Visfatin Serum Levels Predict Mortality in Critically Ill Patients.

The adipokine visfatin, also termed pre-B-cell colony-enhancing factor (PBEF), is mainly derived from adipose tissue but has been implicated in the regulation of innate immune responses. We hypothesized that visfatin could be a potential circulating biomarker in critical illness and sepsis. We therefore measured serum levels of visfatin in a cohort of 229 critically ill medical patients upon admission to the intensive care unit (ICU). In comparison to 53 healthy controls, visfatin levels were significantly elevated in medical ICU patients, especially in patients with sepsis. Visfatin serum concentrations were strongly associated with disease severity and organ failure but did not differ between patients with or without obesity or type 2 diabetes. Visfatin levels correlated with biomarkers of renal failure, liver dysfunction, and other adipokines (e.g., resistin, leptin, and adiponectin) in critically ill patients. High visfatin levels at ICU admission indicated an increased mortality, both at the ICU and during long-term follow-up of approximately two years. Our data therefore demonstrate that circulating visfatin is a valuable biomarker for risk and prognosis assessment in critically ill patients. Furthermore, visfatin seems to be involved in the pathogenesis of excessive systemic inflammation, supporting further research on visfatin as a therapeutic target.

High Circulating Caspase-Cleaved Keratin 18 Fragments (M30) Indicate Short-Term Mortality in Critically Ill Patients.

Caspase-cleaved fragments of the intermediate filament protein keratin 18 (cytokeratin-18 (CK18)) can be detected in serum as M30 levels and may serve as a circulating biomarker indicating apoptosis of epithelial and parenchymal cells. In order to evaluate M30 as a biomarker in critical illness, we analyzed circulating M30 levels in 243 critically ill patients (156 with sepsis, 87 without sepsis) at admission to the medical intensive care unit (ICU), in comparison to healthy controls (n = 32). M30 levels were significantly elevated in ICU patients compared with healthy controls. Circulating M30 was closely associated with disease severity but did not differ between patients with sepsis and ICU patients without sepsis. M30 serum levels were correlated with biomarkers of inflammation, cell injury, renal failure, and liver failure in critically ill patients. Patients that died at the ICU showed increased M30 levels at admission, compared with surviving patients. A similar trend was observed for the overall survival. Regression analyses confirmed that M30 levels are associated with mortality, and patients with M30 levels above 250.8 U/L displayed an excessive short-term mortality. Thus, our data support the utility of circulating levels of the apoptosis-related keratin fragment M30 as a prognostic biomarker at ICU admission.

[Management of Clostridium difficile infections at German intensive care units - results from a survey among intensivists]. / Diagnostik und Therapie von Clostridium-difficile-Infektionen auf deutschen Intensivstationen ­ eine Umfrage unter Intensivmedizinern.

BACKGROUND: Clostridium difficile associated colitis is a frequent cause of nosocomial diarrhea at the intensive care unit (ICU) and is associated with poor prognosis in critically ill patients. Few studies have evaluated the efficacy of treatment options or adherence to guideline recommendations of Clostridium difficile infections at the ICU. METHODS: Therefore, on behalf of the Gastroenterology Intensive Care Medicine working group of the DGVS, we have conducted an online-based survey among leading intensivists in Germany. RESULTS: Out of the 351 invited, 85 (24.2 %), primarily leading executive physicians at primary to tertiary care hospitals, completed the survey. They reported standardized diagnostic algorithms of 79.3 %, in line with current guideline recommendations (i. e., toxin testing in stool, possibly GDH screening, and endoscopy). First-line therapy of Clostridium difficile infections at the ICU was reported to be oral vancomycin in 48.3 % and oral metronidazole in 34.5 %. The success of first-line therapy was estimated at 67 % for clinical cure, 15 % persisting colitis, 5 % sepsis or megacolon, 10 % recurrence, and 3 % death. Hospitals of primary/secondary care more often used metronidazole compared to university hospitals. Standard treatments for recurrent infection were vancomycin orally (40 % alone, 29.1 % combined with metronidazole) or, more rarely, fidaxomicin (25.5 %). Fidaxomicin has been used at least once at the ICU in 79 % of the respondents. Eleven percent have used fecal microbiota transplant (FMT) in selected cases at the ICU. CONCLUSION: Our survey indicated a high awareness of German intensivists for Clostridium difficile infections, but also marked differences in local therapeutic algorithms, especially in first-line treatment.

