High Mortality Of Sepsis Research Articles

A novel cross-linked haemoglobin-based oxygen carrier is beneficial to sepsis in rats

Pathological hypoxia-induced organ dysfunction contributes to the high mortality of sepsis. Because of the microcirculation dysfunction following severe sepsis, it is difficult for erythrocytes to transport oxygen to hypoxic tissues. Haemoglobin-based oxygen carriers (HBOCs) are capable of delivering oxygen to hypoxic tissues. The aim of this study is to observe the potential benefits of a novel bovine-derived, non-polymerized, cell-free HBOC solution, YQ23, on sepsis in rats. Cecum ligation and puncture was performed to induce sepsis in Sprague-Dawley rats. Effects of Lactate Ringer’s solution (LR), YQ23, and whole blood on oxygen delivery and consumption, mitochondrial function, organ protection and animal survival were observed. LR failed to restore oxygen delivery and the therapeutic effects were limited, whereas low dosage of YQ23 and whole blood significantly increased the tissue oxygen delivery and consumption, improved the mitochondrial function of heart, liver, kidney and intestine, prevented the vital organs injuries and improved the animal survival. The effects of 0.15 g·kg−1 YQ23 resembled that of the whole blood. In addition, YQ23 did not induce renal toxicity, severe oxidative effect and acute vasoconstriction. Thus, YQ23 is a safe and effective resuscitation fluid for sepsis.

Minocycline promotes cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy to prevent sepsis-induced cardiac dysfunction by Akt/mTOR signaling.

Myocardial damage is responsible for the high mortality of sepsis. However, the underlying mechanism is not well understood. Cardiomyocyte autophagy alleviates the cardiac injury caused by myocardial infarction. Enhanced cardiomyocyte autophagy also has protective effects against cardiomyocyte mitochondrial injury. Minocycline enhances autophagy in many types of cells under different types of pathological stress and can be easily taken up by cardiomyocytes. The present study investigated whether minocycline prevented myocardial injury caused by sepsis and whether cardiomyocyte autophagy participated in this process. The results indicated that minocycline enhanced cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy and improved myocardial mitochondrial and cardiac function. Minocycline upregulated protein kinase B (Akt) phosphorylation, inhibited mTORC1 expression and enhanced mTORC2 expression. In conclusion, minocycline enhanced cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy and improved cardiac function. The underlying mechanisms were associated with mTORC1 inhibition and mTORC2 activation. Thus, our findings suggest that minocycline may represent a potential approach for treating myocardial injury and provide novel insights into the underlying mechanisms of myocardial injury and dysfunction after sepsis.

640. Prospective Association of Serum Vitamin D Level with Sepsis-Mortality in Postmenopausal Women: Results From the Women’s Health Initiative

BackgroundsVitamin D deficiency has been studied in the critically ill, and has been associated with worse morbidity and mortality rates, especially in those admitted with sepsis. Sepsis is a major cause of ICU admissions and accounts for 250,000 deaths per year. Dihydroxyvitamin D can inhibit the production of interleukins, tumor necrosis factor and can also increase the expression of endogenous antimicrobial peptides. This study sought to assess if low serum concentrations of 25(OH)D were associated with higher sepsis mortality rates.MethodsThis is a prospective study composed of participants from the Women’s health Initiative (WHI) in the Vitamin D/Calcium trial who have been followed for an average of 15 years. The analysis sample consists of participants who had 25(OH)D measured at baseline. Patients with kidney disease and self-reported cancer at enrollment were excluded. Vitamin D deficiency was defined as levels 2 20 ng/mL, which was categorized into severe deficiency [25(OH)D 212 ng/mL] and mild deficiency [25(OH) of 12–20 ng/mL]. Cox proportional hazard model was used to study the association between serum Vitamin D and sepsis mortality.Results10,814 participants were included in the study (mean age = 64.4 years). At baseline, 49.26% (n = 5,328) of the sample had vitamin D deficiency and of those who died from sepsis, 57.7% (n = 41) where found to be vitamin D deficient. We found statistically significant increased hazard ratios (HR) for sepsis mortality in mild (HR = 1.19; 95% CI 1.00–1.41) and severe vitamin D deficiency (HR = 1.82; 95% CI: 1.50–2.21) in age adjusted and fully adjusted models (Table 1).ConclusionVitamin D deficiency is associated with increased risk of sepsis mortality in postmenopausal women, which was seen in all ages. A clinical trial evaluating adequate supplementation in patients with sepsis is recommended to assess clinical significance. Disclosures All authors: No reported disclosures.

