Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department.

OBJECTIVES: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. DESIGN: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. SETTING: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). PATIENTS: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. CONCLUSIONS: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.

Computed tomography in patients with sepsis presenting to the emergency department: exploring its role in light of patient outcomes.

OBJECTIVES: This study aimed to explore the role of CT in septic patients presenting to the emergency department (ED). MATERIALS AND METHODS: We performed a retrospective secondary analysis of 192 septic patients from a prospective observational study, i.e., the "LIFE POC" study. Sepsis was diagnosed in accordance with the Sepsis-3 definition. Clinical and radiological data were collected from the hospital administration and radiological systems. Information on mortality and morbidity was collected. Time-to-CT between CT scan and sepsis diagnosis (ttCTsd) was calculated. Diagnostic accuracy was assessed with the final sepsis source as reference standard. The reference standard was established through the treating team of the patient based on all available clinical, imaging, and microbiological data. RESULTS: Sixty-two of 192 patients underwent a CT examination for sepsis focus detection. The final septic source was identified by CT in 69.4% (n = 43). CT detected septic foci with 81.1% sensitivity (95% CI, 68.0-90.6%) and 55.6% specificity (95% CI, 21.2-86.3%). Patients with short versus long ttCTsd did not differ in terms of mortality (16.1%, n = 5 vs 9.7, n = 3; p = 0.449), length of hospital stay (median 16 d, IQR 9 d 12 h-23 d 18 h vs median 13 d, IQR 10 d 00 h-24 d 00 h; p = 0.863), or duration of intensive care (median 3d 12 h, IQR 2 d 6 h-7 d 18 h vs median 5d, IQR 2 d-11 d; p = 0.800). CONCLUSIONS: Our findings show a high sensitivity of CT in ED patients with sepsis, confirming its relevance in guiding treatment decisions. The low specificity suggests that a negative CT requires further ancillary diagnostic tests for focus detection. The timing of CT did not affect morbidity or mortality outcomes. CLINICAL RELEVANCE STATEMENT: In patients with sepsis who present to the ED, CT can be used to identify infectious foci on the basis of clinical suspicion, but should not be used as a rule-out test. Scientific evidence for the optimal timing of CT beyond clinical decision-making is currently missing, as potential mortality benefits are clouded by differences in clinical severity at the time of ED presentation. KEY POINTS: • In patients with sepsis who present to the ED, CT for focus identification has a high sensitivity and can thereby be valuable for patient management. • As the specificity is considerably lower, a thorough microbiological assessment is important in these cases. • The timing of CT did not affect morbidity and mortality outcomes in this study, which might be due to variability in clinical severity at the time of ED presentation.

Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching.

OBJECTIVE: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS: Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Community-acquired pneumonia as medical emergency: predictors of early deterioration.

BACKGROUND: Early organ dysfunction determines the prognosis of community-acquired pneumonia (CAP), and recognition of CAP as a medical emergency has been advocated. OBJECTIVE: To characterise patients with 'emergency CAP' and evaluate predictors for very early organ failure or death. METHODS: 3427 prospectively enrolled patients of the CAPNETZ cohort were included. Emergency CAP was defined as requirement for mechanical ventilation or vasopressor support (MV/VS) or death within 72 h and 7 days after hospital admission, respectively. To determine independent predictors, multivariate Cox regression was employed. The ATS/IDSA 2007 minor criteria were evaluated for prediction of emergency CAP in patients without immediate need of MV/VS. RESULTS: 140 (4%) and 173 (5%) patients presented with emergency CAP within 3 and 7 days, respectively. Hospital mortality of patients presenting without immediate need of MV/VS was highest. Independent predictors of emergency CAP were the presence of focal chest signs, home oxygen therapy, multilobar infiltrates, altered mental status and altered vital signs (hypotension, raised respiratory or heart rate, hypothermia). The ATS/IDSA 2007 minor criteria showed a high sensitivity and negative predictive value, whereas the positive predictive value was low. Reduction to 6 minor criteria did not alter accuracy. CONCLUSIONS: Emergency CAP is a rare but prognostic relevant condition, mortality is highest in patients presenting without immediate need of MV/VS. Vital sign abnormalities and parameters indicating acute organ dysfunction are independent predictors, and the ATS/IDSA 2007 minor criteria show a high negative predictive value.

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.

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.

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.

Diagnostic Performance of Procalcitonin for the Early Identification of Sepsis in Patients with Elevated qSOFA Score at Emergency Admission.