Growth Differentiation Factor-15 Is a Predictor of Mortality in Critically Ill Patients with Sepsis.

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-ß superfamily related to inflammation and macrophage activation. Serum concentrations of GDF-15 can predict poor survival in chronic diseases, but its role in sepsis is obscure. Therefore, we investigated GDF-15 as a prognostic biomarker in critically ill patients. We measured GDF-15 levels in 219 critically ill patients (146 with sepsis, 73 without sepsis) upon admission to the intensive care unit (ICU), in comparison to 66 healthy controls. GDF-15 levels were significantly increased in ICU patients compared to controls. GDF-15 was further increased in sepsis and showed a strong association with organ dysfunction (kidney, liver and lactate) and disease severity (APACHE II and SOFA score). High GDF-15 concentrations at admission independently predicted ICU (HR 3.42; 95% CI 1.33-8.78) and overall mortality (HR 2.02, 95% CI 1.02-3.88) in all ICU critically ill patients as well as in a large subgroup of sepsis patients (ICU mortality: HR 3.16; 95% CI 1.10-9.07; overall mortality: HR 2.62; 95% CI 1.14-6.02). Collectively, serum GDF-15 levels are significantly increased in critically ill patients, associated with sepsis, organ failure, and disease severity. High GDF-15 levels at ICU admission predict short- and long-term mortality risk.

C-terminal proendothelin-1 (CT-proET-1) is associated with organ failure and predicts mortality in critically ill patients.

BACKGROUND: Endothelin 1 (ET-1) is a strong vasoconstrictor, which is involved in inflammation and reduced tissue perfusion. C-terminal proendothelin-1 (CT-proET-1) is the stable circulating precursor protein of ET-1. We hypothesized that CT-proET-1, reflecting ET-1 activation, is involved in the pathogenesis of critical illness and associated with its prognosis. METHODS: Two hundred seventeen critically ill patients (144 with sepsis, 73 without sepsis) were included prospectively upon admission to the medical intensive care unit (ICU), in comparison to 65 healthy controls. CT-proET-1 serum concentrations were correlated with clinical data and extensive laboratory parameters. Overall survival was followed for up to 3 years. RESULTS: CT-proET-1 serum levels at admission were significantly increased in critically ill patients compared to controls. CT-proET-1 serum levels showed significant correlations to systemic inflammation as well as multiple markers of organ dysfunction (kidney, liver, heart). Patients with sepsis displayed higher circulating CT-proET-1 than ICU patients with non-septic diseases. CT-proET-1 levels >74 pmol/L at ICU admission independently predicted ICU death (adjusted hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.30-5.47) and overall mortality during follow-up (adjusted HR 2.19, 95%-CI 1.21-3.98). CONCLUSIONS: CT-proET-1 serum concentrations at admission are increased in critically ill patients and associated with sepsis, disease severity, organ failure, and mortality.

Relevance of serum sclerostin concentrations in critically ill patients.

PURPOSE: Sclerostin is a negative regulator of bone metabolism and associated with chronic morbidities. We investigated circulating sclerostin in critically ill patients. METHODS: A total of 264 patients (170 with sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7. Patients' survival was followed for up to 3 years. RESULTS: Sclerostin serum levels were significantly elevated in critically ill patients at ICU admission compared with 99 healthy controls. Unlike in healthy controls, sclerostin did not depend on sex or age of ICU patients. Sclerostin was associated with disease severity, independent of the presence of sepsis. Sclerostin levels increased during the first week of treatment at the ICU but were not a predictor of mortality. Sclerostin was elevated in patients with preexisting chronic kidney disease or liver cirrhosis, but was not related to diabetes, obesity, or cardiovascular disease. Circulating sclerostin in ICU patients correlated with biomarkers reflecting renal, hepatic and cardiac dysfunction, and biomarkers reflecting bone metabolism. CONCLUSION: Serum sclerostin concentrations are significantly elevated in critically ill patients, linked to renal or hepatic organ failure, and associated with bone resorption markers, supporting its value as a potential tool for the assessment of ICU-related metabolic bone disease.

