Resuscitation 84 (2013) 13101323

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Resuscitation
journal homepage: www.elsevier.com/locate/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
Claudio Sandroni a, , Fabio Cavallaro a , Clifton W. Callaway b , Tommaso Sanna c , Sonia DArrigo a , Michael Kuiper d , Giacomo Della Marca e , Jerry P. Nolan f
a

Department of Anaesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy Department of Emergency Medicine, University of Pittsburgh, United States c Department of Cardiovascular Sciences, Catholic University School of Medicine, Rome, Italy e Department of Neurology, Catholic University School of Medicine, Rome, Italy d Department of Intensive Care, Medical Center Leeuwarden, Leeuwarden, The Netherlands f Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UK
b

a r t i c l e

i n f o

a b s t r a c t
Aims and methods: To systematically review the accuracy of early (7 days) predictors of poor outcome dened as death or vegetative state (Cerebral Performance Categories [CPC] 45) or death, vegetative state or severe disability (CPC 35) 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, specicity, false positive rates (FPR) for each predictor were calculated and results of predictors with similar time points and outcome denitions were pooled. Quality of evidence (QOE) was evaluated according to the GRADE guidelines. Results: 50 studies (2828 patients) were included in nal analysis. Presence of myoclonus at 2448 h, bilateral absence of short-latency somatosensory evoked potential (SSEP) N20 wave at 2472 h, absence of electroencephalographic activity >2021 V 72 h and absence of pupillary reex at 72 h predicted CPC 45 with 0% FPR and narrow (<10%) 95% condence intervals. Absence of SSEP N20 wave at 24 h predicted CPC 35 with 0% [08] FPR. Serum thresholds for 0% FPR of biomarkers neuron specic 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 reex, bilateral absence of N20 SSEP wave and low EEG voltage each predicted poor outcome early and accurately, but with a relevant risk of bias. 2013 Elsevier Ireland Ltd. All rights reserved.

Article history: Received 13 February 2013 Received in revised form 16 May 2013 Accepted 20 May 2013

Keywords: Cardiac arrest Post-anoxic coma Prognostication

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 Materials and methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 2.1. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 2.1.1. Patient population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 2.1.2. Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 2.1.3. Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 2.1.4. Study type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 2.3. Statistical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312 2.4. Evidence appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1312

A Spanish translated version of the summary of this article appears as Appendix in the nal online version at http://dx.doi.org/10.1016/j.resuscitation.2013.05.013. Corresponding author at: Department of Anaesthesiology and Intensive Care, Catholic University School of Medicine, Largo Gemelli, 8 - 00168 Rome, Italy. E-mail address: sandroni@rm.unicatt.it (C. Sandroni). 0300-9572/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.resuscitation.2013.05.013

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3.

4.

5. 6.

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313 3.1. Study selection (Fig. 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313 3.2. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313 3.3. Clinical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315 3.4. Electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 3.5. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 3.6. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 3.7. Predictors with highest specicity and precision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.1. Myoclonus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.2. Clinical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.3. Somatosensory evoked potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.4. Electroencephalography (EEG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.5. Serum biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 4.6. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320 4.7. Comparison with previous reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320 4.8. Study limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 Conict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321

1. 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 reexes, 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 specic issue of prognostication in hypothermiatreated 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-fullling 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 denition of poor outcome after post-cardiac arrest coma. Some studies dene 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 dened as CPC 35. 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 denitions of poor outcome (CPC 45 or CPC 35); and, nally (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 rst 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. 2. 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 outcome (O)? Given the review question, the only eligible study design (S) for this review was observational prognostic accuracy study, in which a comparison (C) is made between the respective proportions of poor outcome among the patients having a positive test result and those having a negative test result. 2.1. Eligibility criteria 2.1.1. Patient population All studies on adult (16 years) patients who were comatose following resuscitation from cardiac arrest and were not treated with TH were considered for inclusion. Patients dened as unconscious, unresponsive, or having a Glasgow Coma Score (GCS)9 8 were considered as comatose. Studies including non-comatose patients or patients in hypoxic coma from causes other than cardiac arrest (e.g., respiratory arrest, carbon monoxide intoxication, drowning, hanging) were excluded, except when a subpopulation of cardiac arrest patients could be evaluated separately. 2.1.2. Interventions Four types of outcome predictors were assessed: clinical examination, electrophysiology, biomarkers, and imaging.

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Clinical examination: included every clinical sign that can be collected during a bedside neurological examination. For example, brainstem reexes, GCS and its components, and myoclonus. Clinical signs that require instrumental recording for collection (e.g. seizures) were not included in this category. Electrophysiology: those indices require the recording of bioelectrical signal from the central nervous system. They include electroencephalogram (EEG) and evoked potentials (EPs). We also considered for inclusion studies in which the EEG signal had been electronically analysed to produce a summary variable, such as amplitude-integrated EEG (aEEG) or bispectral index (BIS). Biomarkers: we limited our review to the two most commonly available serum biomarkers, neuron specic enolase (NSE) and S-100B protein. Imaging: neuroimaging predictors that were assessed in our review included computed tomography (CT), magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Since we were interested only in the prediction of outcome in comatose patients in the acute phase after resuscitation, we included only studies where the outcome predictor was evaluated within 7 days from cardiac arrest.

For each of the four types of outcome predictors, two authors performed a blinded and independent eligibility assessment. Disagreements between reviewers were resolved by consensus. 2.3. Statistical methods For each study included in the nal analysis, we calculated sensitivity, specicity, false positive rate (FPR) expressed as 1-specicity, positive predictive value (PPV), expressed as TP/(TP + FP) and positive likelihood ratio (LR+). For case series, where only the number of true and false positives is known, we calculated only PPV. In cases when a 100% sensitivity or specicity was encountered, the value 0.5 was added to each cell of the abcd contingency table in order to avoid division by zero in LR calculation. Pooling of the indices was made for studies having in common similar predictors, time points and outcome denitions. Condence intervals for pooled values of proportions were calculated using the F distribution method, according to Blyth.11 If the value of the proportion was 0% or 100%, a z-critical value for one-sided condence interval was used instead of the two-sided value, as recommended.12,13 Pooled values of LR+ with relevant condence intervals were calculated according to the DerSimonianLaird random effect model. Heterogeneity of pooled studies for sensitivity/specicity and LR+ was estimated by: (1) G2 and Q statistics respectively; (2) I2 (inconsistency). Heterogeneity was regarded as signicant when p < 0.1 or I2 > 50%. 2.4. Evidence appraisal Given the absence of specic GRADE recommendations on prognostic accuracy studies, we adapted the GRADE recommendations for diagnostic accuracy studies7 to rate the quality of evidence. Evidence evaluation was performed independently by two authors. According to the GRADE methodology7 the quality of evidence started as high and was graded down based on the following factors: (1) limitations; (2) indirectness; (3) inconsistency; and (4) imprecision. Publication bias was not considered, given the difculty of measuring it in prognostic studies.14 In order to evaluate the presence of limitations (risk of bias), the following information was extracted from included studies: inclusion of a consecutive cohort of patients; blinding of both treatment team and outcome or index evaluators; exclusion of nonneurological causes of death; exclusion of previous neurological diseases; exclusion of sedation (for indexes based on clinical examination or EEG); exclusion of paralysis (for indexes based on clinical examination); length of follow-up. Given the importance of the risk of self-fullling prophecy, limitations were graded as serious when the treating team was not blinded to the results of the predictor of poor outcome that was being studied, regardless of the presence of other limitations. According to the GRADE methodology, the rating should be modied upwards when the magnitude of effect is large. For the purpose of our study, we considered a high predictor performance, dened as a LR+ >10, to be equivalent to a large magnitude of effect. Indirectness was deemed present when the characteristics of the study population did not completely correspond to that described in the inclusion criteria, for example when a study included a minority of patients treated using TH whose data could not be separately analysed. Inconsistency was evaluated after pooling. Inconsistency was graded as serious when heterogeneity was signicant (p < 0.1 or I2 > 50%) for either sensitivity or specicity, and it was graded as very serious when heterogeneity was signicant for both of them. Imprecision. When evaluating the accuracy of predictors of poor outcome in critically ill patients, avoiding false positives is

2.1.3. Outcome We included only studies in which the neurological outcome was described using the ve Cerebral Performance Categories (CPC)10 (See Table E1 on Electronic Supplementary Material [ESM]) or in such a manner that an equivalent CPC could be determined. In those studies, the outcome is usually dichotomized as poor or good according to a predened CPC threshold, either CPC 45 vs. 13 or CPC 35 vs. 12. We accepted both of those denitions for our review. When no threshold had been dened, we dichotomized outcomes as CPC 45 vs. 13. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. In order to calculate both the outcome variables and their condence intervals, we included only studies where the complete contingency table (i.e., the number of true/false negatives and positives for prediction of poor outcome) was reported, or could be calculated from reported data.

