 of patients (3%). Intensivist workload was not independently associated with 28-day patient mortality (adjusted odds ratio, 1.33; 95% CI, 0.92–1.91). CONCLUSIONS:. In our cohort, approximately one in four physicians experienced burnout on the study day. There was no relationship be- tween workload as measured by patient-to-intensivist ratio and burnout. Factors other than the number of patients may be important drivers of burnout among ICU physicians.

Abstract Objective To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. Design As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis. Methods Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. Results The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? Conclusions There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.

Acute Respiratory Distress Syndrome (ARDS) is a severe lung injury with high mortality, primarily characterized by bilateral pulmonary opacities on chest radiographs and hypoxemia. In this work, we trained a convolutional neural network (CNN) model that can reliably identify bilateral opacities on routine chest X-ray images of critically ill patients. We propose this model as a tool to generate predictive alerts for possible ARDS cases, enabling early diagnosis. Our team created a unique dataset of 7800 single-view chest-X-ray images labeled for the presence of bilateral or unilateral pulmonary opacities, or ‘equivocal’ images, by three blinded clinicians. We used a novel training technique that enables the CNN to explicitly predict the ‘equivocal’ class using an uncertainty-aware label smoothing loss. We achieved an Area under the Receiver Operating Characteristic Curve (AUROC) of 0.82 (95% CI: 0.80, 0.85), a precision of 0.75 (95% CI: 0.73, 0.78), and a sensitivity of 0.76 (95% CI: 0.73, 0.78) on the internal test set while achieving an (AUROC) of 0.84 (95% CI: 0.81, 0.86), a precision of 0.73 (95% CI: 0.63, 0.69), and a sensitivity of 0.73 (95% CI: 0.70, 0.75) on an external validation set. Further, our results show that this approach improves the model calibration and diagnostic odds ratio of the hypothesized alert tool, making it ideal for clinical decision support systems.

Expression of the tight junction–associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A –/– mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1β expression. Survival is improved in JAM-A–/– mice. However, intestine-specific JAM-A–/– deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A–/– mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A–/– mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A–/– × RAG–/– mice have improved survival compared with RAG–/– mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A–/– mice, while septic JAM-A–/– mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A–/– mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.

Abstract Objective To expand upon the priorities of fluid resuscitation and vasopressor therapy research priorities identified by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources Original paper and literature search. Study Selection Several members of the original task force with expertise specific to the area of fluid resuscitation and vasopressor therapy. Data Extraction None. Data Synthesis None. Conclusion In the second of a series of manuscripts subsequent to the original paper, members with expertise in the subjects expound upon the three identified priorities related to fluid resuscitation and vasopressor therapies. This analysis summarizes what is known and what were identified as ongoing and future research.

Abstract Objectives Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data sources Original paper, search of the literature. Study selection This study is selected by several members of the original task force with specific expertise in basic/translational science. Data extraction and data synthesis are not available. Conclusions In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma.

OBJECTIVES:. Patients with infection can develop sepsis, and their mortality can be high. An important aspect in the treatment of sepsis is adequate management of the infection. DATA SOURCES:. Using a modified Delphi approach, the Surviving Sepsis Campaign research committee recently published a series of 26 priorities for sepsis and septic shock. STUDY SELECTION:. Task force members with specific expertise were tasked with generating expanded reviews for all infection questions and a subset of adjunctive therapy questions from the larger list of sepsis priorities. Each question was addressed by one of the six task force members. DATA EXTRACTION:. In-depth reviews were then edited by the group as a whole, with added input from the committee cochairs. DATA SYNTHESIS:. Six questions were addressed: 1) should empiric antibiotic combination therapy be used in sepsis or septic shock? 2) does optimization of antimicrobial pharmacokinetics and pharmacodynamics impact patient outcomes in sepsis? 3) should viral reactivation resulting from sepsis-induced immunosuppression be treated with antiviral therapy in critically ill septic patients? 4) should rapid diagnostic tests be implemented in clinical practice? 5) what is the role of lung-protective ventilation in sepsis patients without acute respiratory distress syndrome? and 6) how do we determine the efficacy of “blood purification” therapies such as endotoxin absorbers, cytokine absorbers, and plasmapheresis. CONCLUSIONS:. The research committee members for the Surviving Sepsis Campaign aimed to explore research questions in order to provide existing evidence and highlight areas of uncertainty and future directions.

