Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest

Marion Moseby-Knappe; Niklas Mattsson-Carlgren; Pascal Stammet; Sofia Backman; Kaj Blennow; Josef Dankiewicz; Hans Friberg; Christian Hassager; Janneke Horn; Jesper Kjaergaard; Gisela Lilja; Christian Rylander; Susann Ullén; Johan Undén; Erik Westhall; Matt P. Wise; Henrik Zetterberg; Niklas Nielsen; Tobias Cronberg

doi:10.1007/s00134-021-06481-4

Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest

Marion Moseby-Knappe^*
, Niklas Mattsson-Carlgren
, Pascal Stammet
, Sofia Backman
, Kaj Blennow
, Josef Dankiewicz
, Hans Friberg
, Christian Hassager
, Janneke Horn
, Jesper Kjaergaard
, Gisela Lilja
, Christian Rylander
, Susann Ullén
, Johan Undén
, Erik Westhall
, Matt P. Wise
, Henrik Zetterberg
, Niklas Nielsen
, Tobias Cronberg

^*Corresponding author for this work

Lund University
Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
Medical and Health Department, National Fire and Rescue Corps, Luxembourg, Luxembourg
University of Gothenburg
University of Copenhagen
Vrije Universiteit Amsterdam
Adult Critical Care, University Hospital of Wales, Cardiff, UK
University College London
Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered “indeterminate”. We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1–2) at 6 months. Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2–98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87–95% of patients). Normal S100B and NSE predicted good outcome with NPV 76–82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as “indeterminate outcome” by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.

Original language	English
Pages (from-to)	984-994
Number of pages	11
Journal	Intensive care medicine
Volume	47
Issue number	9
Early online date	2021
DOIs	https://doi.org/10.1007/s00134-021-06481-4
Publication status	Published - Sept 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Blood biomarkers
Cardiac arrest
ERC/ESICM guidelines
Good neurological outcome
Neurofilament light
Prognostication

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Moseby-Knappe, M., Mattsson-Carlgren, N., Stammet, P., Backman, S., Blennow, K., Dankiewicz, J., Friberg, H., Hassager, C., Horn, J., Kjaergaard, J., Lilja, G., Rylander, C., Ullén, S., Undén, J., Westhall, E., Wise, M. P., Zetterberg, H., Nielsen, N., & Cronberg, T. (2021). Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest. Intensive care medicine, 47(9), 984-994. https://doi.org/10.1007/s00134-021-06481-4

@article{cfa89c4d013f418f832bd8b32ab90d6f,

title = "Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest",

abstract = "Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered “indeterminate”. We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1–2) at 6 months. Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2–98\% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87–95\% of patients). Normal S100B and NSE predicted good outcome with NPV 76–82.2\%. Normal NSE correctly identified 67/190 (35.3\%) patients with good outcome among those classified as “indeterminate outcome” by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.",

keywords = "Blood biomarkers, Cardiac arrest, ERC/ESICM guidelines, Good neurological outcome, Neurofilament light, Prognostication",

author = "Marion Moseby-Knappe and Niklas Mattsson-Carlgren and Pascal Stammet and Sofia Backman and Kaj Blennow and Josef Dankiewicz and Hans Friberg and Christian Hassager and Janneke Horn and Jesper Kjaergaard and Gisela Lilja and Christian Rylander and Susann Ull{\'e}n and Johan Und{\'e}n and Erik Westhall and Wise, \{Matt P.\} and Henrik Zetterberg and Niklas Nielsen and Tobias Cronberg",

note = "Funding Information: The authors would like to thank the TTM-trial investigators and the sponsors for their support. We thank the staff at the Clinical Neurochemistry Laboratory in M?lndal, Sweden, Banyan Biomarkers, San Diego, CA, the biochemistry laboratory of the Centre Hospitalier de Luxembourg and the Integrated BioBank of Luxembourg for analysis and storage of samples. Funding Information: Open access funding provided by Lund University. Funding for the study was provided by the Swedish Research Council, Swedish Heart Lung Foundation, Arbetsmarknadens F{\"o}rs{\"a}kringsaktiebolag Insurance Foundation, the Sk{\aa}ne University Hospital Foundations, the Gyllenstierna-Krapperup Foundation, and governmental funding of clinical research within the Swedish National Health System, the County Council of Sk{\aa}ne; the Swedish Society of Medicine; the Koch Foundation; TrygFonden (Denmark); European Clinical Research Infrastructures Network; Thelma Zoega Foundation; Stig and Ragna Gorthon Foundation; Thure Carlsson Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Lions Research fund Sk{\aa}ne; South Swedish Hospital Region Research Funds; the Swedish Brain Foundation; the Lundbeck Foundation; and the Torsten S{\"o}derberg foundation at the Royal Swedish Academy of Sciences. HZ is a Wallenberg Scholar. NMC is a Wallenberg Molecular Medicine Fellow.Role of the Funder/Sponsor: the funding organizations had no role in the design and conduct. of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: MMK, NMC, PS, SB, JD, HF, CH, JH, GL, CR, SU, JH, EW, MW, NN and TC report no conflicts of interest. HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. JK reports funding from NovoNordisk foundation NNF17OC0028706, for work outside the present manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.1007/s00134-021-06481-4",