2.1.4. Study type Only clinical prognostic accuracy studies published in English, French, German, Italian or Spanish as full-text articles on indexed journals were included. Reviews, case reports and studies published in abstract form were excluded. No publication date or publication status restrictions were imposed.

2.2. Search strategy We searched MEDLINE via PubMed, Scopus and the Cochrane Database of Systematic Reviews using the search strings included into the ESM Table E2. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. The automatic alert system of PubMed was activated to identify further studies published during the process of data extraction and analysis. The reference lists of relevant studies were scanned in order to identify other studies of interest. Last search was launched on February 6, 2013.

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particularly important in order to avoid falsely pessimistic predictions. Ideally, for the prediction of a poor outcome the rate of false positives should be zero. However, even a zero FPR has little value when the precision of its estimate is low, i.e., its condence interval (CI) is large. We considered the FPR and the precision of its estimate to be the most important parameters of the indices included in our review. Imprecision was graded as serious when the upper 95% CI of the FPR estimate was greater than 5%, and it was graded as very serious when this value was more than 10%. 3. Results 3.1. 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 identied 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 full inclusion criteria. The remaining 50 studies were included in our review. Excluded studies with reasons for their exclusion are listed in the ESM Table E3 (see Fig. 1).

Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. 3.2. Study characteristics The characteristics of the 50 included studies (2828 patients) are summarised in Table 1. In 38/50 studies (76%) poor outcome was dened as vegetative state or death (CPC 45), while in the remaining 12/50 studies (24%) poor outcome was dened as severe disability, vegetative state or death (CPC 35). Eight studies were based on clinical examination,1522 eighteen on electrophysiology,2340 eight on biomarkers,4148 nine on neuroimaging,4957 and seven on multiple predictors.5864 Sensitivity, FPR (1-specicity), and the quality of evidence for indices based on clinical examination, electrophysiology, biomarkers and neuroimaging are reported on Tables 2a2d. The evidence proles of predictors are reported on ESM Tables E4ad. Results of individual studies are reported in detail on ESM Tables E5ad. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013.

Identification

PubMed: 935 records Scopus: 392 records Cochrane Database of systematic reviews: 11 records 1338 records 34 additional records identified through forward search

1372 records screened

Screening

1159 discarded (duplicates or excluded after title and abstract evaluation)

163 full-text excluded due to 83 22 7 26 20 2 3 Patient characteristics Intervention characteristics Comparison characteristics Outcome characteristics Study characteristics Data could not be extracted Unavailable studies

Eligibility

213 full-text articles assessed for eligibility

Included

50 studies included in qualitative and quantitative synthesis (meta-analysis)

Fig. 1. Flow-chart of study selection.

1314 Table 1 Characteristics of the included studies. Author, year, Reference Clinical Examination Bertini 198915 Earnest 197916 Fischer 2006 17 Krumholz 198818 Pfeifer 2005 19 Thomke 200520 Wijdicks 199421 Young 199022 Electrophysiologic studies Bauer 200323 Berkhoff 200024 Brunko 198725 Chockroverty 197526 Gendo 200127 Grindal 197728 Kaplan 199929 Madl 200130 Nakabayashi 200131 Rothstein 199132 Rothstein 200033 Scollo-Lavizzari 198734 Stelzl199535 Tiainen 200536 Vignaendra 197437 Zanatta 201238 Zandbergen 2006a39 Zhang 201140 Biomarkers Hachimi-Idrissi 200241 Mussack 200242 Reisinger 200743 Rosen 199844 Rosen 200145 Samaniego 201146 Steffen 201047 Tiainen 2003 48 Neuroimaging Choi 200849 Choi 201050 Della Corte 199351 Els 200452 Mlynash 201053 Morimoto 199354 Torbey 200455 Wijdicks 200156 Wijman 200957 IHCA or OHCA No. of patients

C. Sandroni et al. / Resuscitation 84 (2013) 13101323

Males, %

VF/VT %

Mean age, ys [SD] or median (range)

Predictor(s)

Denition of poor outcome (CPC) 45 vs. 13 35 vs. 12 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13(a ) 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 35 vs. 12 45 vs. 13 (a ) 45 vs. 13 35 vs. 12 45 vs. 13 45 vs. 13 45 vs. 13 35 vs. 12 45 vs. 13 45 vs. 13 45 vs. 13 (a ) 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 35 vs 12 45 vs. 13 45 vs. 13 35 vs 12 45 vs. 13 35 vs 12 35 vs 12 45 vs. 13 35 vs 12 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 45 vs. 13 35 vs. 12 45 vs. 13 45 vs. 13 35 vs. 12 35 vs. 12 45 vs. 13 45 vs. 13

Timing of outcome assessment

OHCA OHCA OHCA Mixed Mixed Mixed OHCA N/A Mixed N/A OHCA N/A N/A N/A N/A Mixed OHCA OHCA OHCA N/A N/A OHCA OHCA N/A N/A N/A OHCA OHCA Mixed OHCA OHCA Mixed Mixed OHCA OHCA OHCA N/A N/A Mixed OHCA N/A Mixed Mixed

34 117 62 114 97 50 107 11 305 9 50 12 25 14 18 162 30 40 50 26 13 30 8 6 407 77 58 20 177 41 66 32 73 34 28 39 11 12 12 53 32 10 10 60 30 32 22 75

85 74 76 61.4 71 52 62 73 68 89 N/A 83 80 86 72.2 65 67 58 56 65 62 73 88 N/A 67 46 N/A 70 63 76 76 53 75 71 75 72 45.5 N/A N/A 66 56 50 N/A 82 N/A 47 59 61

74 N/A N/A N/A 47 88 38 N/A 57 N/A N/A N/A 60 N/A N/A 49 N/A N/A N/A N/A N/A 100 N/A 100 68 0 N/A 50 53 80 79 38 55 100 28.5 15 N/A N/A N/A 26.4 40.6 N/A N/A N/A 70 N/A N/A 65

66 [10.4] 62 (median) 55 [16] 57 [ 17.9] 63 (1790) 54 (2083) 63 (2786) 57 [16.7] 57 (1689) 58 (2483) 62 [17] 55 [15.9] 59 (4287) 58 [16.3] 60 [16.2] 57 [16] 63 (1690) 72 (1991) 71 (1991) 61 (1677) 67 (4880) 58 (1875) 53 [13] 63 (3589) 63 [14] 57 [19.2] 64 [ 3] 71 65 [15] 68 (2189) 68[14.6] 55 (1986) 64 59 (1875) 54 (2786) 49 (1889) 40 [16.6] 53 (2771) 52 [17] 51 [22.9] 64 [16.5] 57 [14.1] 54 [15] 62 (1986) 61 (1886) 71 [8.5] 56 [16.9] 66 [13]

PLR, MR PLR, OCR, MR GCS Myoclonus GCS Myoclonus Myoclonus Myoclonus SSEPs EEG (Alpha coma) SSEPs EEG SSEPs Alpha coma EEG SSEPs SSEPs EEG SSEPs EEG SSEPs SSEPs EEG SSEPs SSEPs EEG, SSEPs, BAEPs S-100 S-100B NSE S-100 NSE, S-100 NSE NSE NSE, S-100B Brain CT Brain MRI Brain SPECT Brain MRI Brain MRI Brain CT Brain CT Brain MRI Brain MRI BR, GCS, MR, EEG, SSEPs Brain MRI, SSEPs BR, MR,EEG GCS, FOUR score, brain MRI PLR, CR, VOR, MR, myoclonus, SSEPs, EEG BR, MR, myoclonus, NSE, S-100B, SSEPs, EEG NSE, S-100B, SSEPs

