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Summary While prasugrel is indicated for the treatment of myocardial infarction, its effects in the most severely affected patients requiring intensive care is unknown, so that we measured the antiplatelet effects and sparse pharmacokinetics of prasugrel in critically ill patients. Twenty-three patients admitted to medical intensive care units, who were treated with 10 mg prasugrel once daily, were included in this prospective trial. Critically ill patients responded poorly to daily prasugrel treatment: adenosine diphosphate (ADP)-induced aggregation in whole blood classified 65 % (95 % confidence intervals (CI) 43–84 %) of patients as having high on treatment platelet reactivity, platelet function under high shear rates even 74 % (95 %CI 52–90 %). There was only limited additional inhibition provided 2 hours after the next dose of prasugrel. In contrast, insufficient inhibition of the target was only seen in 26 % (95 %CI 10–48 %) of patients as measured by the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Low effective plasma levels of prasugrel active metabolite were measured at trough [0.5 (quartiles 0.5–1.1) ng/ml at baseline], and 2 hours after intake [5.7 (3.8–9.8) ng/ml], but showed coefficients of variation of ~70 %. In sum, inhibition of platelet aggregation by prasugrel is not uniform but highly variable in critically ill patients, similar to clopidogrel in a general population. The pharmacokinetic measurements indicate that poor absorption/metabolism of prasugrel may partly contribute while inflammation induced heightened intrinsic platelet reactivity may also play a role. Supplementary Material to this article is available online at www.thrombosis-online.com . Note: This work was performed at the Medical University of Vienna, Austria.

Hypoxic hepatitis (HH) is a frequent and life-threatening complication associated with states of oxygen depletion in critically ill patients. Ischemia and reperfusion contribute to liver injury in HH. Experimental data suggest beneficial effects of statins in hepatic ischemia/reperfusion injury. This study was conducted to investigate whether statin treatment prior to intensive care unit (ICU) admission affects incidence rates and severity of HH.Eight hundred fifty-one patients admitted consecutively to three medical ICUs between December 2008 and December 2009 were prospectively screened for new occurrence of HH within 48 h following ICU admission. Statin treatment prior to ICU admission was assessed. 28-day-, 90-day-, and 1-year-survival as well as new-onset of complications in HH patients were prospectively documented.Eighty-seven patients (10%) developed HH. Statin treatment prior to ICU admission was significantly associated with decreased incidence of HH within 48 h after ICU admission in the multivariate analysis (adjusted OR=0.42 (95% CI 0.19-0.95); p0.05). Cardiogenic shock (p0.001), septic shock (p0.001) and active alcohol consumption (p0.01) were identified as independent risk factors for development of HH. 28-day-, 90-day-, and 1-year-mortality rates in HH were 58%, 67%, and 74%, respectively. Statins were associated with improved 28-day-survival in the total study cohort (p0.05), but did not affect 90-day- and 1-year-mortality, respectively.Cardiogenic shock, septic shock, and active alcohol consumption were independent factors predisposing patients to new onset of HH. Statin treatment prior to ICU admission was the only protective factor regarding the new occurrence of HH in critically ill patients.

SummaryAlthough patients admitted to an intensive care unit (ICU) suffer from various pathologies, many develop a systemic inflammatory response syndrome (SIRS). As key regulators of innate immunity, monocytes may be crucially involved in SIRS development. Monocytes can be distinguished into three subsets: Classical monocytes (CD14++CD16−; CM), non-classical monocytes (CD14+CD16++CCR2−; NCM) and intermediate monocytes (CD14++CD16+CCR2+; IM). The aim of this prospective, observational study was to analyse whether monocyte subset distribution is associated with 30-day survival in critically ill patients. A total of 195 consecutive patients admitted to a cardiac ICU at a tertiary-care centre were enrolled, blood was taken at admission and after 72 hours and monocyte subset distribution was analysed. Mean APACHE II score was 19.5 ± 8.1 and 30-day mortality was 25.4 %. At admission, NCM were significantly lower in non-survivors as compared to survivors [2.7 (0.4–5.5) vs 4.2 (1.6–7.5)%; p=0.012] whereas CM and IM did not differ according to 30-day survival. In contrast, 72 hours after admission, monocyte subset distribution shifted towards an increased proportion of IM [8.2 (3.9–13.2) vs 4.2 (2.3–7.9)%; p=0.003] with a concomitant decrease of CM [86.9 (78.6–89.2) vs 89.6 (84.9–93.1)%; p=0.02] in non-survivors vs survivors, respectively. NCM at day 3 were not associated with death at 30 days. These results were independent from age, gender, CRP, APACHE II score and primary diagnosis. In conclusion, circulating monocyte subsets are associated with 30-day mortality in critically ill patients. The innate immune system as reflected by monocyte subset distribution may play a major role in ICU outcome despite varying admittance pathologies.Supplementary Material to this article is available online at www.thrombosis-online.com.

Background Hypoxic hepatitis (HH) is a frequent and potentially life-threatening event typically occurring in critically ill patients as a consequence of hemodynamic impairment. While acute kidney injury (AKI) has been well described in patients with acute liver failure, incidence and outcome of AKI accompanying HH are unclear. The aim of this study was to assess incidence, clinical implications and outcome of AKI and renal replacement therapy (RRT) in critically ill patients with HH. Methods A total of 1948 consecutive critically ill admissions were studied at the Medical University of Vienna. Laboratory and clinical parameters as well as the presence of HH and AKI were assessed on a daily basis. Outcome, renal recovery and length of stay were assessed and documented, and patients were followed for 1 year. Results A total of 295 admissions (15 %) developed HH. Main precipitators were cardiogenic (44 %) and septic shock (36 %). Occurrence of HH was significantly associated with AKI [OR 4.50 (95 % CI 3.30–6.12)] and necessity of renal replacement therapy [RRT; OR 3.36 (95 % CI 2.58–4.37)], p

