Search

Continuous advances in resuscitation care have increased survival, but the rate of favorable neurological outcome remains low. We have shown the usefulness of proteomics in identifying novel biomarkers to predict neurological outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was to assess the predictive value of NfL in comparison with and in addition to our established model. NfL was measured in plasma samples drawn at 48 h after cardiac arrest using single-molecule assays. Neurological function was recorded on the cerebral performance category (CPC) scale at discharge from the intensive care unit and after 6 months. The ability to predict a dichotomized outcome (CPC 1–2 vs. 3–5) was assessed with receiver operating characteristic (ROC) curves. Seventy patients were included in this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1–2), compared with 49 (70%) with an unfavorable outcome (CPC 3–5) at discharge. NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p

Funding Acknowledgements Type of funding sources: None. Background Critically ill patients admitted to an intensive care unit (ICU) exhibit a high mortality rate irrespective of the initial cause of hospitalization. Neprilysin, a neutral endopeptidase degrading an array of vasoactive peptides became a drug target within the treatment of heart failure with reduced ejection fraction.The aim of this study was to analyze whether circulating levels of neprilysin at ICU admission are associated with 30-day mortality. Methods In this single-center prospective observational study, 222 consecutive patients admitted to a tertiary ICU at a university hospital were included. Blood was drawn at admission and soluble neprilysin levels were measured using ELISA. Results In the total cohort, Soluble neprilysin levels did not differ according to survival status after 30 days as well as type of admission. However, in patients after surgery or heart valve intervention, 30-day survivors exhibited significantly lower circulating neprilysin levels as compared to those who died within 30 days (660.2, IQR: 156.4 – 2512.5 pg/ml versus 6532.6, IQR: 1840.1 – 10000.0 pg/ml; p=0.02). Soluble neprilysin predicted mortality independently from age, gender, and commonly used scores of risk-prediction (EuroSCORE II, STS-score, and SAPS II score). Additionally, soluble neprilysin was markedly elevated in patients with sepsis and septic shock (p Conclusion At the time of ICU-admission, circulating levels of neprilysin independently predicted 30-day mortality in patients following cardiac surgery or heart valve intervention, but not in critically ill medical patients. Furthermore, patients suffering from sepsis and septic shock displayed significantly increased circulating neprilysin levels.

Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is a life-saving method for patients with low-output failure after cardiac surgery. However, VA-ECMO therapy may increase left ventricular afterload due to retrograde blood flow in the aorta, which may lead to progression of pulmonary congestion. We examined the predictive value of pulmonary congestion in patients that need VA-ECMO support after cardiovascular surgery.We enrolled a total of 266 adult patients undergoing VA-ECMO support following cardiovascular surgery at a university-affiliated tertiary care centre into our single-center registry. Pulmonary edema was assessed on bedside chest X rays at day 0, 3, 5 after VA-ECMO implantation.Median age was 65 (57-72) years, 69% of patients were male and 30-day survival was 63%. At ICU-admission 20% of patients had mild, 54% had moderate and 26% showed severe pulmonary congestion. Pulmonary congestion at day 0 was not associated with outcome (adjusted HR 1.31; 95%-CI 0.89-1.93;P = 0.18), whereas pulmonary congestion at day 3 (adj. HR 2.81; 95%-CI 1.76-4.46;P0.001) and day 5 (adj. HR 3.01;95%-CI 1.84-4.93;P0.001) was significantly associated with survival. Linear regression revealed that out of left ventricular function, cardiac output, central venous saturation, maximum dobutamine and norepinephrine dose as well as fluid balance solely ECMO rotation was associated with the evolution of pulmonary congestion (P = 0.007).Pulmonary edema three and five days after ECMO implantation are associated with poor survival. Interestingly, a high VA-ECMO output was the most important determinant of worsening pulmonary congestion within the first five days.

Background: Patients treated at medical intensive care units suffer from various pathologies and often present with elevated troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Both markers may reflect different forms of cardiac involvement in critical illness. Therefore, the aim of our study was to examine the synergistic prognostic potential of NT-proBNP and high-sensitivity TnT (hs)TnT in unselected critically ill patients. Methods: We included all consecutive patients admitted to our intensive care unit within one year, excluding those suffering from acute myocardial infarction or undergoing cardiac surgery and measured NT-proBNP and TnT plasma levels on the day of admission and 72 hours thereafter. Results: Of the included 148 patients, 52% were male, mean age was of 64.2 ± 16.8 years and 30-day mortality was 33.2%. Non-survivors showed significantly higher NT-proBNP and TnT plasma levels as compared with survivors (p Conclusions: Our findings regarding the individual predictive properties of NT-proBNP and TnT are in line with literature. However, we were able to highlight that they exhibit additive prognostic potential which exceeds their individual value. This might be attributed to a difference in underlying pathomechanisms and an assessment of synergistic risk factors.