ICU discharge Hospital discharge 12 mo 6 mo 1 mo 48 mo 6 mo Hospital discharge 12 mo 12 mo Hospital discharge Hospital discharge 6 mo 2 mo 10 mo 6 mo 9 mo 2 mo 1 mo N/A N/A 6 mo 14 d 3 mo 12 mo 6 mo Hospital discharge 12 mo 6 mo Hospital discharge 12 mo 3 mo ICU discharge 6 mo Hospital discharge 3 mo 6 mo 6 mo 6 mo 7d Hospital discharge N/A 6 mo 12 mo 1 mo 6 mo 3 mo 3 mo

Multimodal prognostication N/A Bassetti 199658 Berek 1995 Edgren 198760 Topcuoglu 200961 Young 200562
59

OHCA N/A Mixed Mixed

Zandbergen 2006b63

N/A

407

67

68

63 [14]

45 vs. 13

6mo

Zingler 200364

Mixed

27

48

N/A

61 [17.3]

45 vs. 13

3 mo

Abbreviations: BAEPs = Brain stem Auditory Evoked Potentials; CPC = Cerebral Performance Category; CR = Corneal Reex; CT = Computed Tomography; EEG = Electroencephalogram; GCS = Glasgow Coma Score; IHCA = In Hospital Cardiac Arrest; MR = Motor Response; MRI = Magnetic Resonance Imaging; N/A = Not Available; NSE = Neuron-Specic Enolase; OCR = OculoCephalic Reex; OHCA = Out of Hospital Cardiac Arrest; PLR = Pupillary Light Response; SSEPs = Somatosensory Evoked Potentials; SPECT = Single-Photon Emission Computed Tomography; FOUR score = Full Outline of UnResponsiveness score; VOR = Vestibulo-Ocular Reex. a Dened by the reviewer.

C. Sandroni et al. / Resuscitation 84 (2013) 13101323 Table 2a Summary of ndings for predictors based on clinical examination. Timing CPC 45 vs. 13 On admission Index GCS 4 Motor score = 13 Myoclonus status PLR absent >1 BR absenta Motor score = 13 OVR absent PLR absent Reference Fisher, 198817 Bertini, 198915 Wijdicks, 199421 Bertini, 198915 Bassetti, 199658 Bertini, 198915 Bassetti, 199658 Young, 200562 Bertini, 198915 Young, 200562 Zandbergen, 200663 Young, 200562 Zandbergen, 200663 Zandbergen, 200663 Young, 200562 Zandbergen, 200663 Bertini, 198915 Bassetti, 199658 Young, 200562 Zandbergen, 200663 Bertini, 198915 Zandbergen, 200663 Zandbergen, 200663 Zandbergen, 200663 Bertini, 198915 Bassetti, 199658 Zandbergen, 200663 Krumholz, 198818 Zandbergen, 200663 Bertini, 198915 Zandbergen, 200663 Zandbergen, 200663 Topcuoglu, 200961 Pfeifer, 200519 Topcuoglu, 200961 Zandbergen, 200663 Topcuoglu, 200961 Zandbergen, 200663 Bertini, 198915 Zandbergen, 200663 Thomke, 200520 Sensitivity % [95% CI] 74 [5886] 89 [6599] 46 [3557] 33 [1262] 21 [1035] 91 [7998] 42 [2659] 21 [1725] FPR % [95% CI] 40 [19 64] 81 [5496] 0 [014] 25 [752] 0 [0 22] 62 [4180] 0 [031] 9 [418] No. of patients 62 34 107 31 60 72 44 496 Quality of evidence Very low Very low Low Very low Very low Very low Very low Very low 38 [3343] 14 [1018] 63 [4876] 78 [7382] 84 [7293] 9 [713] 19 [1524] 13 [917] 75 [7080] 92 [8098] 31 [2636] 8 [511] 18 [1523] 14 [1018] 88 [6298] 75 [6386] 29 [2334] 74 [6879] 100 [76100] 2 [14] 18 [1030] 5 [117] 6 [030] 45 [2962] 46 [2767] 0 [03] 4 [115] 3 [018] 41 [2461] 14 [433] 10 [227] 0 [05] 0 [08] 0 [015] 33 [478] 7 [124] 5 [025] 27 [1248] 6 [029] 0 [014] 465 386 67 395 83 471 375 338 351 77 341 464 382 289 22 88 295 322 28 300 50 Very low Very low Low Very low Very low Moderate Very low Very low Very low Very low Very low Low Low Very low Very low Very low Very low Very low Very low Very low Very low

1315

At 612 h

At 24 h

CR absent PLR and CR absent Motor score = 1 Motor score = 12 Motor score = 13 Myoclonus (status) At 48 h PLR absent PLR and CR absent Motor score = 12 Motor score = 13 CR absent At 3648 h At 72 h Myoclonus status PLR absent PLR and CR absent FOUR score <8 GCS 5 CR absent Motor score = 12 Motor score = 13 Myoclonus status At 2472 h CPC 35 vs. 12 On admission Myoclonus

PPV 100 [94100]

OCR absent PLR absent Motor score = 13 OVR absent PLR absent CR absent Motor score = 13 OVR absent PLR absent CR absent Motor score = 13

Earnest, 197916 Earnest, 197916 Earnest, 197916 Edgren, 198760 Edgren, 198760 Edgren, 198760 Edgren, 198760 Edgren, 198760 Edgren, 198760 Edgren, 198760 Edgren, 198760

70 [5880] 56 [4367] 68 [5679] 29 [858] 20 [644] 15 [338] 65 [4185] 25 [557] 6 [030] 6 [030] 63 [3585]

28 [1249] 8 [125] 19 [638] 0 [035] 0 [022] 8 [038] 17 [248] 0 [035] 0 [022] 0 [022] 0 [022]

95 98 99 21 32 32 32 19 28 28 28

Very low Very low Very low Very low Very low Very low Very low Very low Very low Very low Low

At 24 h

At 48 h

Abbreviations:: BR = Brainstem Reexes; CI = Condence Intervals; CPC = Cerebral Performance Categories; CR = Corneal Reex; FOUR = Full Outline of Unresponsiveness score; FPR = False Positive Rates; GCS = Glasgow Come Score; No = Number; OCR = Oculocephalic Reex; OVR = Oculovestibular Reex; PLR = Pupillary Light Response. a Corneal, Pupillary, Oculocephalic.

Table 3 lists the most accurate predictors, i.e. those having 0% FPR (100% specicity) and narrowest 95% CIs (upper limit of 95% CI < 10%). 3.3. Clinical examination Absence of brainstem reexes was an important predictor of poor outcome. Absence of oculovestibular reexes predicted CPC 35

or 45 with 0% FPR at 2448 h from cardiac arrest but precision was low, being based on the results of two small studies.60,62 Absence of pupillary light reex (PLR) predicted death or vegetative state with 0% [08] FPR but not earlier than 72 h after cardiac arrest. Absent corneal reex (CR) did not attain a 0% FPR neither at 72 h after cardiac arrest and its combination with PLR did not increase accuracy of absent PLR alone (see Table 2a).

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Table 2b GRADE summary of ndings for predictors based on electrophysiology. Timing CPC 45 vs. 13 At 8 h Index SSEPs N20 absent Reference Brunko, 198725 Nakabayashi, 200131 Stelzl, 199535 Tiainen, 200536 Zandbergen, 200639 Zandbergen, 200639 Rothstein, 200032 Zanatta, 201238 Zandbergen, 200639 Zingler, 200364 Zandbergen, 200639 Rothstein, 199133 Stelzl, 199535 Zandbergen, 200639 Berek, 199559 Zandbergen, 200639 Bauer, 200323 Bassetti, 199658 Young, 200562 Berkhoff, 200024 Bauer, 200323 Zandbergen, 200639 Young, 200562 Bassetti, 199658 Zandbergen, 200639 Young, 200562 Zandbergen, 200639 Young, 200562 Zhang, 201140 Zhang, 201140 Zhang, 201140 Zhang, 201140 Berkhoff, 200024 Vignaendra, 197437 Chokroverty, 197526 Grindal, 197728 Kaplan, 199929 Sensitivity % [95% CI] FPR% [95% CI] No. of patients 80 Quality of evidence Low

84 [7293]

0 [012]

At 24 h

SSEPs N20 absent

295 46 [4053] 0 [05]

Moderate

SSEPs N70 absent

30 [2337]

20 [1035]

212 328

Very low Moderate

At 48 h

SSEPs N20 absent

46 [4052]

0 [05]

SSEPs N70 absent At 48 h At 72 h EEG malignant grade (Synek) SSEPs N20 absent

26 [1835] 42 [2363]

17 [636] 0 [019]