Disturbances of coagulation and hemostasis are common in patients with liver cirrhosis. The typical laboratory pattern mimics disseminated intravascular coagulation (DIC). The aim of this study was to assess the impact of routine coagulation parameters in critically ill cirrhosis patients with regard to new onset of major bleeding and outcome. A total of 1,493 critically ill patients were studied prospectively. Routine coagulation parameters were assessed, and the DIC score was calculated based on platelets, fibrinogen, d-dimer, and prothrombin index. New onset of major bleeding during the stay at the intensive care unit and mortality were assessed. Patients were followed for 1 year. Two hundred eleven patients of the cohort had liver cirrhosis. Platelets, fibrinogen, prothrombin index, activated partial thromboplastin time, and d-dimer as well as the DIC score differed significantly between patients with and without cirrhosis (P0.001 for all). Moreover, fibrinogen, platelets, and activated partial thromboplastin time (but not prothrombin index) differed significantly between cirrhosis patients with and without major bleeding (P0.01 for all). Bleeding on admission, platelet count3010(9) /L, fibrinogen level60 mg/dL, and activated partial thromboplastin time values100 seconds were the strongest independent predictors for new onset of major bleeding in multivariate regression analysis. One-year mortality in cirrhosis patients with and without major bleeding was 89% and 68%, respectively (P0.05 between groups).Abnormal coagulation parameters and high DIC scores (primarily due to fibrinogen and platelets) correspond to increased bleeding risk in patients with liver cirrhosis in the intensive care unit, and fibrinogen and platelet count were identified as the best routine coagulation parameters for prediction of new onset of major bleeding; however, further studies are required to evaluate the potential therapeutic implications of these findings. (Hepatology 2016;64:556-568).

Aim In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls.

Background Veno-arterial extracorporeal membrane oxygenation (ECMO) is rapidly evolving as bailout option in patients with refractory cardiogenic shock after cardiovascular surgery (CV). Cardiac arrest represents a common and severe complication in the immediate post-operative phase. We therefore evaluated the impact of cardiac arrest at time of ECMO implantation on short- and long-term mortality in patients following CV surgery. Methods and Results We included 385 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following CV surgery at a university-affiliated tertiary-care center into our single-center registry. Thirty patients underwent cardiopulmonary resuscitation (CPR) followed by immediate initiation of ECMO support. During a median follow-up time of 44 months (IQR 21–76 months), 68% of patients ( n =262) died. We did not detect a significant impact of CPR during ECMO initiation on 30-day mortality (HR 1.04, 95%CI 0.89–1.83, P =0.86) as well as for long-term mortality (HR 1.01, 95%CI 0.63–1.61, P =0.97). Results were virtually unchanged for 30-day (HR 0.88, 95%CI 0.44–1.73, P =0.70) and long-term mortality (HR 0.93, 95%CI 0.54–1.60, P =0.79) after adjustment for age, sex, left ventricular ejection fraction, SAPS2 score, type of CV surgery, and year of study inclusion in order to unveil a potential negative confounding. Conclusion Cardiac arrest did not affect short-tem and long-term mortality in a large cohort of patients with therapy refractory cardiogenic shock undergoing ECMO support following CV surgery. Our results suggest that the decision to initiate ECMO support in this specific patient population should not be influenced by the occurrence of cardiac arrest.

Background Pulmonary hypertension (PH) can lead to right-side heart failure (RHF) and death. There are no therapeutic recommendations for patients experiencing acute RHF in the course of PH. This study aimed to examine the safety and efficacy of inhaled iloprost in patients with precapillary PH and RHF. Methods and Results Between October 2007 and December 2008, 7 patients with precapillary PH and RHF were enrolled. Per protocol, iloprost was inhaled hourly for a minimum of 12 hours during a 24-hour period. The starting dose of 2.5 μg was increased hourly by 2.5 μg as long as the increases were tolerated. Safety and efficacy were determined by continuous invasive monitoring of systemic and pulmonary hemodynamic parameters. Systemic pressures remained stable during inhalation (66.1 ± 6.9 mm Hg at baseline and 69.1 ± 6.4 mm Hg immediately after inhalation therapy, P = 0.48). Cardiac index increased from 2.4 ± 0.7 L/min/m2 to 2.9 ± 0.9 L/min/m2 (P = .008). Pulmonary vascular resistance decreased from 634.6 ± 218.3 dyn·s·cm−5 to 489.6 ± 173.8 dyn·s·cm−5 (P = .044), and N-terminal B-type natriuretic peptide levels decreased from 13,591 ± 10,939 pg/mL to 9,944 ± 8,569 pg/mL (P = .051). Conclusion Blood pressure-guided hourly inhalation of iloprost may offer a safe and effective strategy for the treatment of PH patients with RHF.

Hypoxic hepatitis (HH) is a form of hepatic injury following arterial hypoxemia, ischemia, and passive congestion of the liver. We investigated the incidence and the prognostic implications of HH in the medical intensive care unit (ICU). A total of 1,066 consecutive ICU admissions at three medical ICUs of a university hospital were included in this prospective cohort study. All patients were screened prospectively for the presence of HH according to established criteria. Independent risk factors of mortality in this cohort of critically ill patients were identified by a multivariate Poisson regression model. A total of 118 admissions (11%) had HH during their ICU stay. These patients had different baseline characteristics, longer median ICU stay (8 vs. 6 days, p

Hypoxic hepatitis (HH) is a frequent cause of acute hepatocellular damage at the intensive care unit. Although mortality is reported to be high, risk factors for mortality in this population are unknown.One-hundred and seventeen consecutive patients with HH were studied prospectively at three medical intensive care units of a university hospital.The main causes of hypoxic hepatitis were low cardiac output and septic shock, and most patients (74%) had more than one underlying factor. Peak aspartate transaminase (P = 0.02), lactate dehydrogenase (P = 0.03), INR (P0.001) and lactate (P0.01) were higher in non-survivors. Prolonged duration of HH caused higher overall mortality rate (P = 0.03). INR2 (P = 0.02), septic shock (P = 0.01) and SOFA score10 (P = 0.04) were risk factors of mortality in the regression model.Hypoxic hepatitis is the consequence of multiorgan injury. Outcome is influenced by the severity of liver impairment and the etiology and severity of the basic disease.