Clinical relevance and cellular source of elevated soluble urokinase plasminogen activator receptor (suPAR) in acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with a high mortality rate. The expression of urokinase plasminogen activator receptor (uPAR, CD87) and release of its shedded receptor into serum as soluble uPAR (suPAR) have been closely related to immune activation and prognosis in systemic inflammation and cirrhosis. We now aimed at investigating the clinical relevance and cellular source of uPAR and circulating suPAR in ALF. METHODS: Serum suPAR concentrations were measured in 48 ALF patients and 62 healthy controls from a German liver transplantation centre. Hepatic immune cell subsets and uPAR expression were studied by FACS, qPCR and immunohistochemistry. RESULTS: Circulating suPAR levels were significantly increased in ALF patients, independent from the underlying aetiology, in comparison to controls. Serum suPAR concentrations were closely correlated with parameters reflecting liver cell injury, decreased liver function and the model of end-stage liver disease (MELD) score in ALF patients. By immunohistochemistry from explanted livers, ALF was associated with distinct immune cell accumulation and strong up-regulation of intrahepatic uPAR mRNA expression. CD87 (uPAR) expression was specifically detected on intrahepatic 'non-classical' monocytes (CD14(+) CD16(+) ), NKT and CD56(dim) NK cells isolated from human liver, but not on parenchymal or other non-parenchymal hepatic cell types. Membrane-bound uPAR was rapidly cleaved from monocytes upon inflammatory stimulation by lipopolysaccharide (LPS) and partially by co-cultured lymphocytes. CONCLUSIONS: Similar to its prognostic properties in patients with sepsis or cirrhosis, intrahepatic uPAR activation and serum suPAR concentrations might serve as an interesting biomarker in ALF.

Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea.

PURPOSE: Proton pump inhibitors (PPIs) effectively prevent gastrointestinal bleedings in critically ill patients at the intensive care unit (ICU). In non-ICU hospitalized patients, PPI administration increases the risk of infectious complications, especially Clostridium difficile-associated diarrhea (CDAD); but no such data are available for the ICU setting. MATERIALS AND METHODS: This is a retrospective, observational, single-center analysis (1999-2010) including 3286 critically ill patients. RESULTS: A total of 91.3% of patients received stress ulcer prophylaxis by PPI (55.6%), histamine 2 receptor antagonists (5.8%), sucralfate (10.1%), or combinations (19.8%). Only 29 (0.9%) of 3286 patients developed gastrointestinal bleedings during the course of ICU treatment, independent from the type of prophylaxis. The PPIs were not an independent risk factor for nosocomial pneumonia. One hundred and ten (3.3%) patients developed CDAD during the course of ICU treatment, which was associated with prolonged ICU stay and increased ICU mortality (odds ratio, 1.59). Similar to fluoroquinolones and cephalosporins, PPI was identified as an independent risk factor (odds ratio, 3.11) for developing CDAD at the ICU by multivariate analysis. CONCLUSIONS: Proton pump inhibitor therapy was an independent risk factor for CDAD in medical ICU patients. Instead of routine PPI use for bleeding prophylaxis, further trials should investigate risk-adjusted algorithms, balancing benefits, and threats of PPI medication.

Regulation and prognostic relevance of symmetric dimethylarginine serum concentrations in critical illness and sepsis.

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

Elevated asymmetric dimethylarginine levels predict short- and long-term mortality risk in critically ill patients.

