Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators

Marion Moseby-Knappe, Helena Levin, Kaj Blennow, Susann Ullén, Henrik Zetterberg, Gisela Lilja, Josef Dankiewicz, Janus Christian Jakobsen, Alice Lagebrant, Hans Friberg, Alistair Nichol, Kate Ainschough, Glenn M. Eastwood, Matt P. Wise, Matthew Thomas, Thomas Keeble, Alain Cariou, Christoph Leithner, Christian Rylander, Joachim DüringJan Bělohlávek, Anders Grejs, Ola Borgquist, Johan Undén, Maryline Simon, Vinzent Rolny, Alex Piehler, Tobias Cronberg, Niklas Nielsen

Research output: Contribution to journalArticlepeer-review


Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0–3 vs. 4–6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95–100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Original languageEnglish
Article number100258
JournalResuscitation Plus
Publication statusPublished - 2022 Jun

Subject classification (UKÄ)

  • Neurology
  • Cardiac and Cardiovascular Systems

Free keywords

  • Brain injury markers
  • Cardiac arrest
  • GFAP, S100
  • Neurofilament light
  • Neuron specific enolase
  • NFL
  • NSE
  • Prognostication, outcome, biomarkers
  • Protocol
  • Total-tau, glial fibrially acidic protein

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