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1312 C.Sandroni et al./ Resuscitation 84 (2013) 13101323
Clinical examination: included every clinical sign that can be
collected during a bedside neurological examination. For exam-
ple, brainstem reflexes, 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 bio-
electrical signal from the central nervous system. They include
electroencephalogram(EEG) andevoked potentials (EPs). Wealso
considered forinclusion studies in which theEEG signalhad 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 specific enolase (NSE) and
S-100B protein. Imaging: neuroimaging predictors that were assessed in our
reviewincludedcomputed tomography (CT),magneticresonance
imaging (MRI) and single-photon emission computed tomogra-
phy (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.
2.1.3. Outcome
We included only studies in which the neurological outcome
was described using the five 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 predefined CPC threshold, either CPC 45 vs.
13 or CPC 35 vs. 12. We accepted both of those definitions for
ourreview. When no thresholdhad been defined, 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 con-
fidence intervals, we included only studies where the complete
contingency table (i.e.,the numberof true/false negatives andposi-
tives 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 pub-
lished 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.
For each of the four types of outcome predictors, two authors
performed a blinded and independent eligibility assessment. Dis-
agreements between reviewers were resolved by consensus.
2.3. Statistical methods
Foreachstudyincluded in thefinalanalysis, wecalculated sensi-
tivity, specificity, falsepositiverate (FPR)expressedas 1-specificity,
positive predictive value (PPV), expressed as TP/(TP+ FP) and posi-
tive 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 specificity 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, timepoints and outcome definitions. Confidence
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
confidence interval was used instead of the two-sided value, as
recommended.12,13 Pooled values of LR+ with relevant confidence
intervals were calculated according to the DerSimonianLaird
random effect model. Heterogeneity of pooled studies for sensi-
tivity/specificity and LR+ was estimated by: (1)G2 and Qstatistics
respectively; (2) I2 (inconsistency). Heterogeneity was regarded as
significant whenp50%.
2.4. Evidence appraisal
Given the absence of specific GRADE recommendations on
prognostic accuracy studies, we adapted the GRADE recommen-
dations 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 fac-
tors: (1) limitations; (2) indirectness; (3) inconsistency; and (4)
imprecision. Publication bias was not considered, given the diffi-culty 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
treatmentteam and outcome or indexevaluators; exclusion of non-
neurological causes of death; exclusion of previous neurological
diseases; exclusionof sedation (for indexes based on clinical exam-
ination or EEG); exclusionof paralysis (for indexes based on clinical
examination); length of follow-up.
Given the importance of the risk of self-fulfilling prophecy, lim-
itations 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 bemodified upwards when the magnitude of effect is large. For the
purpose of our study, we considered a high predictor performance,
definedas a LR+>10,to be equivalent to a large magnitudeof effect.
Indirectnesswasdeemed present when thecharacteristics 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 significant (p< 0 .1 or
I2 >50%) for either sensitivity or specificity, and it was graded as
very serious when heterogeneity was significant for both of them.
Imprecision. When evaluating the accuracy of predictors of
poor outcome in critically ill patients, avoiding false positives is
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C. Sandroni et al. / Resuscitation 84 (2013) 13101323 1313
particularly important in order to avoid falsely pessimistic pre-
dictions. 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 confidence
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 identi-
fied 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 inclu-
sion criteria.The remaining 50 studies were included in ourreview.
Excluded studies with reasons for their exclusion are listed in theESM 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 defined as vegetative state or death(CPC 45), while in the remaining 12/50 studies (24%) poor
outcome was defined 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-specificity), and the quality of evidence for
indices based on clinical examination, electrophysiology, biomark-
ers and neuroimaging are reported on Tables 2a2d. The evidence
profiles 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.
PubMed: 935 records
Scopus: 392 records
Cochrane Database of systematicreviews: 11 records
1338 records34 additional records identified
through forward search
1372 records screened
1159 discarded
(duplicates or excluded aftertitle and abstract evaluation)
213 full-text articlesassessed for eligibility
163 full-text excluded due to
83 Patient characteristics
22 Intervention characteristics
7 Comparison characteristics26 Outcome characteristics
20 Study characteristics
2 Data could not be extracted3 Unavailablestudies
50 studies included inqualitative and quantitative
synthesis
(meta-analysis)
Identification
Screening
Eligibility
Included
Fig. 1. Flow-chart of study selection.
http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013 -
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Table 1
Characteristics of the included studies.