Plasma N-terminal pro-B-type natriuretic peptide (Nt-pro-BNP) levels are frequently elevated in critically ill patients and are associated with an increased mortality. In this study, we determined Nt-pro-BNP levels in patients with cardiogenic shock (CS) and evaluated its association with clinical and hemodynamic parameters and 30-day mortality.Retrospective study.Two, eight-bed intensive care units at a university and a community hospital.Retrospective study on stored plasma samples of 58 patients with CS, obtained at admission to the intensive care unit.None.Massively elevated Nt-pro-BNP concentrations showed no significant association with duration of shock, total Sequential Organ Failure Assessment score, or invasive hemodynamic parameters at the time of blood sampling but a significant association with estimated glomerular filtration rate (p0.001), C-reactive protein (p = 0.03), age (p = 0.005), and body weight (p = 0.03). Both in univariate and multivariate survival analyses, Nt-pro-BNP levels above the median (12,782 pg/mL) were significant predictors of 30-day mortality (p0.001) and showed a complementary role with interleukin (IL)-6 in predicting outcome. Patients with IL-6195 pg/mL and Nt-pro-BNP above the median value had the highest 30-day mortality (93.7%), whereas patients with lower IL-6 levels together with lower Nt-pro-BNP levels had significantly better survival (mortality rate 26.3%). Among patients who had acute myocardial infarction, those with Nt-pro-BNP concentrations above the median level showed a highly impaired clinical course even if coronary revascularization was successful (30-day mortality 90.9% vs. 29.4%, p = 0.001), whereas survival of patients with unsuccessful revascularization did not differ significantly with respect to the median of Nt-pro-BNP (30-day survival rate 81.8% vs. 75.0%, p = 0.71).The massive elevations of Nt-pro-BNP observed in the early phase of CS seem to be independent of ventricular performance. Nt-pro-BNP levels are nevertheless predictive of 30-day survival in patients with CS especially in those with successful revascularization and might be used in combination with IL-6 for estimation of outcome early on.

Amiodarone (AMIO), a widely used anti-arrhythmic drug, has been shown to reduce the incidence of atrial fibrillation after cardiac surgery and also to exert immunomodulatory actions in vitro and proinflammatory effects in vivo. The present study investigated the immunomodulatory properties of AMIO in the inflammatory response induced by cardiac surgery with cardiopulmonary bypass (CPB).In this double-blind, placebo-controlled trial, 20 patients undergoing elective coronary artery bypass graft were randomized to receive placebo or AMIO 600 mg day(-1) orally for seven days before surgery and 45 mg hr(-1) intravenously for 48 hr postoperatively. Plasma levels of the proinflammatory markers C-reactive protein (CRP), fibrinogen (FBG), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and the antiinflammatory marker IL-10, were compared before and after surgery.Ninety-six hours after start of surgery, plasma levels of FBG had more than doubled (2.2 +/- 0.5-fold increase, P0.0001). Overall, FBG formation was significantly increased in the AMIO group (P = 0.048). Monocyte chemoattractant protein 1 secretion transiently increased four hours after start of surgery (6.6 +/- 4.5-fold increase) but rapidly declined thereafter, (P0.0001). There was a trend toward higher MCP-1 plasma concentrations in the AMIO group (P = 0.13). The plasma levels of CRP, TNF-alpha, IL-6 and Il-10 changed significantly over time, but were not altered by AMIO treatment.In the inflammatory response induced by cardiac surgery with CPB, our data suggest that AMIO treatment is associated with a selective trend toward proinflammatory actions.

OBJECTIVES Despite underlying pathologies leading to ICU admittance are heterogeneous, many patients develop a systemic inflammatory response syndrome often in the absence of microbial pathogens. Mitochondrial DNA that shows similarities to bacterial DNA may be released after tissue damage and activates the innate immune system by binding to toll-like receptor-9 on immune cells. The aim of this study was to analyze whether levels of mitochondrial DNA are associated with 30-day survival and whether this predictive value is modified by the expression of its receptor toll-like receptor-9. DESIGN Single-center, prospective, observational study. SETTING A tertiary ICU in a university hospital. PATIENTS Two hundred twenty-eight consecutive patients admitted to a medical ICU between August 2012 and August 2013. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Blood was taken within 24 hours after ICU admission, and the levels of circulating mitochondrial DNA were quantified by real-time polymerase chain reaction. Toll-like receptor-9 expression in monocytes was measured by flow cytometry. Median acute physiology and chronic health evaluation II score was 20, and 30-day mortality was 25%. Median mitochondrial DNA levels at admission were significantly higher in nonsurvivors when compared with survivors (26.9, interquartile range = 11.2-60.6 ng/mL vs 19.7, interquartile range = 9.5-34.8 ng/mL; p 38.2 ng/mL) had a 2.6-fold higher risk (p < 0.001) of dying, independently of age, gender, diagnosis, and acute physiology and chronic health evaluation II score. Mitochondrial DNA improved the c-statistic of acute physiology and chronic health evaluation II score (p < 0.05) and showed enhancement in individual risk prediction indicated by a net reclassification improvement of 32.3% (p < 0.05). Stratification of patients according to toll-like receptor-9 expression above/below median demonstrated that only patients with high expression of toll-like receptor-9 showed an increased risk associated with increased mitochondrial DNA levels (odds ratio, 2.7; p < 0.01), whereas circulating mitochondrial DNA was not associated with mortality in patients with low toll-like receptor-9 expression (odds ratio, 1.1; p = 0.98). CONCLUSIONS Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.

BACKGROUND: An important proportion of critically ill patients who survives their acute illness remains in a critical state requiring intensive care management for weeks to months. Nevertheless, data on risk factors for in-hospital mortality and especially for long-term mortality and functional capacity are scarce. This study investigated outcome and prognostic factors in long-term critically ill patients. METHODS: This retrospective observational cohort study was performed at our mixed adult 8-bed cardiologic ICU at a 2200-bed University Hospital. Patient data from our local database connected to an Austrian multicenter program for quality assurance in intensive care were analyzed. Data were collected between March 1st, 1998 and December 31st, 2003. Patients with an ICU stay ≥30 days formed the long-term study group. Morbidity and functional capacity were assessed using the Barthel mobility index in telephone interviews. RESULTS: Patients spending ≥30 days in the ICU numbered 135 (10%) and occupied 5962 bed-days, representing 40.9% of the total bed-days. Compared with patients with an ICU stay

The use of ECMO to stabilize critically ill patients with severely depressed cardiac function and hemodynamics increased in the last years due to broader availability, better performance and easier implantation of the devices. The present guidelines of the Austrian Society of Cardiology focus on the use of ECMO in adult non-operated patients with cardiac diseases. Not only indications and contraindications are highlighted, but also the equally important issues of monitoring, complication management, measures during implantation and operation, and weaning of the devices are treated in detail. Thereby the present guidelines aim to optimize the use of ECMO in the individual centers, and aim to help current non-ECMO centers in developing a local ECMO-program or to contact ECMO-centers for discussion of individual patients.