Objectives Neurologic outcome prediction in out-of-hospital cardiac arrest survivors is highly limited due to the lack of consistent predictors of clinically relevant brain damage. The present study aimed to identify novel biomarkers of neurologic recovery to improve early prediction of neurologic outcome. Design Prospective, single-center study, SETTING:: University-affiliated tertiary care center. Patients We prospectively enrolled 96 out-of-hospital cardiac arrest survivors into our study. Interventions None. Measurements and main results Neurologic outcome was assessed by the Cerebral Performance Categories score. To identify plasma biomarkers for poor neurologic outcome (Cerebral Performance Categories score ≥ 3), we performed a three-step proteomics strategy of preselection by shotgun analyses, crosschecking in brain tissue samples, and verification by targeted proteomic analyses using a multistep statistical modeling approach. Sixty-three patients (66%) had a poor neurologic outcome. Out of a total of 299 proteins, we identified α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein as novel biomarkers for poor neurologic outcome. The implementation of these biomarkers into a clinical multimarker model, consisting of previously identified covariates associated to outcome, resulted in a significant improvement of neurologic outcome prediction (C-index, 0.70; explained variation, 11.9%; p for added value, 0.019). Conclusions This study identified four novel biomarkers for the prediction of poor neurologic outcome in out-of-hospital cardiac arrest survivors. The implementation of α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein into a multimarker predictive model along with previously identified risk factors significantly improved neurologic outcome prediction. Each of the proteomically identified biomarkers did not only outperform current risk stratification models but may also reflect important pathophysiologic pathways undergoing during cerebral ischemia.

SummaryBackgroundMatrix metalloproteinases (MMPs) are involved in systemic inflammatory responses and organ failure. The aim of this study was to evaluate early circulating plasma levels of MMP‑2, MMP‑9 and their inhibitors TIMP‑1 and TIMP‑2 and their prognostic significance in critically ill patients on admission to the intensive care unit (ICU).MethodsIn a single center prospective study 120 consecutive patients (72.5% male, mean age 66.8 ± 13.3 years, mean simplified acute physiology score [SAPS II] score 52.9 ± 21.9) were enrolled on transfer to the ICU of a cardiology department. The most common underlying conditions were cardiac diseases (n = 42.5%), respiratory failure (n = 10.8%) and sepsis (n = 6.7%). Blood samples were taken within 12 h of ICU admission. The MMP‑2, MMP‑9, TIMP‑1 and TIMP‑2 levels in plasma were evaluated in terms of 30-day survival, underlying condition and clinical score.ResultsOn ICU admission 30-day survivors had significantly lower plasma MMP‑9 (odds ratio, OR 1.67 per 1 SD; 95% confidence interval, CI 1.10−2.53;p = 0.016) and TIMP‑1 (OR 2.15 per 1 SD; 95% CI 1.27−3.64;p = 0.004) levels than non-survivors; furthermore, MMP‑9 and TIMP‑1 correlated well with SAPS II (bothp p = 0.002) and TIMP‑1 (p = 0.01) were independent predictors of survival (Cox regression). No significant correlation was found between MMP‑2 and TIMP‑2 levels, MMP/TIMP ratios and 30-day mortality.ConclusionThe MMP‑9 and TIMP‑1 levels are significantly elevated in acute critical care settings with increased short-term mortality risk, especially in patients with underlying heart disease. These findings support the value of MMPs and TIMPs as prognostic markers and potential therapeutic targets in conditions leading to systemic inflammation and acute organ failure.

