Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study

Introduction

Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients.

Methods

ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, ≥2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC).

Results

Among the 126 patients (71 men, 55 women; median age: 54 years [19–96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL-2R (p = 0.04), IL-1β (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis.

Conclusions

Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients.     

Long Term Health-Related Quality of Life in Survivors of Sepsis in South West Wales: An Epidemiological Study

Introduction

Survivors of sepsis report persistent problems that can last years after hospital discharge. The main aim of this study was to investigate long-term health-related quality of life in survivors of SIRS and sepsis compared with Welsh normative data, controlling for age, length of stay and pre-existing conditions. The second aim was to investigate any differences in long-term health-related quality of life specifically with the patients categorised into three groups; SIRS, uncomplicated sepsis and severe sepsis/septic shock.

Methods

A prospective study design was used in order to investigate all sepsis patients either presenting to the Emergency Department or admitted to the Intensive Care Unit of a regional trauma centre. Baseline demographics, clinical characteristics and outcomes were collected and surviving patients were sent a SF-12v2 survey at between six months to two years post-hospital discharge.

Results

Quality of life was significantly reduced in all patients when compared to local normative data (all p<0.0001). Reductions in the physical components of health-related quality of life were more pronounced in severe sepsis/septic shock patients when compared to uncomplicated sepsis and SIRS patients, when controlling for age, pre-existing conditions, hospital and ICU length of stay.

Conclusions

This is the first observational study to specifically focus on the different groups of SIRS and sepsis patients to assess long-term quality of life. Local population norms were used for comparison, rather than UK-wide norms that fail to reflect the intricacies of a country’s population.     

The Innate Immune Response in HIV/AIDS Septic Shock Patients: A Comparative Study

Introduction

In recent years, the incidence of sepsis has increased in critically ill HIV/AIDS patients, and the presence of severe sepsis emerged as a major determinant of outcomes in this population. The inflammatory response and deregulated cytokine production play key roles in the pathophysiology of sepsis; however, these mechanisms have not been fully characterized in HIV/AIDS septic patients.

Methods

We conducted a prospective cohort study that included HIV/AIDS and non-HIV patients with septic shock. We measured clinical parameters and biomarkers (C-reactive protein and cytokine levels) on the first day of septic shock and compared these parameters between HIV/AIDS and non-HIV patients.

Results

We included 30 HIV/AIDS septic shock patients and 30 non-HIV septic shock patients. The HIV/AIDS patients presented low CD4 cell counts (72 [7-268] cells/mm³), and 17 (57%) patients were on HAART before hospital admission. Both groups were similar according to the acute severity scores and hospital mortality. The IL-6, IL-10 and G-CSF levels were associated with hospital mortality in the HIV/AIDS septic group; however, the CRP levels and the surrogates of innate immune activation (cytokines) were similar among HIV/AIDS and non-HIV septic patients. Age (odds ratio 1.05, CI 95% 1.02-1.09, p=0.002) and the IL-6 levels (odds ratio 1.00, CI 95% 1.00-1.01, p=0.05) were independent risk factors for hospital mortality.

Conclusions

IL-6, IL-10 and G-CSF are biomarkers that can be used to predict prognosis and outcomes in HIV/AIDS septic patients. Although HIV/AIDS patients are immunocompromised, an innate immune response can be activated in these patients, which is similar to that in the non-HIV septic population. In addition, age and the IL-6 levels are independent risk factors for hospital mortality irrespective of HIV/AIDS disease.     

Gu-4 suppresses affinity and avidity modulation of CD11b and improves the outcome of mice with endotoxemia and sepsis

Background

Systemic leukocyte activation and disseminated leukocyte adhesion will impair the microcirculation and cause severe decrements in tissue perfusion and organ function in the process of severe sepsis. Gu-4, a lactosyl derivative, could selectively target CD11b to exert therapeutic effect in a rat model of severe burn shock. Here, we addressed whether Gu-4 could render protective effects on septic animals.