BACKGROUND: The aim of this study was to assess the dynamics of inflammation parameters prior to a tachyarrhythmic event in critically ill patients. We evaluated the course of inflammation parameters over 48 hours before the occurrence of tachyarrhythmias. METHODS: Prospective observational study conducted at a cardiologic medical-postoperative tertiary intensive care unit at the Vienna university hospital. Between November 1996 and July 1999 all consecutive patients (n = 756) were screened for the occurrence of arrhythmias. Patients with sustained tachyarrhythmias (n = 119) form the basis of the report. The tachyarrhythmia episodes were related to the evolution of C-reactive protein, leukocytes and fibrinogen during the 48 hours before the arrhythmic event. RESULTS: A total of 278 tachyarrhythmia episodes was identified (wide QRS complex tachycardia, n = 168; narrow QRS complex tachycardia, n = 108; ventricular fibrillation, n = 2). The body temperature on the day of arrhythmia was 37.4 ± 1°C. Overall, there was no statistically significant change in any inflammation parameter within 48 hours prior to tachyarrhythmias (C-reactive protein: 17.4 ± 12 [–48 h], 16.2 ± 11 [–24 h], 15.2 ± 12 [0 h] mg/dl, p = 0.2). When stratifying for different levels of C-reactive protein on the day of arrhythmia, the trend was inhomogeneous. For lower strata, values were significantly decreasing towards arrhythmias; for higher strata, an increase in C-reactive protein was observed (stratum A: 8.5 ± 7.2 [–48 h], 6.6 ± 4.9 [–24 h], 4.8 ± 2.9 mg/dl [0 h], p = 0.0001; stratum B: 16.0 ± 7.1 [–48 h], 13.8 ± 6.0 [–24 h], 14.4 ± 2.6 mg/dl [0 h], p = 0.09; stratum C: 21.2 ± 7.4 [–48 h], 21.5 ± 7.5 [–24 h], 24.9 ± 3.0 mg/dl [0 h], p = 0.008; stratum D: 34.3 ± 13.4 [–48 h], 35.7 ± 9.0 [–24 h], 39.7 ± 5.5 mg/dl [0 h], p = 0.13). CONCLUSION: In this group of critically ill patients, inflammation parameters did not change significantly during the 48 hours prior to the arrhythmic event. For different levels of C-reactive protein at the time of arrhythmia, no clear dynamics of inflammatory signs were observed.

Levosimendan (LS) ist eine neue Substanz aus der Gruppe der Kalziumsensitiser, welche in therapeutischer Dosierung im Gegensatz zu Katecholaminen seine inotrope Wirkung nicht uber eine Erhohung des intrazellularen cAMP oder Kalziums entfaltet und damit ungunstige Nebeneffekte anderer Inotropika vermeidet. LS bewirkt zusatzlich uber eine Offnung von Kalium-Kanalen an glatten Gefasmuskelzellen eine arterielle und venose Vasodilatation. Daruber hinaus steigert LS den myokardialen Sauerstoffbedarf nicht und besitzt „anti-Stunning”-Effekte. LS selbst besitzt eine kurze Eliminationshalbwertszeit, bildet aber aktive Metaboliten mit Eliminationshalbwertszeiten bis zu 80 Stunden. In drei hamodynamischen Studien bewirkte LS im empfohlenen Dosisbereich einen Anstieg des Herzminutenvolumens um 8–30% und eine Reduktion des pulmokapillaren Verschlussdrucks um 11–28%. Unter einer LS-Infusion kam es auch zu einem signifikanten Abfall des peripheren Gefaswiderstandes und zu einem tendenziellen Abfall des arteriellen Blutdruckes. Die hamodynamischen Effekte von LS wurden durch gleichzeitige Gabe von β-Blockern nicht verringert, sondern trendmasig sogar gesteigert. Zwei grose randomisierte kontrollierte Studien bei Patienten mit chronischer und akuter Herzinsuffizienz zeigten eine geringere Letalitat in den mit LS behandelten Gruppen. Gegenuber mit Dobutamin behandelten Patienten zeigte sich in der LIDO-Studie am Tag 31 ein 52,9%-Uberlebensvorteil. In der RUSSLAN-Studie konnte gegenuber Plazebo am Tag 14 nach Therapiebeginn ein 40%-Uberlebensvorteil demonstriert werden. Die Daten hinsichtlich des Einsatzes von LS im intensivmedizinischen Bereich sind noch sparlich, LS scheint jedoch im postoperativen Einsatz sowie in der Behandlung bei Patienten im kardiogenen Schock vielversprechend. Das Nebenwirkungsprofil von LS ist gunstig, die Verwendung bei dekompensierter Herzinsuffienz ist fur 24 Stunden zugelassen. Als wichtigste Nebenwirkung kann es unter LS zu einem Blutdruckabfall kommen, der insbesondere bei reduzierten Vorlast-Bedingungen verstarkt werden kann. Weitere Morbiditats- und Letalitatsstudien mussen die Ergebnisse der LIDO- und RUSSLAN-Studie noch absichern. Allerdings unterstutzen die bereits vorliegenden Daten den Gebrauch von LS als bevorzugte inotrope Therapie bei Patienten mit dekompensierter Herzinsuffizienz und systolischem arteriellen Blutdruck uber 90 mmHg.

Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC 0-8 ) for muscle tissue (AUC 0-8 muscle ) to the AUC 0-8 for free drug in plasma (AUC 0-8 plasma free ) (AUC 0-8 muscle /AUC 0-8 plasma free ratio) of 0.85. The individual values of tissue penetration and maximum concentration ( C max ) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 μg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 μg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual C max /MIC and AUC 0-8 muscle /AUC 0-8 plasma free ratios ( R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 μg/ml.

Purpose: To study the dynamics of carotid stent healing over a 2-year period using duplex ultrasound imaging. Methods: One hundred twelve patients with 121 successfully stented carotid arteries were examined with color-coded duplex ultrasound the day after the stent procedure and at 1, 3, 6, 12, and 24 months in follow-up. The maximal thickness and echogenicity of the layer between the stent and the perfused lumen (SPL) were evaluated. Echogenicity was classified as echogenic if the SPL layer was clearly detected in B mode and echolucent if the SPL layer was barely visible in B mode, its border defined by assistance of color-coded flow. Results: At day 1, an echolucent SPL layer with a median thickness of 0.7 mm was interpreted as a thrombotic layer, which decreased at 1 month to practically zero (i.e., not detectable). In follow-up, increases in thickness (mainly up to 6 months) and echogenicity (up to 12 months) of the SPL layer were interpreted as neointimal ingrowth. At 3, 6, and 12 months, the median maximal thickness of the SPL layer was 0.5 mm, 0.9 mm, and 1.0 mm, respectively, whereas the percentage of patients with an echogenic SPL layer was 27% (32/119), 56% (66/117), and 95% (105/110), respectively, at the same time intervals. No further change was observed at the 24-month examination. Conclusions: Three phases of carotid stent incorporation are defined: (1) an early unstable period soon after stent placement with an echolucent (thrombotic) SPL layer, (2) a moderately unstable phase with ingrowing neointima (1–12 months), and (3) a stable phase from the second year on. These data may indicate the need for different intensities of therapy and surveillance intervals.

