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.

2nd Department of Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Adult Critical Care University Hospital of Wales Cardiff United Kingdom

AG Emergency and Critical Care Neurology Campus Virchow Klinikum Department of Neurology Charité Universitätsmedizin Berlin Berlin Germany

Anaesthesiology and Intensive Care Department of Surgical Sciences Uppsala University Uppsala Sweden

Australian and New Zealand Intensive Care Research Centre School of Public Health and Preventive Medicine Monash University Melbourne Australia

Biostatistical Department Roche Diagnostics International AG Rotkreuz Switzerland

Clinical Development Department Roche Diagnostics International AG Rotkreuz Switzerland

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Clinical Studies Sweden Forum South Skåne University Hospital Lund Sweden

Department of Anaesthesiology and Intensive Care Medicine Aarhus University Hospital Aarhus Denmark

Department of Clinical Medicine Aarhus University Aarhus Denmark

Department of Clinical Sciences Lund Anaesthesia and Intensive Care Lund University Department of Cardiothoracic Surgery Skåne University Hospital Lund Sweden

Department of Clinical Sciences Lund Anaesthesia and Intensive Care Lund University Helsingborg Hospital Lund Sweden

Department of Clinical Sciences Lund Anaesthesia and Intensive Care Lund University Skåne University Hospital Malmö Sweden

Department of Clinical Sciences Lund Anaesthesiology and Intensive Care Research and Education Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Lund Cardiology Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Lund Neurology Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Malmö Dept Operation and Intensive Care Lund University Hallands Hospital Halmstad Halmstad Sweden

Department of Intensive Care Austin Hospital Melbourne VIC Australia

Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London United Kingdom

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy University of Gothenburg Sweden

Department of Regional Health Research The Faculty of Health Sciences University of Southern Denmark Denmark

Essex Cardiothoracic Centre MSE Basildon Essex United Kingdom

Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Hong Kong China

Intensive Care Unit Alfred Hospital Melbourne Australia

Intensive Care Unit University Hospitals Bristol and Weston England United Kingdom

Medical Intensive Care Unit AP HP Cochin Hospital Paris France Paris Cité University Paris France

MTRC Anglia Ruskin School of Medicine Chelmsford Essex United Kingdom

The Australian and New Zealand Intensive Care Research Centre Monash University Melbourne Australia

The Copenhagen Trial Unit Centre for Clinical Intervention Research Denmark

UK Dementia Research Institute at UCL London United Kingdom

University College Dublin Clinical Research Centre St Vincent's University Hospital Dublin Ireland

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