Improvements in Compliance of Resuscitation Bundles and Achievement of End Points After an Educational Program on the Management of Severe Sepsis and Septic Shock.
Shock. 2012 Jan 31;
Authors: Jeon K, Shin TG, Sim MS, Suh GY, Lim SY, Song HG, Jo IJ
Abstract
ABSTRACT: The objectives of this study were to determine whether an educational program could improve compliance with resuscitation bundles and the outcomes of patients with severe sepsis or septic shock and to evaluate which resuscitation bundle end points were associated with in-hospital mortality. This was a retrospective observational study of 366 patients (163 of historical controls and 203 of treatment patients) with severe sepsis or septic shock who presented to the emergency department between May 2007 and July 2009. Compliance with resuscitation bundles and achievement of the corresponding end points were compared before and after the three-month educational program. Compliance with central line insertion and monitoring of central venous pressure (CVP) (29% vs. 67%, p < 0.001) and central venous oxygen saturation (ScvO2) (25% vs. 68%, p < 0.001) was significantly improved after the educational program. The achievement of target ScvO2 within the first six hours was significantly improved (62% vs. 88%, p < 0.001). In-hospital mortality was independently associated with adequate fluid challenge (OR, 0.161; 95% CI, 0.046 – 0.559) and the achievement of target mean arterial pressure (MAP) (OR 0.056; 95% CI, 0.008 – 0.384) and ScvO2 (OR, 0.251; 95% CI, 0.072 – 0.875) among the five sepsis resuscitation bundles. In conclusion, an educational program can improve compliance with resuscitation bundles and achievement of their corresponding end points.
PMID: 22301605 [PubMed - as supplied by publisher]
Structural Changes of the Heart During Severe Sepsis or Septic Shock.
Shock. 2012 Jan 31;
Authors: Smeding L, Plötz FB, Groeneveld AB, Kneyber MC
Abstract
ABSTRACT: Cardiovascular dysfunction is common in severe sepsis or septic shock. Although functional alterations are often described, the elevated serum levels of cardiac proteins and autopsy findings of myocardial immune cell infiltration, edema and damaged mitochondria suggest that structural changes to the heart during severe sepsis and septic shock may occur and may contribute to cardiac dysfunction. We explored the available literature on structural (vs functional) cardiac alterations during experimental and human endotoxaemia and/or sepsis. Limited data suggests that the structural changes could be prevented and myocardial function improved by (pre-) treatment with platelet activating factor (PAF), ciclosporin A (CsA), glutamine, caffeine, simvastatin or caspase inhibitors.
PMID: 22301606 [PubMed - as supplied by publisher]
Guanine-Nucleotide Exchange Factor-H1 Mediates Lipopolysaccharide-Induced Interleukin-6 and Tumor Necrosis Factor α Expression in Endothelial Cells Via Activation of Nuclear Factor- kappaB.
