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      Sustained Elevation of Resistin, NGAL and IL-8 Are Associated with Severe Sepsis/Septic Shock in the Emergency Department

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          Abstract

          Objective

          To identify biomarkers which distinguish severe sepsis/septic shock from uncomplicated sepsis in the Emergency Department (ED).

          Methods

          Patients with sepsis underwent serial blood sampling, including arrival in the ED and up to three subsequent time points over the first 24 hours. Messenger RNA (mRNA) levels of 13 genes representing arms of the innate immune response, organ dysfunction or shock were measured in peripheral blood leucocytes using quantitative PCR, and compared with healthy controls. Serum protein concentrations of targets differentially expressed between uncomplicated sepsis and severe sepsis/septic shock were then measured at each time point and compared between the two patient groups.

          Results

          Of 27 participants (median age 66 years, (IQR 35, 78)), 10 had uncomplicated sepsis and 17 had sepsis with organ failure (14 septic shock; 3 had other sepsis-related organ failures). At the time of first sample collection in the ED, gene expression of Interleukin (IL)-10 and Neutrophil Gelatinase Associated Lipocalin (NGAL) were significantly higher in severe sepsis than uncomplicated sepsis. Expression did not significantly change over time for any target gene. Serum concentrations of IL-6, IL-8, IL-10, NGAL and Resistin were significantly higher in severe sepsis than uncomplicated sepsis at the time of first sample collection in the ED, but only IL-8, NGAL and Resistin were consistently higher in severe sepsis compared to uncomplicated sepsis at all time points up to 24 h after presentation.

          Conclusions

          These mediators, produced by both damaged tissues and circulating leukocytes, may have important roles in the development of severe sepsis. Further work will determine whether they have any value, in addition to clinical risk parameters, for the early identification of patients that will subsequently deteriorate and/or have a higher risk of death.

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          Most cited references 25

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          Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

          Objective To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock,” published in 2004. Design Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. Methods We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation [1] indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations [2] indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. Results Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥ 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B). Conclusion There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.
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            The effect of age on the development and outcome of adult sepsis.

            Sepsis is an increasingly common and lethal medical condition that occurs in people of all ages. The influence of age on sepsis risk and outcome is incompletely understood. We sought to determine the independent effect of age on the incidence, severity, and outcome of adult sepsis. Longitudinal observational study using national hospital discharge data. Approximately 500 geographically separated nonfederal acute care hospitals in the United States. Patients were 10,422,301 adult sepsis patients hospitalized over 24 yrs, from 1979 to 2002. None. Incident sepsis cases were age adjusted and characterized by demographics, sources and types of infection, comorbid medical conditions, and hospital discharge status. Elderly patients (> or = 65 yrs of age) accounted for 12% of the U.S. population and 64.9% of sepsis cases, yielding a relative risk of 13.1 compared with younger patients (95% confidence interval, 12.6-13.6). Elderly patients were more likely to have Gram-negative infections, particularly in association with pneumonia (relative risk, 1.66; 95% confidence interval, 1.63-1.69) and to have comorbid medical conditions (relative risk, 1.99; 95% confidence interval, 1.92-2.06). Case-fatality rates increased linearly by age; age was an independent predictor of mortality in an adjusted multivariable regression (odds ratio, 2.26; 95% confidence interval, 2.17-2.36). Elderly sepsis patients died earlier during hospitalization, and elderly survivors were more likely to be discharged to a nonacute health care facility. The incidence of sepsis is disproportionately increased in elderly adults, and age is an independent predictor of mortality. Compared with younger sepsis patients, elderly nonsurvivors of sepsis die earlier during hospitalization and elderly survivors more frequently require skilled nursing or rehabilitative care after hospitalization. These findings have implications for patient care and health care resource prioritization and provide insights for expanded scientific investigations and potential patient interventions.
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              Severe sepsis and septic shock.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                24 October 2014
                : 9
                : 10
                Affiliations
                [1 ]Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, Australia
                [2 ]Discipline of Emergency Medicine, School of Primary, Aboriginal and Rural Health Care, University of Western Australia, Perth, Australia
                [3 ]Emergency Department, Armadale Health Service, Perth, Australia
                [4 ]Emergency Department, Royal Perth Hospital, Perth, Australia
                University of Leicester, United Kingdom
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SM SS CN PvE SB. Performed the experiments: CN. Analyzed the data: SM SS SB. Wrote the paper: SM SS DF GA SB. Recruited patients and reviewed clinical data: SM DF GA SB.

                Article
                PONE-D-14-20722
                10.1371/journal.pone.0110678
                4208806
                25343379

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 9
                Funding
                SB is supported by a NHMRC Career Development Fellowship Award ID1023265. Additional funding was received from the Royal Perth Hospital Medical Research Foundation and the University of Western Australia. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Biomarkers
                Immunology
                Clinical Immunology
                Infectious Disease Immunology
                Molecular Biology
                Molecular Biology Techniques
                Medicine and Health Sciences
                Clinical Medicine
                Critical Care and Emergency Medicine
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Sepsis
                Severe Sepsis
                Research and Analysis Methods
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. Our data is now publicly available via Research Data Online@ 123456UWA and has been assigned the identifier https://researchdataonline.research.uwa.edu.au/handle/123456789/1702.

                Uncategorized

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