A systematic investigation on animal models of cyclosporine A combined with Escherichia coli to simulate the immunosuppressive status of sepsis patients before onset

Immunosuppression is an important mechanism for the development of sepsis pathology, and is the key to the high mortality of sepsis. However, patients appear to be immunocompromised before sepsis onset due to lack of enough attention. Present sepsis models cannot fully mimic the onset of sepsis in patients. Hence, effective treatments in animal experiments could not be transformed into clinical application. In the present study, we improved the animal model of sepsis and used cyclosporine A immunosuppressive mice to make it closer to immune status before the onset of sepsis, followed by the intraperitoneal injection of Escherichia coli (E. coli) CMCC (B) 44,102 standard strain to produce the immunocompromised sepsis model. This trial systematically evaluates the new immunosuppressive sepsis model. Compared with routine sepsis models, the release of inflammatory factors in the new sepsis model was insufficient, blood bacteria were more cultured, diffuse intravascular coagulation (DIC) was more severe, lung, liver and kidney damage were heavier, and mortality rate was higher. In conclusion, the new sepsis model can mimic the patient's pre-onset immunocompromised state, is suitable for the development and evaluation of new methods of sepsis, and solves the controversy of sepsis treatment, providing new ideas and direction.

Nucleic-acid based gene therapy approaches for sepsis

Despite advances in overall medical care, sepsis and its sequelae continue to be an embarrassing clinical entity with an unacceptably high mortality rate. The central reason for high morbidity and high mortality of sepsis and its sequelae is the lack of an effective treatment. Previous clinical trials have largely failed to identify an effective therapeutic target to improve clinical outcomes in sepsis. Thus, the key goal favoring the outcome of septic patients is to devise innovative and evolutionary therapeutic strategies. Gene therapy can be considered as one of the most promising novel therapeutic approaches for nasty disorders. Since a number of transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), play a pivotal role in the pathophysiology of sepsis that can be characterized by the induction of multiple genes and their products, sepsis may be regarded as a gene-related disorder and gene therapy may be considered a promising novel therapeutic approach for treatment of sepsis. In this review article, we provide an up-to-date summary of the gene-targeting approaches, which have been developed in animal models of sepsis. Our review sheds light on the molecular basis of sepsis pathology for the development of novel gene therapy approaches and leads to the conclusion that future research efforts may fully take into account gene therapy for the treatment of sepsis.

Defects in innate and adaptive immunity in patients with sepsis and health care associated infection.

Recent advances in sepsis therapy exclusively involve improvements in supportive care, while sepsis mortality rates remain disturbingly high at 30%. These persistently high sepsis mortality rates arise from the absence of sepsis specific therapies. However with improvements in supportive care, patients with septic shock commonly partially recover from the infection that precipitated their initial illness, yet they frequently succumb to subsequent health care associated infections. Remarkably today the pathophysiology of sepsis in humans, a common disease in western society, remains largely a conundrum. Conventionally sepsis was regarded as primarily a disorder of inflammation. More recently the importance of immune compromise in the pathophysiology of sepsis and health care associated infection has now become more widely accepted. Accordingly a review of the human evidence for this novel sepsis paradigm is timely. Septic patients appear to exhibit a complex and long-lasting immune deficiency state, involving lymphocytes of both the innate and adaptive immune responses that have been linked with mortality and the occurrence of health care associated infection. Such is the pervasive nature of immune compromise in sepsis that ultimately immune modulation will play a crucial role in sepsis therapies of the future.

Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition.

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

Defining Sepsis Mortality Clusters in the United States.