The present study was undertaken to investigate the target site penetration properties of fosfomycin, an antibiotic particularly suitable for treatment of soft tissue infections (STIs) in critically ill patients.The study population included nine patients with sepsis. Penetration of fosfomycin into the interstitial space fluid of skeletal muscle was measured using the microdialysis technique, following a single intravenous administration of 8.0 g of fosfomycin to patients. The median (range) fosfomycin area under the concentration versus time profile for plasma and skeletal muscle were 673 (459-1108) and 477 (226-860) mg x h/L (P0.011), respectively. Interstitial maximum concentrations were lower than plasma values (P0.029). Median fosfomycin concentrations in the interstitium and plasma exceeded 70 mg/L throughout the observation period of 4 h and covered MICs for Streptococcus pyogenes, Staphylococcus aureus and Pseudomonas aeruginosa. Simulation of bacterial growth inhibition of S. pyogenes, based on tissue concentration data, confirmed the bactericidal properties of fosfomycin described in previous studies.Fosfomycin concentrations in muscle interstitium and plasma exceeded the MICs for a range of clinically relevant pathogens in critically ill patients. Thus, fosfomycin exhibits a tissue pharmacokinetic profile, which appears to offer an alternative to other broad-spectrum antibiotics in intensive care patients suffering from STI.

To further reduce low-density lipoprotein-cholesterol (LDL-C), atorvastatin treatment was investigated in patients with homozygous (n = 4) and heterozygous (n = 10) familial hypercholesterolemia (FH) undergoing LDL-apheresis. After a wash-out period of 4 weeks, atorvastatin therapy was administered in escalating doses (10 up to 80 mg/d). LDL-apheresis was performed at weekly intervals during the entire study period. The LDL-C concentration decreased from 240 [plusmn] 35 mg/dL after the wash-out period to 206 [plusmn] 63 mg/dL during treatment with 10 mg atorvastatin. Four weeks of treatment with 80 mg atorvastatin resulted in an additional 24% ( P [lt ] .05) reduction in LDL-C. LDL-C increased from 28.8 [plusmn] 14.2 mg/dL immediately after apheresis to 156.6 [plusmn] 25.5 mg/dL at day 7. LDL-C values remained below the recommended target range for an extended duration of 48 hours in atorvastatin-treated patients, but not in those without concomitant lipid-lowering drug therapy. The levels of high-density lipoprotein-cholesterol (HDL-C) and plasma fibrinogen were unchanged during the entire study period. No adverse events were observed with atorvastatin treatment. Finally, high-dose atorvastatin therapy resulted in a 40% reduction in LDL-apheresis sessions in these patients. Our results show that LDL-C reduction by atorvastatin is a safe and effective therapy in LDL-apheresis patients with severe heterozygous or homozygous FH.

Background: Patients suffering from acute heart failure (AHF) requiring admission to an intensive care unit (ICU) have a poor prognosis. Activation of the innate immune system contributes to the pathogenesis of AHF. Mitochondrial DNA that shows similarities to bacterial DNA may be released after

Background Critically ill patients admitted to a medical intensive care unit exhibit a high mortality rate irrespective of the cause of admission. Besides its role in fluid and electrolyte balance, vasopressin has been described as a stress hormone. Copeptin, the C-terminal portion of provasopressin mirrors vasopressin levels and has been described as a reliable biomarker for the individual’s stress level and was associated with outcome in various disease entities. The aim of this study was to analyze whether circulating levels of copeptin at ICU admission are associated with 30-day mortality. Methods In this single-center prospective observational study including 225 consecutive patients admitted to a tertiary medical ICU at a university hospital, blood was taken at ICU admission and copeptin levels were measured using a commercially available automated sandwich immunofluorescent assay. Results Median acute physiology and chronic health evaluation II score was 20 and 30-day mortality was 25%. Median copeptin admission levels were significantly higher in non-survivors as compared with survivors (77.6 IQR 30.7–179.3 pmol/L versus 45.6 IQR 19.6–109.6 pmol/L; p = 0.025). Patients with serum levels of copeptin in the third tertile at admission had a 2.4-fold (95% CI 1.2–4.6; p = 0.01) increased mortality risk as compared to patients in the first tertile. When analyzing patients according to cause of admission, copeptin was only predictive of 30-day mortality in patients admitted due to medical causes as opposed to those admitted after cardiac surgery, as medical patients with levels of copeptin in the highest tertile had a 3.3-fold (95% CI 1.66.8, p = 0.002) risk of dying independent from APACHE II score, primary diagnosis, vasopressor use and need for mechanical ventilation. Conclusion Circulating levels of copeptin at ICU admission independently predict 30-day mortality in patients admitted to a medical ICU.

Patients after successful cardiopulmonary resuscitation have been shown to exhibit elevated plasma concentrations of plasminogen activator inhibitor (PAI) type 1, the main circulating antifibrinolytic protein. It has been suggested that elevations in PAI-1 contribute to cerebral no-reflow after successful cardiopulmonary resuscitation. We analyzed whether PAI-1 concentrations might predict cerebral outcome after cardiopulmonary resuscitation.Prospective, controlled study.Intensive care unit at a university hospital.Thirty-five patients after successful cardiopulmonary resuscitation and 35 control patients who were not critically ill.Blood sampling for determination of plasma concentrations of active and total PAI-1 antigen.Plasma concentrations of total and active PAI-1 antigen on the second day after successful cardiopulmonary resuscitation were significantly higher in patients after cardiopulmonary resuscitation than in controls (p.0001) and were unrelated to duration of cardiopulmonary resuscitation. Both active and total PAI-1 antigen were higher in patients who developed acute renal failure after cardiopulmonary resuscitation. Patients with an unfavorable cerebral outcome after cardiopulmonary resuscitation had higher total PAI-1 antigen concentrations compared with patients with good outcome after cardiopulmonary resuscitation (p =.026). We identified 180 ng/mL as the best cutoff value for total PAI-1 antigen with respect to cerebral outcome (chi-square 11.8, p =.001). In a logistic regression analysis, only systemic inflammatory response syndrome (p =.028), acute renal failure after cardiopulmonary resuscitation (p =.017), and cardiopulmonary resuscitation duration15 mins (p =.042) were significantly and independently associated with cerebral outcome after cardiopulmonary resuscitation. Total PAI-1 antigen reached only borderline significance (p =.058) but nevertheless slightly improved the correct prediction of cerebral outcome after cardiopulmonary resuscitation.Acute renal failure after cardiopulmonary resuscitation, systemic inflammatory response syndrome, and cardiopulmonary resuscitation duration are better predictors of cerebral outcome after cardiopulmonary resuscitation than PAI-1 antigen, but determination of total PAI-1 antigen nevertheless might improve the early prediction of cerebral outcome after cardiopulmonary resuscitation. Whether elevated PAI-1 concentrations, possibly via prothrombogenic/antifibrinolytic effects, contribute causally to cerebral no-reflow and acute renal failure after cardiopulmonary resuscitation remains to be clarified.