Purpose: The question of whether cancer patients with severe respiratory failure benefit from veno-venous extracorporeal membrane oxygenation (vv-ECMO) remains unanswered. We, therefore, analyzed clinical characteristics and outcomes of a large cohort of cancer patients treated with vv-ECMO with the aim to identify prognostic factors. Methods: 297 cancer patients from 19 German and Austrian hospitals who underwent vv-ECMO between 2009 and 2019 were retrospectively analyzed. A multivariable cox proportional hazards analysis for overall survival was performed. In addition, a propensity score-matched analysis and a latent class analysis were conducted. Results: Patients had a median age of 56 (IQR 44–65) years and 214 (72%) were males. 159 (54%) had a solid tumor and 138 (47%) a hematologic malignancy. The 60-day overall survival rate was 26.8% (95% CI 22.1–32.4%). Low platelet count (HR 0.997, 95% CI 0.996–0.999; p = 0.0001 per 1000 platelets/µl), elevated lactate levels (HR 1.048, 95% CI 1.012–1.084; p = 0.0077), and disease status (progressive disease [HR 1.871, 95% CI 1.081–3.238; p = 0.0253], newly diagnosed [HR 1.571, 95% CI 1.044–2.364; p = 0.0304]) were independent adverse prognostic factors for overall survival. A propensity score-matched analysis with patients who did not receive ECMO treatment showed no significant survival advantage for treatment with ECMO. Conclusion: The overall survival of cancer patients who require vv-ECMO is poor. This study shows that the value of vv-ECMO in cancer patients with respiratory failure is still unclear and further research is needed. The risk factors identified in the present analysis may help to better select patients who may benefit from vv-ECMO.

Skeletal muscle area (SMA) in the computed tomography (CT) at the third lumbar vertebra (L3) level is a proxy for whole-body muscle mass but is only performed for clinical reasons. Ultrasound is a promising tool to determine muscle mass at the bedside. It is still unclear how well ultrasound and which ultrasound measuring points can predict CT L3 SMA.This prospective observational trial included 200 non-critically ill patients, who underwent an abdominal CT scan for any clinical reason within 48 h before the ultrasound examination. Ultrasound muscle thickness was evaluated at 3 measuring points on the thigh and 2 measuring points on the upper arm with minimal compression. On the CT scan, the entire L3 SMA was measured based on Hounsfield units. Using a model selection algorithm based on the Bayesian information criterion (BIC) and clinical considerations, a linear prediction model for CT L3 SMA based on the ultrasound muscle thickness and other independent variables was fitted and assessed with cross-validation.67,5% and 32,5% of the patients were from surgical and medical wards, respectively. Mean ultrasound muscle thickness values were between 2,2 and 3,6 cm on the thigh and between 1,4 and 2,8 cm on the upper arm. All ultrasound muscle thickness values were higher in men than in women (P 0,05). CT L3 SMA was 40 cmOne single ultrasound measuring point at the thigh together with sex, height and weight very well predicts CT L3 SMA across different clinical populations. Ultrasound is a safe and bedside method to measure muscle thickness longitudinally to monitor the effects of nutrition and physical therapy.

Extracorporeal membrane oxygenation (ECMO) has established as a cornerstone therapy in severe acute respiratory distress syndrome and refractory hemodynamic failure. As circuit integrity is crucial for adequate organ support, component failure may necessitate a system exchange. In this retrospective study, incidence and etiology of system exchanges during applications of venovenous, venoarterial ECMO, and extracorporeal CO2 removal were examined. Sixty-three (44.4%) of 142 patients were affected by one or more exchanges, totaling 105 replaced circuits. The predominant exchange reason was clotting (n = 20), followed by hemolysis (n = 19), systemic coagulation disorders (n = 13), reconfiguration (n = 13), impaired gas exchange (n = 10), mechanical complications (n = 8), bleeding (n = 6), failed weaning (n = 5), prophylactic exchange (n = 3), and undocumented/other (n = 8). Nineteen (18.1%) events were classified as acute and 70 (66.7%) events as elective exchanges. Patients with circuit exchanges more frequently underwent renal replacement therapy at ECMO initiation (49.2% vs. 29.1%; p = 0.023), had a longer ECMO treatment duration (18 vs. 7.5 days, p < 0.001), and lower hospital survival (29.5% vs. 57.1%; p = 0.002). Considering the high occurrence of coagulation complications, further optimization of coagulation management is deemed necessary.