In the United States, sepsis is a major public health problem accounting for over 200,000 annual deaths. The aims of this study were to identify U.S. counties with high sepsis mortality and to assess the community characteristics associated with increased sepsis mortality. We performed a descriptive analysis of 2003 through 2012 Compressed Mortality File data. We defined sepsis deaths as deaths associated with an infection, classified according to the International Classification of Diseases, 10th Version. Three thousand one hundred and eight counties in the contiguous U.S. counties, excluding Hawaii and Alaska. Using geospatial autocorrelation methods, we defined county-level sepsis mortality as strongly clustered, moderately clustered, and nonclustered. We approximated the mean crude, age-adjusted, and community-adjusted sepsis mortality rates nationally and for clustering groups. We contrasted demographic and community characteristics between clustering groups. We performed logistic regression for the association between strongly clustered counties and community characteristics. Among 3,108 U.S. counties, the age-adjusted sepsis mortality rate was 59.6 deaths per 100,000 persons (95% CI, 58.9-60.4). Sepsis mortality was higher in the Southern U.S. and clustered in three major regions: Mississippi Valley, Middle Georgia, and Central Appalachia. Among 161 (5.2%) strongly clustered counties, age-adjusted sepsis mortality was 93.1 deaths per 100,000 persons (95% CI, 90.5-95.7). Strongly clustered sepsis counties were more likely to be located in the south (92.6%; p < 0.001), exhibit lower education, higher impoverished population, without medical insurance, higher medically uninsured rates, and had higher unemployment rates (p < 0.001). Sepsis mortality is higher in the Southern United States, with three regional clusters: "Mississippi Valley," "Middle Georgia," and "Central Appalachia": Regions of high sepsis mortality are characterized by lower education, income, employment, and insurance coverage.

The protective role of neuregulin-1: A potential therapy for sepsis-induced cardiomyopathy

The extremely high mortality of sepsis in intensive care units, caused primarily by sepsis-induced cardiomyopathy, is a pressing issue. Current studies have revealed the importance of the neuregulin-1 (NRG-1)/ErbB signaling axis at the cardiovascular level and the positive effect of NRG-1 on cardiac function in patients with heart failure. To investigate the protective mechanism of NRG-1 against myocardial injury in septic rats, a cecal ligation and puncture (CLP) model was applied. Animals were administered either a vehicle or recombinant human NRG-1 (rhNRG-1, 10μg/kg). Their survival rates were noted 24h after CLP. The hemodynamic method was used to evaluate their cardiac function. The myocardial morphology was observed. An enzyme-linked immunosorbent assay was used to detect the level of cardiac troponin-T (cTn-T), cytokines, and angiotensin II (Ang II) in the serum and myocardium. Compared with the vehicle, rhNRG-1 improved survival of rats and prevented hemodynamic derangement, as reflected in the increased mean arterial pressure, left ventricular systolic pressure, ±dp/dt max, and decreased left ventricular end-diastolic pressure (P<0.05). Furthermore, the serum levels of cTn-T and pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6) were significantly increased in vehicle-treated rats but reduced in rhNRG-1-treated rats. The latter also showed decreased concentration of macrophage inhibitory factor and Ang II in the myocardium (P<0.05). These results suggest that NRG-1 improved cardiac function and protected cardiomyocytes of rats from CLP-induced sepsis by suppressing the immune inflammatory response and excessive activation of the renin–angiotensin–aldosterone system. Ultimately, NRG-1 increased the survival rate of rats.

Infection site is predictive of outcome in acute lung injury associated with severe sepsis and septic shock.

Sepsis is a leading cause of acute lung injury (ALI); however, the characteristics and outcome of sepsis-associated ALI are poorly understood. We aimed to elucidate factors that predict patient outcome in sepsis-associated ALI. Secondary analysis of a multicenter, prospective, observational study was performed. Among 624 patients with severe sepsis and septic shock, 251 (40.2%) fulfilled the definition of American-European Consensus Conference definition of ALI. All-cause 28-day and in-hospital mortalities were 30.7% and 38.6%, respectively. More than 40% of ALI patients had neurological, cardiovascular and haematological dysfunctions or disseminated intravascular coagulation, all of which were associated with higher mortality. We report a significant correlation between infection site and mortality in patients with ALI, but not in those without ALI. The proportion of ALI was significantly higher in pulmonary sepsis; further, a complication of ALI was associated with higher mortality in sepsis from pulmonary and other sources, but not in abdominal sepsis. Among the other sepsis sites, urinary tract, central nervous system, catheter-related and undetermined foci of infection had worse outcomes when associated with ALI. None of the individual severe sepsis bundles, including fluid resuscitation and early antibiotic administration, correlated with mortality. Compliance with a set of sepsis management bundles was associated with better outcomes. In severe sepsis and septic shock, the proportion and effect on outcome was not uniform among infection sites. The infection site was predictive of outcome in patients with ALI but not in those without ALI.

Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and TRAF6 Expression.

Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in innate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus-expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR-control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IκBα phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-κB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR-146a attenuates sepsis-induced cardiac dysfunction by preventing NF-κB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells.

Alterations of dendritic cells in sepsis: featured role in immunoparalysis.

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.

Cardiac fibroblasts: contributory role in septic cardiac dysfunction

BackgroundCardiac dysfunction is a frequent and severe complication of septic shock and contributes to the high mortality of sepsis. Although several mechanisms have been suspected to be responsible for sepsis-associated cardiac dysfunction, the precise cause(s) remains unclear to date. Materials and methodsWe tested the hypothesis that cardiac fibroblasts may play a critical role as a disease modifier involved in sepsis-associated cardiac dysfunction. Human cardiac fibroblasts (HCFs) cultured in vitro were exposed to lipopolysaccharide (LPS). Changes in cardiac morphology and function were assessed in mice with cecal ligation and puncture-induced sepsis. ResultsIn LPS-stimulated HCFs, messenger RNA and protein levels of proinflammatory molecules, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1, were strikingly upregulated. LPS also increased expression and activity of matrix metalloproteinase (MMP)-9, but not MMP-2. LPS-induced expression of α-smooth muscle actin, a classical marker for myoblast differentiation, which was abrogated when MMP-9 small interfering RNA was transfected into HCFs. High gene expression levels of proinflammatory cytokines and MMP-9 were observed in the heart tissues of cecal ligation and puncture-induced septic mice. Histology sections of the hearts from septic mice showed perivascular and interstitial cardiac fibrosis, and echocardiography demonstrated that septic mice had profound cardiac dysfunction. The broad-spectrum MMP inhibitor ONO-4817 significantly alleviated these histologic and functional changes during the acute phase. ConclusionsWe suggest that cardiac fibroblasts are of pathogenetic importance in inflammation and fibrosis in the heart during sepsis, leading to cardiac dysfunction that would affect the outcome of sepsis syndrome.

Diagnostic characteristics of a clinical screening tool in combination with measuring bedside lactate level in emergency department patients with suspected sepsis.

Early identification of sepsis and initiation of aggressive treatment saves lives. However, the diagnosis of sepsis may be delayed in patients without overt deterioration. Clinical screening tools and lactate levels may help identify sepsis patients at risk for adverse outcomes. The objective was to determine the diagnostic characteristics of a clinical screening tool in combination with measuring early bedside point-of-care (POC) lactate levels in emergency department (ED) patients with suspected sepsis. This was a prospective, observational study set at a suburban academic ED with an annual census of 90,000. A convenience sample of adult ED patients with suspected infection were screened with a sepsis screening tool for the presence of at least one of the following: temperature greater than 38°C or less than 36°C, heart rate greater than 90 beats/min, respiratory rate greater than 20 breaths/min, or altered mental status. Patients meeting criteria had bedside POC lactate testing following triage, which was immediately reported to the treating physician if ≥2.0 mmol/L. Demographic and clinical information, including lactate levels, ED interventions, and final diagnosis, were recorded. Outcomes included presence or absence of sepsis using the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions and intensive care unit (ICU) admissions, use of vasopressors, and mortality. Diagnostic test characteristics were calculated using 2-by-2 tables with their 95% confidence intervals (CIs). The association between bedside lactate and ICU admissions, use of vasopressors, and mortality was determined using logistic regression. A total of 258 patients were screened for sepsis. Their mean (± standard deviation [SD]) age was 64 (±19) years; 46% were female, and 82% were white. Lactate levels were 2.0 mmol/L or greater in 80 (31%) patients. Patients were confirmed to meet sepsis criteria in 208 patients (81%). The diagnostic characteristics for sepsis of the combined clinical screening tool and bedside lactates were sensitivity 34% (95% CI = 28% to 41%), specificity 82% (95% CI = 69% to 90%), positive predictive value 89% (95% CI = 80% to 94%), and negative predictive value 23% (95% CI = 17% to 30%). Bedside lactate levels were associated with sepsis severity (p < 0.001), ICU admission (odds ratio [OR] = 2.01; 95% CI = 1.53 to 2.63), and need for vasopressors (OR = 1.54; 95% CI = 1.13 to 2.12). Use of a clinical screening tool in combination with early bedside POC lactates has moderate to good specificity but low sensitivity in adult ED patients with suspected sepsis. Elevated bedside lactate levels are associated with poor outcomes.