Objective: Pulmonary endothelial activation caused by high pulmonary capillary pressures may be involved in the pathogenesis of cardiogenic pulmonary edema (CPE). We studied soluble selectins and soluble ICAM-1 as markers of cell activation in the systemic and pulmonary circulation of patients with respiratory failure (RF) due to CPE (RFCPE) as compared to patients with RF due to pulmonary infection (RFPI). Setting: Cardiovascular Intensive Care Unit at a university hospital. Patients: Twenty patients with RFCPE, 20 patients with RFPI and 17 critically ill patients without RF. Interventions: Blood samples were obtained from the arterial and the pulmonary capillary circulation and sE-, sL-, and sP-selectin as well as sICAM-1 were determined. To distinguish between systemic and pulmonary endothelial activation, transpulmonary gradients (concentrationarterial blood – concentrationpulmonary capillary blood) were calculated. Results: Systemic concentration of sL-selectin was lower in patients with RFCPE and RFPI than in patients without RF (RFCPE: 719.0±243.9 ng/ml, RFPI: 528.5±220.8 ng/ml, no RF: 882.4±222.6 ng/ml; P

Various LDL-apheresis systems have gained wider clinical acceptance in recent years to treat patients with severe familial hypercholesterolaemia, in particular in patients with coronary artery disease. For each single device data on efficacy have been provided, but up to now no comparative analysis including the novel direct adsorption of lipoproteins from whole blood has been reported. This prospectively designed cross-over comparison of three commercially available LDL-apheresis systems (immunoadsorption, IMAL; dextran sulphate adsorption, DSA; direct adsorption of lipoproteins, DALI) was performed in eight patients with homozygous (n = 3) and heterozygous (n = 5) familial hypercholesterolaemia. Removal of atherogenic lipoproteins was highly effective in all systems, for LDL-cholesterol in particular: DSA: - 84.3 +/- 6.2%; IMAL: -82.1 +/- 8.3%; DALI: -76.6 +/- 7.2% (P < 0.05 as compared DALI versus IMAL and DSA). A reduction in Lp(a) of about 63% was achieved by each device. Loss in HDL-cholesterol was highest with IMAL (-21.3 +/- 4.9%, P < 0.05) as compared to the other two treatment modalities. DSA decreased HDL-cholesterol by - 10.4 +/- 6.1% and the DALI system by -12.7 +/- 5.0%. Remarkable differences were found for the removal of fibrinogen (DSA: -29.8 +/- 14.7%, (P < 0.05 versus DALI/IMAL); IMAL: -21.4 +/- 10.1% (P < 0.05 versus DALI); DALI: -14.8 +/- 8.0%). The shortest duration for treatment was achieved by the DALI system (135 +/- 20 min, P < 0.05 versus IMAL (195 +/- 20 min) and DSA (187 +/- 29 min)). No side effects were recorded in the total of 96 treatments performed during the study. Long-term observations have yet to prove whether these differences in efficacy may be of clinical relevance.

BACKGROUND Treatment with the PDE-III inhibitor milrinone improves hemodynamics in patients with heart failure. We examined whether therapy with milrinone is safe and effective in critically ill patients with catecholamine-dependent heart failure and whether treatment with milrinone facilitates weaning from prolonged catecholamine therapy. METHODS Twenty adult patients with reduced left ventricular function and prolonged (7+/-4 days) catecholamine therapy in whom attempts at catecholamine weaning had failed were examined. Patients were prospectively randomised either to group A (addition of a fixed dose of 0.5 microg x kg(-1) x min(-1) milrinone to catecholamine therapy) or to group B (continued catecholamine therapy without milrinone). Dobutamine and norepinephrine treatment and fluid intake were titrated according to predefined hemodynamic goals. Hemodynamic parameters, fluid requirements and catecholamine dose were monitored. RESULTS After 24 h of study treatment goup A showed a significant increase in cardiac index (2.2+/-0.4 1 min(-1) x m(-2) to 2.7+/-0.51 min(-1) x m(-2); P

Objective: To test the hypothesis that the prevalence of hyperhomocysteinemia is increased in critically ill patients and correlates with disease severity and mortality in these patients. Design: A prospective study. Setting: Three medical intensive care units at the University of Vienna Medical School serving both medical and surgical patients. Patients: All consecutive admissions (n = 56) during a period of 4 wks. A total of 112 age- and gender-matched healthy individuals constituted the control group. Interventions: None. Measurements and Main Results: Blood samples were drawn within 24 hrs after admission for analysis of total homocysteine (tHcy), folate, vitamin B 6 levels, and vitamin B 12 levels as well as to identify the 677C→T polymorphism in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase. Acute Physiology and Chronic Health Evaluation III scores at admission and 24 hrs after admission as well as 30-day survival were documented in all patients. Hyperhomocysteinemia was more prevalent in critically ill patients (16.1%; 95% confidence interval, 7.6% to 28.3%) compared with age- and gender-matched healthy individuals (5.4%; 95% confidence interval, 2.0% to 11.3%; chi-square test; p =.022). There was no difference in tHcy plasma concentrations in the first 24 hrs after admission to an intensive care unit between survivors and nonsurvivors. The 5,10-methylenetetrahydrofolate reductase 677C→T polymorphism had no influence on tHcy levels and survival of intensive care unit patients. Conclusions: The prevalence of hyperhomocysteinemia is increased in critically ill patients compared to age- and gender-matched healthy individuals. The clinical significance of this finding remains to be determined.

Recent studies suggest prophylactic intraaortic balloon-pulsation (IABP) in patients undergoing coronary reperfusion therapy. However, variable effects of IABP on coronary blood flow are reported. It is suggested that augmentation of coronary flow is more effective in patients with a compromised hemodynamic status, which might have potential relevance in selecting IABP treatment in patients undergoing reperfusion therapy.

