title: 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.
abstract: 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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  NCT01020916.
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wiberg
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Hassager
authors.affiliation: Department of Anaesthesia and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: Pascal
authors.initials: P
authors.lastname: Stammet
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Matilde
authors.initials: M
authors.lastname: Winther-Jensen
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jakob Hartvig
authors.initials: JH
authors.lastname: Thomsen
authors.affiliation: Department of Cardiology, Skåne University Hospital, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Wanscher
authors.affiliation: Department of Anaesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Nielsen
authors.affiliation: Department of Intensive Care, Santa Maria degli Angeli, Pordenone, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pellis
authors.affiliation: Department of Intensive Care, Liverpool hospital, Sydney, New South Wales, Australia.
authors.forename: Anders
authors.initials: A
authors.lastname: Åneman
authors.affiliation: Department of Anaesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Friberg
authors.affiliation: Department of Anaesthesia and Intensive Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Hovdenes
authors.affiliation: Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: Copenhagen Trial Unit, Centre of Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Bro-Jeppesen
authors.affiliation: Department of Intensive Care, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Wise
authors.affiliation: Department of Intensive Care, Leeuwarden Medical Center, Leeuwarden, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Lund University, Skane University Hospital, Department of Clinical Sciences, Neurology, Lund, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Cronberg
authors.affiliation: Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Gasche
authors.affiliation: Cardiovascular Research Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Devaux
authors.affiliation: Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjaergaard
mesh_terms: D015415:Biomarkers / Q000097:blood; D006801:Humans; D007036:Hypothermia, Induced; D058687:Out-of-Hospital Cardiac Arrest / Q000401:mortality* / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000097:blood*; D011446:Prospective Studies; D017694:Rewarming; D016896:Treatment Outcome; D014474:Unconsciousness / Q000473:pathology*
chemical_list: D015415:Biomarkers; D010751:Phosphopyruvate Hydratase