Elsevier

Resuscitation

Volume 84, Issue 10, October 2013, Pages 1310-1323
Resuscitation

Review article
Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: A systematic review and meta-analysis. Part 1: Patients not treated with therapeutic hypothermia

https://doi.org/10.1016/j.resuscitation.2013.05.013Get rights and content

Abstract

Aims and methods

To systematically review the accuracy of early (≤7 days) predictors of poor outcome defined as death or vegetative state (Cerebral Performance Categories [CPC] 4–5) or death, vegetative state or severe disability (CPC 3–5) in comatose survivors from cardiac arrest not treated using therapeutic hypothermia (TH). PubMed, Scopus and the Cochrane Database of Systematic reviews were searched for eligible studies. Sensitivity, specificity, false positive rates (FPR) for each predictor were calculated and results of predictors with similar time points and outcome definitions were pooled. Quality of evidence (QOE) was evaluated according to the GRADE guidelines.

Results

50 studies (2828 patients) were included in final analysis. Presence of myoclonus at 24–48 h, bilateral absence of short-latency somatosensory evoked potential (SSEP) N20 wave at 24–72 h, absence of electroencephalographic activity >20–21 μV ≤72 h and absence of pupillary reflex at 72 h predicted CPC 4–5 with 0% FPR and narrow (<10%) 95% confidence intervals. Absence of SSEP N20 wave at 24 h predicted CPC 3–5 with 0% [0–8] FPR. Serum thresholds for 0% FPR of biomarkers neuron specific enolase (NSE) and S-100B were highly inconsistent among studies. Most of the studies had a low or very low QOE and did not report blinding of the treating team from the results of the investigated predictor.

Conclusions

In comatose resuscitated patients not treated with TH presence of myoclonus, absence of pupillary reflex, bilateral absence of N20 SSEP wave and low EEG voltage each predicted poor outcome early and accurately, but with a relevant risk of bias.

Introduction

Accurate and early prognostication of unfavourable neurological outcome in comatose survivors of cardiac arrest is of paramount importance because futile treatments for unsalvageable patients can be avoided and realistic expectations can be given to relatives. Past studies investigated neurological reflexes, biomarkers, electrophysiological studies, and neuroimaging as predictors of poor neurological outcome. In 2006, the Quality Standards Subcommittee of the American Academy of Neurology (AAN) summarised the available evidence in its recommendations for prediction of outcome in comatose survivors after cardiopulmonary resuscitation (CPR).1 This and previous reviews,2, 3 however, were based only on evidence obtained from patients not treated with therapeutic hypothermia (TH). Since the completion of these reviews, several further studies have been published, most of which addressed the specific issue of prognostication in hypothermia-treated patients. Moreover, prior reviews did not comply with the standard recommendations for data reporting in systematic reviews and meta-analysis, such as PRISMA,4 and did not adequately address some important limitations of the included studies. Those include the low precision of most predictors and the risk of ‘self-fulfilling prophecy’, which is a bias present in most studies on prognostication after cardiac arrest wherein the treating physicians are not blinded to the results of the outcome predictor and use it to make a decision to withdraw treatment.5, 6 Finally, there is no consensus in the literature on the definition of poor outcome after post-cardiac arrest coma. Some studies define poor outcome as persistent vegetative state or death, corresponding to Cerebral Performance Categories (CPC) 4 or 5, while other studies include severe disability within the poor neurological outcomes cohort, so that poor outcome is defined as CPC 3–5.

The aim of the current work is to perform a new systematic review that, in comparison with previous reviews, (a) incorporates any missed studies and/or studies published more recently; (b) implements a more robust and complete meta-analysis of the evidence, including more strict criteria for study inclusion, and an improved approach for the evaluation of main sources of bias and statistical heterogeneity; (c) complies with the most recognised standards for evidence evaluation and data reporting; (d) summarises the evidence in relation to both definitions of poor outcome (CPC 4–5 or CPC 3–5); and, finally (e) addresses prognostication both in patients who have not been treated with TH and in TH-treated patients.

The evidence evaluation in this review has been performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines,7 in order to provide grounds for future recommendations, as part of a staged approach.

The first part of this review, included in the present report, deals with prognostication in patients who have not been treated with TH. The second part of the review, documented in a separate report, evaluates predictors in patients treated with TH.

Section snippets

Materials and methods

This is a systematic review and aggregate data meta-analysis of prognostic accuracy studies. Data reporting is consistent with the recommendations included in the PRISMA statement.8 According to the PICOS template, the review question was formulated as follows: In adult patients who are comatose following resuscitation from cardiac arrest (P), does the use of predictors based on clinical examination, electrophysiology, serum biomarkers or neuroimaging (I) allow accurate prediction of poor

Study selection (Fig. 1)

The initial search produced 935 records from PubMed, 392 records from Scopus and 11 records from the Cochrane Database of Systematic Reviews. Thirty-four additional records were identified through forward search. After duplicate removal and abstract screening, 213 studies were considered for full-text analysis. Among them, 163 were excluded because they did not fulfil inclusion criteria. The remaining 50 studies were included in our review. Excluded studies with reasons for their exclusion are

Discussion

Our results indicate that in comatose resuscitated patients who have not been treated using therapeutic hypothermia presence of myoclonus or myoclonus status at 24–48 h, bilateral absence of SSEP N20 wave or absence of EEG activity > 20–21 μV at 24–72 h and absence of pupillary light reflex at 72 h each predicted death or vegetative state with 0% FPR and narrow CIs. In addition, the absence of SSEP N20 wave at 24 h predicted death, vegetative state or severe disability with 0% FPR and narrow CIs.