The aim of the study was to investigate (1) the safety and efficacy of the application of a collagen plug (Vasoseal®) at arterial puncture sites, (2) the hemostasis time, and (3) the comfort for the patient of a collagen plug (Vasoseal®) when compared with manual compression. Sixty-two patients were randomized either for application of a collagen plug (Vasoseal®, group A, n=33) or manual compression (group B, n=29) after cardiac catheterization. All patients were evaluated for subjective pain score ranging from 1 to 5 (1= no pain up to 5 =very strong pain). In addition the authors measured the time until hemostasis could be achieved. The patients were evaluated by duplex sonography for complications at days 1 and 7 after the procedure. The pain score demonstrated a signif icantly lower score in group A when compared with group B (P=0.01). The mean time for hemostasis was significantly lower in group A (mean 9.6 minutes) when compared with group B (mean 23.6 minutes) (P=0.0001). Regarding the complication rate there was no significant difference between the groups (group A vs group B, P=0.82). The authors conclude that the application of a collagen plug at the arterial puncture site is a safe and time-saving method. In addition it is less painful and therefore better tolerated than manual compression.

Information on predisposing risk factors influencing long-term survival after extracorporeal membrane oxygenation (ECMO) support remains scarce. In critically ill patients chronic obstructive pulmonary disease (COPD) is an independent risk factor for mortality and morbidity. We assessed the influence of COPD on cardiovascular and all-cause mortality in patients undergoing ECMO therapy. We prospectively included 191 patients undergoing veno-arterial ECMO therapy following cardiovascular surgery at a university-affiliated tertiary care center into our registry. The median follow-up time was 51 months (IQR 34–71 months) corresponding to 4,197 overall months of follow-up. A total of 125 patients (65 %) died; 88 % of deaths were due to cardiovascular causes. Long-term survival was decreased in patients with COPD after 1 year (23 % vs. 44 %) and after 6 years (14 % vs. 35 %) compared to patients without COPD. COPD was independently associated with all-cause mortality with a hazard ratio of 4.22 (95 % CI 1.04–17.11, p = 0.04) and cardiovascular mortality with a hazard ratio of 5.87 (95 % CI 1.41–24.47, p = 0.02). We identified COPD as a strong and independent predictor of long-term all-cause mortality and cardiovascular mortality in patients undergoing ECMO therapy following cardiovascular surgery. The current study presents valuable information for a comprehensive decision-making process prior to ECMO implantation and helps to identify high-risk patients that may benefit from intensified treatment of co-morbidities and close check-ups after hospital discharge.

A decrease in sinus node dysfunction and pacemaker requirement after orthotopic heart transplantation was observed over a 6.5-year period, probably indicating the effect of a learning curve. Indirect evidence suggests a traumatic genesis of sinus node dysfunction after cardiac transplantation.

Background Catheter ablation of the posteroseptal right atrium has been proposed for control of ventricular rate in patients with tachycardic atrial fibrillation (AF). However, the exact mechanism of rate control is unclear. Because the ablation site corresponds to the location of the slow pathway in patients with AV nodal reentry tachycardia (AVNRT), we investigated whether selective ablation of this posterior AV nodal input can provide a sufficient reduction in heart rate during AF. Methods and Results In 30 patients with AVNRT, conduction properties of the AV nodal pathways were determined before and after slow pathway ablation. AF was induced by burst pacing at baseline and after ablation, and the mean ventricular cycle length was determined. After slow pathway ablation, the mean ventricular cycle length during AF increased (449±98 versus 515±129 milliseconds, P r =.90) and fast ( r =.86) pathways. After ablation, the mean ventricular cycle length was extremely well determined by the Wenckebach cycle length of the fast pathway ( r =.94). However, the slope of the regression line was significantly steeper compared with baseline (1.50 versus 0.77, P Conclusions Selective elimination of the slow pathway reduces ventricular rate during AF. However, in patients with a short Wenckebach cycle length of the anterior AV nodal input that causes tachycardic AF, this effect may be insufficient to provide adequate control of ventricular rate.

Venous thromboembolism is a frequent complication in critically ill patients that has a negative impact on patient outcomes. Critically ill patients have significantly lower plasma anti-factor-Xa activity levels compared with control patients after administration of subcutaneous heparin. The clinical relevance of the different anti-factor-Xa levels after prophylactic doses of low molecular weight heparin (LMWH) in critically ill patients is not completely understood.The standard dose of 40 mg enoxaparin led to a significant increase in anti-FXa levels in this selected cohort of ICU patients with normal renal function. This study found only subtle pharmacokinetic differences, but a comparable pharmacodynamic action, after enoxaparin administration in critically ill and normal medical ward patients. Thrombin generation with TGA RC-low and TGARC-high reagents was significantly reduced in ICU and normal ward patients after receiving LMWH. Both readouts appear equally useful for estimating the pharmacodynamics of enoxaparin. The ex vivo model of thrombosis was used for the first time in patients to evaluate the anti-thrombotic activity of LMWH. This method did not show any difference in thrombus formation after administration of enoxaparin in the individual group of patients.In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls.A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40-65], with a median Simplified Acute Physiology Score of 30 [IQR 18-52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured.The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml-1 [IQR 0-0.22 IU ml-1] vs. 0.2 IU ml-1 [IQR 0.15-0.27 IU ml-1],respectively, P = 0.13). The area under the anti-FXa activity curve from 0–12 h was similar between the groups (median 0.97 IU ml-1 h [IQR0.59-2.1] and 1.48 IU ml-1 h1 [IQR 0.83-1.62], P = 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with pre-dose (P = 0.029) and was not different between the groups.Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.