Methodology/Principal Findings

On a murine model of endotoxemia induced by lipopolysaccharide (LPS), we found that the median effective dose (ED50) of Gu-4 was 0.929 mg/kg. In vivo treatment of Gu-4 after LPS challenge prominently attenuated LPS-induced lung injury and decreased lactic acid level in lung tissue. Using the ED50 of Gu-4, we also demonstrated that Gu-4 treatment significantly improved the survival rate of animals underwent sepsis induced by cecal ligation and puncture. By adhesion and transwell migration assays, we found that Gu-4 treatment inhibited the adhesion and transendothelial migration of LPS-stimulated THP-1 cells. By flow cytometry and microscopy, we demonstrated that Gu-4 treatment inhibited the exposure of active I-domain and the cluster formation of CD11b on the LPS-stimulated polymorphonuclear leukocytes. Western blot analyses further revealed that Gu-4 treatment markedly inhibited the activation of spleen tyrosine kinase in LPS-stimulated THP-1 cells.

Conclusions/Significance

Gu-4 improves the survival of mice underwent endotoxemia and sepsis, our in vitro investigations indicate that the possible underlying mechanism might involve the modulations of the affinity and avidity of CD11b on the leukocyte. Our findings shed light on the potential use of Gu-4, an interacting compound to CD11b, in the treatment of sepsis and septic shock.     

Epidemiology and Outcome of Severe Sepsis and Septic Shock in Intensive Care Units in Mainland China

Introduction

Information about sepsis in mainland China remains scarce and incomplete. The purpose of this study was to describe the epidemiology and outcome of severe sepsis and septic shock in mixed ICU in mainland China, as well as the independent predictors of mortality.

Methods

We performed a 2-month prospective, observational cohort study in 22 closed multi-disciplinary intensive care units (ICUs). All admissions into those ICUs during the study period were screened and patients with severe sepsis or septic shock were included.

Results

A total of 484 patients, 37.3 per 100 ICU admissions were diagnosed with severe sepsis (n = 365) or septic shock (n = 119) according to clinical criteria and included into this study. The most frequent sites of infection were the lung and abdomen. The overall ICU and hospital mortality rates were 28.7% (n = 139) and 33.5% (n = 162), respectively. In multivariate analyses, APACHE II score (odds ratio[OR], 1.068; 95% confidential interval[CI], 1.027–1.109), presence of ARDS (OR, 2.676; 95%CI, 1.691–4.235), bloodstream infection (OR, 2.520; 95%CI, 1.142–5.564) and comorbidity of cancer (OR, 2.246; 95%CI, 1.141–4.420) were significantly associated with mortality.

Conclusions

Our results indicated that severe sepsis and septic shock were common complications in ICU patients and with high mortality in China, and can be of help to know more about severe sepsis and septic shock in China and to improve characterization and risk stratification in these patients.     

The Novel Role of Platelet-Activating Factor in Protecting Mice against Lipopolysaccharide-Induced Endotoxic Shock

Background

Platelet-activating factor (PAF) has been long believed to be associated with many pathophysiological processes during septic shock. Here we present novel activities for PAF in protecting mice against LPS-mediated endotoxic shock.

Principal Findings

In vivo PAF treatment immediately after LPS challenge markedly improved the survival rate against mortality from endotoxic shock. Administration of PAF prominently attenuated LPS-induced organ injury, including profound hypotension, excessive polymorphonuclear neutrophil infiltration, and severe multiple organ failure. In addition, PAF treatment protects against LPS-induced lymphocytes apoptosis. These protective effects of PAF was correlated with significantly decreases in the production of the inflammatory mediators such as TNF-α, IL-1β, IL-12, and IFN-γ, while increasing production of the anti-inflammatory cytokine IL-10 in vivo and in vitro.

Conclusions

Taken together, these results suggest that PAF may protect mice against endotoxic shock via a complex mechanism involving modulation of inflammatory and anti-inflammatory mediators.     

CRISPLD2 Is Expressed at Low Levels during Septic Shock and Is Associated with Procalcitonin

Introduction

Previous studies have shown that cysteine-rich secretory protein containing LCCL domain 2 (CRISPLD2) is a novel lipopolysaccharide (LPS)-binding protein, and the upregulation of CRISPLD2 expression protects mice against LPS-induced lethality. The aim of this study was to examine the expression of CRISPLD2 in patients with sepsis and characterize the association of this protein with procalcitonin.

Methods

The expression of CRISPLD2 was determined in100 healthy volunteers and 119 septic patients. According to the definition of sepsis, patients were divided into three groups sepsis, severe sepsis, and septic shock. The relationship between CRISPLD2 levels and procalcitonin was also examined and statistically analyzed.