Early prognostication in post-cardiac arrest (CA) patients remains challenging and biomarkers have evolved as helpful tools in risk assessment. The stress-response cytokine growth differentiation factor-15 (GDF-15) is dramatically up-regulated during various kinds of tissue injury and predicts outcome in many pathological conditions. We aimed to assess the predictive value of circulating GDF-15 in post-CA patients.This prospective observational study included 128 consecutive patients (median age 60.3 years, 75.8% male) with return of spontaneous circulation after in- or out-of-hospital CA who were treated at a tertiary university hospital. GDF-15 serum levels were determined at admission.A total of 52 patients (40.6%) died during the 6-month follow-up. Median GDF-15 levels were significantly lower in survivors (1601 ng/L (interquartile range: 1114-2983 ng/L) than in non-survivors (3172 ng/L (1927-8340 ng/L); p 0.001). GDF-15 levels were also significantly lower in patients with favourable neurological 6-month outcome (cerebral performance category (CPC) 1-2) than in those with poor neurological outcome (CPC 3-5; p 0.001). GDF-15 significantly predicted 6-month mortality in univariate Cox regression analysis (hazard ratio (HR) per 1-standard deviation increase 1.76 [95% confidence interval (CI) 1.35-2.31; p 0.001] and remained significant after multivariable adjustment (HR 1.57 [95% CI 1.19-2.07; p = 0.001]). Subgroup analysis revealed that the association between GDF-15 and 6-month outcome was present both in patients with in- and out-of-hospital CA.GDF-15 predicts poor survival and neurological outcome in post-CA patients. GDF-15 may reflect the extent of hypoxic injury to the brain and other organs and might help to improve early risk stratification after CA.

Background Acute heart failure and cardiogenic shock are associated with an impaired intestinal perfusion, which may lead to a release of cytoplasmatic proteins by hypoxic epithelial injury. Intestinal fatty acid binding protein (iFABP), highly specific for the small bowel enterocyte, may pose a useful novel and very sensitive biomarker for predicting outcome of these patients.The aim of this study was to investigate whether circulating levels of iFABP are associated with mortality in patients with acute heart failure or cardiogenic shock requiring intensive care unit (ICU) admission. Methods We included 90 consecutive patients with cardiogenic shock (74.4%) or severe acute heart failure (25.6%) admitted to a cardiac ICU. Blood samples were taken at day 0 and day 3. Median age was 64.7 (49.4-74.3), 76.7% of patients were male and median NT-proBNP levels were 4,986 (1,525-23,842) pg/mL. 30-day survival was 64.4%. Results Patients with serum levels of iFABP at day 0 in the highest quartile (iFABP ≥ 588.4 pg/mL) had a 2.5-fold risk (P = 0.02) of dying independent of demographics, NT-proBNP levels, and vasopressor use. Extensively elevated admission levels of iFABP above the 90th percentile (iFABP ≥ 10208.4 pg/mL) were associated with an excessive mortality rate of 88.9%. In contrast, iFABP levels at day 3 were not associated with outcome. Conclusion Circulating levels of iFABP at admission predict mortality. This suggests that early inadequate perfusion of the small intestine may be associated with a dramatically decreased survival in patients with cardiogenic shock or severe acute heart failure.

Objective: Patients on extracorporeal membrane oxygenation are frequently in need for sedation. Use of propofol has been associated with impaired oxygenator function due to adsorption to the membrane as well as lipid load. The aim of our retrospective analysis was to compare two different sedation regimens containing either propofol or midazolam with respect to oxygenator running time. Methods: Midazolam was used in 73 patients whereas propofol was used in 49 patients, respectively. In the propofol group, veno-arterial–extracorporeal membrane oxygenation was used predominantly (84%), while veno-venous–extracorporeal membrane oxygenation was used more often in the midazolam group (64%). Results: Oxygenator running time until first exchange was 7 days in both groups ( p = 0.759). No statistically significant differences could be observed between the subgroup of patients receiving lipid-free (n = 24) and lipid-containing (n = 31) parenteral nutrition, respectively. Laboratory parameters like triglycerides, free hemoglobin, fibrinogen, platelets, and activated partial thromboplastin time were not significantly different between both sedation regimens ( p = 0.462, p = 0.489, p = 0.960, p = 0.134, and p = 0.843) and were not associated with oxygenator running time. Conclusion: The use of propofol as sedative seems suitable in patients undergoing extracorporeal membrane oxygenation therapy.

