Survival In Severe Sepsis Research Articles

High C-reactive protein and low cholesterol levels are prognostic markers of survival in severe sepsis

High C-reactive protein and low cholesterol levels are prognostic markers of survival in severe sepsis

Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge

AbstractPharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4−/−) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C–deficient (PC+/−) mice. Transgenic mice overexpressing human PF4 (hPF4+) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC+/− mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4+ and PC+/−/hPF4+ mice had improved survival. Further, infusion of hPF4+ platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.

High C-reactive protein and low cholesterol levels are prognostic markers of survival in severe sepsis

Study Objective To evaluate serum C-reactive protein and cholesterol as a prognostic factor for survival in patients with severe sepsis. Design Prospective study. Setting University hospital. Patients The study population consisted of 96 patients (age range, 18-75 years; median, 56 years; men/women ratio, 40:56) in whom severe sepsis was diagnosed. Interventions Patients' serum levels of C-reactive protein and cholesterol were measured upon admission to an intensive care unit, two days later, and on the day of discharge from the intensive care unit or on the day of death. Measurements and Main Results Cholesterol levels were significantly lower among the nonsurviving patients (day 1, 92.2 ± 25.1 mg/dL; day 2, 92.1 ± 21.7 mg/dL; death/discharge day, 92.2 ± 21.7 mg/dL) than surviving patients (day 1, 175.1 ± 38.6 mg/dL [ P < 0.001]; day 2, 173.0 ± 39.3 mg/dL [ P < 0.001]; death/discharge day, 171.8 ± 39.6 mg/dL [ P = 0.010]). Median C-reactive protein levels were significantly higher among the nonsurvivors (day 1, 32 mg/dL [range, 20.5-64.5 mg/dL]; day 2, 33 mg/dL [range, 22-74.5 mg/dL]; death/discharge day, 30 mg/dL [range, 22-57 mg/dL]) than survivors (day 1, 10 mg/dL [range, 6-14 mg/dL]; day 2, 9 mg/dL [range, 5-10 mg/dL]; death/discharge day, 6 mg/dL [range, 3-9 mg/dL]; P < 0.001). Conclusion Serum C-reactive protein and cholesterol are a predictor of survival in patients with severe sepsis. Low cholesterol and high C-reactive protein levels appear as a valuable tool for individual risk assessment in severe sepsis patients and for stratification of high-risk patients in future intervention trials.

Early changes in organ function predict eventual survival in severe sepsis

Early changes in organ function predict eventual survival in severe sepsis

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C

Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing.

DIAGNOSTIC MARKERS OF SEPSIS IN THE EMERGENCY DEPARTMENT

Sepsis is defined as the systemic inflammatory response to infection. However, changes in body temperature, heart and respiratory rate and white cell count (the “SIRS” criteria) are not specific enough to identify infected patients in the emergency department. Among many biological parameters, measurement of lactate, central venous oxygen saturation (ScvO2), C-reactive protein (CRP) and procalcitonin (PCT) are of particular interest.Early (within 6h) and goal-directed (ScvO2 > 70%) resuscitation increases survival in severe sepsis and septic shock, particularly in patients with high lactate clearances. CRP and PCT are both useful markers of sepsis but PCT increases earlier, better differentiates infective from non-infective causes of inflammation, more closely correlates with sepsis severity in terms of shock and organ dysfunction and better predicts outcome when followed in time. However, PCT measurement is more costly, time-consuming, and not widespread available. New markers for rapid diagnosis of sepsis (e.g. TREM-1) are under investigation.

ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis

MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.