Impact of Gender on Sepsis Mortality and Severity of Illness for Prepubertal and Postpubertal Children

To investigate differences in sepsis mortality between prepubertal and postpubertal males and females. This was a retrospective review of the Virtual PICU Systems (VPS) database (including 74 pediatric intensive care units [PICUs]) for 2006-2008. We included prepubertal (aged 2-7 years) and postpubertal (aged 16-21 years) children with a primary diagnosis of sepsis admitted to a participating PICU. Prepubertal females (n = 272; 9.9% mortality) and prepubertal males (n = 303; 10.9% mortality) had similar mortality and severity of illness (Pediatric Index of Mortality 2 risk of mortality [PIM 2 ROM]). Postpubertal females (n = 233; mortality, 5.6%) had lower mortality than postpubertal males (n = 212; mortality, 11.8%; P = .03). PIM 2 ROM was higher for postpubertal males than postpubertal females (P = .02). After controlling for hospital specific effects with multivariate modeling, in postpubertal children, female gender was independently associated with a lower initial severity of illness (PIM 2 ROM: OR, 0.77; 95% CI, 0.62-0.96; P = .02). Sepsis mortality is similar in prepubertal males and females. However, postpubertal males have a higher sepsis mortality than postpubertal females, likely related to their greater severity of illness on PICU admission. These outcome differences in postpubertal children may reflect a hormonal influence on the response to infection or differences in underlying comorbidities, source of infection, or behavior.

Hypogammaglobulinemia in sepsis is not correlated to high circulating angiopoietin-2 levels

Hypogammaglobulinemia has been frequently found in adult patients with severe sepsis and septic shock. Furthermore, it seems that at least a low serum level of IgM is correlated with higher mortality in sepsis. The mechanisms of hypogammaglobulinemia in septic shock have not yet been explained. It has been hypothesized that outflow of immunoglobulins into the extravascular space due to increased capillary permeability could reduce immunoglobulin serum concentrations. Angiopoietin-2, which directly disrupts the endothelial barrier, is markedly elevated in sepsis and other inflammatory states and its serum level has been correlated with microvascular leakage, end-organ dysfunction and death in sepsis.

The Cardioprotective Effect of Hypertonic Saline Is Associated with Inhibitory Effect on Macrophage Migration Inhibitory Factor in Sepsis

Sepsis can cause myocardial dysfunction, which contributes to the high mortality of sepsis. Hypertonic saline (HS) has been reported to increase myocardial contractility in sepsis. In the present study, mechanisms of action of HS resuscitation (4 mL of 7.5% NaCl per kilogram) on cardiac function have been evaluated in septic rats. HS was administered 1 h after LPS (10 mg/kg, i.v.) challenge. The mean arterial blood pressure significantly decreased 4 h after LPS challenge, and septic shock was observed at the end of experiment (6 h). Posttreatment with HS prevented hypotension caused by LPS and significantly improved cardiac function, evidenced by increases in left ventricular developed pressure, mean +dP/dt and −dP/dt. The amplitude of electrical-stimulated intracellular Ca2+ transient in isolated single cardiomyocytes was significantly reduced after 6 h LPS insult, which was recovered by HS. In addition, LPS resulted in significant increases in neutrophil myeloperoxidase activity, macrophage migration inhibitory factor (MIF), and NF-κB phospho-p65 protein levels in myocardium at 6 h, which were significantly attenuated by HS. In conclusion, HS improved myocardial contractility and prevented circulatory failure induced by endotoxemia, which may attribute to improvement of intracellular calcium handling process and inhibitory effects on neutrophil infiltration and MIF production in hearts.

Immunotherapy - a potential new way forward in the treatment of sepsis

A recent randomized controlled clinical trial of the immunostimulatory agent thymosin alpha-1 was conducted and showed a trend toward improved survival in patients receiving the drug (P = 0.06). Although this was a relatively small study and the exact mechanism of action of thymosin alpha-1 is not known, the present results further support the evolving concept that, as sepsis persists, a hypoinflammatory and immunosuppressive condition ensues and therapy that augments host immunity may be advantageous. Other immunomodulatory agents including granulocyte-macrophage colony-stimulating factor have shown promise in small trials in sepsis. In addition, there are a number of new immunoadjuvant agents such as IL-7 and anti-programmed cell death-1 that are showing remarkable abilities to enhance host immunity and improve outcomes in a variety of clinical disorders, including cancer and chronic viral infections. Animal studies show that these new immunoadjuvant agents improve survival in several clinically relevant models of sepsis. Given the relative safety of thymosin alpha-1 and these other new immunomodulatory agents as well as the persisting high mortality of sepsis, a strong case can be made for larger well-designed trials using immunoadjuvant therapy in patients who have documented immune suppression. Immunotherapy offers new hope in the treatment of sepsis and may dramatically change the face of the disease.