Infectious biomarkers such as procalcitonin (PCT) can help overcome the lack of sensitivity of the quick Sequential Organ Failure Assessment (qSOFA) score for early identification of sepsis in emergency departments (EDs) and thus might be beneficial as point-of-care biomarkers in EDs. Our primary aim was to investigate the diagnostic performance of PCT for the early identification of septic patients and patients likely to develop sepsis within 96 h of admission to an ED among a prospectively selected patient population with elevated qSOFA score. In a large multi-centre prospective cohort study, we included all adult patients (n = 742) with a qSOFA score of at least 1 who presented to the ED. PCT levels were measured upon admission. Of the study population 27.3% (n = 202) were diagnosed with sepsis within the first 96 h. The area under the curve for PCT for the identification of septic patients in EDs was 0.86 (95% confidence interval (CI): 0.83-0.89). The resultant sensitivity for PCT at a cut-off of 0.5 µg/L was 63.4% (95% CI: 56.3-70.0). Furthermore, specificity was 89.2% (95% CI: 86.3-91.7), the positive predictive value was 68.8% (95% CI: 62.9-74.2), and the negative predictive value was 86.7% (95% CI: 84.4-88.7). The early measurement of PCT in a patient population with elevated qSOFA score served as an effective tool for the early identification of sepsis in ED patients.

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 x 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 x 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.

Effect of positive end-expiratory pressure and positioning on jugular vein expansion in emergency department patients.

OBJECTIVE: Guidelines recommend Trendelenburg position for central venous cannulation. Critically ill patients in the emergency department often do not tolerate this positioning or have contraindications. Thirty-degree dorsal elevated position with positive end-expiratory pressure by noninvasive ventilation could pose an alternative. This is the first trial to investigate the feasibility of alternative for central venous cannulation in critically ill emergency department patients. METHODS: Ninety-one critically ill patients in the emergency department of Jena University Hospital were examined between August 2014 and May 2015. The cross-sectional area of the right internal jugular vein was measured in 3 different positions: 30° elevation, supine, and Trendelenburg position. Measurements were repeated with a continuous application of noninvasive ventilation. RESULTS: Cross-sectional area of the right internal jugular vein in Trendelenburg position was largest (0.99 ± 0.66 cm) compared to supine (0.57 ± 0.58 cm) and 30° elevated position (0.25 ± 0.41 cm). In 30° elevated positioning, application of positive end-expiratory pressure significantly enlarged cross-sectional area (0.62 ± 0.70 cm). Noninvasive ventilation was a well-tolerated procedure (98%). In 30° elevated positioning with positive end-expiratory pressure a safe puncture (cross-sectional area ≥ 0.4 cm) could be expected in 68.1% of cases. CONCLUSION: Thirty-degree elevated positioning with positive end-expiratory pressure via noninvasive ventilation could be a safe and well-tolerated alternative for central venous cannulation, especially for critically ill patients in emergency department unable to remain in Trendelenburg position. This proof-of-concept trial enables further studies with actual central venous cannulation.

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 x 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.

German critical incident reporting system database of prehospital emergency medicine: Analysis of reported communication and medication errors between 2005-2015.

BACKGROUND: Communication failure in prehospital emergency medicine can affect patient safety as it does in other areas of medicine as well. We analyzed the database of the critical incident reporting system for prehospital emergency medicine in Germany retrospectively regarding communication errors. METHODS: Experts of prehospital emergency medicine and risk management screened the database for verbal communication failure, non-verbal communication failure and missing communication at all. RESULTS: Between 2005 and 2015, 845 reports were analyzed, of which 247 reports were considered to be related to communication failure. An arbitrary classification resulted in six different kinds: 1) no acknowledgement of a suggestion; 2) medication error; 3) miscommunication with dispatcher; 4) utterance heard/understood improperly; 5) missing information transfer between two persons; and 6) other communication failure. CONCLUSION: Communication deficits can lead to critical incidents in prehospital emergency medicine and are a very important aspect in patient safety.

The impact of cardiac ischemia and reperfusion on markers of activated haemostasis and fibrinolysis during cardiopulmonary bypass: comparison of plasma levels in arterial and coronary venous blood.