Early changes in organ function predict eventual survival in severe sepsis*

Early identification and treatment of severe sepsis can significantly reduce mortality rate. We hypothesized that a risk prediction model based on early (baseline to day 1 of study) response to standard care should be significantly related to 28-day survival. Analysis of organ dysfunction data from two placebo-controlled severe sepsis trials (PROWESS and secretory phospholipase A2 inhibitor trials). Research laboratory. The placebo arms of two randomized, double-blind sepsis trials were combined (n = 1036). These patients met criteria for severe sepsis and received supportive standard intensive care and fluid resuscitation. None. Sequential Organ Failure Assessment (SOFA) scores were calculated daily using the most aberrant physiologic or laboratory variables. Baseline and post-baseline SOFA scores categorized as improved, unchanged, or worsened were used in regression analyses correlating organ dysfunction changes with 28-day mortality. Improvement in cardiovascular (p = .0010), renal (p < .0001), or respiratory (p = .0469) function from baseline to day 1 was significantly related to survival. Odds ratios (95% confidence intervals) associated with improved vs. worsened respiratory, cardiovascular, or renal function before start of day 1 were 0.56 (0.35-0.91), 0.33 (0.18-0.59), and 0.30 (0.17-0.52), respectively. Continued improvement in cardiovascular function before start of day 2 and start of day 3 was associated with further improvement in survival (p <. 0001), with odds ratios of 0.15 (0.06-0.39) and 0.11 (0.04-0.31) for patients who improved compared with those who worsened. No other organ system was retained in the model, and improvement beyond day 1 in any other organ function did not add to the model's predictive power. These analyses suggest that outcomes for patients with severe sepsis are closely related to early (baseline to day 1 here) improvement, or lack thereof, in organ function. Also, clinical improvement on subsequent days may have little additional impact on the likelihood of survival.

Endothelial Microparticles (EMP) Expressing CD31 but Not CD62E Correlate with Improved Survival in Severe Sepsis.

BACKGROUND.. The endothelium plays a central role in sepsis, but monitoring endothelial function is difficult because it is inaccessible for direct sampling. EMP, small vesicles released from activated or apoptotic endothelim, can serve as a useful proxy, but it has been established that they are heterogenous in phenotype and function. Recently, we studied different species of EMP in severe sepsis, and demonstrated that certain subsets are good predictors of survival as early as day 1 of admission, and that survival correlated with elevation of inflammatory indicators. The present study refines that work by examining the differential levels of two phenotypic species of EMP, those positive for CD62E (EMP62E) vs. CD31 (EMP31), because of evidence that the latter is associated mainly with inflammation, the former with thrombosis. Evidence for this includes (i) in inflammatory disorders such as acute multiple sclerosis, EMP31 are predominant species [Neurology 56:1319, 2001]; (ii) in thrombotic disorders such as acute TTP, EMP62E are usually much higher than EMP31 [BJH 123:896, 2003]; (iii) in vitro experiments showed that EMP31 were 3-fold more active than EMP62E in binding to and activating leukocytes [Jy et al Frontiers Biosci, in press].METHODS. Thirty-five patients who met the criteria of severe sepsis were recruited for the study. Laboratory and clinical evaluations were performed in day 1, 2, 3 and weekly for total 28 days. Patients were divided into survivors (S) and nonsurvivors (NS) according to the 28 days all-cause mortality. EMP were analyzed by flow cytometry using fluorescent mAb to CD62E and CD31 as described [BJH 123:896, 2003]. Results were log-normalized, analyzed using repeated measures ANOVA, and are expressed as geometric means.RESULTS. EMP31 levels expressed as geometric means were significantly higher in S than NS patients, 668 and 309 respectively for day 1 and the difference persisted through days 2 (634 vs. 247 counts/μL) and 3 (631 vs. 284 counts/μL). (p<0.0001). However, levels of EMP62E were not significantly different between S and NS, 365 vs. 343 counts/μL on day 1, and 287 vs. 340 counts/μL and 294 vs. 362 counts/μL for days 2 and 3 respectively (p=0.45). Similarly, the ratio EMP31/EMP62 was about 2 to 3-fold higher in S than NS (day 1, 1.83 vs. 0.89; days2, 2.20 vs. 0.72; days 3, 2.14 vs. 0.78) (ANOVA p=0.0007). Levels of EMP31 did not significantly change over the 3 days post-enrollment in either of the 2 groups (ANOVA p for time of measurement and group by time interaction >0.05).CONCLUSIONS. In survivors, EMP31 were significantly elevated compared to EMP62E as early as day 1 of enrollment, and this difference persisted. In nonsurvivors, both phenotypes were nearly equal and neither increased with time. This tends to confirm that EMP31, not EMP62E, is an inflammation-specific marker, and may have proinflammatory functional activity beneficial to immune response in sepsis. These findings also confirm heterogeneity of EMP in various clinical disorders. Our data suggest that clinical application of EMP assay may be improved by measuring different species of EMP in different diorders.

Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections.

This study was performed to evaluate the impact of pro- and anti-inflammatory molecules and human leukocyte antigen DR (HLA-DR) expression as markers of immune status for the final outcome of septic patients. The study included 30 patients with severe sepsis due to community-acquired infections. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, IL-10, and transforming growth factor beta1 (TGF-beta1) in serum, as well as monocyte HLA-DR expression, were determined on admission and on days 3, 10, 13, and 17 during hospitalization. Of the 30 patients enrolled, 13 survived, while 17 died during their hospital stay. All patients had significantly lower HLA-DR expression and higher pro- and anti-inflammatory cytokine levels than healthy individuals. HLA-DR expression was significantly decreased in nonsurvivors at almost all time points. In nonsurvivors, higher levels in serum of TNF-alpha on days 13 and 17; IL-6 levels on day 3; and IL-10 on days 3, 10, and 13 were found. Baseline levels of TGF-beta1 were significantly higher in survivors. Independent risk factors of mortality were IL-10 levels on days 3 and 10, while monocyte HLA-DR expression on admission was a good predictor for survival. Several pro- and anti-inflammatory cytokines are oversynthesized during severe infections, especially in patients with a poor outcome. Monocyte HLA-DR expression is an early and constant predictive marker for survival in severe sepsis, while serum IL-10 levels on days 3 and 10 have negative prognostic value for the final outcome.

Recently published papers: inflammation, elucidation, manipulation?

Recently published papers: inflammation, elucidation, manipulation?

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.

Recombinant protein improves survival in severe sepsis

Recombinant protein improves survival in severe sepsis

Sepsis Bundle Adherence Is Associated with Improved Survival in Severe Sepsis or Septic Shock.

IntroductionThere have been conflicting data regarding the relationship between sepsis-bundle adherence and mortality. Moreover, little is known about how this relationship may be moderated by the anatomic source of infection or the location of sepsis declaration.MethodsThis was a multi-center, retrospective, observational study of adult patients with a hospital discharge diagnosis of severe sepsis or septic shock. The study included patients who presented to one of three Los Angeles County Department of Health Services (DHS) full-service hospitals January 2012 to December 2014. The primary outcome of interest was the association between sepsis-bundle adherence and in-hospital mortality. Secondary outcome measures included in-hospital mortality by source of infection, and the location of sepsis declaration.ResultsAmong the 4,582 patients identified with sepsis, overall mortality was lower among those who received bundle-adherent care compared to those who did not (17.9% vs. 20.4%; p=0.035). Seventy-five percent (n=3,459) of patients first met sepsis criteria in the ED, 9.6% (n=444) in the intensive care unit (ICU) and 14.8% (n=678) on the ward. Bundle adherence was associated with lower mortality for those declaring in the ICU (23.0% adherent [95% confidence interval{CI} {16.8–30.5}] vs. 31.4% non-adherent [95% CI {26.4–37.0}]; p=0.063), but not for those declaring in the ED (17.2% adherent [95% CI {15.8–18.7}] vs. 15.1% non-adherent [95% CI {13.0–17.5}]; p=0.133) or on the ward (24.8% adherent [95% CI {18.6–32.4}] vs. 24.4% non-adherent [95% CI {20.9–28.3}]; p=0.908). Pneumonia was the most common source of sepsis (32.6%), and patients with pneumonia had the highest mortality of all other subsets receiving bundle non-adherent care (28.9%; 95% CI [25.3–32.9]). Although overall mortality was lower among those who received bundle-adherent care compared to those who did not, when divided into subgroups by suspected source of infection, a statistically significant mortality benefit to bundle-adherent sepsis care was only seen in patients with pneumonia.ConclusionIn a large public healthcare system, adherence with severe sepsis/septic shock management bundles was found to be associated with improved survival. Bundle adherence seems to be most beneficial for patients with pneumonia. The overall improved survival in patients who received bundle-adherent care was driven by patients declaring in the ICU. Adherence was not associated with lower mortality in the large subset of patients who declared in the ED, nor in the smaller subset of patients who declared in the ward.