Shock. 2012 Jan 31;
Authors: Guo F, Xing Y, Zhou Z, Dou Y, Tang J, Gao C, Huan J
Abstract
ABSTRACT: The development of sepsis is multifactorial. Tissue damage and organ dysfunction may be caused not only by the microorganisms but also by the inflammatory mediators released in response to the infection. Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels in serum are well known to be up-regulated in septic humans and can be used to predict outcome. Using human umbilical vein endothelial cells (HUVECs), we analyzed the role of Guanine-nucleotide exchange factor-H1 (GEF-H1) on lipopolysaccharide (LPS)-dependent IL-6/TNF-α expression in endothelial cells. Lipopolysaccharide upregulated IL-6 secretion in a dose- and time-dependent manner. Specific inactivation of RhoA/Cdc42/Rac1 by Clostridium difficile toxin B-10463 (TcdB-10463) reduced LPS-induced nuclear factor- kappaB (NF-κB)/p65 phosphorylation, IL-6/TNF-α messenger RNA (mRNA), and IL-6/TNF-α protein productions. GEF-H1 protein expression remained on a high level among 1 to 9 hours in response to LPS challenge of endothelial cells. Inhibition of GEF-H1 by specific siRNA or inactivation of ROCK (Rho-associated kinase) with Y-27632, not only significantly reduced LPS-induced p38 and ERK1/2 activities, but also blocked LPS-induced NF-κB translocation and activation, thereby inhibited IL-6/TNF-α mRNA and protein productions. Furthermore, SB203580 (p38 inhibitor) but not PD98059 (ERK1/2 inhibitor) blocked LPS-induced NF-κB activation, however, both inhibitors significantly suppressed IL-6/TNF-α mRNA and protein expression. In summary, our data suggest that LPS rapidly upregulates GEF-H1 expression. Activated ROCK by GEF-H1 subsequently activates p38 and ERK1/2, thereby increases IL-6/TNF-α expression in endothelial cells. P38 and ERK1/2 regulate LPS-induced IL-6/TNF-α expression through a NF-κB-dependent manner and a NF-κB-independent manner, respectively.
PMID: 22301607 [PubMed - as supplied by publisher]
ABSTRACT: Hypothermia is considered an independent predictor of death after trauma. The aim of this study was to assess these premises based on data from the TraumaRegistry DGU® (TR-DGU) using its outcome predication tool, the Revised Injury Severity Classification (RISC) score, in comparison with three previously published regression models by Shafi, Martin, and Wang. We hypothesized that body temperature on admission would improve accuracy of the RISC score. Data of 5,197 patients with documented body temperature on admission (T) and complete data for RISC score prognosis were selected from TR-DGU. Hypothermia was defined as T of 35°C or less. Patients were divided into hypothermia and normothermia group. Differences were assessed using Mann-Whitney U and chi-squared tests. Statistical significance was accepted at P < 0.01(*). Moreover, we performed multivariate logistic regression analyses using TR-DGU data on the four models (including RISC) with hospital mortality as dependant variable. Results are given as mean or odds ratio (OR) with 95% confidence intervals (95% CIs). Hypothermic patients were more severely injured (Injury Severity Score, 35.0 vs. 29.2 points*) and had higher rates of shock (38.3 vs. 16.8%*), organ failure (71.8 vs. 46%*), and sepsis (17.5 vs. 10.6%*). Survival was worse (29.2 vs. 13.7%*). Comparison of the above models revealed hypothermia as an independent risk factor (Martin: OR, 1.43 [95% CI, 2.21-1.42*]; and Wang: OR, 1.77 [95% CI, 2.21-1.42*]) only, although it would drop out from the model (RISC: OR, 1.12 [95% CI, 1.41-0.89; P = 0.33] and Shafi: OR, 1,.21 [95% CI, 1.60-0.92; P = 0.17]) as long as parameters to indicate hemorrhage and/or coagulopathy were included in sufficient number, a finding confirmed by a subsequent sensitivity analysis. We conclude that hypothermia is a result of injury severity and therefore unlikely to be an independent predictor of mortality. Our data suggest that hypothermia belongs closely to the hemorrhage/coagulopathy group of predictors.
Adenosine A2A Receptor Upregulation in Human PMNs Is Controlled by miRNA-214, miRNA-15, and miRNA-16.