language = "English",

volume = "47",

pages = "984--994",

journal = "Intensive care medicine",

issn = "0342-4642",

publisher = "Springer Verlag",

number = "9",

}

Moseby-Knappe, M, Mattsson-Carlgren, N, Stammet, P, Backman, S, Blennow, K, Dankiewicz, J, Friberg, H, Hassager, C, Horn, J, Kjaergaard, J, Lilja, G, Rylander, C, Ullén, S, Undén, J, Westhall, E, Wise, MP, Zetterberg, H, Nielsen, N & Cronberg, T 2021, 'Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest', Intensive care medicine, vol. 47, no. 9, pp. 984-994. https://doi.org/10.1007/s00134-021-06481-4

TY - JOUR

T1 - Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest

AU - Moseby-Knappe, Marion

AU - Mattsson-Carlgren, Niklas

AU - Stammet, Pascal

AU - Backman, Sofia

AU - Blennow, Kaj

AU - Dankiewicz, Josef

AU - Friberg, Hans

AU - Hassager, Christian

AU - Horn, Janneke

AU - Kjaergaard, Jesper

AU - Lilja, Gisela

AU - Rylander, Christian

AU - Ullén, Susann

AU - Undén, Johan

AU - Westhall, Erik

AU - Wise, Matt P.

AU - Zetterberg, Henrik

AU - Nielsen, Niklas

AU - Cronberg, Tobias

N1 - Funding Information: The authors would like to thank the TTM-trial investigators and the sponsors for their support. We thank the staff at the Clinical Neurochemistry Laboratory in M?lndal, Sweden, Banyan Biomarkers, San Diego, CA, the biochemistry laboratory of the Centre Hospitalier de Luxembourg and the Integrated BioBank of Luxembourg for analysis and storage of samples. Funding Information: Open access funding provided by Lund University. Funding for the study was provided by the Swedish Research Council, Swedish Heart Lung Foundation, Arbetsmarknadens Försäkringsaktiebolag Insurance Foundation, the Skåne University Hospital Foundations, the Gyllenstierna-Krapperup Foundation, and governmental funding of clinical research within the Swedish National Health System, the County Council of Skåne; the Swedish Society of Medicine; the Koch Foundation; TrygFonden (Denmark); European Clinical Research Infrastructures Network; Thelma Zoega Foundation; Stig and Ragna Gorthon Foundation; Thure Carlsson Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Lions Research fund Skåne; South Swedish Hospital Region Research Funds; the Swedish Brain Foundation; the Lundbeck Foundation; and the Torsten Söderberg foundation at the Royal Swedish Academy of Sciences. HZ is a Wallenberg Scholar. NMC is a Wallenberg Molecular Medicine Fellow.Role of the Funder/Sponsor: the funding organizations had no role in the design and conduct. of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: MMK, NMC, PS, SB, JD, HF, CH, JH, GL, CR, SU, JH, EW, MW, NN and TC report no conflicts of interest. HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. JK reports funding from NovoNordisk foundation NNF17OC0028706, for work outside the present manuscript. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered “indeterminate”. We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1–2) at 6 months. Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2–98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87–95% of patients). Normal S100B and NSE predicted good outcome with NPV 76–82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as “indeterminate outcome” by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.

AB - Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered “indeterminate”. We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1–2) at 6 months. Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2–98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87–95% of patients). Normal S100B and NSE predicted good outcome with NPV 76–82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as “indeterminate outcome” by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.

KW - Blood biomarkers

KW - Cardiac arrest

KW - ERC/ESICM guidelines

KW - Good neurological outcome

KW - Neurofilament light

KW - Prognostication

UR - https://www.scopus.com/pages/publications/85113165680

U2 - 10.1007/s00134-021-06481-4

DO - 10.1007/s00134-021-06481-4

M3 - Article

C2 - 34417831

SN - 0342-4642

VL - 47

SP - 984

EP - 994

JO - Intensive care medicine

JF - Intensive care medicine

IS - 9

ER -

Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest

Abstract

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Keywords

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