148 40 293

Very low Very low Low

46 [4052] 86 [42100] 9 [613]

0 [09] 0 [026] 8 [127]

SSEPs N20 mono or bilaterally absent EEG status epilepticus At 72 h

17 283 408

Very low Very low Low

SSEPs N20 absent

45 [3951]

1 [05] PPV 100 [48100] 5 470 Very low Very low

SSEPs N20 absent SSEPs N70 absent

49 [4454]

8 [416]

EEG Grade IVV EEG Burst-suppression

42 [2857] 15 [1119]

0 [024] 2 [012]

59 349

Very low Very low

EEG voltage 2021 V

28 [2334]

0 [06]

355

Low

At 17d

SSEPs N20 absent Unfavourable EEG Unreactive EEG BAEP wave V absent EEG alpha (theta) coma EEG alpha coma

70 [5780] 97 [89100] 92 [8397] 62 [4974]

0 [024] 64 [3189] 45 [1777] 9 [041] PPV 100 [84100] PPV 88 [7596]

77 77 77 77 17 43

Low Very low Very low Very low Very low Very low

At 13d At 16d

CPC 35 vs. 12 At 24 h

SSEPs N20 absent SSEPs N70 >127 ms or absent EEG Grade IIIV

Madl, 200030 Gendo, 200127 Madl, 200030 Edgren, 198760 Edgren, 198760 Scollo-Lavizzari, 198734 Edgren, 198760 Edgren, 1987
60

37 [2946] 88 [8192] 36 [1365] 36 [1169] 50 [2971]

0 [08] 2 [012]

159 187

Low Very low

0 [022] 0 [024] 0 [078] PPV 100 [37100] PPV 83 [36100]

26 22 26 3 6

Very low Very low Very Low Very low Very low

At 48 h At 72 h At 24 h At 48 h

EEG Grade IIIV EEG Grade IVV EEG alpha coma EEG alpha coma

Abbreviations: BAEP = Brainstem Auditory Evoked Potentials; CI = Condence Intervals; CPC = Cerebral Performance Categories; EEG = Electroencephalogram; FPR = False Positive Rate; No = Number; SSEPs = Somatosensory Evoked Potentials.

C. Sandroni et al. / Resuscitation 84 (2013) 13101323 Table 2c GRADE summary of ndings for predictors based on biomarkers. Timing CPC 45 vs. 13 On admission At 24 h Index S-100B NSE NSE S-100B S-100B S-100B At 48 h NSE NSE S-100B S-100B NSE NSE S-100B CPC 35 vs. 12 At 12-24 h At 24 h At 48 h Reference Hachimi-Idrissi, 200241 Zandbergen, 200663 Zingler, 200364 Rosen, 199844 Hachimi-Idrissi, 200241 Zandbergen, 200663 Zingler, 200364 Zandbergen, 200663 Reisinger, 200743 Rosen, 199844 Zandbergen, 200663 Samaniego, 201146 Zandbergen, 200663 Reisinger, 200743 Zandbergen, 200663 Cutoff (g l1 ) 0.7 33 47.6 0.2 0.7 5.2 33 65 0.2 0.7 33 80 0.7 Sensitivity % [95% CI] 67 [4882] 48 [4255] 53 [2877] 77 [4695] 57 [5163] 35 [1462] 61 [5468] 62 [4775] 79 [4995] 51 [4458] 55 [4863] 43 [2958] 42 [3450] FPR% [95% CI] 13 [334] 0 [08] 0 [026] 19 [542] 10 [421] 0 [026] 0 [08] 0 [03] 0 [012] 5 [118] 3 [014] 0 [03] 0 [08] No. of patients 56 272 27 34 330 27 241 156 38 238 221 152 207

1317

Quality of evidence Very low Moderate Very low Very low Very low Very low Low Moderate Very low Very low Very low Moderate Low

At 72 h

S-100B S-100B NSE NSE NSE S-100B S-100B NSE NSE

Tiainen, 200348 Mussack, 200242 Tiainen, 200348 Tiainen, 200348 Rosen, 200145 Tiainen, 200348 Rosen, 200145 Rosen, 200145 Steffen, 201047

0.19 0.76 13.3 8.8 25.0 0.12 0.25 15.0 22.4

59 [3382] 53 [2877] 59 [3382] 75 [4893] 37 [2254] 88 [6298] 68 [5182] 71 [5584] 86 [7892]

0 [017] 0 [063] 0 [017] 0 [017] 0 [012] 0 [017] 0 [012] 0 [012] 10 [227]

33 20 33 32 61 32 61 65 133

Very low Very low Very low Very low Very low Very low Very low Very low Very low

At 72 h

Abbreviations: CI = Condence Interval; CPC = Cerebral Performance Categories; FPR = False Positive Rate; No = number; NSE = Neuron-Specic Enolase.

Presence of myoclonus or myoclonus status predicted death or vegetative state with 0% [014] FPR when recorded on admission, and remained predictive during the rst 72 h, with high precision (95%CI 03 at 24 h) but low sensitivity (89%; see Table 2a). No value of either GCS or GCS motor score consistently predicted CPC 45 with zero FPR.

3.5. Biomarkers The highest threshold of NSE or S-100B serum concentrations associated with a 0% FPR varied with studies, timing and denition of poor outcome. For poor outcome dened as CPC 45, this threshold for NSE was 47.6 g l1 , 65 g l1 and 80 g l1 at 24 h, 48 h, and 72 h, respectively (see Table 2c).43,64 For S-100B, single studies reported a threshold of 5.2 g l1 at 24 h64 and of 0.7 g l1 at 72 h.63 For poor outcome dened as CPC 35, this threshold for NSE was 13.3 g l1 at 24 h and 25 g l1 at 48 h while for S-100B it was 0.76 and 0.25 g l1 , respectively. At 72 h, a single study45 reported an NSE threshold of 15 g l1 for 0% FPR, but in a larger study47 a NSE level of 22.4 g l1 was associated with a 10% [227] FPR. All studies in which poor outcome was dened as CPC 35 had a very low quality of evidence.

3.4. Electrophysiology Bilateral absence of the N20 wave of short-latency somatosensory evoked potentials (SSEPs) predicted death or vegetative state with 0% [012] FPR as early as 8 h from cardiac arrest, and it remained predictive during the rst 72 h with a consistent sensitivity (4546%). A single large study on 159 patients30 conrmed bilateral absence of SSEP N20 at 24 h to be an accurate predictor of CPC 35 as well (FPR 0% [08]). Among all patients in whom N20 SSEP wave was absent in the rst 7 days from cardiac arrest there was only one case of false positive result.62 Conversely, none of the studies assessing the predictive value of a delayed or absent N70 SSEP wave documented a 0% FPR (see Table 2b). A Grade IIIV EEG according to Edgren et al60 at 24 predicted poor outcome (CPC 35) with 0% [022] FPR. EEG Grades IVV according to Synek et al65 and Bassetti et al58 at 48 h and 72 h respectively, predicted poor outcome (CPC 45) with 0% FPR (95% CIs 019 and 024 respectively) and 42% sensitivity (see ESM Table E8 for a comparison of EEG grading systems). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. In two large cohort studies,62,63 a low-voltage EEG (2021 V) at 24 h72 h predicted poor outcome with 0% [08] FPR. Presence of alpha coma was not consistently associated with poor outcome.24,37,60

3.6. Imaging The number of patients studied with imaging techniques was relatively small, except for CT scan. In 3 studies on a total of 113 patients, diffuse brain swelling on brain CT scan within 72 h predicted an almost invariably poor outcome (FPR 5% [025]) with 54% [4364] sensitivity (see Table 2d). In two small studies (total 22 patients), presence of extensive brain abnormalities at 432 h52 or reduction of absolute diffusion coefcient (ADC) below 650 106 mm2 /s in more than 10% of brain volume at 49108 h57 on diffusion weighted (DWI) MRI predicted poor outcome with 0% FPR but wide 95% CI (045 and 078, respectively). Elevated lactate on MRI spectroscopy within 96 h predicted a poor outcome (CPC 35) with 71% [4292] sensitivity and 0% [035] FPR in a study including 21 patients.59 Reduction of either cerebral blood ow (CBF) below 30 ml/100 g/min or cerebral oxygen

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C. Sandroni et al. / Resuscitation 84 (2013) 13101323