Shock. 2012 Feb;37(2):156-63
Authors: Heyn J, Ledderose C, Hinske LC, Limbeck E, Möhnle P, Lindner HA, Kreth S
Abstract
ABSTRACT: Immunosuppressive signaling via the adenosine A2A receptor (A2AR) is an important pathway to control inflammation. In immune cells, expression levels of A2ARs influence responsiveness to inflammatory stimuli. However, mechanisms driving expressional changes of A2ARs are still largely elusive. In the current study, we have investigated the impact of microRNAs (miRNAs) on A2AR expression in human polymorphonuclear leukocytes (PMNs) and T cells. Bioinformatic analyses and reporter gene assays revealed that A2AR expression is controlled by miRNA-214, miRNA-15, and miRNA-16. We detected all three miRNAs in both human PMNs and T cells. However, in PMNs, up to 10-fold higher levels of miRNA-16 and miRNA-214 were detected as compared with T cells. Upon in vitro stimulation, no significant expressional changes occurred. Expression levels of all three miRNAs strongly differed between individuals. A2AR expression also exhibited significant differences between PMNs and T cells: In PMNs, more than a 60-fold increase was seen upon LPS stimulation, whereas in T cells only a 2-fold increase was observed upon anti-CD3/CD28 activation. The extent of A2AR upregulation in PMNs strongly differed between individuals (from less than 10-fold to more than 100-fold). In PMNs, the increase in A2AR mRNA expression upon stimulation was inversely correlated with the expression levels of miRNA-214, miRNA-15, and miRNA-16 (R = -0.87, P < 0.0001); no correlation was found in human T cells. These results indicate that individual miRNA profiles gain important influence on A2AR expression regulation in PMNs upon stimulation. Determination of miRNA expression levels may help to identify patients with an increased risk for severe inflammation.
LIPOCALIN-2 Is a Major Acute-Phase Protein in a Rat and Mouse Model of Sterile Abscess.
Shock. 2012 Feb;37(2):191-6
Authors: Sultan S, Pascucci M, Ahmad S, Malik IA, Bianchi A, Ramadori P, Ahmad G, Ramadori G
Abstract
Lipocalin-2 (LCN-2) is a 25-kDa secretory protein currently used as a biomarker for renal injury and inflammation. Its source and cause of the increased serum levels are unclear. The current study compares LCN-2 gene expression with known major acute-phase proteins in the liver in a rat and mouse model of turpentine oil-induced sterile abscess. Serum LCN-2 concentrations increased dramatically up to 200-fold (20 μg/mL) at 48 h after turpentine oil injection. A strong elevation of LCN-2 mRNA in rat liver was observed starting from 4 h up to 48 h after injection, with a maximum (8,738 ± 2,104-fold) at 24 h, which was further confirmed by Western blot analysis. In contrast, the increases in gene expression of α2-macroglobulin, the major acute-phase protein, and hemoxygenase 1, a positive acute-phase protein, were only 1,025 ± 505-fold and 47 ± 12-fold, respectively, during acute-phase reaction (APR). No considerable change was observed in LCN-2 mRNA in rat kidney and other organs as compared with liver. Using wild-type mice, a massive increase in gene expression of LCN-2, with a maximum of 2,498 ± 84-fold in liver, which is similar to that for serum amyloid A (2,825 ± 233-fold), a major mouse acute-phase protein. However, such an increase was significantly inhibited in interleukin 6 knockout mice during APR. Interleukin 6-treated rat hepatocytes induced a significant time-dependent upregulation of LCN-2.Lipocalin-2 is the major acute-phase protein in rat as compared with α2-macroglobulin and hemoxygenase 1 and comparable with serum amyloid A in mouse whose gene expression is mainly controlled by interleukin 6. The liver is the main source of serum LCN-2 in the case of APR. : ABBREVIATIONS-LCN-2-lipocalin-2-α2M-α2-macroglobulin-HO-1-hemoxygenase 1-IL-6-interleukin 6-SAA-serum amyloid A-TO-turpentine oil-APR-acute-phase reaction.
Endotoxemia is Associated With Partial Uncoupling of Cardiac Pacemaker From Cholinergic Neural Control in Rats.
