Johannes Winning

Anti-platelet drugs and outcome in severe infection: Clinical impact and underlying mechanisms

Platelet activation contributes to microvascular thrombosis and organ failure in systemic inflammation. We tested the hypothesis whether anti-platelet drugs might favourably affect outcome in patients at risk for organ failure as well as in a mouse model of endotoxin shock. Two hundred twenty-four consecutive patients who were admitted for community acquired pneumonia over a time period of 5 years to a University Hospital were enrolled; about 20% of whom received anti-platelet drugs (acetylsalicylic acid, thienopyridines) for secondary prevention of cardiovascular disease. Patients with anti-platelet drugs were about 12 years old but did not differ in SOFA score and routine laboratory parameters at admission. Logistic regression and 2 × 2 table analysis in age-matched subgroups indicated that anti-platelet drugs may reduce the need of intensive care treatment (odds ratio (OR) 0.32 [95% confidential interval: 0.10–1.00] and 0.19 [0.04–0.87], respectively). In age-matched subgroups, the use of anti-platelet drugs was also associated with a shorter stay in hospital (13.9 ± 6.2 vs. 18.2 ± 10.2 days; p < 0.02). In the animal model Balb/c mice were pre-treated with clopidogrel (added to drinking water) for 4 days prior to intraperitoneal (i.p.) administration of endotoxin (lipopolsaccharide (LPS) from Escherichia coli 0111:B4). Within the first 48 hours after LPS there were no differences between clopidogrel and control animals (n = 26 each) in macro-haemodynamics. However, clopidogrel abolished the LPS-induced drop in platelet count and reduced fibrin deposition in lung tissue. Using DNA microarray technology, we could show that clopidogrel suppressed endotoxin-induced up-regulation of inflammation-relevant genes, including arachidonate-5-lipoxygenase activating protein and leukotriene B4 receptor 1. According to our data a possible benefit of anti-platelet drugs in patients on risk for systemic inflammation and organ failure should be tested in a prospective trial.

Antiplatelet drugs and outcome in mixed admissions to an intensive care unit.

Objective:Platelet activation has been implicated in microvascular thrombosis and organ failure. We tested the hypothesis that antiplatelet drugs favorably affect outcome in patients nonelectively admitted to an intensive care unit. Design:Retrospective cohort study. Setting:A 22-bed intensive care unit of a tertiary care center. Patients:Six hundred fifteen consecutive patients admitted to an intensive care unit within 24 hrs after hospitalization were enrolled, approximately 25% of whom received antiplatelet drugs (acetylsalicylic acid, clopidogrel) for secondary prevention of vascular disease. Impact of antiplatelet drugs and established risk factors on mortality were assessed by logistic regression and 2 × 2 table analysis. Interventions:None. Measurements and Main Results:Patients on antiplatelet drugs were markedly older and presented higher Acute Physiology and Chronic Health Evaluation II scores on intensive care unit admission. There was no significant difference in injury severity scores in trauma patients with (21 [range, 13–29]) or without antiplatelet drugs (18 [range, 12–29]). Using logistic regression analysis, a significant reduction of mortality was estimated for the use of antiplatelet drugs in various subgroups of patients with normal or high bleeding risk (odds ratios, 0.04–0.34). Significant benefit was also estimated by 2 × 2 table analysis of Acute Physiology and Chronic Health Evaluation II-matched samples (Acute Physiology and Chronic Health Evaluation II >20) of internal medicine patients and/or patients receiving medical treatment. No significant benefit but also no harm of antiplatelet drugs was estimated in Acute Physiology and Chronic Health Evaluation II-matched samples of patients with increased bleeding risk: patients from surgery departments overall, patients with surgical treatment, trauma, active bleeding, or transfusion (odds ratios, 0.51–0.88). Conclusions:Our data are consistent with prevention of organ dysfunction by antiplatelet drugs, which may be masked in some patients by concomitant bleeding risk. Antiplatelet drugs might offer a novel therapeutic option to prevent organ failure, at least in the absence of active bleeding. This hypothesis warrants testing in a prospective trial.