Current guidelines suggest the use of epinephrine in patients with cardiac arrest (CA). However, evidence for increased survival in good neurological condition is lacking. In experimental settings, epinephrine-induced impairment of microvascular flow was shown. The aim of our study was to analyze the association between epinephrine treatment and intestinal injury in patients after CA.We have included 52 patients with return of spontaneous circulation (ROSC) after CA admitted to our medical intensive care unit (ICU). Blood was taken on admission and levels of circulating intestinal fatty acid binding protein (iFABP) were analyzed.Patients were 64 (49.8-73.8) years old and predominantly male (76.9%). After six months, 50% of patients died and 38.5% of patients had a cerebral performance category (CPC)-score of 1-2. iFABP levels were lower in survivors (234 IQR 90-399 pg/mL) as compared to non-survivors (283, IQR 86-11500 pg/mL; p 0.05). Plasma levels of iFABP were not associated with time to ROSC but correlated with epinephrine-dose (R = 0.32; p 0.05). 40% of patients receiving ≥3 mg of epinephrine as compared to 10.5% of patients treated with3 mg (p 0.05) developed iFABP plasma levels1500 pg/mL, which was associated with dramatically increased mortality (HR4.87, 95%CI 1.95-12.1; p 0.001). iFABP levels predicted mortality independent from time to ROSC and the disease severity score SAPS II. In contrast to mortality, iFABP plasma levels were not associated with neurological outcome.In this small, single centre study, cumulative dose of epinephrine used in cardiac arrest patients was associated with an increase in biomarker indicative of intestinal injury and 6-month mortality.

Hypoxic-ischemic brain injury can affect and disturb the autonomous nervous system (ANS), which regulates various visceral systems including the gastro-intestinal and emetic system. The present study aimed to analyze the predictive value of gastric regurgitation (GReg) for neurological outcome in out-of-hospital cardiac arrest (OHCA) survivors. In this prospective, single-center study, 79 OHCA survivors treated at a university-affiliated tertiary care centre were included and GReg was measured at the first day after successful cardiopulmonary resuscitation. Neurological outcome was assessed by the Cerebral Performance Categories score at discharge. Seventy-six percent of the study population had a poor neurological outcome. GReg was found to be associated with poor neurological outcome with an adjusted OR of 5.37 (95% CI 1.41–20.46; p = 0.01). The area under the ROC curve for GReg was 0.69 (95% CI, 0.56–0.81) for poor neurological outcome. GReg on the first day after OHCA is an early, strong and independent predictor for poor neurological outcome in comatose OHCA survivors. These results are particularly compelling because measurement of GReg is inexpensive and routinely performed in critical care units.

Background In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. Methods A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24–36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80–94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80–94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. Discussion Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. Trial registration EU Clinical Trials Register; EudraCT, 2017-002138-22. Registered on 8 August 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-3024-6) contains supplementary material, which is available to authorized users.

Patients admitted to a medical intensive care unit (ICU) are characterized by an activated immune system and exhibit a high mortality rate irrespective of the underlying cause of admission. Interleukin (IL)-33 has been shown to be protective in experimental sepsis models and it has been demonstrated that circulating levels of its "decoy" receptor soluble ST2 (sST2) are associated with outcome in critically ill patients. The aim of the present study was to investigate whether circulating IL-33 is associated with 30-day mortality in patients admitted to a medical ICU. In this prospective, observational study, both IL-33 and sST2 levels were assessed in 223 consecutive patients at ICU admission using specific enzyme-linked immunosorbent assays (ELISAs). During the 30-day follow-up, 58 patients (26%) died. Circulating IL-33 was detectable in 166 patients and in 57 patients, serum IL-33 was below the detection limit. Both detectable IL-33 and sST2 below the median were strong predictors of survival in critically ill patients independent of acute physiology and chronic health evaluation II (APACHE II) score. IL-33 and sST2 predicted risk independent from each other. Patients with both, non-detectable levels of IL-33 and sST2 levels above the median, showed a dramatically increased mortality risk (HR 6.9 95% CI 3.0-16.2; p