OBJECTIVE: Serum concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may contribute to endothelial dysfunction and organ failure in sepsis. We aimed at investigating ADMA levels as a potential diagnostic or prognostic biomarker in critically ill patients. METHODS: Two hundred fifty-five patients (164 with sepsis, 91 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 78 healthy controls. ADMA serum concentrations were correlated with clinical data and extensive laboratory parameters. Patients' survival was followed up for up to 3 years. RESULTS: ADMA serum levels were significantly elevated in critically ill patients at admission compared to controls. ADMA levels did not differ between patients with or without sepsis, but were closely related to hepatic and renal dysfunction, metabolism and clinical scores of disease severity. ADMA levels further increased during the first week of ICU treatment. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU, but also for unfavorable long-term survival. CONCLUSION: Serum ADMA concentrations are significantly elevated in critically ill patients, associated with organ failure and related to short- and long-term mortality risk.

Serum concentrations of A Proliferation-Inducing Ligand (APRIL) are elevated in sepsis and predict mortality in critically ill patients.

INTRODUCTION: Inflammatory and autoimmune diseases have been associated with the tumor necrosis factor superfamily member "A PRoliferation Inducing Ligand" (APRIL). However, up to now, APRIL has not been investigated in critical illness or sepsis. We therefore analyzed APRIL serum concentrations in a large cohort of well-characterized intensive care unit patients. METHODS: Serum concentrations of APRIL were measured in 246 critically ill patients, of which 157 fulfilled sepsis criteria in comparison with 81 healthy controls. Clinical data were recorded and correlated with APRIL serum levels. RESULTS: We detected strongly elevated serum levels of APRIL in critically ill patients compared with healthy controls. Levels of APRIL were further elevated in sepsis and significantly correlated with classical markers of inflammation, bacterial infection, or multiorgan failure. Consequently, high APRIL levels were associated with an unfavorable prognosis and predicted mortality with higher diagnostic accuracy than established prognostic scoring systems such as the Acute Physiology and Chronic Health Evaluation II score. CONCLUSION: Serum levels of APRIL were significantly elevated in intensive care unit patients, with the highest concentrations in septic patients, and associated with unfavorable outcome. Besides being used as a single marker, APRIL may be implemented into established scoring systems to further improve their sensitivity and specificity in predicting patient's prognosis.

Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU.

INTRODUCTION: Hepatic dysfunction is a common finding in critically ill patients on the ICU and directly influences survival. Liver stiffness can be measured by the novel method of transient elastography (fibroscan) and is closely associated with hepatic fibrosis in patients with chronic liver disease, but also is increased in patients with acute hepatitis, acute liver failure and cholestasis. We investigated liver stiffness as a potentially useful tool for early detection of patients with hepatic deterioration and risk stratification with respect to short- and long-term mortality. METHODS: We prospectively evaluated 108 consecutive critically ill patients at our medical intensive care unit (ICU) with subsequent longitudinal liver stiffness measurements (admission, Day 3, Day 7 and weekly thereafter) during the course of ICU treatment. Outcome was followed after discharge (median observation time 237 days). RESULTS: Liver stiffness could be reliably measured in 71% of ICU patients at admission (65% at Day 3, 63% at Day 7). Critically ill patients (n = 108) had significantly increased liver stiffness compared to sex- and age-matched standard care patients (n = 25). ICU patients with decompensated cirrhosis showed highest liver stiffness, whereas other critical diseases (for example, sepsis) and comorbidities (for example, diabetes, obesity) did not impact stiffness values. At admission to the ICU, liver stiffness is closely related to hepatic damage (liver synthesis, cholestasis, fibrosis markers). During the course of ICU treatment, fluid overload (renal failure, volume therapy) and increased central venous pressure (mechanical ventilation, heart failure) were major factors determining liver stiffness. Liver stiffness values > 18 kilopascal (kPa) at ICU admission were associated with increased ICU and long-term mortality, even in non-cirrhotic patients. CONCLUSIONS: Considering that liver stiffness cannot be validly measured in about 30% of ICU patients, transient elastography performed at ICU admission might be a useful tool to early identify liver dysfunction and predict mortality in critically ill patients at a medical ICU.