Table 2d GRADE summary of ndings for predictors based on imaging. Timing CPC 45 vs. 13 At 432 h At 72 h Index Extensive DWI alterations (MRI) Brain swelling (CT) Reference Els, 200452 Choi, 200849 Morimoto, 199354 Torbey, 200455 Mlynash, 201053 Mlynash, 2010
53

Sensitivity % [95% CI] 100 [65100] 54 [4364]

FPR% [95% CI] 0 [045] 5 [025]

No. of patients 12 113

Quality of evidence Very low Very low

Median 80 h (IQR 55117)

Abnormalities in basal ganglia (MR-DWI) Diffuse moderate to severe cortical FLAIR-DWI alterations (MRI) > 10% Brain volume with ADC < 650 x 106 mm2 /s (MRI) CBF (dynamic SPECT) < 30 ml/100 g/min CMRO2 (dyn. SPECT) < 2.5 ml/100 g/min Extensive cortical FLAIR alterations (MRI) Extensive lesion pattern (MRI DWI)

100 [55100] 80 [2899] 88 [47100] 100 [61100] 100 [61100] 100 [61100] 93 [66100]

43 [1082] 0 [035] 0 [078] 0 [045] 0 [045] 0 [078] 0 [078]

12 12 10 11 11 8 16

Very low Very low Very low Very low Very low Very low Verylow

At 49108 h

Wijman, 200957 Della Corte 199351 Della Corte 199351 Wijdicks, 200156 Topcuoglu, 200961

At 72120 h

At 7d

CPC 35 vs. 12 At <96 h At <120 h

Lactate positive (Magnetic Resonance Spectroscopy) (MRI) Extensive lesion pattern (MRI)

Berek, 199559 Choi, 200850

71 [4292] 77 [5691]

0 [035] 8 [036]

21 39

Very low Low

Abbreviations: ADC = Apparent Diffusion Coefcient; CBF = Cerebral Blood Flow; CI = Condence Intervals; CMRO2 = Cerebral Metabolic Rate of Oxygen; CPC = Cerebral Performance Categories; CT = Computed Tomography; DWI = Diffusion Weighted Imaging; FLAIR = Fluid Attenuated Inversion Recovery; FPR = False Positive Rates; IQR = Interquartile Range; MRI = Magnetic Resonance Imaging; No = Number; SPECT = Single-Photon Emission Computed Tomography.

consumption (CMRO2 ) below 2.5 ml/100 g/min detected on Single Photon Emission Computed Tomography (SPECT) within 120 h predicted poor outcome with 0% [045] FPR in a single study including 11 patients.51 3.7. Predictors with highest specicity and precision Table 3 includes the list of predictors with 0% FPR and upper 95% CI limit < 10%. For prediction of poor outcome dened as CPC 45, these predictors include presence of myoclonus or myoclonus status at 24 h and 48 h, bilateral absence of N20 SSEP wave at 2472 h, absence of EEG activity above 2021 V at 2472 h, and absent

PLR at 72 h. In a single study, however, there was one case of false positive result among patients with bilateral absence of N20 SSEP within 72 h.62 Serum NSE levels above 33 g l1 at 24 h also predicted CPC 45 with 0 [08] FPR. However, in another study with lower precision included in our review64 a NSE threshold of 47.6 g l1 for 0% [026] FPR at 24 h was reported. NSE thresholds of 65 g l1 and 80 g l1 for prediction with 0% FPR and CIs < 10% at 48 h and 72 h, respectively, were reported in a single, good-quality study.43 For prediction of poor outcome dened as CPC 35, only the absence of N20 SSEP wave at 24 h had sufcient specicity and precision to be included in this list.

Table 3 Predictors of poor outcome with 0% FPR and upper 95%CI limit<10%. Timing CPC 45 vs. 13 At 24 h Index Myoclonus SSEPs N20 wave absent NSE 33 g l1 a Myoclonus SSEPs N20 wave absent NSE 33 g l1 NSE 65 g l1 PLR absent SSEPs N20 wave absentb NSE 80 g l1 S-100 0.7 g l1 EEG voltage 2021 V Sensitivity % [95% CI] 9 [713] 46 [4053] 48 [4255] 8 [511] 46 [4052] 61 [5468] 62 [4775] 18 [1523] 46 [4052] 43 [2958] 42 [3450] 28 [2334] FPR % [95% CI] 0 [03] 0 [05] 0 [08] 0 [05] 0 [05] 0 [08] 0 [03] 0 [08] 0 [09] 0 [03] 0 [08] 0 [06] LR+ [95% CI] 20 [1532] 21 [3142] 36 [2563] 4 [072] 11 [343] 45 [3709] 129 [82062] 10 [171] 18 [3122] 89 [61447] 30 [2476] 11 [175] No. of patients (studies) 471 (2) 295 (3) 272 (1) 464 (2) 328 (4) 241 (1) 156 (1) 382 (2) 293 (2) 152 (1) 207 (1) 355 (2) Quality of evidence Moderate Moderate Moderate Low Moderate Low High Low Low High Low Low

At 48 h

At 72 h

At 72 h CPC 35 vs. 12 At 24 h

SSEPs N20 absent

37 [2946]

0 [08]

27 [2424]

159 (1)

Low

Abbreviations: CI = Condence Intervals; CPC = Cerebral Performance Categories; EEG = Electroencephalogram; FPR = False Positive Rate; No = Number; NSE = Neuron Specic Enolase; PLR = Pupillary Light Response; SSEPs = Somatosensory Evoked Potentials. a In another study, the NSE threshold for 0% FPR at 24 h was 47.6 g/L (95%CI 026). b In a pooled series of three papers on SSEP N20 at 72 h (408 patients) there was one false positive (FPR 1 [06]).

C. Sandroni et al. / Resuscitation 84 (2013) 13101323

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4. Discussion Our results indicate that in comatose resuscitated patients who have not been treated using therapeutic hypothermia presence of myoclonus or myoclonus status at 2448 h, bilateral absence of SSEP N20 wave or absence of EEG activity > 2021 V at 2472 h and absence of pupillary light reex 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. Serum NSE was also described to predict poor outcome with 0% FPR and narrow CIs but its thresholds varied widely and inconsistently among studies. 4.1. Myoclonus Myoclonus, a series of sudden, involuntary, brief jerks of peripheral or axial musculature,66 was a relatively infrequent, but early and highly specic predictor of poor outcome in studies included in our review. Characteristics of myoclonus in studies included in our review were inconsistent: three over ve studies18,21,63 reported status myoclonus, dened in one of these studies as myoclonus persisting for at least 30 min. Others20,62 described myoclonus as intermittent or even single myoclonic jerks. Distribution of myoclonus ranged from segmental and limited to the head, to bilateral, multifocal or generalised. The EEG of those patients documented malignant patterns, mainly burst-suppression or epileptiform discharges, and less frequently alpha coma (see ESM Table E9 for details). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. At least six comatose patients with subsequent good neurological outcome despite post-arrest myoclonus have been described in case series or case reports.6770 These rare cases may be partly explained by the presence of a chronic benign form of myoclonus, known as LanceAdams syndrome, which is usually caused from anoxic coma due to respiratory causes71 ; this is an action myoclonus which becomes evident after the recovery of consciousness when a patient intentionally moves his/her limbs and it is restricted to the limb being moved.70 Unfortunately, in the acute post-arrest phase the presence of consciousness may be masked by sedation and by myoclonus itself.72 Misinterpretation of an early-onset Lance-Adams syndrome as a malignant myoclonus could lead to a falsely pessimistic prediction. We suggest that in patients with post-cardiac arrest myoclonus, an accurate clinical neurological evaluation should be made off sedation and an EEG performed, in order to both assess the level of consciousness and identify the presence of associated epileptiform activity. 4.2. Clinical examination Apart from myoclonus and absent PLR at 72 h, no other clinical sign was included in our list of most accurate predictors. Absence of oculovestibular reexes was highly specic but precision of the estimate was low because few patients have been studied. Absence of corneal reex did not attain 100% specicity and its combination with PLR did not increase accuracy of absent PLR alone (see Table 2a). We cannot exclude that some cases of false positive prediction, i.e., patients with initially absent corneal reex and subsequent good neurological outcome, may have been due to a residual effects of sedation or paralysis. Indeed, suspension of sedation before clinical examination was reported in only 5/12 (42%) studies included in our review.

