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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.

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.

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.

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.

Background: Out of hospital cardiac arrest (OHCA) is a life-threatening event. Continuous advances in management increased initial survival, but the rate of favorable neurological outcome remains low. We have previously shown the usefulness of proteomics to identify novel biomarkers to predict this outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was thus to assess the predictive value of NfL and compare it to our established model.Methods: NfL was measured in plasma samples from OHCA drawn at 48 hours after the event using single molecule assays. Neurological function at discharge from ICU was recorded on the cerebral performance category (CPC) scale. Predictive ability was assessed for NfL and compared to an established multimarker model.Results: Seventy patients were included into this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2) compared to 49 (70%) with an unfavorable outcome (CPC 3 - 5). NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p

International audience; Background: In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement.Research question: This study investigated factors associated with mortality in this specific ARDS population, including factors related to respiratory mechanics (plateau pressure [Pplat,rs], compliance [Crs], and driving pressure [ΔPrs]).Study design and methods: This study consisted of a predefined secondary analysis of the EFRAIM data. Overall, 789 of 1,611 patients met the Berlin criteria for ARDS, and Pplat,rs, ΔPrs, and Crs were available for 494 patients. A hierarchical model was used to assess factors at ARDS onset independently associated with hospital mortality.Results: Hospital mortality was 56.3%. After adjustment, variables independently associated with hospital mortality included ARDS of undetermined etiology (OR, 1.66; 95% CI, 1.01-2.72), need for vasopressors (OR, 1.91; 95% CI, 1.27-2.88), and need for renal replacement therapy (OR, 2.02; 95% CI, 1.37-2.97). ARDS severity according to the Berlin definition, neutropenia on admission, and the type of underlying disease were not significantly associated with mortality. Before adjustment, higher Pplat,rs, higher ΔPrs, and lower Crs were associated with higher mortality. Addition of each of these individual variables to the final hierarchical model revealed a significant association with mortality: ΔPrs (OR, 1.08; 95% CI, 1.05-1.12), Pplat,rs (OR, 1.07; 95% CI, 1.04-1.11), and Crs (OR, 0.97; 95% CI, 0.95-0.98). Tidal volume was not associated with mortality.Interpretation: In immunocompromised patients with ARDS, respiratory mechanics provide additional prognostic information to predictors of hospital mortality. Studies designed to define lung-protective ventilation guided by these physiological variables may be warranted in this specific population.

Background After successful cardiopulmonary resuscitation with return of spontaneous circulation (ROSC), many patients show signs of an overactive immune activation. Monocytes are a heterogenous cell population that can be distinguished into three subsets. Purpose The aim of this prospective, observational study was to analyze whether monocyte subset distribution is associated with mortality at 6 months in patients after cardiac arrest. Methods We included 53 patients admitted to our medical ICU after cardiac arrest. Blood was taken on admission and monocyte subset distribution was analyzed by flow cytometry and distinguished into classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+CCR2+) and non-classical monocytes (NCM; CD14+CD16++CCR2-). Results Median age was 64.5 (IQR 49.8–74.3) years and 75.5% of patients were male. Mortality at 6 months was 50.9% and survival with good neurological outcome was 37.7%. Of interest, monocyte subset distribution upon admission to the ICU did not differ according to survival. However, patients that died within 6 months showed a strong increase in the pro-inflammatory subset of intermediate monocytes (8.3% (3.8–14.6)% vs. 4.1% (1.5–8.2)%; p=0.025), and a decrease of classical monocytes (87.5% (79.9–89.0)% vs. 90.8% (85.9–92.7)%; p=0.036) 72 hours after admission. In addition, intermediate monocytes were predictive of outcome independent of initial rhythm and time to ROSC and correlated with the CPC-score at 6 months (R=0.32; p=0.043). Discussion Monocyte subset distribution is associated with outcome in patients surviving a cardiac arrest. This suggests that activation of the innate immune system may play a significant role in patient outcome after cardiac arrest. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FWF - Fonds zur Förderung der wissenschaftlichen Forschung

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

The generation of harmful reactive oxygen species (ROS), including hydrogen peroxide, in out-of-hospital cardiac arrest (OHCA) survivors causes systemic ischemia/reperfusion injury that may lead to multiple organ dysfunction and mortality. We hypothesized that the antioxidant enzyme catalase may attenuate these pathophysiological processes after cardiac arrest. Therefore, we aimed to analyze the predictive value of catalase levels for mortality in OHCA survivors. In a prospective, single-center study, catalase levels were determined in OHCA survivors 48 h after the return of spontaneous circulation. Thirty-day mortality was defined as the study end point. A total of 96 OHCA survivors were enrolled, of whom 26% (n = 25) died within the first 30 days after OHCA. The median plasma intensity levels (log2) of catalase were 8.25 (IQR 7.64–8.81). Plasma levels of catalase were found to be associated with mortality, with an adjusted HR of 2.13 (95% CI 1.07–4.23, p = 0.032). A Kaplan–Meier analysis showed a significant increase in 30-day mortality in patients with high catalase plasma levels compared to patients with low catalase levels (p = 0.012). High plasma levels of catalase are a strong and independent predictor for 30-day mortality in OHCA survivors. This indicates that ROS-dependent tissue damage is playing a crucial role in fatal outcomes of post-cardiac syndrome patients.