Background and aim of the study: Non-occlusive mesenteric ischaemia (NOMI) is characterised by hypoperfusion of the intestines without evidence of mechanical obstruction, potentially leading to extensive ischaemia and necrosis. Low cardiac output appears to be a major risk factor. Cardiopulmonary resuscitation aims at restoring blood flow after cardiac arrest. However, post restoration of spontaneous circulation, myocardial stunning limits immediate recovery of sufficient cardiac function. Since after successful cardiopulmonary resuscitation patients are often ventilated and sedated, NOMI might be underdiagnosed and potentially life-saving treatment delayed. Material and methods: A prospectively maintained multi-purpose cohort of out of hospital cardiac arrest survivors, who had successful restoration of spontaneous circulation, was used for this retrospective database analysis. Patients’ charts were screened for clinical, radiological or pathological evidence of NOMI and clinical data were collected. Results: Between 2000 and 2014, 1780 patients who were successfully resuscitated after out of hospital cardiac arrest were screened for NOMI. Twelve patients (0.68 %) suffered from NOMI and six of those died (50 %). Patients suffering from NOMI tended to have a longer duration until restoration of spontaneous circulation (27 vs. 20 min, p=0.128) and had significantly higher lactate (14 mmol/l vs. 8 mmol/l, p=0.002) and base deficit levels at admission (−17 vs. −10, p=0.012). Median leukocyte counts in NOMI patients peaked at the day of diagnosis. Conclusion: NOMI is a rare but life-threatening and potentially curable complication following successful cardiopulmonary resuscitation. Lactate and base deficit at admission could help to identify patients at risk for developing NOMI who might benefit from increased clinical attention.

BACKGROUND Toll-like receptors (TLRs) play an important role in inflammatory processes in critically ill patients by binding to pathogen-associated molecular patterns and danger-associated molecular patterns (DAMPs). Whether neutrophil or monocyte TLR expression patterns are associated with outcome in critical illness is unknown. OBJECTIVES To answer this question, we conducted a prospective, observational study including 215 consecutive patients admitted to a medical ICU at a tertiary care center. METHODS Blood was drawn at admission and expression of TLR-2, TLR-4, and TLR-9 on neutrophils and monocytes were analyzed by flow cytometry. RESULTS Median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 19, and 30-day mortality was 26%. TLR-2 expression on neutrophils was associated with APACHE II, Simplified Acute Physiology Score II, and Sepsis-related Organ Failure Assessment score. TLR-2 (P

Background: Inflammation is regarded as an important trigger for disease progression in heart failure. Particularly in severe acute heart failure, tissue hypoxia may lead to cellular damage and the release of intracellular mitochondrial DNA, which acts as an activator of the immune system due to its resemblance to bacterial DNA. It may therefore serve as a mediator of disease progression. The aim of this study was to determine circulating levels of mitochondrial DNA and its association with mortality in patients with heart failure in different presentations. Methods: Plasma levels of circulating mitochondrial DNA were measured in 90 consecutive patients with severe acute heart failure admitted to our medical intensive care unit as well as 109 consecutive chronic heart failure patients. Results: In patients admitted to our medical intensive care unit (median age 64 (49–74) years, median NT-pro-brain natriuretic peptide 4986 (1525–23,842) pg/mL, 30-day survival 64.4%), mitochondrial DNA levels were significantly higher in patients who died within 30 days after intensive care unit admission, and patients with plasma levels of mitochondrial DNA in the highest quartile had a 3.4-fold increased risk (P=0.002) of dying independent of renal function, vasopressor use and NT-pro-brain natriuretic peptide, troponin T, lactate levels or CardShock and acute physiology and chronic health evaluation II score. However, mitochondrial DNA did not provide incremental prognostic accuracy on top of the current gold standard acute physiology and chronic health evaluation II. Patients with severe acute heart failure showed significantly higher mitochondrial DNA levels (P Conclusions: The release of mitochondrial DNA into the circulation is associated with mortality in patients with severe acute heart failure but not in patients with chronic heart failure. The release of mitochondrial DNA may therefore play a role within the pathophysiology of acute heart failure, which warrants further research. However, the use of mitochondrial DNA as a biomarker for risk stratification in these patients is of limited utility.

Vitamin D deficiency is frequent in cancer patients and a risk factor for morbidity and mortality during critical illness. This single-center retrospective study analyzed 25-hydroxyvitamin D levels in critically ill cancer patients (n = 178, hematologic, n = 108, solid, n = 70) enrolled in a prospective ICU registry. The primary analysis was the prevalence of vitamin D deficiency (&lt, 20 ng/mL) and the severe deficiency (&le, 12 ng/mL). Secondary analyses included risk factors for vitamin D deficiency and its impact on ICU, hospital, and 1-year mortality. The prevalence of vitamin D deficiency and severe deficiency was 74% (95% CI: 67&ndash, 80%) and 54% (95% CI: 47&ndash, 61%). Younger age, relapsed/refractory disease, and a higher sepsis-related organ failure assessment (SOFA) score were independent risk factors for vitamin D deficiency (p &lt, 0.05). After adjusting for relapsed/refractory disease, infection, the SOFA score, and the early need for life-supporting interventions, severe vitamin D deficiency was an independent predictor of hospital mortality (OR: 2.21, 95% CI: 1.03&ndash, 4.72, p = 0.04) and 1-year mortality (OR: 3.40, 95% CI: 1.50&ndash, 7.71, p &lt, 0.01), but not of ICU mortality. Conclusion: Vitamin D deficiency is common in critically ill cancer patients requiring ICU admission, but its impact on short-term mortality in this group is uncertain. The observed association of severe vitamin D deficiency with the post-ICU outcome warrants clinical consideration and further study.