IMPORTANCE:. Altered heart rate variability has been associated with autonomic dysfunction in a number of disease profiles, in this work we elucidate differences in the biomarker among patients with all-cause sepsis and coronavirus disease 2019. OBJECTIVES:. To measure heart rate variability metrics in critically ill coronavirus disease 2019 patients with comparison to all-cause critically ill sepsis patients. DESIGN, SETTING, AND PARTICIPANTS:. Retrospective analysis of coronavirus disease 2019 patients admitted to an ICU for at least 24 hours at any of Emory Healthcare ICUs between March 2020 and April 2020 up to 5 days of ICU stay. The comparison group was a cohort of all-cause sepsis patients prior to coronavirus disease 2019 pandemic. MAIN OUTCOMES AND MEASURES:. Continuous waveforms were captured from the patient monitor. The electrocardiogram was then analyzed for each patient over a 300 seconds observational window that was shifted by 30 seconds in each iteration from admission till discharge. A total of 23 heart rate variability metrics were extracted in each iteration. We use the Kruskal-Wallis and Steel-Dwass tests (p < 0.05) for statistical analysis and interpretations of heart rate variability multiple measures. RESULTS:. A total of 141 critically ill coronavirus disease 2019 patients met inclusion criteria, who were compared with 208 patients with all-cause sepsis. Three nonlinear markers, including the ratio of standard deviation derived from the Poincaré plot, sample entropy, and approximate entropy and four linear features, including mode of beat-to-beat interval, acceleration capacity, deceleration capacity, and the proportion of consecutive RR intervals that differ by more than 50 ms, were all statistically significant (p < 0.05) between the coronavirus disease 2019 and all-cause sepsis cohorts. The three nonlinear features and acceleration capacity, deceleration capacity, and beat-to-beat interval (mode) were statistically significant (p < 0.05) when comparing pairwise analysis among the combinations of survivors and nonsurvivors between the coronavirus disease 2019 and sepsis cohorts. Temporal analysis of the main markers showed low variability across the 5 days of analysis compared with sepsis patients. CONCLUSIONS AND RELEVANCE:. In this descriptive statistical study, heart rate variability measures were found to be statistically different across critically ill patients infected with severe acute respiratory syndrome coronavirus 2 and distinct from bacterial sepsis.

Abstract Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.

TIGIT is a recently identified coinhibitory receptor that is upregulated in the setting of cancer and functionally contributes to the impairment of antitumor immunity. However, its role during sepsis is unknown. Because patients with cancer are 10 times more likely to die of sepsis than previously healthy (PH) patients with sepsis, we interrogated the role of TIGIT during sepsis in the context of preexistent malignancy. PH mice or cancer (CA) mice inoculated with lung carcinoma cells were made septic by cecal ligation and puncture (CLP). We found that sepsis induced TIGIT upregulation predominantly on Tregs and NK cells in both PH and CA mice. Anti-TIGIT Ab improved the 7-d survival of CA septic mice but not PH mice after CLP. Treatment of CA septic animals but not PH septic animals with anti-TIGIT mAb significantly reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Foxp3+ Treg, and CD19+ B cells in the spleen, which was the result of decreased caspase-3+ apoptotic cells. In sum, we found that anti-TIGIT Ab reversed sepsis-induced T cell apoptosis in CA septic mice and led to a significant survival benefit, suggesting its use as a potential immunotherapy to improve outcomes in septic patients with cancer.

Mounting evidence suggests that the balance of T cell costimulatory and coinhibitory signals contributes to mortality during sepsis. Here, we identified a critical role of the coinhibitory molecule T cell Ig and ITIM domain (TIGIT) in regulating sepsis mortality. Because TIGIT is significantly upregulated on memory T cells, we developed a “memory mouse” model to study the role of TIGIT during sepsis in a more physiologically relevant context. Mice received sequential pathogen exposure and developed memory T cell frequencies, similar to those observed in adult humans, and were then subjected to sepsis induction via cecal ligation and puncture. Our results show that targeting the TIGIT pathway during sepsis is fundamentally different in previously naive versus memory mice, in that αTIGIT Ab had no effect on survival in previously naive septic mice but sharply worsened survival in memory septic mice. Mechanistically, αTIGIT increased apoptosis of memory T cells, decreased T cell function, and downregulated the costimulatory receptor DNAM on memory CD8+ T cells in memory septic mice, but not in previously naive septic mice. Additionally, αTIGIT diminished Helios expression in Tregs in memory but not previously naive septic mice. These data highlight fundamental differences in the pathophysiological impact of targeting TIGIT in immunologically experienced versus previously naive hosts during sepsis.

Summary: Sepsis is a leading cause of morbidity and mortality associated with significant impairment in memory T cells. These changes include the upregulation of co-inhibitory markers, a decrease in functionality, and an increase in apoptosis. Due to recent studies describing IL-27 regulation of TIGIT and PD-1, we assessed whether IL-27 impacts these co-inhibitory molecules in sepsis. Based on these data, we hypothesized that IL-27 was responsible for T cell dysfunction during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we found that IL-27Rα was associated with the upregulation of TIGIT on memory CD4+ T cells following CLP. However, IL-27 was not associated with sepsis mortality.