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 (HF) and activation of the inflammatory system was implicated in the pathophysiology of acute heart failure (AHF). Toll-like receptors (TLRs) play an important role in acute inflammatory processes in critically ill patients by binding to pathogen associated molecular patterns (PAMP) and danger associated molecular patterns (DAMP). However, it is not known whether the expression patterns of TLRs on neutrophils and monocytes are associated with outcome in patients with severe AHF requiring intensive care unit (ICU) admission. The aim of this prospective, observational study was to analyze whether TLR-expression on monocytes or neutrophils is associated with 30-day survival in patients with severe AHF. Methods We included 84 patients with severe AHF admitted to a cardiac ICU. Blood was taken at admission and mean fluorescence activity (MFI) of TLR-2, TLR-4 and TLR-9 on monocytes and neutrophils was analyzed by flow cytometry. Results Median age was 64 (IQR 48–74) years and 76.2% of patients were male. Median NT-proBNP was 4941 (IQR 1298–12273) pg/mL and 30-day mortality was 33.3%. TLR-4 expression on monocytes in survivors (740 IQR 694–854) was significantly lower than in non-survivors (871 IQR 723–979; p Conclusion Monocyte TLR-4 expression predicts mortality in patients admitted to a cardiac ICU for severe acute heart failure. This suggests that activation of the innate immune system by TLR-binding of DAMPS may play a significant role in critically ill acute heart failure patients.

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.

Beta-blockers are a potential option to manage peri-operative atrial fibrillation. Landiolol is a new ultra-short beta-blocker with a half-life of only 4 minutes and very high beta-1 selectivity which has been used for treatment and prevention of atrial fibrillation in pulmonary surgery and gastro-intestinal surgery. Due to its limited negative inotropic effect and high beta-1 selectivity landiolol allows for control of heart rate with minimal impact on blood pressure. Landiolol is well tolerated by the respiratory system. Additional benefits are related to the regulation of the inflammatory response and blunting of the adrenergic pathway. There is a limited number of trials with total of 61 patients undergoing lung resection or oesophagectomy who developed post-operative atrial fibrillation and were treated with landiolol. The experience with landiolol for prevention is more documented than landiolol application for treatment of post-operative atrial fibrillation. There are 9 comparative studies with a total of 450 patients administered landiolol for prevention of post-operative atrial fibrillation. The use of low dosage (5-10mcg/kg/min) is usually sufficient to rapidly control heart rate which is associated with earlier and higher rate of conversion to sinus rhythm as compared to the controls. The excellent tolerance of landiolol at lower dosage (3-5mcg/kg/min) allows to initiate prophylactic use during surgery and postoperatively. Landiolol prophylaxis is associated with reduced incidence of post-operative atrial fibrillation without triggering adverse events related to a beta-blockade.

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.

Background Jaundice and cholestatic hepatic dysfunction are frequent findings in critically ill patients associated with increased mortality. Cholestasis in critically ill patients is closely associated with stimulation of pro-inflammatory cytokines resulting in impaired bile secretion and subsequent accumulation of bile acids. Aim of this study was to evaluate the clinical role of circulating bile acids in critically ill patients. Methods Total and individual serum bile acids were assessed via high-performance liquid chromatography in 320 critically ill patients and 19 controls. Results Total serum bile acids were threefold higher in septic than cardiogenic shock patients and sixfold higher than in post-surgical patients or controls (p

Background Acid–base disturbances are frequently observed in critically ill patients at the intensive care unit. To our knowledge, the acid–base profile of patients with acute-on-chronic liver failure (ACLF) has not been evaluated and compared to critically ill patients without acute or chronic liver disease. Results One hundred and seventy-eight critically ill patients with liver cirrhosis were compared to 178 matched controls in this post hoc analysis of prospectively collected data. Patients with and without liver cirrhosis showed hyperchloremic acidosis and coexisting hypoalbuminemic alkalosis. Cirrhotic patients, especially those with ACLF, showed a marked net metabolic acidosis owing to increased lactate and unmeasured anions. This metabolic acidosis was partly antagonized by associated respiratory alkalosis, yet with progression to ACLF resulted in acidemia, which was present in 62% of patients with ACLF grade III compared to 19% in cirrhosis patients without ACLF. Acidemia and metabolic acidosis were associated with 28-day mortality in cirrhosis. Patients with pH values

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.

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 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.

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.

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.