Background The impact of levosimendan treatment on clinical outcome in patients undergoing extracorporeal membrane oxygenation (ECMO) support after cardiovascular surgery is unknown. We hypothesized that the beneficial effects of levosimendan might improve survival when adequate end-organ perfusion is ensured by concomitant ECMO therapy. We therefore studied the impact of levosimendan treatment on survival and failure of ECMO weaning in patients after cardiovascular surgery. Methods We enrolled a total of 240 patients undergoing veno-arterial ECMO therapy after cardiovascular surgery at a university-affiliated tertiary care centre into our observational single-centre registry. Results During a median follow-up period of 37 months (interquartile range 19–67 months), 65% of patients died. Seventy-five per cent of patients received levosimendan treatment within the first 24 h after initiation of ECMO therapy. Cox regression analysis showed an association between levosimendan treatment and successful ECMO weaning [adjusted hazard ratio (HR) 0.41; 95% confience interval (CI) 0.22–0.80; P=0.008], 30 day mortality (adjusted HR 0.52; 95% CI 0.30–0.89; P=0.016), and long-term mortality (adjusted HR 0.64; 95% CI 0.42–0.98; P=0.04). Conclusions These data suggest an association between levosimendan treatment and improved short- and long-term survival in patients undergoing ECMO support after cardiovascular surgery.

OBJECTIVES Extracorporeal membrane oxygenation represents a valuable and rapidly evolving therapeutic option in patients with severe heart or lung failure following cardiovascular surgery. However, survival remains poor and accurate risk stratification challenging. Therefore, we evaluated the predictive value of urinary output within 24 hours after extracorporeal membrane oxygenation initiation on mortality in patients undergoing venoarterial extracorporeal membrane oxygenation support following cardiovascular surgery and aimed to improve established risk prediction models. DESIGN Single-center, observational registry. SETTING University-affiliated tertiary care center. PATIENTS We included 205 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following cardiovascular surgery at a university-affiliated tertiary-care center into our single-centre registry. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS During a median follow-up time of 35 months (interquartile range, 19-69), 64% of patients died. Twenty-four-hour urinary output was the strongest predictor of outcome among renal function variables with an adjusted hazard ratio per 1 SD of 0.55 (95% CI, 0.40-0.76; p < 0.001) for 30-day mortality and of 0.65 (95% CI, 0.53-0.86; p = 0.002) for 2-year long-term mortality. Most remarkably, 24-hour urinary output showed additional prognostic value beyond that achievable with the simplified acute physiology score-3 and sequential organ failure assessment score indicated by improvements in the category-free net reclassification index for 30-day mortality (simplified acute physiology score-3: 36%, p = 0.015; sequential organ failure assessment score: 36%, p = 0.02), as well as for 2-year mortality (simplified acute physiology score-3: 33%, p = 0.02; sequential organ failure assessment score: 43%, p = 0.005). CONCLUSIONS We identified 24-hour urinary output as a strong and easily available predictor of mortality in patients undergoing extracorporeal membrane oxygenation therapy following cardiovascular surgery. Implementation of 24-hour urinary output leads to a substantial improvement of established risk prediction models in this vulnerable patient population. These results are particularly compelling because measurement of urinary output is inexpensive and routinely performed in all critical care units.

