Review articlePredictors 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☆
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)
- et al.
Systematic review of early prediction of poor outcome in anoxic-ischaemic coma
Lancet
(1998) - et al.
Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke
Resuscitation
(2008) - et al.
Assessment of coma and impaired consciousness. A practical scale
Lancet
(1974) - et al.
Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow Coma Scale
Resuscitation
(2005) - et al.
Myoclonus status in comatose patients after cardiac arrest
Lancet
(1994) - et al.
Postanoxic alpha (theta) coma: a reappraisal of its prognostic significance
Clin Neurophysiol
(2000) - et al.
Prognostic value of early cortical somatosensory evoked potentials after resuscitation from cardiac arrest
Electroencephalogr Clin Neurophysiol
(1987) - et al.
Etiology, neurologic correlations, and prognosis in alpha coma
Clin Neurophysiol
(1999) - et al.
Predicting outcome in hypoxic-ischemic coma. A prospective clinical and electrophysiologic study
Electroencephalogr Clin Neurophysiol
(1991) - et al.
S-100 protein as early predictor of regaining consciousness after out of hospital cardiac arrest
Resuscitation
(2002)
Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest
Resuscitation
Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest
Resuscitation
Post-hypoxic myoclonic status: the prognosis is not always hopeless
Crit Care Resusc
Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group
Lancet
Interobserver variation in the interpretation of SSEPs in anoxic-ischaemic coma
Clin Neurophysiol
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
Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest
JAMA
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
BMJ
Poor survival after cardiac arrest resuscitation: a self-fulfilling prophecy or biologic destiny?
Crit Care Med
Grading quality of evidence and strength of recommendations for diagnostic tests and strategies
BMJ
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration
BMJ
Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest
N Engl J Med
Approximate binomial confidence limits
J Am Stat Assoc
If nothing goes wrong, is everything all right? Interpreting zero numerators
JAMA
Confidence interval calculator for a completion rate
Reporting bias in diagnostic and prognostic studies: time for action
Clin Chem
Prognostic significance of early clinical manifestations in postanoxic coma: a retrospective study of 58 patients resuscitated after prehospital cardiac arrest
Crit Care Med
Quality of survival after out-of-hospital cardiac arrest: predictive value of early neurologic evaluation
Neurology
Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis
Crit Care Med
Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus
Neurology
Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus
BMC Neurol
The significance of myoclonic status epilepticus in postanoxic coma
Neurology
Electrophysiological assessment of the afferent sensory pathway in cardiac arrest survivors
Eur J Clin Invest
Alpha-like” rhythms in electroencephalograms in coma after cardiac arrest
Neurology
Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors
Intensive Care Med
Alpha-pattern coma: 24 cases with 9 survivors
Ann Neurol
Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment
Crit Care Med
Immediate prediction of recovery of consciousness after cardiac arrest
Intensive Care Med
The role of evoked potentials in anoxic-ischemic coma and severe brain trauma
J Clin Neurophysiol
Prognostic value of EEG in post-anoxic coma after cardiac arrest
Eur Neurol
A comparison of the prognostic value of neuron-specific enolase serum levels and somatosensory evoked potentials in 13 reanimated patients
Eur J Emerg Med
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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.