INTRODUCTION: Activation of coagulation and fibrinolysis is common among patients undergoing cardiopulmonary bypass (CPB) surgery. Little is known, however, about the impact of myocardial ischemia and reperfusion on coagulation activation and fibrinolysis in this clinical setting. STUDY DESIGN AND METHODS: We determined the levels of coagulation activation and fibrinolysis markers (CAFM) in 19 patients with severe coronary heart disease (CHD) during CPB surgery. FXIIa, tissue factor (TF), FVIIa, tissue plasminogen activator/plasminogen activator inhibitor-1 complexes (tPA/PAI-1), prothrombin fragments 1+2 (F1+2), D-dimers (DD) and plasmin-plasmin inhibitor complexes (PPI) were measured at baseline, prior to and after cardioplegic myocardial ischemia. Simultaneous blood samples were drawn from the aorta and the coronary sinus to evaluate arteriovenous CAFM plasma level gradients. RESULTS: Myocardial ischemia induced significant increases in gradients of FXIIa and F1+2 levels across the coronary circulation without influencing systemic levels of these markers significantly. Systemic levels of FXIIa, tPA/PAI-1, F1+2, DD and PPI increased significantly during CPB operation. There was a significant linear correlation between FXIIa, FVIIa, F1+2, DD and PPI. CONCLUSIONS: Myocardial ischemia induces contact activation and thrombin generation rather than release of tPA and might thus contribute to postoperative thromboembolic complications. Surgery itself and CPB cause activation of coagulation and fibrinolysis as already described. A significant association between FXIIa, FVIIa, F1+2, DD and PPI suggests a relationship between contact activation, thrombin generation, fibrin formation and fibrinolysis.

Design and effectiveness of a membrane-pump-driven ventilator for mice.

To perform mechanical ventilation of mice in the absence of highly expensive commercially available devices, we developed a membrane-pump-driven respirator and studied its practicability. The continuous airflow generated by the membrane pump was changed into an intermittent flow by using a multifunction timer. Tidal volume was adjusted by a rotary dimmer regulating the electric power onto the pump. The expiration air left the circuit through openings at the tube connection. Mice were ventilated with room air for 5 h with a tidal volume of approximately 200 muL. In group 1 (n = 6), ventilation was performed with a frequency of 110 min-1, in group 2 (n = 6) with a frequency of 150 min-1. Spontaneously breathing anesthetized mice (n = 6) served as controls. In addition we performed single-lung open-chest ventilation for 1 h in two animals. The parameters of arterial blood gas analyses were within the normal range except for moderate hyperventilation in group 2. Single-lung ventilation led to a significant decline (P < 0.05) of pO2 and SO2, whereas the pCO2 remained within the normal range. Respiratory rate, tidal volume and pressure limitation can be adjusted for optimal ventilation. In addition, the device provides a minimalized dead space and impedes potential alveolar damage caused by negative pressure generated by spontaneous inspiration during positive-pressure ventilation.

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 ß-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.

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 Youden's 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.

Quantifying the Hawthorne Effect in Hand Hygiene Compliance Through Comparing Direct Observation With Automated Hand Hygiene Monitoring.

OBJECTIVE: To quantify the Hawthorne effect of hand hygiene performance among healthcare workers using direct observation. DESIGN: Prospective observational study. SETTING: Intensive care unit, university hospital. METHODS: Direct observation of hand hygiene compliance over 48 audits of 2 hours each. Simultaneously, hand hygiene events (HHEs) were recorded using electronic alcohol-based handrub dispensers. Directly observed and electronically recorded HHEs during the 2 hours of direct observation were compared using Spearman correlations and Bland-Altman plots. To quantify the Hawthorne effect, we compared the number of electronically recorded HHEs during the direct observation periods with the re-scaled electronically recorded HHEs in the 6 remaining hours of the 8-hour working shift. RESULTS: A total of 3,978 opportunities for hand hygiene were observed during the 96 hours of direct observation. Hand hygiene compliance was 51% (95% CI, 49%-53%). There was a strong positive correlation between directly observed compliance and electronically recorded HHEs (ρ=0.68 [95% CI, 0.49-0.81], P<.0001). In the 384 hours under surveillance, 4,180 HHEs were recorded by the electronic dispensers. Of those, 2,029 HHEs were recorded during the 96 hours in which direct observation was also performed, and 2,151 HHEs were performed in the remaining 288 hours of the same working shift that were not under direct observation. Healthcare workers performed 8 HHEs per hour when not under observation compared with 21 HHEs per hour during observation. CONCLUSIONS: Directly and electronically observed HHEs were in agreement. We observed a marked influence of the Hawthorne effect on hand hygiene performance.

Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1-adrenoceptor stimulation.