Results

The CRISPLD2 levels in healthy individuals were 219.3±69.1 µg/ml. Patients with sepsis exhibited higher CRISPLD2 levels than observed in healthy individuals (p = 0.001), but CRISPLD2 expression was not upregulated in patients with septic shock. No significant differences were observed between the levels of CRISPLD2 in surviving and non-surviving spesis patients. CRISPLD2 levels were negatively correlated with procalcitonin levels(r = −0.334, p<0.001).

Conclusions

The present study is the first to demonstrate the decreased expression of CRISPLD2 in septic shock and its association with PCT in sepsis. Further studies are needed to clarify the potential association between CRISPLD2 expression and clinical outcomes to determine if it could be used as a novel sepsis biomarker.     

Changes in Circulating Procalcitonin Versus C-Reactive Protein in Predicting Evolution of Infectious Disease in Febrile,Critically Ill Patients

Objective

Although absolute values for C-reactive protein (CRP) and procalcitonin (PCT) are well known to predict sepsis in the critically ill, it remains unclear how changes in CRP and PCT compare in predicting evolution of: infectious disease, invasiveness and severity (e.g. development of septic shock, organ failure and non-survival) in response to treatment. The current study attempts to clarify these aspects.

Methods

In 72 critically ill patients with new onset fever, CRP and PCT were measured on Day 0, 1, 2 and 7 after inclusion, and clinical courses were documented over a week with follow up to Day 28. Infection was microbiologically defined, while septic shock was defined as infection plus shock. The sequential organ failure assessment (SOFA) score was assessed.

Results

From peak at Day 0–2 to Day 7, CRP decreased when (bloodstream) infection and septic shock (Day 0–2) resolved and increased when complications such as a new (bloodstream) infection or septic shock (Day 3–7) supervened. PCT decreased when septic shock resolved and increased when a new bloodstream infection or septic shock supervened. Increased or unchanged SOFA scores were best predicted by PCT increases and Day 7 PCT, in turn, was predictive for 28-day outcome.

Conclusion

The data, obtained during ICU-acquired fever and infections, suggest that CRP may be favoured over PCT courses in judging response to antibiotic treatment. PCT, however, may better indicate the risk of complications, such as bloodstream infection, septic shock, organ failure and mortality, and therefore might help deciding on safe discontinuation of antibiotics. The analysis may thus help interpreting current literature and design future studies on guiding antibiotic therapy in the ICU.     

Neutralisation of Peritoneal IL-17A Markedly Improves the Prognosis of Severe Septic Mice by Decreasing Neutrophil Infiltration and Proinflammatory Cytokines

Purpose

The current study aimed to elucidate the role of peritoneal fluid IL-17A in septic mice, and the effects of intraperitoneal or intravenous blockade of the IL-17A pathway by anti-IL17A antibody on survival, plasma, and peritoneal cavity cytokine profile in a murine caecal ligation and puncture (CLP) sepsis model. The main source of peritoneal fluid IL-17A in septic mice was identified.

Methods

Male C57BL/6 mice that underwent severe CLP or sham surgery were intraperitoneally or intravenously administered anti-IL17A antibodies or isotype antibodies. The survival rates were observed. IL-17A, TNF-α, and IL-6 cytokine levels were measured by ELISA. Surface and intracellular IL-17A immunofluorescence stains were detected by flow cytometry to identify the IL-17A–producing cells.

Results

The IL-17A level was elevated much higher and earlier in peritoneal fluid than in the blood of the CLP mice. The intraperitoneal IL-17A blockade more significantly protects against CLP-induced mortality than intravenous blockade because of decreased TNF-α and IL-6 levels both in peritoneal fluid and blood, neutrophil infiltration in the peritoneal cavity, and lung injury. γδ T lymphocytes were identified to be the main source of IL-17A in the peritoneal fluid of septic mice.

Conclusions

The earlier and higher elevated IL-17A derived from γδ T cells in peritoneal fluid plays a critical role during polymicrobial severe sepsis and effect of intraperitoneal IL-17A antibody administration superior to intravenous administration on survival of severe CLP-induced septic mice. The intraperitoneal blockade of IL-17A decreases proinflammatory cytokine production, neutrophil infiltration, and lung injury, thereby improving septic mice survival, which provides a new potential therapy target for sepsis.     