Shock. 2012 Feb;37(2):219-27
Authors: Gholami M, Mazaheri P, Mohamadi A, Dehpour T, Safari F, Hajizadeh S, Moore KP, Mani AR
Abstract
ABSTRACT: Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. It is known that greater regularity in a complex system could indicate uncoupling of the system’s components. The present study aimed to test the hypothesis that impaired responsiveness of cardiac pacemaker to autonomic nervous system may lead to uncoupling of the cardiovascular regulatory mechanisms during systemic inflammation. Systemic inflammation was induced by intraperitoneal injection of endotoxin (lipopolysaccharide, 1 mg/kg) in rats. Cardiovascular signals were recorded in conscious animals using a telemetric system. Heart rate dynamics was analyzed using Poincaré plot, and cardiac cycle regularity was assessed by sample entropy analysis. Spontaneously beating atria were isolated, and chronotropic responsiveness to adrenergic and cholinergic stimulation was assessed using standard organ bath. Sample entropy decreased significantly 4 h after endotoxin injection in conscious rats. Vagal modulation of cardiac cycle (as assessed by Poincaré plot) also exhibited a significant reduction in endotoxemic rats. Acute endotoxin challenge was associated with a significant hyporesponsiveness of isolated spontaneously beating atria to cholinergic stimulation. The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin-treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation.
Abnormal Baroreflex Function is Dissociated from Central Angiotensin II Receptor Expression in Chronic Heart Failure.
Shock. 2012 Jan 17;
Authors: Fahim M, Gao L, Mousa TM, Liu D, Cornish KG, Zucker IH
Abstract
ABSTRACT: Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (bpm/mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals; control, one week CHF, two week CHF and three week CHF. CHF was induced by ventricular pacing at 360 bpm and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening and an increase in LVESD & LVEDD was observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA(% of maximum) after 1 week of pacing, a small but insignificant rise in RSNA was seen at 2 weeks and a significant rise in RSNA was observed at 3 weeks. AT1 receptor protein (Western Blot) and mRNA (RT-PCR) expression in the rostral ventrolateral medulla (RVLM) exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympatho-excitation and over-expression of AT1 receptors with the progression of CHF causing further impairment of cardiovascular control.
PMID: 22258229 [PubMed - as supplied by publisher]
Delta Neutrophil Index (DN): A Promising Diagnostic and Prognostic Marker for Sepsis.
Shock. 2012 Jan 17;
Authors: Seok Y, Choi JR, Kim J, Kim YK, Lee J, Song J, Kim SJ, Lee KA
Abstract
ABSTRACT: Delta neutrophil index (DN) is the immature granulocyte fraction provided by a blood cell analyzer (ADVIA 2120; Siemens Healthcare Diagnostics, IL), which is determined by subtracting the fraction of mature polymorphonuclear leukocytes from the sum of myeloperoxidase (MPO)-reactive cells. The purpose of this study is to define the role of DN in differential diagnosis and prognosis prediction of patients with sepsis. Hospital records of 273 patients were retrospectively collected: 47 with systemic inflammatory response syndrome (SIRS), 78 with sepsis, 51 with severe sepsis, and 97 controls. DN and C-reactive protein (CRP) data on the day of the first blood culture were compared among the groups and 28-day mortality associated with sepsis was assessed. Median values of DN were 0.0% (interqurtile range [IQR], 0.0-0.0) in the control group, 0.8% (0.0-1.7) in the SIRS group, 3.4% (1.5-5.3) in the sepsis group, and 18.6% (9.3-24.7) in the severe sepsis group. Furthermore, there were significant differences among the groups. The receiver operating characteristic curves showed that DN was a better predictor of sepsis than CRP. The best cut-off value for DN for predicting sepsis was 2.7%. DN was significantly higher in those who died than in the survivors (median [IQR]: 11.5% [3.5-25.0] vs 4.7% [2.2-10.6], p=0.008) and was identified to be an independent predictor for 28-day mortality in patients with sepsis by Cox proportional hazards model. DN may serve as a facile and useful marker for early diagnosis and prognostic assessment of patients with sepsis, as it is included in a routine complete blood count.
PMID: 22258230 [PubMed - as supplied by publisher]
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