Single versus Serial Measurements of Neuron-Specific Enolase and Prediction of Poor Neurological Outcome in Persistently Unconscious Patients after Out-Of-Hospital Cardiac Arrest - A TTM-Trial Substudy

PLoS One. 2017 Jan 18;12(1):e0168894. doi: 10.1371/journal.pone.0168894. eCollection 2017.


Background: Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron-specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population.

Methods: This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33°C or 36°C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5.

Results: A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58-0.84 versus 0.83).

Conclusion: NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort.

Trial registration: NCT01020916.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Biomarkers / blood
  • Humans
  • Hypothermia, Induced
  • Out-of-Hospital Cardiac Arrest / mortality*
  • Out-of-Hospital Cardiac Arrest / pathology*
  • Phosphopyruvate Hydratase / blood*
  • Prospective Studies
  • Rewarming
  • Treatment Outcome
  • Unconsciousness / pathology*


  • Biomarkers
  • Phosphopyruvate Hydratase

Associated data


Grant support

The TTM-Trial was funded by independent research grants from the Swedish Heart Lung Foundation; Arbetsmarknadens Försäkringsaktiebolag Insurance Foundation; Swedish Research Council; regional research support, Region Skåne; governmental funding of clinical research within the Swedish National Health Services; Thelma Zoega Foundation; Krapperup Foundation; Thure Carlsson Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Skåne University Hospital, Sweden; TrygFonden, Denmark; the European Clinical Research Infrastructures Network; and the European Critical Care Research Network. There was no commercial funding. Funding organizations neither had any access to the data nor had any influence on the analysis or interpretation.