Objectives:. Coronavirus disease 2019 is associated with high mortality rates and multiple organ damage. There is increasing evidence that these patients are at risk for various cardiovascular insults; however, there are currently no guidelines for the diagnosis and management of such cardiovascular complications in patients with coronavirus disease 2019. We share data and recommendations from a multidisciplinary team to highlight our institution’s clinical experiences and guidelines for managing cardiovascular complications of coronavirus disease 2019. Design, Setting, and Patients:. This was a retrospective cohort study of patients admitted to one of six ICUs dedicated to the care of patients with coronavirus disease 2019 located in three hospitals within one academic medical center in Atlanta, Georgia. Measurements/Interventions:. Chart review was conducted for sociodemographic, laboratory, and clinical data. Rates of specific cardiovascular complications were assessed, and data were analyzed using a chi-square or Wilcoxon rank-sum test for categorical and continuous variables. Additionally, certain cases are presented to demonstrate the sub committee’s recommendations. Main Results:. Two-hundred eighty-eight patients were admitted to the ICU with coronavirus disease 2019. Of these, 86 died (29.9%), 242 (84.03%) had troponin elevation, 70 (24.31%) had dysrhythmias, four (1.39%) had ST-elevation myocardial infarction, eight (2.78%) developed cor pulmonale, and 190 (65.97%) with shock. There was increased mortality risk in patients with greater degrees of troponin elevation (p < 0.001) and with the development of arrhythmias (p < 0.001), cor pulmonale (p < 0.001), and shock (p < 0.001). Conclusions:. While there are guidelines for the diagnosis and management of pulmonary complications of coronavirus disease 2019, there needs to be more information regarding the management of cardiovascular complications as well. These recommendations garnered from the coronavirus disease 2019 cardiology subcommittee from our institution will add to the existing knowledge of these potential cardiovascular insults as well as highlight suggestions for the diagnosis and management of the range of cardiovascular complications of coronavirus disease 2019. Additionally, with the spread of coronavirus disease 2019, our case-based recommendations provide a bedside resource for providers newly caring for patients with coronavirus disease 2019.

Abstract Background The gut is hypothesized to be the “motor” of critical illness. Under basal conditions, the gut plays a crucial role in the maintenance of health. However, in critical illness, all elements of the gut are injured, potentially worsening multiple organ dysfunction syndrome. Main body Under basal conditions, the intestinal epithelium absorbs nutrients and plays a critical role as the first-line protection against pathogenic microbes and as the central coordinator of mucosal immunity. In contrast, each element of the gut is impacted in critical illness. In the epithelium, apoptosis increases, proliferation decreases, and migration slows. In addition, gut barrier function is worsened via alterations to the tight junction, resulting in intestinal hyperpermeability. This is associated with damage to the mucus that separates the contents of the intestinal lumen from the epithelium. Finally, the microbiome of the intestine is converted into a pathobiome, with an increase in disease-promoting bacteria and induction of virulence factors in commensal bacteria. Toxic factors can then leave the intestine via both portal blood flow and mesenteric lymph to cause distant organ damage. Conclusion The gut plays a complex role in both health and critical illness. Here, we review gut integrity in both health and illness and highlight potential strategies for targeting the intestine for therapeutic gain in the intensive care unit.

Abstract Background Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. Objective To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. Methods A total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013). Results Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers. Conclusions We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

Abstract Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK−/− and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK−/− mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK−/− mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK−/− mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK−/− mice; however, survival was similar between septic MLCK−/− mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

Sepsis is a major cause of morbidity and mortality worldwide despite numerous attempts to identify effective therapeutics. While some sepsis deaths are attributable to tissue damage caused by inflammation, most mortality is the result of prolonged immunosuppression. Ex vivo, immunosuppression during sepsis is evidenced by a sharp decrease in the production of pro-inflammatory cytokines by T cells and other leukocytes and increased lymphocyte apoptosis. This allows suppressive cytokines to exert a greater inhibitory effect on lymphocytes upon antigen exposure. While some pre-clinical and clinical trials have demonstrated utility in targeting cytokines that promote lymphocyte survival, this has not led to the approval of any therapies for clinical use. As cytokines with a more global impact on the immune system are also altered by sepsis, they represent novel and potentially valuable therapeutic targets. Recent evidence links interleukin (IL)-17, IL-27, and IL-33 to alterations in the immune response during sepsis using patient serum and murine models of peritonitis and pneumonia. Elevated levels of IL-17 and IL-27 are found in the serum of pediatric and adult septic patients early after sepsis onset and have been proposed as diagnostic biomarkers. In contrast, IL-33 levels increase in patient serum during the immunosuppressive stage of sepsis and remain high for more than 5 months after recovery. All three cytokines contribute to immunological dysfunction during sepsis by disrupting the balance between type 1, 2, and 17 immune responses. This review will describe how IL-17, IL-27, and IL-33 exert these effects during sepsis and their potential as therapeutic targets.