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Circulating Bile Acids Predict Outcome in Critically Ill Patients

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Circulating Bile Acids Predict Outcome in Critically Ill Patients View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Horvatits et al. Ann. Intensive Care (2017) 7:48 DOI 10.1186/s13613-017-0272-7 RESEARCH Open Access Circulating bile acids predict outcome in critically ill patients Thomas Horvatits1,2†, Andreas Drolz1,2†, Karoline Rutter1,2, Kevin Roedl1,2, Lies Langouche3, Greet Van den Berghe3, Günter Fauler4, Brigitte Meyer5, Martin Hülsmann6, Gottfried Heinz6, Michael Trauner1 and Valentin Fuhrmann1,2* Abstract Background: Jaundice and cholestatic hepatic dysfunction are frequent fndings in critically ill patients associated with increased mortality. Cholestasis in critically ill patients is closely associated with stimulation of pro-infammatory 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 < 0.001). Elevated bile acid levels correlated with severity of illness, renal dysfunction and infammation (p < 0.05). Total bile acids predicted 28-day mortality independently of sex, age, serum bilirubin and severity of illness (HR 1.041, 95% CI 1.013–1.071, p < 0.005). Best prediction of mortality of total bile acids was seen in patients sufering from septic shock. Conclusions: Individual and total BAs are elevated by various degrees in diferent shock conditions. BAs represent an early predictor of short-term survival in a mixed cohort of ICU patients and may serve as marker for early risk stratif- cation in critically ill patients. Future studies should elucidate whether modulation of BA metabolism and signalling infuences the clinical course and outcome in critically ill patients. Keywords: Bile acids, Cholestasis, Cardiogenic shock, Septic shock, Critically ill patients, ICU Background may not be sufciently refected by bilirubin [6, 11]. Jaundice and cholestatic liver dysfunction are found in Although hyperbilirubinemia and accumulation of serum 10–20% of critically ill patients and are associated with BAs are frequent fndings in critically ill patients, under- markedly increased mortality [1–6]. Cholestasis in criti- lying molecular pathways and clinical implications are cally ill patients is associated with the presence of shock, still poorly understood. Te clinical impact of serum BAs sepsis, major surgery, hepatotoxicity of drugs and paren- in critically ill patients has been assessed in a few studies teral nutrition [4, 6–8]. While no universal defnition of focusing on sepsis [2, 6, 12, 13]. cholestasis has been established [1, 6, 7, 9, 10], the com- Cholestasis and sepsis are closely connected as expres- plexity of cholestasis, characterized by impaired bile for- sion of pro-infammatory cytokines results in impaired mation and fow and subsequent bile acid (BA) retention, bile secretion [1, 3, 13–15]. BAs are primarily synthesized in the liver out of cholesterol undergoing enterohepatic circulation (biliary excretion/ileal reabsorption) and *Correspondence: [email protected] then converted to secondary BAs by the gut microbiota † Thomas Horvatits and Andreas Drolz contributed equally to the work [15–24] BA’s metabolic (regulation of lipid and energy 2 Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany homeostasis) and signalling properties are regulated Full list of author information is available at the end of the article via a complex network of nuclear receptors (NRs) such © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Horvatits et al. Ann. Intensive Care (2017) 7:48 Page 2 of 10 farnesoid-X-receptor (FXR) and G-protein-coupled BA (taurochenodeoxycholic acid); TLC (taurolithocholic receptor (TGR5) [17, 22–24]. BAs are directly vasoactive acid); GCDC (glycochenodeoxycholic acid); GC (glyco- mediators and furthermore are capable of stimulating cholic acid); GDC (glycodeoxycholic acid); GUDC (gly- hepatocytes’ production of proinfammatory cytokines coursodeoxycholic acid); GLC (glycolithocholic acid); [25–29]. Furthermore, BAs directly infuence cardiac UDC (ursodeoxycholic acid); CL (cholic acid); CDC (che- function (myocardial contractility and relaxation) [30, nodeoxycholic acid); DC (deoxycholic acid); LC (litho- 31]. Whether BA retention is a distinct pathophysiologi- cholic acid); and TBA (total bile acids) were determined. cal entity or a biochemical epiphenomenon of severity of Fasting TBAs range between 1.5 and 3.1 μmol/l [35, 36]. critical illness or even a compensatory mechanism with potential benefcial (e.g. metabolic or even anti-infam- Defnitions matory) efects remains unclear [6]. Cardiogenic shock was defned by (1) low systolic blood Aim of this study was to assess the clinical relevance of pressure (<90 mmHg) without use of inotropes/vaso- circulating BAs in a large cohort of critically ill patients. pressors, (2) decreased cardiac output assessed by any method, reduced mixed or central venous oxygen satu- Patients and methods ration, (3) absence of hypovolemia, (4) signs of organ Patients and serum analysis malperfusion (oliguria, lactate-acidosis, cyanosis, cen- Serum samples were taken from ICU patients (n = 320), tralization, changes in mental status) [37, 38]. enrolled in a prospective observational study performed Septic shock was defned as sepsis (suspected/pre- at the University Hospital of Vienna [32]. For reasons of sent source of infection) and ≥2 systemic infammatory comparison, 19 controls undergoing elective restorative response syndrome (SIRS) criteria: tachycardia (>90 rectal surgery (matched to a general ICU population) beats per minute); tachypnea (>20 breaths/minute or par- were included [2]. Te study was approved by the ethics tial pressure of carbon dioxide < 32 mmHg); temperature 9 committee of the Medical University of Vienna. Patients’ (>38.3/<36 °C); white blood cell count (>12/<4 × 10 /l) informed consent was obtained. plus hypotension [39, 40]. ICU patients were classifed in four groups based on admission diagnoses (cardiogenic shock, septic shock, Management post-surgical admission and others). Inclusion criteria Patients with cardiogenic or septic shock were treated were ICU admission and age >18 years. Patients with according to standardized protocols [37, 39]. Intravenous liver cirrhosis and primary cholestatic disorders were fuid administration as well as vasopressor therapy was initi- excluded from the study. ated in patients meeting shock criteria aiming to maintain Data collection was performed on a daily basis. Sim- a mean arterial blood pressure of >65 mmHg. Early initia- plifed Acute Physiology Score 2 (SAPS2) [33], as well as tion of broad-spectrum antibiotic treatment was performed Acute Physiology And Chronic Health Evaluation Score according standardized protocols [39]. Antimicrobial ther- 2 (APACHE2) [34], was calculated on admission. Clini- apy was adapted to culture results. Dialysis was performed cal characteristics as well as 28-day mortality and ICU- in patients with renal failure and/or metabolic acidosis. survival were recorded. Statistical analysis Bile acids Continuous variables were described as median and Serum BAs were measured in samples obtained from 25–75% interquartile range (IQR), and for categori- patients on admission and 48 h thereafter. BAs (as listed cal variables absolute and relative parameters were pre- below) were assessed as unconjugated acids and taurine sented. Correlation analysis was performed using and glycine conjugates by tandem mass spectrometry. Spearman’s correlation. Continuous variables were com- Free BAs and conjugates were detected by three mul- pared using Mann–Whitney U test, and categorical vari- tiple reaction monitoring (MRM) experiments, within ables were compared using Chi square tests. A forward one high-performance liquid chromatography (HPLC) stepwise procedure was used to identify most potent run, due to variable ionization and fragment properties. predictors of outcome variable. Te overall diagnostic HPLC was performed on a reversed phase (C18) column test accuracy of BAs was assessed by receiver operating using a methanol–water gradient for chromatographic characteristics expressed as their area under the receiver solution of isobaric BA. Quantifcation was done using operating characteristics curve (AUROC). For data man- deuterated internal standards and correlation of peak agement and analyses, we used MS Excel 2008 for Mac area ratios in linear regression. (Microsoft Corp., Redmond, WA, USA), SPSS 17 for Mac TUDC (tauroursodeoxycholic acid); TC (tauro- (SPSS, Inc. Chicago, IL). All p values reported are two- cholic acid); TDC (taurodeoxycholic acid); TCDC sided, and p < 0.05 was considered as signifcant. Horvatits et al. Ann. Intensive Care (2017) 7:48 Page 3 of 10 Results Total serum bile acids and individual composition Baseline characteristics
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