title: Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest.
abstract: Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA).
  
  
  
  In this post hoc study, we analyzed 163 comatose patients included at a single center in the target temperature management (TTM) trial, randomly assigned to TTM at 33°C or 36°C for 24h. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis.
  
  
  
  By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3ng/ml (p=0.01))), endothelial activation (sE-selectin (2.0ng/ml (p=0.03))) and endothelial damage (thrombomodulin 0.7ng/ml (p=0.0005)) at 24h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48h (1.7 (0.9-2.4), p<0.0001) and 72h (1.5 (0.6-2.3), p<0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36°C group (-55ng/ml (95%CI: -53 to -58ng/ml), p=0.005) compared to the 33°C group. High levels of thrombomodulin at 24h (HR=2.1 (1.3-3.3), p=0.001) and 48h (HR=1.75 (1.0-2.8), p=0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses.
  
  
  
  In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36°C compared to 33°C after OHCA was associated with lower endothelial activation, but not endothelial damage.
  
  
  
  URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916.
authors: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark. Electronic address: jbj@dadlnet.dk.
authors: John
authors: J
authors: Bro-Jeppesen
authors: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Surgery, Division of Acute Care Surgery, Centre for Translational Injury Research (CeTIR), University of Texas Medical School at Houston, TX, USA.
authors: Pär I
authors: PI
authors: Johansson
authors: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors: Christian
authors: C
authors: Hassager
authors: Department of Cardiothoracic Anesthesiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors: Michael
authors: M
authors: Wanscher
authors: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors: Sisse R
authors: SR
authors: Ostrowski
authors: The Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Denmark.
authors: Mette
authors: M
authors: Bjerre
authors: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors: Jesper
authors: J
authors: Kjaergaard
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001831:Body Temperature; D003128:Coma / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D003718:Denmark / Q000453:epidemiology; D004727:Endothelium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D063305:Organ Dysfunction Scores; D058687:Out-of-Hospital Cardiac Arrest / Q000150:complications / Q000401:mortality; D012720:Severity of Illness Index; D013223:Statistics as Topic; D016019:Survival Analysis; D053668:Syndecan-1 / Q000032:analysis*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018180:Thrombomodulin / Q000032:analysis*
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D053668:Syndecan-1; C546931:THBD protein, human; D018180:Thrombomodulin
keywords: Cardiac arrest; Endothelial damage; Inflammation; Outcome; Post-cardiac arrest syndrome