Conclusions

Our systematic review showed that in comatose patients resuscitated from cardiac arrest and not treated using therapeutic hypothermia, (a) presence of myoclonus at 24–48 h, bilateral absence of SSEP N20 wave or absence of EEG activity > 20–21 μV at 24–72 h, and absence of PLR at 72 h each predicted death or vegetative state with zero FPR and narrow CIs, and (b) absence of SSEP N20 wave at 24 h predicted death, vegetative state or severe disability with zero FPR and narrow CIs. In addition, a serum NSE 

Conflict of interest statement

Claudio Sandroni, Fabio Cavallaro, Clifton Callaway, Tommaso Sanna, Sonia D’Arrigo and Michael Kuiper have no conflicts of interest to declare.

Jerry Nolan is Editor-in-Chief of Resuscitation.

Acknowledgements

We gratefully thank the following investigators for having provided original data from their studies:

  • 1.

    Dr. Albert Hijdra, Department of Neurology, Academic Medical Centre, University of Amsterdam, The Netherlands;

  • 2.

    Dr. Michael Mlynash, Stanford Stroke Centre, Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA

  • 3.

    Dr. Kyu Nam Park, Department of Emergency Medicine, Seoul St. Mary's Hospital, Seoul Korea;

  • 4.

    Dr. Johann Reisinger, Department of Internal

References (82)

  • H. Rosen et al.

    Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest

    Resuscitation

    (2001)
  • M.T. Torbey et al.

    Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest

    Resuscitation

    (2004)
  • S. Datta et al.

    Post-hypoxic myoclonic status: the prognosis is not always hopeless

    Crit Care Resusc

    (2009)
  • E. Edgren et al.

    Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group

    Lancet

    (1994)
  • E.G. Zandbergen et al.

    Interobserver variation in the interpretation of SSEPs in anoxic-ischaemic coma

    Clin Neurophysiol

    (2006)
  • E.F. Wijdicks et al.

    Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology

    Neurology

    (2006)
  • C.M. Booth et al.

    Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest

    JAMA

    (2004)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    BMJ

    (2009)
  • R.G. Geocadin et al.

    Poor survival after cardiac arrest resuscitation: a self-fulfilling prophecy or biologic destiny?

    Crit Care Med

    (2012)
  • H.J. Schunemann et al.

    Grading quality of evidence and strength of recommendations for diagnostic tests and strategies

    BMJ

    (2008)
  • A. Liberati et al.

    The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

    BMJ

    (2009)
  • Brain Resuscitation Clinical Trial I Study Group

    Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest

    N Engl J Med

    (1986)
  • C.R. Blyth

    Approximate binomial confidence limits

    J Am Stat Assoc

    (1986)
  • J.A. Hanley et al.

    If nothing goes wrong, is everything all right? Interpreting zero numerators

    JAMA

    (1983)
  • J. Sauro

    Confidence interval calculator for a completion rate

    (2012)
  • N. Rifai et al.

    Reporting bias in diagnostic and prognostic studies: time for action

    Clin Chem

    (2008)
  • G. Bertini et al.

    Prognostic significance of early clinical manifestations in postanoxic coma: a retrospective study of 58 patients resuscitated after prehospital cardiac arrest

    Crit Care Med

    (1989)
  • M.P. Earnest et al.

    Quality of survival after out-of-hospital cardiac arrest: predictive value of early neurologic evaluation

    Neurology

    (1979)
  • C. Fischer et al.

    Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis

    Crit Care Med

    (2006)
  • A. Krumholz et al.

    Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus

    Neurology

    (1988)
  • F. Thomke et al.

    Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus

    BMC Neurol

    (2005)
  • G.B. Young et al.

    The significance of myoclonic status epilepticus in postanoxic coma

    Neurology

    (1990)
  • E. Bauer et al.

    Electrophysiological assessment of the afferent sensory pathway in cardiac arrest survivors

    Eur J Clin Invest

    (2003)
  • S. Chokroverty

    Alpha-like” rhythms in electroencephalograms in coma after cardiac arrest

    Neurology

    (1975)
  • A. Gendo et al.

    Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors

    Intensive Care Med

    (2001)
  • A.B. Grindal et al.

    Alpha-pattern coma: 24 cases with 9 survivors

    Ann Neurol

    (1977)
  • C. Madl et al.

    Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment

    Crit Care Med

    (2000)
  • M. Nakabayashi et al.

    Immediate prediction of recovery of consciousness after cardiac arrest

    Intensive Care Med

    (2001)
  • T.L. Rothstein

    The role of evoked potentials in anoxic-ischemic coma and severe brain trauma

    J Clin Neurophysiol

    (2000)
  • G. Scollo-Lavizzari et al.

    Prognostic value of EEG in post-anoxic coma after cardiac arrest

    Eur Neurol

    (1987)
  • T. Stelzl et al.

    A comparison of the prognostic value of neuron-specific enolase serum levels and somatosensory evoked potentials in 13 reanimated patients

    Eur J Emerg Med

    (1995)
  • Cited by (167)

    View all citing articles on Scopus

    A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2013.05.013.

    View full text