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Introduction: Pediatric Thrombocytopenia-Associated Multiple Organ Failure (TAMOF), defined as greater than 2 organ failures and platelet count < 100,000/uL, is associated with high mortality in sepsis. Plasma exchange (PEx) has been suggested to improve survival (Nguyen et al., CCM, 2008). In preliminary prospective studies of the multicenter Prospective TAMOF Network, PEx was associated with increased likelihood of survival (Fortenberry, CCM, 2011 abstr). A subset of gravely ill patients received PEx while on ECMO. We evaluated this subgroup to better determine response and outcome. Hypothesis: Patients on ECMO receiving PEx have greater severity of illness and greater likelihood of death than non-ECMO patients receiving PEx. Methods: Analysis of data from network prospective observational trial of 81 children 1 mth-21 years diagnosed with TAMOF. Pts.on ECMO receiving PEx were compared to non-ECMO pts. for severity of illness scores, outcome. ADAMTS-13 levels and platelet counts were serially obtained. Results: PEx pts had lower survival (53.8%) than non-ECMO PEx patients (79.4%; p = 0.05), but not lower than ECMO non-PEx patients (50%; p = NS). PELOD scores >21 did not predict outcome difference. PELOD scores remained higher over time in ECMO PEx pts. and in non-survivors (N-S) (p=.009). ECMO PEx pts had greater PELOD score improvement over time than non-ECMO PEx pts (p=.0077). Platelet counts were lower in non-ECMO PEx N-S, but were improved in ECMO pts vs. non-ECMO PEx, likely due to platelet therapy on ECMO. ECMO PEx survivors showed a trend for improvement in ADAMTS-13 vs. N-S (p=0.0615) and with time (p <.001). Conclusions: TAMOF patients on ECMO who received PEx were more critically ill at onset and more likely to die than TAMOF non-ECMO patients, but had significant improvement in PELOD score and reasonable survival for severity of illness. Stratification for ECMO should be considered for future PEx RCTs.

Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis*

To determine the role of Toll-like receptor 3 in cardiac dysfunction during polymicrobial sepsis. Controlled animal study. University research laboratory. Male C57BL/6, wild-type, Toll-like receptor 3-/-. Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. Toll-like receptors (TLRs) play a critical role in the pathophysiology of sepsis/septic shock. TLR3 is located in intracellular endosomes, and recognizes double-stranded RNA. This study examined the role of TLR3 in cardiac dysfunction following cecal ligation and puncture (CLP)-induced sepsis. TLR3 knockout (TLR3-/-, n=12) and age-matched wild-type (n=12) mice were subjected to CLP. Cardiac function was measured by echocardiography before and 6 hrs after CLP. CLP resulted in significant cardiac dysfunction as evidenced by decreased ejection fraction by 25.7% and fractional shortening by 29.8%, respectively. However, TLR3-/- mice showed a maintenance of cardiac function at pre-CLP levels. Wild-type mice showed 50% mortality at 58 hrs and 100% mortality at 154 hrs after CLP. In striking contrast, 70% of TLR3-/- mice survived indefinitely, that is, >200 hrs. TLR3 deficiency significantly decreased CLP-induced cardiac-myocyte apoptosis and attenuated CLP-induced Fas and Fas ligand expression in the myocardium. CLP-activation of TLR4-mediated nuclear factor-κB and Toll/IL-1 receptor-domain-containing adapter-inducing interferon-β-dependant interferon signaling pathways was prevented by TLR3 deficiency. In addition, CLP-increased vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression, and neutrophil and macrophage sequestration in the myocardium were also attenuated in septic TLR3-/- mice. More significantly, adoptive transfer of wild-type bone-marrow stromal cells to TLR3-/- mice abolished the cardioprotective effect in sepsis. These data indicate that TLR3 plays a deleterious role in mediating cardiac dysfunction in sepsis. Thus, modulation of the TLR3 activity may be useful in preventing cardiac dysfunction in sepsis.