Characteristics of Clinical Sepsis Reflected in a Reliable and Reproducible Rodent Sepsis Model

BACKGROUND Sepsis models are frequently based on induction of peritonitis, with cecal ligation and puncture reflecting the prototypical model. However, there is an ongoing discussion about the limitations of these models due to their variability in progression and outcome. Since standardization is a cornerstone of experimental models, we aimed to develop a reliable and reproducible procedure for induction of peritonitis. MATERIALS AND METHODS A human stool batch was processed for -80° storage. For induction of peritonitis in fluid-resuscitated rats, a defined volume of stool suspension from this batch was injected intraperitoneally. For characterization of the model, physiologic and inflammatory changes were evaluated after sepsis induction. Survival analyses with the same batch were repeated in four independent experiments over a time period of 16 mo. RESULTS The polymicrobial infection resulted in severe peritoneal inflammation with a systemic increase in cytokines. The mortality rate at 15 h was 29% and this was reproducible over a 16 mo time period. If antibiotic treatment was applied, a 50% survival was achieved. Laboratory markers indicated a progressive multi-organ dysfunction, while blood gas analysis showed respiratory compensation of a metabolic acidosis, and maintenance of PaO(2). Intravital microscopy of the liver revealed an impaired microcirculation. A decreased hemostatic potential was demonstrated by rotational thromboelastometry. Despite clinical recovery within 3 d, surviving animals showed laboratory and histologic signs of persisting inflammation even after 2 wk. CONCLUSIONS This model reflects many features of human sepsis. Application of an infectious focus that is both quantitatively and qualitatively defined assures high reproducibility. Moreover, the procedure is simple and can be easily standardized.

Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock

Sepsis and its sequelae of multiple organ failure is one of the leading causes of death in the industrial countries. Several studies have shown that patients who are treated with low-dose acetyl salicylic acid (ASA) for secondary prevention of atherothrombosis may have a lower risk to develop organ failure in the case of critical illness. The benefit of ASA is probably due to an inhibition of platelet activation as well as an increase in the formation of anti-inflammatory lipoxin A4. On the other hand, the effect of ASA could be – at least partially – an indirect one, caused by atherosclerotic vascular diseases as the cause of ASA treatment. Atherosclerosis is considered as a moderate systemic inflammation and we hypothesise that this chronic condition could have an impact on the outcome in sepsis. To get more information on the benefit of ASA in critically ill patients and on possible interference with atherosclerotic vascular diseases, we analysed the medical records of 886 septic patients who were admitted to the surgical intensive care unit (ICU) of a university hospital. Logistic regression analysis indicated that patients who were treated during the ICU stay with ASA (100 mg/d) had a significantly lower mortality. Odds ratios (ORs; with 95% confidential intervals) of 0.56 (0.37–0.84) and 0.57 (0.39–0.83) were calculated for ICU and hospital mortality, respectively. In contrast, statin treatment did not have significant effect on mortality. Diagnosis of atherosclerotic vascular diseases according to ICD classification did not influence ICU mortality but lowered hospital mortality (OR = 0.71 (0.52–0.99)). Subgroup analysis provided preliminary evidence that clopidogrel when given as only anti-platelet drug may have a similar benefit as ASA, but the combination of ASA and clopidogrel failed to improve the outcome. The time course of plasma fibrinogen and procalcitonin levels indicate that ASA seems to reduce the activation of haemostasis and increase the resolution of inflammation. It is concluded that prospective interventional studies should be done to test the use of ASA as novel therapeutic approach in critically ill patients.