Elevated Cardiac Troponin I in Sepsis and Septic Shock: No Evidence for Thrombus Associated Myocardial Necrosis

Background

Elevated cardiac troponin I (cTnI) is frequently observed in patients with severe sepsis and septic shock. However, the mechanisms underlying cTnI release in these patients are still unknown. To date no data regarding coagulation disturbances as a possible mechanism for cTnI release during sepsis are available.

Methodology/Principal Findings

Consecutive patients with systemic inflammatory response syndrome (SIRS), sepsis or septic shock without evidence of an acute coronary syndrome were analyzed. Coagulation parameters (clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), α-angle) were assessed in native whole blood samples, and using specific activators to evaluate the extrinsic and intrinsic as well as the fibrin component of the coagulation pathway with the use of rotational thrombelastometry (ROTEM).Thirty-eight patients were included and 22 (58%) were cTnI-positive. Baseline characteristics between TnI-positive and -negative patients were similar. The CT, CFT, MCF and the α-angle were similar between the groups with trends towards shorter CT in the extrinsic and fibrin activation.

Conclusions/Significance

We found no differences in coagulation parameters analyzed with rotational thrombelastometry between cTnI-positive and -negative patients with SIRS, severe sepsis, and septic shock. These findings suggest that pathophysiological mechanisms other than thrombus-associated myocardial damage might play a major role, including reversible myocardial membrane leakage and/or cytokine mediated apoptosis in these patients.     

Endogenous Morphine Levels Are Increased in Sepsis: A Partial Implication of Neutrophils

Background

Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis.

Methodology

The presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. μ opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested.

Principal Findings

We confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca²⁺. LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca²⁺. LPS treatment increased μ opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine.

Conclusions

Our results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils.     

Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis

Background

The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting.

Methods and Findings

We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis.

Conclusion

It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.     

The Effect of Hospital Volume on Mortality in Patients Admitted with Severe Sepsis

Importance

The association between hospital volume and inpatient mortality for severe sepsis is unclear.

Objective

To assess the effect of severe sepsis case volume and inpatient mortality.

Design Setting and Participants

Retrospective cohort study from 646,988 patient discharges with severe sepsis from 3,487 hospitals in the Nationwide Inpatient Sample from 2002 to 2011.

Exposures

The exposure of interest was the mean yearly sepsis case volume per hospital divided into tertiles.

Main Outcomes and Measures

Inpatient mortality.

Results

Compared with the highest tertile of severe sepsis volume (>60 cases per year), the odds ratio for inpatient mortality among persons admitted to hospitals in the lowest tertile (≤10 severe sepsis cases per year) was 1.188 (95% CI: 1.074–1.315), while the odds ratio was 1.090 (95% CI: 1.031–1.152) for patients admitted to hospitals in the middle tertile. Similarly, improved survival was seen across the tertiles with an adjusted inpatient mortality incidence of 35.81 (95% CI: 33.64–38.03) for hospitals with the lowest volume of severe sepsis cases and a drop to 32.07 (95% CI: 31.51–32.64) for hospitals with the highest volume.

Conclusions and Relevance

We demonstrate an association between a higher severe sepsis case volume and decreased mortality. The need for a systems-based approach for improved outcomes may require a high volume of severely septic patients.     

Mortality after fluid bolus in children with shock due to sepsis or severe infection: a systematic review and meta-analysis

Introduction

Sepsis is one of the leading causes of childhood mortality, yet controversy surrounds the current treatment approach. We conducted a systematic review to assess the evidence base for fluid resuscitation in the treatment of children with shock due to sepsis or severe infection.

Methods

We searched 3 databases for randomized trials, quasi-randomized trials, and controlled before-after studies assessing children with septic shock in which at least one group was treated with bolus fluids. The primary outcome was mortality at 48 hours. Assessment of methodological quality followed the GRADE criteria. Relative risks (RRs) and 95% confidence intervals (CI) were calculated and data pooled using fixed-effects method.