Induction of heme oxygenase (HO)-1 may confer hepatocellular protection, e.g., in reperfusion injury. Previous reports suggest that intracellular cAMP up-regulates HO-1. The aim of the present study was to assess the role of adrenoceptor agonists as a means to induce HO-1 and to assess molecular mechanisms of HO-1 gene expression by adrenoceptor agonists. Induction of HO-1 in primary cultures of hepatocytes and in rat liver in vivo was assessed by Northern blot, Western blot, and immunohistochemistry. The beta-receptor agonists (+/-)isoproterenol and (-)isoproterenol induced HO-1 in primary cultures of hepatocytes but not the inactive enantiomer (+)isoproterenol. No induction of HO-1 was observed after alpha1, alpha2, beta2, or beta 3 agonists. beta1-Receptor agonists dobutamine and xamoterol induced HO-1 dose dependently, whereas the beta1-receptor antagonist metoprolol attenuated HO-1 induction by beta1-receptor agonists. Furthermore, 8 Br-cAMP and forskolin induced HO-1. Inhibition of protein kinase A (PKA) abolished induction by dobutamine and 8 Br-cAMP. Parallel changes were observed for the transcription factor AP-1. In vivo infusion of dobutamine for 6 h induced HO-1 in rat livers. Immunohistochemical detection of HO-1 revealed a pericentral expression pattern of HO-1 in hepatocytes, i.e., the area at risk for ischemia/reperfusion injury. These results suggest induction of HO-1 by beta1-adrenoceptor agonists via the PKA pathway in hepatocytes, reflecting a potential means for "pharmacological preconditioning."

Long-term cell survival and hemodynamic improvements after neonatal cardiomyocyte and satellite cell transplantation into healed myocardial cryoinfarcted lesions in rats.

Cell engraftment is a new strategy for the repair of ischemic myocardial lesions. The hemodynamic effectiveness of this strategy, however, is not completely elucidated yet. In a rat model of cryothermia-induced myocardial dysfunction, we investigated whether syngeneic transplantation of neonatal cardiomyocytes or satellite cells is able to improve left ventricular performance. Myocardial infarction was induced in female Lewis rats by a standardized cryolesion to the obtuse margin of the left ventricle. After 4 weeks, 5 x 10(6) genetically male neonatal cardiomyocytes (n = 16) or satellite cells (n = 16) were engrafted into the myocardial scar. Sham-transplanted animals (n = 15) received injections with cell-free medium. Sham-operated animals (n = 15) served as controls. Left ventricular performance was analyzed 4 months after cell engraftment. Chimerism after this sex-mismatched transplantation was evaluated by detection of PCR-amplified DNA of the Y chromosome. The average heart weight of the infarcted animals significantly exceeded that of controls (p < 0.05). In sham-transplanted animals, mean aortic pressure, left ventricular systolic pressure, aortic flow (indicator of cardiac output), and left ventricular systolic reserve were significantly lower (p < 0.05) compared with sham-operated controls. This was associated with deterioration of ventricular diastolic function (maximal negative dP/dt, time constants of isovolumic relaxation; p < 0.05). Transplantation of satellite cells was found more effective than transplantation of neonatal cardiomyocytes, resulting in i) normalization of mean aortic pressure compared with sham-operated controls, and ii) significantly improved left ventricular systolic pressure and aortic flow (p < 0.05) compared with sham-transplanted animals. Left ventricular systolic reserve and diastolic function, however, were improved by neither satellite cell nor neonatal cardiomyocyte transplantation. Analysis of male genomic DNA revealed 3.98 +/- 2.70 ng in hearts after neonatal cardiomyocyte engraftment and 6.16 +/- 4.05 ng in hearts after satellite cell engraftment, representing approximately 10(3) viable engrafted cells per heart. Our study demonstrates i) long-term survival of both neonatal cardiomyocytes and satellite cells after transplantation into cryoinfarcted rat hearts, ii) slight superiority of satellite cells over neonatal cardiomyocytes in improving global left ventricular pump performance, and iii) no effect of both transplant procedures on diastolic dysfunction.

Transit thrombus entrapped in a patent foramen ovale.

We describe the case of a 39-year-old man with a diagnosis of inferior vena cava compression caused by metastases of a testicular seminoma, who developed massive pulmonary embolism. Emergency operation was performed because of acute hemodynamic deterioration. Preoperatively, a free-floating mass was seen echocardiographically in the right atrium. Intraoperatively, a thrombus entrapped in a patent foramen ovale with a short free-floating end in the left atrium and a long end in the right atrium was found in addition to the pulmonary emboli. The thrombus was removed, the foramen ovale was closed by direct suture, and pulmonary embolectomy was performed. Histological examination confirmed thrombi but no malignant tissue. Further diagnostic studies documented a malignant seminoma with paraaortic lymph node metastases giving rise to the thrombembolism. Three years after oncologic therapy, he is alive and free from recurrence of embolic and malignant disease.