title: Serum levels of caspase-cleaved cytokeratin-18 in patients with severe traumatic brain injury are associated with mortality: a pilot study.
abstract: OBJECTIVE
  There have been found apoptotic changes in brain tissue samples from animals and humans after a traumatic brain injury (TBI). The protein cytokeratin 18 (CK-18), present in epithelial cells, is cleaved by the action of caspases during apoptosis, and the resulting fragments are released into the blood as caspase-cleaved CK (CCCK)-18. Circulating levels of CCCK-18, as biomarker of apoptosis, have been determined in patients with different processes; however, it has not been explored in TBI patients. Thus, the objective of this study was to determine whether there is an association between serum CCCK-18 levels and mortality and whether such levels could be used as a biomarker to predict outcomes in TBI patients.
  
  
  METHODS
  A prospective, observational, multicenter study carried out in six Spanish Intensive Care Units. We included patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9; and were excluded those patients with Injury Severity Score (ISS) in non-cranial aspects higher than 9. We measured serum CCCK-18 levels at admission. The end-point of the study was 30-day mortality.
  
  
  RESULTS
  Surviving patients (n = 73) showed lower serum CCCK-18 levels (P = 0.003) than non-survivors (n = 27). On ROC analysis, the area under the curve (AUC) for serum CCCK-18 levels as predictor of 30-day mortality was 0.69 (95% CI = 0.59-0.78; P = 0.006). We found in survival analysis that patients with serum CCCK-18 higher than 201 u/L had higher 30-day mortality than patients with lower levels (Hazard ratio = 3.9; 95% CI = 1.81-8.34; P<0.001). Regression analyses showed that serum CCCK-18 levels higher than 201 u/L were associated with 30-day mortality (OR = 8.476; 95% CI = 2.087-34.434; P = 0.003) after controlling for age and GCS.
  
  
  CONCLUSIONS
  The novel finding of our study was that serum CCCK-18 levels are associated with 30-day mortality and could be used as a prognostic biomarker in patients with severe TBI.
authors.affiliation: Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lorente
authors.affiliation: Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Martín
authors.affiliation: Laboratory Deparment, Hospital Universitario de Canarias, Laguna, Tenerife, Spain.
authors.forename: Agustín F
authors.initials: AF
authors.lastname: González-Rivero
authors.affiliation: Intensive Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Argueso
authors.affiliation: Intensive Care Unit, Hospital General de La Palma, Breña Alta, La Palma, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Ramos
authors.affiliation: Intensive Care Unit, Hospital Universitario Dr. Negrín, CIBERES, Las Palmas de Gran Canaria, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Solé-Violán
authors.affiliation: Intensive Care Unit, Hospital Insular, Las Palmas de Gran Canaria, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cáceres
authors.affiliation: Research Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Laboratory Deparment, Hospital Universitario de Canarias, Laguna, Tenerife, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Borreguero-León
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001930:Brain Injuries / Q000097:blood* / Q000401:mortality*; D020169:Caspases / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D013030:Spain / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D053538:Keratin-18; D010446:Peptide Fragments; D020169:Caspases
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