An Early Warning Scoring System to Identify Septic Patients in the Prehospital Setting: The PRESEP Score

OBJECTIVES The objective was to develop and evaluate an early sepsis detection score for the prehospital setting. METHODS A retrospective analysis of consecutive patients who were admitted by emergency medical services (EMS) to the emergency department of the Jena University Hospital was performed. Because potential predictors for sepsis should be based on consensus criteria, the following parameters were extracted from the EMS protocol for further analysis: temperature, heart rate (HR), respiratory rate (RR), oxygen saturation (SaO2 ), Glasgow Coma Scale score, blood glucose, and systolic blood pressure (sBP). Potential predictors were stratified based on inspection of Loess graphs. Backward model selection was performed to select risk factors for the final model. The Prehospital Early Sepsis Detection (PRESEP) score was calculated as the sum of simplified regression weights. Its predictive validity was compared to the Modified Early Warning Score (MEWS), the Robson screening tool, and the BAS 90-30-90. RESULTS A total of 375 patients were included in the derivation sample; 93 (24.8%) of these had sepsis, including 60 patients with severe sepsis and 12 patients with septic shock. Backward model selection identified temperature, HR, RR, SaO2 , and sBP for inclusion in the PRESEP score. Simplified weights were as follows: temperature > 38°C = 4, temperature < 36°C = 1, HR > 90 beats/min = 2, RR > 22 breaths/min = 1, SaO2 < 92% = 2, and sBP < 90 mm Hg = 2. The cutoff value for a possible existing septic disease based on maximum Youdens index was ≥4 (sensitivity 0.85, specificity 0.86, positive predictive value [PPV] 0.66, and negative predictive value [NPV] 0.95). The area under the receiver operating characteristic curve (AUC) of the PRESEP score was 0.93 (95% confidence interval [CI] = 0.89 to 0.96) and was larger than the AUC of the MEWS (0.93 vs. 0.77, p < 0.001). The PRESEP score surpassed MEWS and BAS 90-60-90 for sensitivity (0.74 and 0.62, respectively), specificity (0.75 and 0.83), PPV (0.45 and 0.51), and NPV (0.91 and 0.89). The Robson screening tool had a higher sensitivity and NPV (0.95 and 0.97), but its specificity and PPV were lower (0.43 and 0.32). CONCLUSIONS The PRESEP score could be a valuable tool for identifying septic patients in the prehospital setting in the case of suspected infection. It should be prospectively validated.

Do Aspirin and Other Antiplatelet Drugs Reduce the Mortality in Critically Ill Patients

Platelet activation has been implicated in microvascular thrombosis and organ failure in critically ill patients. In the first part the present paper summarises important data on the role of platelets in systemic inflammation and sepsis as well as on the beneficial effects of antiplatelet drugs in animal models of sepsis. In the second part the data of retrospective and prospective observational clinical studies on the effect of aspirin and other antiplatelet drugs in critically ill patients are reviewed. All of these studies have shown that aspirin and other antiplatelet drugs may reduce organ failure and mortality in these patients, even in case of high bleeding risk. From the data reviewed here interventional prospective trials are needed to test whether aspirin and other antiplatelet drugs might offer a novel therapeutic option to prevent organ failure in critically ill patients.

Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients.

Analyzing medical records of 979 patients with severe sepsis or septic shock provided some evidence that the use of low-dose aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) was associated with decreased hospital mortality. However, the benefit was abolished when aspirin and NSAIDs were given together.

Potential effect of physiotherapeutic treatment on mortality rate in patients with severe sepsis and septic shock: A retrospective cohort analysis

PURPOSE The aim of the study was to examine the onset and frequency of physiotherapeutic interventions (PTI) and their potential effects on the intensive care unit (ICU) mortality rate in patients with severe sepsis or septic shock. MATERIAL AND METHODS Retrospective data analysis. Univariate and multivariate Cox proportional-hazards regression analyses were performed. RESULTS About 6.2% of all patients (n = 999, length of ICU stay 12 days, averaged SOFA score 14) developed sepsis within three years. Of these, 77% received at least once PTI. The relative number of PTI (RNPTI index, individually calculated by the number of PTI/length of stay) in patients with sepsis was 42%. The first physiotherapeutic treatment was five days after ICU admission. Cox regression multivariate analysis adjusted by disease severity scores, sedation state and other clinical variables found RNPTI index as significant risk factor for the ICU mortality rate (hazard ratio, 0.982; 95% confidence interval, 0.974-0.990; P < .001). CONCLUSIONS Physiotherapists routinely assess and treat patients with sepsis. The frequency of PTI was associated with an improved outcome. Prospective studies are necessary to confirm the potential favorable impact.

Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model.

To the Editor: We read with great interest the study by Hagiwara et al. (1), BAdenosine Diphosphate Receptor Antagonist Clopidogrel Sulfate Attenuates LPS-Induced Systemic Inflammation in a Rat Model,[ which found that a pretreatment with clopidogrel (CS) reduced the LPS-induced increase in proinflammatory cytokines IL-6 and TNF-! and reduced LPS-induced expression of high mobility group box 1 (HMGB1) in lung and liver tissues in LPS-treated rats. In addition, LPS-induced histological alterations (e.g., interstitial edema, inflammatory cell infiltration, etc.) were attenuated in CS-pretreated rats. Although we observed similar results in LPS and sepsis models (2, 3), we could further demonstrate a potential for antiplatelet drugs in critically ill patients: In 2 clinical retrospective studies (2, 4), we tested the hypothesis whether antiplatelet drugs might favorably affect outcome in patients at risk for organ dysfunction: The first analysis included 615 patients consecutively admitted to an ICU. Approximately 25% of those patients had received a continous medication with antiplatelet drugs (acetylsalicylic acid, clopidogrel) for secondary prevention of vascular disease before admission. The impact of antiplatelet drugs and established risk factors on mortality were assessed by logistic regression and 2 2 table analysis. Patients on antiplatelet drugs were markedly older and presented higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores on ICU admission. Both, logistic regression analysis and comparison of APACHE II score-matched samples of patients (APACHE II 920) by 2 2 table analysis indicated that antiplatelet drugs were associated with substantially lower mortality in internal medicine patients (odds ratios of 0.20 and 0.36, respectively). In a second retrospective analysis, 224 patients who were consecutively admitted to a University Hospital for communityacquired pneumonia over a period of 5 years were enrolled. Twenty percent of those patients received antiplatelet drugs (acetylsalicylic acid, thienopyridines) for secondary prevention of cardiovascular disease. Patients with antiplatelet drugs were about 12 years older but did not differ in Sepsis-Related Organ Failure Assessment score and routine laboratory parameters at admission. Antiplatelet drugs were associated with decreased odds ratios for admission to ICU according to logistic regression in all patients as well as in age-matched subgroups (odds ratio, 0.32 and 0.19, respectively). In age-matched subgroups, the use of antiplatelet drugs was also associated with a shorter stay in the hospital (13.9 T 6.2 vs. 18.2 T 10.2 days; P G 0.02). Our data add evidence to the previously mentioned study by Hagiwara et al. and suggest that pretreatment with CS or other antiplatelet drugs may indeed have value as a potential therapeutic tool in systemic inflammation.

Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP and iNOS signalling

AIMS Sepsis-induced myocardial depression (SIMD), an early and frequent event of infection-induced systemic inflammatory response syndrome (SIRS), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase γ (PI3Kγ) is known to prevent β-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kγ in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kγ in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS PI3Kγ knockout mice (PI3Kγ(-/-)), mice expressing catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type mice (P3Kγ(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic inflammation and assessed for survival, cardiac autonomic nervous system function, and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyse PI3Kγ effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kγ(-/-) mice, followed by reduced contractility. In contrast, P3Kγ(+/+) mice and PI3Kγ(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kγ(+/+) and PI3Kγ(KD/KD) mice, cardiomyocytes from PI3Kγ(-/-) mice showed an enhanced and prolonged cAMP-mediated signalling upon norepinephrine and an intensified LPS-induced proinflammatory response characterized by nuclear factor of activated T-cells-mediated inducible nitric oxide synthase up-regulation. CONCLUSIONS This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses.