title: Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunction.
abstract: BACKGROUND
  Severe sepsis, septic shock, and resulting organ failure represent the most common cause of death in intensive care medicine, with mortality ranging from 40% to 70%. It is still unclear whether necrosis or apoptosis plays the predominant role in severe sepsis. Determining the prevalent mode of cell death would be valuable, as new therapeutic agents (eg, antiapoptotic drugs such as caspase inhibitors) may improve unsatisfactory outcomes in patients with severe sepsis. Furthermore, the prognostic value of newly developed cell death serum biomarkers is of great interest.
  
  
  METHODS
  In total, 147 patients (101 patients with severe sepsis, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled. Baseline and clinical data were evaluated. Blood samples from patients with severe sepsis were collected at the time of sepsis diagnosis, and 48 and 120 hours later; samples from healthy volunteers were collected once, and from postoperative patients, once immediately after surgery. We measured caspase-cleaved and uncleaved cytokeratin-18 (CK-18, intermediate filament protein) as a marker of cell death, isolated CK-18 fragments as a marker of apoptosis, as well as IL-6, soluble vascular cell adhesion molecule, and soluble intercellular adhesion molecule.
  
  
  RESULTS
  Age and sex of patients with severe sepsis and postoperative patients were comparable, whereas healthy volunteers were significantly younger. In healthy volunteers, the mode of cellular turnover was primarily apoptotic cell death. Postoperative patients showed comparable levels of apoptotic activity, but necrotic cell death was markedly increased, probably due to surgical tissue injury. In contrast, patients with severe sepsis, and especially non-survivors of the septic group showed increased levels of markers for both apoptotic and necrotic cell death. In severe septic patients with liver dysfunction, necrosis is increased relative to severe septic patients with intact hepatic function. For severe septic patients with liver dysfunction, a cut-off value for caspase-cleaved and uncleaved cytokeratin-18 could be calculated, in order to identify patients at high risk for death due to severe sepsis.
  
  
  CONCLUSIONS
  The measurement of caspase-cleaved and uncleaved cytokeratin-18 appears to be an early predictor for survival in severe septic patients with hepatic dysfunction. Furthermore, the loss of parenchymal cells due to necrosis may be the primary mode of cell death in these patients. This may limit possible therapeutic options.
authors.affiliation: Department of Anaesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Stefan.Hofer@med.uni-heidelberg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Hofer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Brenner
authors.forename: Christian
authors.initials: C
authors.lastname: Bopp
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Christoph
authors.initials: C
authors.lastname: Lichtenstern
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Bruckner
authors.forename: Eike
authors.initials: E
authors.lastname: Martin
authors.forename: Ursula
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Markus A
authors.initials: MA
authors.lastname: Weigand
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016923:Cell Death; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053538:Keratin-18 / Q000097:blood*; D017114:Liver Failure, Acute / Q000097:blood* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000401:mortality; D011379:Prognosis; D018805:Sepsis / Q000097:blood* / Q000401:mortality; D016019:Survival Analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D053538:Keratin-18; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1