In the AAN 2006 review,1 an absent or extensor motor response to pain at 72 h was recommended as a reliable predictor of poor neurological outcome, dened as CPC 45 after 1 month or CPC 35 after 6 months. Our data do not support this conclusion. The recommendation above was based on three cohort studies,63,73,74 two of which did not full the inclusion criteria for our review. In the remaining study,63 absent or extensor motor response to pain at 72 h was associated with recovery of consciousness at six months in seven patients, which corresponded to a FPR of 35%. 4.3. Somatosensory evoked potentials In this review, bilateral absence of N20 SSEP was the only index to be almost 100% accurate with narrow CIs for prediction of poor outcome either dened as CPC 45 or as CPC 35. Among a total of 432 patients with bilaterally absent N20 SSEP recorded during the rst 7 days after cardiac arrest only one (0.23%) achieved a good outcome. Moreover, among the predictors with high specicity and precision, absent SSEP was the one with the highest number of supporting studies. In comparison with predictors based on clinical examination, SSEPs have the important advantage of being only minimally affected by sedation. However, SSEP recording requires the availability of appropriate equipment and skills. Moreover, in the intensive care environment, electrical interference from muscular artefacts, electrical beds, infusion pumps, or ventilators may make detection of the N20 SSEP wave difcult and potentially cause falsely pessimistic predictions.75,76 Finally, SSEP may be affected by neurological diseases involving the primary sensory pathway. Bilaterally absent SSEP have been described in patients with multiple sclerosis and bilateral thalamic infarcts.32 4.4. Electroencephalography (EEG) A series of grading systems, most of which include ve grades of increasing severity, have been employed by various authors to classify post-cardiac arrest EEG (see ESM Table E8). Because of the heterogeneity and the complexity of the different EEG classications and grades, we focused on the predictive value of single EEG patterns. While the presence of typically malignant patterns, such as alpha coma, burst-suppression or epileptiform activity was compatible with recovery, the presence of a low-voltage EEG predicted poor outcome (CPC 45) with 0% FPR and a high precision. However, the application of this last index for prognostication requires caution. In fact, the amplitude of the EEG signal may depend on a variety of technical conditions such as skin and scalp impedance, inter-electrode distances, size, type and placement of the exploring electrodes, and type of lters adopted.77 The major limitation of EEG as a prognostic tool in comatose resuscitated patients is its sensitivity to the effects of toxicmetabolic derangements or sedative drugs used in the intensive care unit. Barbiturates, opiates and benzodiazepines can induce alpha coma, while propofol and barbiturates at high doses can induce burst-suppression. Among 11 studies on EEG included in our review, only four (36.7%) excluded the presence of sedation during recording. We therefore cannot exclude the presence of pharmacological confounders in the remaining studies. 4.5. Serum biomarkers NSE and S-100B are protein biomarkers that come from neurons and from astroglial and Schwann cells, respectively. Presence of elevated blood values of NSE or S-100B is an index of massive neuronal loss. NSE and S-100B concentrations are believed to correlate with the extent of anoxic-ischaemic neurological injury due to cardiac arrest and, therefore, with the severity of neurological

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prognosis. Advantages of serum markers over both EEG and clinical examination include quantitative results and likely independence from the effects of sedative drugs. However, we could not identify a consistent NSE or S-100B threshold corresponding to a zero FPR. The 2006 AAN review1 identied an NSE threshold of 33 g l1 at days 13 for prediction poor outcome with 0% FPR, based on the result of a single large cohort study.63 However, in another study64 included in that review this threshold was 47.6 g l1 at 24 h, while in a large cohort study43 of 157 normothermic patients published after the AAN review, this threshold was 65.0 g l1 at 48 h and 80 g l1 at 72 h. In one study19 included in our review, a NSE cut-off level of 65 g l1 was still compatible with good outcome. In another study,35 two patients with NSE levels of 36 g l1 and 76 g l1 recovered. Finally, Krumnikl et al78 reported the case of a 31-year old woman resuscitated after prolonged cardiac arrest with a good neurological outcome and in whom the NSE levels on the rst and second day after resuscitation were 102 g l1 and 116.8 g l1 , respectively. We also found some inconsistencies in the reported S-100B thresholds. For example, for prediction of poor outcome (CPC 45) at 48 h an S-100 blood value of 0.2 g l1 was associated with a lower FPR (0%) than a value of 0.7 g l1 (5% FPR) (see Table 2c). Possible reasons for these inconsistencies include the presence of extracerebral sources of biomarkers and the use of heterogeneous immunoenzyme measurement techniques.79 Moreover, serum markers cannot distinguish the location of neuronal or glial loss, which may account for some dissociation between biomarker values and neurological function. 4.6. Imaging The main CT nding of anoxic-ischaemic cerebral insult is brain swelling, which appears as a reduction of ventricles and sulci and an attenuation of the greywhite matter interface, and it has been quantied as a reduction of the density ratio (measured in Hounseld units), between the grey matter of the caudate and the white matter of the posterior internal capsula. In a study included in our review, a density ratio <1.22 within 24 h predicted poor outcome as CPC 45 with 0% FPR.49 However, in another study,55 at least one patient with a density ratio <1.18 within 48 h recovered (17% FPR). At the moment, detection of brain swelling on CT scan for outcome prediction after resuscitation from cardiac arrest does not appear to be based on a sufciently consistent evidence. MRI has only recently been investigated as a tool for outcome prediction in comatose patients resuscitated from cardiac arrest. Advantages of MRI over brain CT include better spatial denition and high sensitivity to anoxic-ischaemic injury. However, high cost and limited feasibility in the most unstable patients have hindered its use in the acute phase after cardiac arrest. The earliest post-anoxic MRI change is hyperintensity on Diffuse Weighted Imaging (DWI) sequences, which reects a restriction of water diffusion through neuronal membrane caused by ischaemic dysfunction of the membrane-bound Na-K-ATPase pump. Presence of extensive DWI changes measured qualitatively at 432 h predicted poor outcome with 0% FPR in one study included in our review.52 Apparent diffusion coefcient (ADC) is a quantitative measure of ischaemic MRI changes based on computer processing of DWI images. In a paper included in our review57 presence of >10% of brain volume with an ADC < 650 106 mm2 /s was associated invariably with a poor outcome. ADC cortical changes began at 36 h and peaked at 35 days.53 A later, qualitative MRI sign is hyperintensity on T2-weighted and FLAIR images, due to vascular disruption and formation of methaemoglobin,80 which becomes apparent days after injury.

MRI is a promising tool for prognostication in comatose resuscitated patients, especially when quantitative techniques as ADC are used, but present evidence is based on a limited number of studies. Cost, feasibility, complexity of spatial distribution of described changes, and need of advanced data processing may limit MRI application. 4.7. Comparison with previous reviews Our ndings differ from previous reviews on the same subject.13 In particular, we could not conrm the accurate predictive value of indices such as corneal reex, extensor or absent motor response to pain at 72 h, and NSE levels > 33 g l1 at 2472 h that were previously recommended in the AAN 2006 review (see the ESM Table E6 for details). There are several possible explanations for this. Firstly, we excluded some studies73,74,81 that were included in previous reviews because hypoxic coma was reportedly due to causes other than cardiac arrest or occurred in children. Secondly, we used evidence from more recent studies43,46,61 that was not available to previous reviewers. Thirdly, the 95% CIs we calculated were sometimes wider than in previous reviews, partly because of the conservative estimate we adopted for 95% CI calculation. For some predictors with FPR > 0% reported in the PROPAC study63 the FPRs we calculated were much higher than in the original paper, where a nonconventional denition of FPR was used (for details see the extended version of this manuscript available as ESM, Appendix 1). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. Unlike previous reviews, we accepted both the denition of poor outcome as CPC 45 or CPC 35 and reported the relevant data separately, because there is no consensus in literature on what represents a poor outcome after an acute coma. While many would consider CPC 12 (absent, or mild to moderate disability) as the only acceptable neurological outcome after cardiac arrest, others may argue that even a CPC 3 (awake patient with severe disability) could be acceptable, especially when considering that some CPC 3 patients may further improve after acute care. For example, the PROPAC study63 found that among 22 patients with absent pupillary and corneal reexes and CPC = 3 at one month from cardiac arrest, 12 improved to a CPC = 12 at 3 months, and further 2 improved to a CPC = 2 at 6 months. These data suggest that a follow-up of at least 6 months is required to adequately evaluate poor outcomes after cardiac arrest, especially when CPC 3 is dened as a poor outcome. The Multi-Society Task Force on persistent vegetative state (PVS)82 recommends at least 3 months to establish PVS following an anoxic insult. Unfortunately, in studies included in our review only 18/38 studies (47%) with poor outcome dened as CPC 45 had a follow-up 3 months and only 7/12 studies (58%) with poor outcome dened as CPC 35 had a follow-up 6 months. This is the rst review on prognostication after cardiac arrest to use GRADE for evidence appraisal. Using this methodology, we found that the quality of evidence was low or very low for the vast majority of studies. The main reasons for this were low precision because of the small population sizes, and presence of limitations, especially lack of blinding of the treating team to the results of the predictor being tested, which makes studies prone to self-fullling prophecy. Among 50 studies included in our review, only ve (10%) reported blinding of the treating team from the results of predictors under investigation (see ESM Table E7 for details). In one of these studies, despite treating physicians being blinded for the results of the SSEP and biomarkers until 72 h, treatment had been restricted in 23% of patients at

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24 h and in 28% at 48 h. In the same study, results of three predictors under investigation (SSEP, EEG and motor response) were also used as a guideline for treatment decisions.63 The risk of self-fullling prophecy is particularly high for predictors based on clinical examination, for which blinding is virtually impossible. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2013.05.013. Another common limitation we found was presence of sedation, which may have affected both clinical examination and EEG. Among 23 studies included in our review in which suspension of sedation at the moment of index recording would have been appropriate, only 9 (39%) reported it. 4.8. Study limitations Our review has several limitations. Firstly, the lack of specic guidelines for evaluation of prognostic accuracy studies required us to adapt the GRADE guidelines for diagnostic studies. Some of our choices, such as assigning a serious limitation to studies which lacked blinding, may be considered arbitrary. However, lack of blinding and the consequent risk of self-fullling prophecy have long been recognised as a major limitation of prognostic accuracy studies in post-cardiac arrest patients.3,6 Secondly, studies included in our review did not have a consistent timing of outcome measurement, since we choose to include studies regardless of the length of their follow-up. As a consequence, prediction of poor outcome refers to a period ranging from discharge to 48 months. As discussed above, outcome evaluation undertaken too early may overestimate the number of patients assigned CPC 3. Thirdly, we could not address the quality of treatment as confounder for the association between a predictor and its predicted nal outcome. The studies we included spanned 37 years, from 1974 to 2011, during which, even before the advent of therapeutic hypothermia, the standard of intensive treatment would have changed signicantly. The results of most studies included in our review therefore could not be necessarily applicable to patients treated according to the current standards of post-resuscitation care except therapeutic hypothermia. The upcoming results from the recently completed TTM trial, where patients in the control arm have been kept at a target temperature of 36 C will possibly add useful information on prognostication in these patients. Fourthly, none of the predictors identied in the studies we included was validated prospectively. Given the low quality of the available evidence, a large, good-quality multicentre inception cohort study followed by a prospective validation study are warranted. 5. Conclusions Our systematic review showed that in comatose patients resuscitated from cardiac arrest and not treated using therapeutic hypothermia, (a) presence of myoclonus at 2448 h, bilateral absence of SSEP N20 wave or absence of EEG activity > 2021 V at 2472 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 65 g l1 at 48 h or 80 g l1 at 72 h also predicted death or vegetative state with 0% FPR and low CIs in one study, but the NSE thresholds for 0% FPR prediction varied largely and inconsistently. The quality of evidence of the vast majority of the studies included in our review was low or very low and only a few studies reported blinding of the treating team from the results of the investigated predictor.

These predictors need to be conrmed in a prospective validation study. 6. Conict of interest statement Claudio Sandroni, Fabio Cavallaro, Clifton Callaway, Tommaso Sanna, Sonia DArrigo and Michael Kuiper have no conicts 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. Marys Hospital, Seoul Korea; 4. Dr. Johann Reisinger, Department of Internal Medicine/ Cardiology, Krankenhaus Barmherzige Schwestern, Linz, Austria 5. Dr. Mehmet Akif Topcuoglu, NeuroICU, Hacettepe University Hospitals, Ankara, Turkey 6. Dr. Eveline Zandbergen, Rijnstate Hospital, Arnhem, The Netherlands. We also gratefully thank Dr. Lorenzo Compieta for providing statistical advice during data analysis. References
1. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. 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;67: 20310. 2. Booth CM, Boone RH, Tomlinson G, Detsky AS. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004;291:8709. 3. Zandbergen EG, de Haan RJ, Stoutenbeek CP, Koelman JH, Hijdra A. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998;352:180812. 4. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 5. Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientic 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;79:35079. 6. Geocadin RG, Peberdy MA, Lazar RM. Poor survival after cardiac arrest resuscitation: a self-fullling prophecy or biologic destiny? Crit Care Med 2012;40:97980. 7. Schunemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008;336:110610. 8. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. 9. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:814. 10. Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med 1986;314:397403. 11. Blyth CR. Approximate binomial condence limits. J Am Stat Assoc 1986;81:84355. 12. Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 1983;249:17435. 13. Sauro J. Condence interval calculator for a completion rate; 2012. http://www.measuringusability.com/wald.htm [last accessed 03.11.12].

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C. Sandroni et al. / Resuscitation 84 (2013) 13101323 46. Samaniego EA, Mlynash M, Cauleld AF, Eyngorn I, Wijman CA. Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia. Neurocrit Care 2011;15:1139. 47. Steffen IG, Hasper D, Ploner CJ, et al. Mild therapeutic hypothermia alters neuron specic enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care 2010;14:R69. 48. Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specic enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003;34:28816. 49. Choi SP, Park HK, Park KN, et al. The density ratio of grey to white matter on computed tomography as an early predictor of vegetative state or death after cardiac arrest. Emerg Med J 2008;25:6669. 50. Choi SP, Park KN, Park HK, et al. Diffusion-weighted magnetic resonance imaging for predicting the clinical outcome of comatose survivors after cardiac arrest: a cohort study. Crit Care 2010;14:R17. 51. Della Corte F, Barelli A, Giordano A, Iacobucci T, Valente MR, Pennisi MA. CBF determination in post-ischemic-anoxic comatose patients. Minerva Anestesiol 1993;59:63741. 52. Els T, Kassubek J, Kubalek R, Klisch J. Diffusion-weighted MRI during early global cerebral hypoxia: a predictor for clinical outcome? Acta Neurol Scand 2004;110:3617. 53. Mlynash M, Campbell DM, Leproust EM, et al. Temporal and spatial prole of brain diffusion-weighted MRI after cardiac arrest. Stroke 2010;41: 166572. 54. Morimoto Y, Kemmotsu O, Kitami K, Matsubara I, Tedo I. Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome. Crit Care Med 1993;21:10410. 55. Torbey MT, Geocadin R, Bhardwaj A. Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest. Resuscitation 2004;63:5563. 56. Wijdicks EF, Campeau NG, Miller GM. MR imaging in comatose survivors of cardiac resuscitation. AJNR Am J Neuroradiol 2001;22:15615. 57. Wijman CA, Mlynash M, Cauleld AF, et al. Prognostic value of brain diffusionweighted imaging after cardiac arrest. Ann Neurol 2009;65:394402. 58. Bassetti C, Bomio F, Mathis J, Hess CW. Early prognosis in coma after cardiac arrest: a prospective clinical, electrophysiological, and biochemical study of 60 patients. J Neurol Neurosurg Psychiatry 1996;61:6105. 59. Berek K, Lechleitner P, Luef G, et al. Early determination of neurological outcome after prehospital cardiopulmonary resuscitation. Stroke 1995;26:5439. 60. Edgren E, Hedstrand U, Nordin M, Rydin E, Ronquist G. Prediction of outcome after cardiac arrest. Crit Care Med 1987;15:8205. 61. Topcuoglu MA, Oguz KK, Buyukserbetci G, Bulut E. Prognostic value of magnetic resonance imaging in post-resuscitation encephalopathy. Intern Med 2009;48:163545. 62. Young GB, Doig G, Ragazzoni A. Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:15964. 63. Zandbergen EG, Hijdra A, Koelman JH, et al. Prediction of poor outcome within the rst 3 days of postanoxic coma. Neurology 2006;66:628. 64. Zingler VC, Krumm B, Bertsch T, Fassbender K, Pohlmann-Eden B. Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurobiochemical and electrophysiological investigations may provide high prognostic certainty in patients after cardiac arrest. Eur Neurol 2003;49:7984. 65. Synek VM. EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults. Clin Electroencephalogr 1988;19: 1606. 66. Lu-Emerson C, Khot S. Neurological sequelae of hypoxic-ischemic brain injury. NeuroRehabilitation 2010;26:3545. 67. Celesia GG, Grigg MM, Ross E. Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Arch Neurol 1988;45:7814. 68. Datta S, Hart GK, Opdam H, Gutteridge G, Archer J. Post-hypoxic myoclonic status: the prognosis is not always hopeless. Crit Care Resusc 2009;11: 3941. 69. English WA, Gifn NJ, Nolan JP. Myoclonus after cardiac arrest: pitfalls in diagnosis and prognosis. Anaesthesia 2009;64:90811. 70. Morris HR, Howard RS, Brown P. Early myoclonic status and outcome after cardiorespiratory arrest. J Neurol Neurosurg Psychiatry 1998;64:2678. 71. Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963;86:11136. 72. Arnoldus EP, Lammers GJ. Postanoxic coma: good recovery despite myoclonus status. Ann Neurol 1995;38:6978. 73. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet 1994;343:10559. 74. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:14206. 75. Bouwes A, Binnekade JM, Kuiper MA, et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol 2012;71:20612. 76. Zandbergen EG, Hijdra A, de Haan RJ, et al. Interobserver variation in the interpretation of SSEPs in anoxic-ischaemic coma. Clin Neurophysiol 2006;117:152935. 77. Reilly EL. EEG recording and operation of the apparatus. In: Niedermeyer E, Lopes da Silva F, editors. Electroencephalography. Basic principles, clinical applications and related elds. Baltimore, Maryland, USA: Williams & Wilkins; 1993. p. 10424.