Results

13 studies met our inclusion criteria. No bolus has significantly better mortality outcomes at 48 hours for children with general septic shock (RR 0.69; 95%CI 0.54–0.89), and children with malaria (RR 0.64; 95%CI 0.45–0.91) when compared to giving any bolus. This result is largely driven by a single, high quality trial (the FEAST trial). There is no evidence investigating bolus vs no bolus in children with Dengue fever or severe malnutrition. Colloid and crystalloid boluses were found to have similar effects on mortality across all sub-groups (general septic shock, malaria, Dengue fever, and severe malnutrition).

Conclusions

The majority of all randomized evidence to date comes from the FEAST trial, which found that fluid boluses were harmful compared to no bolus. Simple algorithms are needed to support health-care providers in the triage of patients to determine who could potentially be harmed by the provision of bolus fluids, and who will benefit.     

Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma

Objective

Major trauma is characterized by a pro-inflammatory response, followed by an immunosuppression. Recently, in trauma patients, the lack of recovery of monocyte Human Leukocyte Antigen DR (mHLA-DR, a biomarker of ICU-acquired immunosuppression) between days 1–2 and days 3–4 has been demonstrated to be independently associated with sepsis development. The main objective of this study was to determine whether early measurements of IL-6 (interleukin-6) and IL-10 plasma concentrations (as markers of initial severity) could improve, in association with mHLA-DR recovery, the prediction of sepsis occurrence in severe trauma patients.

Design

Prospective observational study over 24 months in a Trauma ICU at university hospital.

Patients

Trauma patients with an ISS over 25 and age over 18 were included.

Measurements and Main Results

mHLA-DR was assessed by flow cytometry, IL-6 and IL-10 concentrations by ELISA. 100 consecutive severely injured patients were monitored (mean ISS 37±10). 37 patients developed sepsis. IL-6 concentrations and slope of mHLA-DR expression between days 1–2 and days 3–4 were significantly different between septic and non-septic patients. IL-10 was not detectable in most patients. After adjustment for usual clinical confounders, when assessed as a pair, multivariate logistic regression analysis revealed that a slope of mHLA-DR expression (days 3–4/days 1–2)≤1.1 and a IL-6 concentration ≥ 67.1 pg/ml remained highly associated with the development of sepsis (adjusted OR 18.4, 95% CI 4.9; 69.4, p = .00002).

Conclusions

After multivariate regression logistic analysis, when assessed as a pair, a high IL-6 concentration and a persistent mHLA-DR decreased expression were found to be in relation with the development of sepsis with the best predictive value. This study underlines the usefulness of daily monitoring of immune function to identify trauma patients at a high risk of infection.     

An Increase in Mean Platelet Volume from Baseline Is Associated with Mortality in Patients with Severe Sepsis or Septic Shock

Introduction

Mean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (ΔMPV_72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock.

Methods

We prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including ΔMPV_72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of ΔMPV_72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis.

Results

Thirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, ΔMPV_72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01–2.06; P = 0.044).

Conclusions

An increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock.     

A biomimetic membrane device that modulates the excessive inflammatory response to sepsis

Objective

Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host''s response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis.

Design

Laboratory investigation.

Setting

University of Michigan Medical School.

Subjects

Pigs weighing 30-35 kg.

Interventions

To assess the effect of the SCD in septic shock, pigs were administered 30×10¹⁰ bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD.

Measurements and Main Results

In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation.

Conclusions

These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway.     

Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis

Background

The potential benefits of corticosteroids for septic shock may depend on initial mortality risk.

Objective

We determined associations between corticosteroids and outcomes in children with septic shock who were stratified by initial mortality risk.

Methods

We conducted a retrospective analysis of an ongoing, multi-center pediatric septic shock clinical and biological database. Using a validated biomarker-based stratification tool (PERSEVERE), 496 subjects were stratified into three initial mortality risk strata (low, intermediate, and high). Subjects receiving corticosteroids during the initial 7 days of admission (n = 252) were compared to subjects who did not receive corticosteroids (n = 244). Logistic regression was used to model the effects of corticosteroids on 28-day mortality and complicated course, defined as death within 28 days or persistence of two or more organ failures at 7 days.

