Jan Bruensing

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.

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

IntroductionHepatic 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.MethodsWe 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).ResultsLiver 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.ConclusionsConsidering 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.

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.

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

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.

Gastrointestinale Blutungen als Komplikation von Patienten mit Leberzirrhose auf der Intensivstation

Due to portal hypertension and bleeding disorders, patients with liver cirrhosis are at increased risk for severe gastrointestinal bleedings (GIB), commonly requiring therapy at the intensive care unit (ICU). In order to identify epidemiological and prognostic factors for GIB in cirrhotic patients, we retrospectively analysed patients from our medical ICU from 1999 to 2010. Among 7376 critically ill patients, 650 (8.8 %) were diagnosed with liver cirrhosis. Hepatic cirrhosis was frequently found in ICU patients admitted due to severe GIB (23.2 % of 711 patients had cirrhosis). Moreover, patients with cirrhosis were at increased risk to develop severe GIB during intensive care treatment (40.9 % of 44 patients with GIB during ICU stay had cirrhosis). Besides the high rate of variceal bleedings (64.4 %) in cirrhotic patients, non-variceal haemorrhages were also common (28.5 %). We identified the MELD score and necessity of mechanical ventilation as independent risk factors for mortality in cirrhotic patients with severe GIB. Patients with liver cirrhosis and severe GIB had significantly impaired prognosis (case-related fatality rate of 26.1 % with cirrhosis vs. 6.8 % without cirrhosis), especially in cases of newly developed GIB during ICU therapy. Advanced therapeutic approaches and novel strategies are warranted to improve the critical prognosis of these high-risk patients.

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-β 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.

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.