14. Rifai N, Altman DG, Bossuyt PM. Reporting bias in diagnostic and prognostic studies: time for action. Clin Chem 2008;54:11013. 15. Bertini G, Margheri M, Giglioli C, et al. Prognostic signicance of early clinical manifestations in postanoxic coma: a retrospective study of 58 patients resuscitated after prehospital cardiac arrest. Crit Care Med 1989;17:62733. 16. Earnest MP, Breckinridge JC, Yarnell PR, Oliva PB. Quality of survival after out-of-hospital cardiac arrest: predictive value of early neurologic evaluation. Neurology 1979;29:5660. 17. Fischer C, Luaute J, Nemoz C, Morlet D, Kirkorian G, Mauguiere F. Improved prediction of awakening or nonawakening from severe anoxic coma using treebased classication analysis. Crit Care Med 2006;34:15204. 18. Krumholz A, Stern BJ, Weiss HD. Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus. Neurology 1988;38:4015. 19. Pfeifer R, Borner A, Krack A, Sigusch HH, Surber R, Figulla HR. Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuronspecic enolase and protein S-100 and the Glasgow Coma Scale. Resuscitation 2005;65:4955. 20. Thomke F, Marx JJ, Sauer O, et al. Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus. BMC Neurol 2005;5:14. 21. Wijdicks EF, Young GB. Myoclonus status in comatose patients after cardiac arrest. Lancet 1994;343:16423. 22. Young GB, Gilbert JJ, Zochodne DW. The signicance of myoclonic status epilepticus in postanoxic coma. Neurology 1990;40:18438. 23. Bauer E, Funk GC, Gendo A, et al. Electrophysiological assessment of the afferent sensory pathway in cardiac arrest survivors. Eur J Clin Invest 2003;33:2837. 24. Berkhoff M, Donati F, Bassetti C. Postanoxic alpha (theta) coma: a reappraisal of its prognostic signicance. Clin Neurophysiol 2000;111:297304. 25. Brunko E, Zegers de Beyl D. Prognostic value of early cortical somatosensory evoked potentials after resuscitation from cardiac arrest. Electroencephalogr Clin Neurophysiol 1987;66:1524. 26. Chokroverty S. Alpha-like rhythms in electroencephalograms in coma after cardiac arrest. Neurology 1975;25:65563. 27. Gendo A, Kramer L, Hafner M, et al. Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors. Intensive Care Med 2001;27: 130511. 28. Grindal AB, Suter C, Martinez AJ. Alpha-pattern coma: 24 cases with 9 survivors. Ann Neurol 1977;1:3717. 29. Kaplan PW, Genoud D, Ho TW, Jallon P. Etiology, neurologic correlations, and prognosis in alpha coma. Clin Neurophysiol 1999;110:20513. 30. Madl C, Kramer L, Domanovits H, et al. Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment. Crit Care Med 2000;28:7216. 31. Nakabayashi M, Kurokawa A, Yamamoto Y. Immediate prediction of recovery of consciousness after cardiac arrest. Intensive Care Med 2001;27:12104. 32. Rothstein TL. The role of evoked potentials in anoxic-ischemic coma and severe brain trauma. J Clin Neurophysiol 2000;17:48697. 33. Rothstein TL, Thomas EM, Sumi SM. Predicting outcome in hypoxic-ischemic coma. A prospective clinical and electrophysiologic study. Electroencephalogr Clin Neurophysiol 1991;79:1017. 34. Scollo-Lavizzari G, Bassetti C. Prognostic value of EEG in post-anoxic coma after cardiac arrest. Eur Neurol 1987;26:16170. 35. Stelzl T, von Bose MJ, Hogl B, Fuchs HH, Flugel KA. A comparison of the prognostic value of neuron-specic enolase serum levels and somatosensory evoked potentials in 13 reanimated patients. Eur J Emerg Med 1995;2:247. 36. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med 2005;33:173640. 37. Vignaendra V, Wilkus RJ, Copass MK, Chatrian GE. Electroencephalographic rhythms of alpha frequency in comatose patients after cardiopulmonary arrest. Neurology 1974;24:5828. 38. Zanatta P, Messerotti Benvenuti S, Baldanzi F, Bosco E. Pain-related middlelatency somatosensory evoked potentials in the prognosis of post anoxic coma: a preliminary report. Minerva Anestesiol 2012;78:74956. 39. Zandbergen EG, Koelman JH, de Haan RJ, Hijdra A. SSEPs and prognosis in postanoxic coma: only short or also long latency responses? Neurology 2006;67:5836. 40. Zhang Y, Su YY, Haupt WF, et al. Application of electrophysiologic techniques in poor outcome prediction among patients with severe focal and diffuse ischemic brain injury. J Clin Neurophysiol 2011;28:497503. 41. Hachimi-Idrissi S, Van der Auwera M, Schiettecatte J, Ebinger G, Michotte Y, Huyghens L. S-100 protein as early predictor of regaining consciousness after out of hospital cardiac arrest. Resuscitation 2002;53:2517. 42. Mussack T, Biberthaler P, Kanz KG, et al. Serum S-100B and interleukin8 as predictive markers for comparative neurologic outcome analysis of patients after cardiac arrest and severe traumatic brain injury. Crit Care Med 2002;30:266974. 43. Reisinger J, Hollinger K, Lang W, et al. Prediction of neurological outcome after cardiopulmonary resuscitation by serial determination of serum neuronspecic enolase. Eur Heart J 2007;28:528. 44. Rosen H, Rosengren L, Herlitz J, Blomstrand C. Increased serum levels of the S-100 protein are associated with hypoxic brain damage after cardiac arrest. Stroke 1998;29:4737. 45. Rosen H, Sunnerhagen KS, Herlitz J, Blomstrand C, Rosengren L. Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest. Resuscitation 2001;49:18391.

C. Sandroni et al. / Resuscitation 84 (2013) 13101323 78. Krumnikl JJ, Bottiger BW, Strittmatter HJ, Motsch J. Complete recovery after 2 h of cardiopulmonary resuscitation following high-dose prostaglandin treatment for atonic uterine haemorrhage. Acta Anaesthesiol Scand 2002;46: 116870. 79. Bloomeld SM, McKinney J, Smith L, Brisman J. Reliability of S100B in predicting severity of central nervous system injury. Neurocrit Care 2007;6: 12138.

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80. Hecht-Leavitt C, Gomori JM, Grossman RI, et al. High-eld MRI of hemorrhagic cortical infarction. AJNR Am J Neuroradiol 1986;7:5815. 81. Snyder BD, Ramirez-Lassepas M, Lippert DM. Neurologic status and prognosis after cardiopulmonary arrest: I. A retrospective study. Neurology 1977;27:80711. 82. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state (2). The Multi-Society Task Force on PVS. N Engl J Med 1994;330:15729.