OBJECTIVES Although extracorporeal membrane oxygenation (ECMO) represents a rapidly evolving treatment option in patients with refractory heart or lung failure, survival remains poor and appropriate risk stratification challenging because established risk prediction models have not been validated for this specific population. METHODS This observational single-centre registry included a total of 240 patients treated with venoarterial ECMO therapy following cardiovascular surgery and analysed the discriminatory power of the European System of Cardiac Operative Risk Evaluation (EuroSCORE) additive, the EuroSCORE II, the Sequential Organ Failure Assessment (SOFA) score, the Simplified Acute Physiology Score (SAPS) II, the SAPS III, the Acute Physiology and Chronic Health Evaluation (APACHE) II, the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage renal failure (RIFLE) classification, the survival after venoarterial ECMO (SAVE) score, the prEdictioN of Cardiogenic shock OUtcome foR AMI patients salvaGed by VA-ECMO (ENCOURAGE) score and the Society of Thoracic Surgeons (STS) risk model for outcome prediction. RESULTS During a median follow-up time of 37 months (interquartile range 19–67), 65% of the patients died. Only the SAVE score and the SAPS II were significantly associated with the 30-day mortality rate with a hazard ratio (HR) of 1.06 [95% confidence interval (CI) 1.02–1.11; P = 0.002] for the SAVE score and an HR of 1.02 (95% CI 1.01–1.03; P = 0.004) for the SAPS II with a modest discriminatory power displayed by a C-index of 0.61 and 0.57, respectively. Seven out of 10 scoring systems revealed significant association with long-term mortality, with the SAVE score and the SAPS II remaining the strongest predictors of long-term mortality with an HR of 1.06 (95% CI 1.03–1.09; P CONCLUSIONS Risk assessment based on established risk models in patients with ECMO remains difficult. Only the SAPS II and the SAVE score were exclusively found to be suitable for short- and long-term outcome prediction in this specific vulnerable patient population.

Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half‐life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP‐induced aggregometry in whole blood classified 74% (95% confidence intervals 59–87%) of critically ill patients as poor responders (n = 43), and 65% (49–79%) responded poorly according to the vasodilator‐stimulated phosphoprotein phosphorylation (VASP‐P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30‐fold, the parent drug levels even exceeded those of the metabolite 2‐fold in critically ill patients. The half‐life of pantoprazole was several‐fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5‐fold increase in half‐life of pantoprazole. Thus, high‐risk patients may benefit from treatment with alternative platelet inhibitors.

Background Extracorporeal membrane oxygenation following cardiac surgery safeguards end‐organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular ( RV ) dysfunction. We sought to determine the prognostic impact of RV function and to improve established risk‐prediction models in this vulnerable patient cohort. Methods and Results Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60‐74), and 74 patients were male. During a median follow‐up of 27 months (interquartile range 16‐63), 75 patients died. Fifty‐one patients died within 30 days, 75 during long‐term follow‐up (median follow‐up 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function ( P RV free‐wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score‐3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95% CI 0.24‐0.68; P =0.001) for 30‐day mortality and 0.48 (95% CI 0.33‐0.71; P SD ( SD =−6%) change in RV free‐wall strain. Combined assessment of the additive Euro SCORE and RV free‐wall strain improved risk classification by a net reclassification improvement of 57% for 30‐day mortality ( P =0.01) and 56% for long‐term mortality ( P =0.02) compared with the additive Euro SCORE alone. Conclusions RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for short‐ and long‐term mortality.

The overall therapeutic goal of venoarterial extracorporeal membrane oxygenation (ECMO) in patients with postcardiotomy shock is bridging to myocardial recovery. However, in patients with irreversible myocardial damage prolonged ECMO treatment would cause a delay or even withholding of further permanent potentially life-saving therapeutic options. We therefore assessed the prognostic effect of duration of ECMO support on survival in adult patients after cardiovascular surgery.We enrolled into our single-center registry a total of 354 patients who underwent venoarterial ECMO support after cardiovascular surgery at a university-affiliated tertiary care center.Through a median follow-up period of 45 months (interquartile range, 20-81 months), 245 patients (69%) died. We observed an increase in mortality with increasing duration of ECMO support. The association between increased duration of ECMO support and mortality persisted in patients who survived ECMO support with a crude hazard ratio of 1.96 (95% confidence interval, 1.40-2.74; P .001) for 2-year mortality compared with the third tertile and the second tertile of ECMO duration. This effect was even more pronounced after multivariate adjustment using a bootstrap-selected confounder model with an adjusted hazard ratio of 2.30 (95% confidence interval, 1.52-3.48; P .001) for 2-year long-term mortality.Prolonged venoarterial ECMO support is associated with poor outcome in adult patients after cardiovascular surgery. Our data suggest reevaluation of therapeutic strategies after 7 days of ECMO support because mortality disproportionally increases afterward.

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.

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).

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.

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 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.