Results

Subjects who received corticosteroids had greater organ failure burden, higher illness severity, higher mortality, and a greater requirement for vasoactive medications, compared to subjects who did not receive corticosteroids. PERSEVERE-based mortality risk did not differ between the two groups. For the entire cohort, corticosteroids were associated with increased risk of mortality (OR 2.3, 95% CI 1.3–4.0, p = 0.004) and a complicated course (OR 1.7, 95% CI 1.1–2.5, p = 0.012). Within each PERSEVERE-based stratum, corticosteroid administration was not associated with improved outcomes. Similarly, corticosteroid administration was not associated with improved outcomes among patients with no comorbidities, nor in groups of patients stratified by PRISM.

Conclusions

Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort.     

Lactobacillus rhamnosus GG and Bifidobacterium longum Attenuate Lung Injury and Inflammatory Response in Experimental Sepsis

Introduction

Probiotic use to prevent nosocomial gastrointestinal and potentially respiratory tract infections in critical care has shown great promise in recent clinical trials of adult and pediatric patients. Despite well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to reduce lung injury following infection and shock has not been well explored.

Objective

Evaluate if Lactobacillus rhamnosus GG (LGG) or Bifidobacterium longum (BL) treatment in a weanling mouse model of cecal ligation and puncture (CLP) peritonitis will protect against lung injury.

Methods

3 week-old FVB/N mice were orally gavaged with 200 µl of either LGG, BL or sterile water (vehicle) immediately prior to CLP. Mice were euthanized at 24 h. Lung injury was evaluated via histology and lung neutrophil infiltration was evaluated by myeloperoxidase (MPO) staining. mRNA levels of IL-6, TNF-α, MyD88, TLR-4, TLR-2, NFΚB (p50/p105) and Cox-2 in the lung analyzed via real-time PCR. TNF-α and IL-6 in lung was analyzed via ELISA.

Results

LGG and BL treatment significantly improved lung injury following experimental infection and sepsis and lung neutrophil infiltration was significantly lower than in untreated septic mice. Lung mRNA and protein levels of IL-6 and TNF-α and gene expression of Cox-2 were also significantly reduced in mice receiving LGG or BL treatment. Gene expression of TLR-2, MyD88 and NFΚB (p50/p105) was significantly increased in septic mice compared to shams and decreased in the lung of mice receiving LGG or BL while TLR-4 levels remained unchanged.

Conclusions

Treatment with LGG and BL can reduce lung injury following experimental infection and sepsis and is associated with reduced lung inflammatory cell infiltrate and decreased markers of lung inflammatory response. Probiotic therapy may be a promising intervention to improve clinical lung injury following systemic infection and sepsis.     

C-Reactive Protein/Albumin Ratio Predicts 90-Day Mortality of Septic Patients

Introduction

Residual inflammation at ICU discharge may have impact upon long-term mortality. However, the significance of ongoing inflammation on mortality after ICU discharge is poorly described. C-reactive protein (CRP) and albumin are measured frequently in the ICU and exhibit opposing patterns during inflammation. Since infection is a potent trigger of inflammation, we hypothesized that CRP levels at discharge would correlate with long-term mortality in septic patients and that the CRP/albumin ratio would be a better marker of prognosis than CRP alone.

Methods

We evaluated 334 patients admitted to the ICU as a result of severe sepsis or septic shock who were discharged alive after a minimum of 72 hours in the ICU. We evaluated the performance of both CRP and CRP/albumin to predict mortality at 90 days after ICU discharge. Two multivariate logistic models were generated based on measurements at discharge: one model included CRP (Model-CRP), and the other included the CRP/albumin ratio (Model-CRP/albumin).

Results

There were 229 (67%) and 111 (33%) patients with severe sepsis and septic shock, respectively. During the 90 days of follow-up, 73 (22%) patients died. CRP/albumin ratios at admission and at discharge were associated with a poor outcome and showed greater accuracy than CRP alone at these time points (p = 0.0455 and p = 0.0438, respectively). CRP levels and the CRP/albumin ratio were independent predictors of mortality at 90 days (Model-CRP: adjusted OR 2.34, 95% CI 1.14–4.83, p = 0.021; Model-CRP/albumin: adjusted OR 2.18, 95% CI 1.10–4.67, p = 0.035). Both models showed similar accuracy (p = 0.2483). However, Model-CRP was not calibrated.

Conclusions

Residual inflammation at ICU discharge assessed using the CRP/albumin ratio is an independent risk factor for mortality at 90 days in septic patients. The use of the CRP/albumin ratio as a long-term marker of prognosis provides more consistent results than standard CRP values alone.