The impact of levosimendan treatment on clinical outcome in patients undergoing extracorporeal membrane oxygenation (ECMO) support following cardiovascular (CV) surgery is unknown. It is tempting to speculate that the benefical effects of levosimendan are more efficiently translated into improved

Extracorporeal membrane oxygenation (ECMO) is an effective treatment to ensure continuous organ perfusion and oxygenation in patients following cardiovascular surgery. Nevertheless, survival is still low and risk stratification challenging. Therefore we investigated the significance of eight

Introduction Oxidative stress affects clinical outcome in critically ill patients. Although high-density lipoprotein (HDL) particles generally possess anti-oxidant capacities, deleterious properties of HDL have been described in acutely ill patients. The impact of anti-oxidant HDL capacities on clinical outcome in critically ill patients is unknown. We therefore analyzed the predictive value of anti-oxidant HDL function on mortality in an unselected cohort of critically ill patients. Method We prospectively enrolled 270 consecutive patients admitted to a university-affiliated intensive care unit (ICU) and determined anti-oxidant HDL function using the HDL oxidant index (HOI). Based on their HOI, the study population was stratified into patients with impaired anti-oxidant HDL function and the residual study population. Results During a median follow-up time of 9.8 years (IQR: 9.2 to 10.0), 69% of patients died. Cox regression analysis revealed a significant and independent association between impaired anti-oxidant HDL function and short-term mortality with an adjusted HR of 1.65 (95% CI 1.22–2.24; p = 0.001) as well as 10-year mortality with an adj. HR of 1.19 (95% CI 1.02–1.40; p = 0.032) when compared to the residual study population. Anti-oxidant HDL function correlated with the amount of oxidative stress as determined by Cu/Zn superoxide dismutase (r = 0.38; p

Variability of ventricular rate was quantified by two measures of heart rate variability: the SD of the mean R-R interval (SDNN) and the SD of the 5-minute mean R-R interval (SDANN). In 35 patients with atrial fibrillation and advanced heart failure (left ventricular ejection fraction 20% ± 9%, cardiac index 2.4 ± 0.7 L/min/m 2 ), SDNN and SDANN were compared to 13 preselected clinical and hemodynamic variables for prediction of outcome. During a 12-month follow-up period, 8 (23%) patients deteriorated clinically; 3 (9%) died, and 5 (14%) underwent heart transplantation. SDNN and SDANN correlated to the difference of the mean R-R interval between night (2 am to 3 pm) and day (11 am to noon) with r values of 0.62 and 0.77, respectively. From 15 preselected variables, only SDANN ( χ 2 = 6.7, p = 0.01) was independently associated with survival on multivariate analysis. Dichotomized SDANN at 100 msec accurately predicted 12-month survival in 28 (80%) patients (relative risk=9.77, p = 0.001). In conclusion, analysis of heart rate variability is useful in quantifying diurnal variation of ventricular rate in atrial fibrillation and might be useful in predicting survival in patients with advanced heart failure.

In order to describe adequately the process of healing in the intermediate degrees, we investigated microcirculatory changes in the venous ulcers at well-defined stages of wound repair. We investigated dynamic changes in microcirculation during the healing process of venous ulcers. Ten venous ulcers were investigated in three consecutive clinical stages of wound healing: non granulation tissue (NGTA), GTA and scar. Subpapillary microcirculation was measured by laser Doppler perfusion (LDP) imaging and expressed using LDP values in arbitrary units. Nutritive perfusion by capillary microscopy and expressed as capillary density (CD) - the number of capillaries per square millimetre. Before the development of GTA the LDP was low (median 1·35; lower-upper quartiles 0·71-1·83) accompanied with zero CD in all but one patient who had a density of 1. With the first appearance of GTA in the same area, the LDP was improved (2·22; 1·12-2·33; P = 0·0024) when compared with NGTA, in combination with a significant increase in CD (1·75; 0-3; P = 0·0054). In scar, the LDP was similar to that in the NGTA (1·03; 0·77-1·83; P = 0·278), combined with the highest CD (5·75; 4·5-8) in comparison with the previous stages of the area (for both pairs, P < 0·0001). Venous ulcers are caused by poor nutritive and subpapillary perfusion. Subpapillary perfusion plays a major role in the formation of GTA. In a scar, the increased nutritive perfusion is sufficient to cover the blood supply and keep skin viable while subpapillary perfusion is low.

Hypoxic hepatitis (HH) is the most frequent cause of acute liver injury in critically ill patients. No clinical data exist about new onset of jaundice in patients with HH. This study aimed to evaluate the incidence and clinical effect of jaundice in critically ill patients with HH. Two hundred and six consecutive patients with HH were screened for the development of jaundice during the course of HH. Individuals with preexisting jaundice or liver cirrhosis at the time of admission (n 5 31) were excluded from analysis. Jaundice was diagnosed in patients with plasma total bilirubin levels >3 mg/dL. One-year-survival, infections, and cardiopulmonary, gastrointestinal (GI), renal, and hepatic complications were prospectively documented. New onset of jaundice occurred in 63 of 175 patients with HH (36%). In patients who survived the acute event of HH, median duration of jaundice was 6 days (interquartile range, 3-8). Patients who developed jaundice (group 1) needed vasopressor treatment (P < 0.05), renal replacement therapy (P < 0.05), and mechanical ventilation (P < 0.05) more often and had a higher maximal administered dose of norepinephrine (P < 0.05), compared to patients without jaundice (group 2). One-year survival rate was significantly lower in group 1, compared to group 2 (8% versus 25%, respectively; P < 0.05). Occurrence of jaundice was associated with an increased frequency of complications during follow-up (54% in group 1 versus 35% in group 2; P < 0.05). In particular, infections as well as renal and GI complications occurred more frequently in group 1 during follow-up. Conclusion: Jaundice is a common finding during the course of HH. It leads to an increased rate of complications and worse outcome in patients with HH. (HEPATOLOGY 2012;56:2297-2304)

In the present study, the annual incidence of postoperative sinus node dysfunction and the type of sinus node abnormality after cardiac transplantation were followed over a 6 1/2-year period in 185 patients. Each year the sinus node function was systematically characterized by rhythm and corrected sinus node recovery time in a significant number of patients. Over the entire study period, there were 131 patients with normal sinus node function (corrected sinus node recovery time 318 +/- 55 msec) while 54 patients had latent (n = 24, sinus rhythm, corrected sinus node recovery time 8,053 +/- 2,198 msec) or manifest (n = 30, absence of sinus rhythm or pacemaker dependence) sinus node dysfunction. Twenty-nine patients had pacemaker placement. The incidence of sinus node dysfunction declined in absolute terms and when indexed by the actual number of patients transplanted per year (index 1987: 38.5; 1998: 17.6; 1989: 23.2; 1990: 29.1; 1991: 10.4; 1992: 7.5; 1993: 2.2). Among those with sinus node dysfunction, the annual percentage of patients presenting with prolonged recovery time, escape rhythm, and those reverting back to sinus rhythm until discharge did not change significantly over the study period (P = 0.22). On multivariate analysis, only the date of transplantation was significantly associated with the occurrence of postoperative sinus node deficiency (P = 0.0007) while age of recipient (P = 0.85) or donor (P = 0.96), the type of cardioplegia used (P = 0.09) and ischemic time (P = 0.09) were insignificant.(ABSTRACT TRUNCATED AT 250 WORDS)