Author, year,
Reference
IHCA or
OHCA
No. of
patients
Males, % VF/VT % Mean age, ys [SD]
or median (range)
Predictor(s) Definition of
poor outcome
(CPC)
Timing of outcome
assessment
Clinical Examination
Bertini 198915 OHCA 34 85 74 66 [10.4] PLR, MR 45 vs. 13 ICU discharge
Earnest 197916 OHCA 117 74 N/A 62 (median) PLR, OCR, MR 35 vs. 12 Hospital discharge
Fischer 200617 OHCA 62 76 N/A 55 [16] GCS 45 vs. 13 12 mo
Krumholz 198818
Mixed 114 61.4 N/A 57 [ 17.9] Myoclonus 45 vs. 13 6 moPfeifer 200519 Mixed 97 71 47 63 (1790) GCS 45 vs. 13 1 mo
Thomke 200520 Mixed 50 52 88 54 (2083) Myoclonus 45 vs. 13 48 mo
Wijdicks 199421 OHCA 107 62 38 63 (2786) Myoclonus 45 vs. 13 6 mo
Young 199022 N/A 11 73 N/A 57 [16.7] Myoclonus 45 vs. 13(a) Hospital discharge
Electrophysiologic studies
Bauer 200323 Mixed 305 68 57 57 (1689) SSEPs 45 vs. 13 12 mo
Berkhoff200024 N/A 9 89 N/A 58 (2483) EEG (Alpha coma) 45 vs. 13 12 mo
Brunko 198725 OHCA 50 N/A N/A 62 [17] SSEPs 45 vs. 13 Hospital discharge
Chockroverty 197526 N/A 12 83 N/A 55 [15.9] EEG 45 vs. 13 Hospital discharge
Gendo 200127 N/A 25 80 60 59 (4287) SSEPs 35 vs. 12 6 mo
Grindal 197728 N/A 14 86 N/A 58 [16.3] Alpha coma 45 vs. 13 (a) 2 mo
Kaplan 199929 N/A 18 72.2 N/A 60 [16.2] EEG 45 vs. 13 10 mo
Madl 200130 Mixed 162 65 49 57 [16] SSEPs 35 vs. 12 6 mo
Nakabayashi 200131 OHCA 30 67 N/A 63 (1690) SSEPs 45 vs. 13 9 mo
Rothstein 199132 OHCA 40 58 N/A 72 (1991) EEG 45 vs. 13 2 mo
Rothstein 200033 OHCA 50 56 N/A 71 (1991) SSEPs 45 vs. 13 1 mo
Scollo-Lavizzari 198734 N/A 26 65 N/A 61 (1677) EEG 35 vs. 12 N/AStelzl199535 N/A 13 62 N/A 67 (4880) SSEPs 45 vs. 13 N/A
Tiainen 200536 OHCA 30 73 100 58 (1875) SSEPs 45 vs. 13 6 mo
Vignaendra 197437 OHCA 8 88 N/A 53 [13] EEG 45 vs. 13 (a) 14 d
Zanatta 201238 N/A 6 N/A 100 63 (3589) SSEPs 45 vs. 13 3 mo
Zandbergen 2006a39 N/A 407 67 68 63 [14] SSEPs 45 vs. 13 12 mo
Zhang 201140 N/A 77 46 0 57 [19.2] EEG, SSEPs, BAEPs 45 vs. 13 6 mo
Biomarkers
Hachimi-Idrissi 200241 OHCA 58 N/A N/A 64 [ 3] S-100 45 vs. 13 Hospital discharge
Mussack 200242 OHCA 20 70 50 71 S-100B 35 vs 12 12 mo
Reisinger 200743 Mixed 177 63 53 65 [15] NSE 45 vs. 13 6 mo
Rosen 199844 OHCA 41 76 80 68 (2189) S-100 45 vs. 13 Hospital discharge
Rosen 200145 OHCA 66 76 79 68[14.6] NSE, S-100 35 vs 12 12 mo
Samaniego 201146 Mixed 32 53 38 55 (1986) NSE 45 vs. 13 3 mo
Steffen 201047 Mixed 73 75 55 64 NSE 35 vs 12 ICU discharge
Tiainen 200348 OHCA 34 71 100 59 (1875) NSE, S-100B 35 vs 12 6 mo
NeuroimagingChoi 200849 OHCA 28 75 28.5 54 (2786) Brain CT 45 vs. 13 Hospital discharge
Choi 201050 OHCA 39 72 15 49 (1889) Brain MRI 35 vs 12 3 mo
Della Corte 199351 N/A 11 45.5 N/A 40 [16.6] Brain SPECT 45 vs. 13 6 mo
Els 200452 N/A 12 N/A N/A 53 (2771) Brain MRI 45 vs. 13 6 mo
Mlynash 201053 Mixed 12 N/A N/A 52 [17] Brain MRI 45 vs. 13 6 mo
Morimoto 199354 OHCA 53 66 26.4 51 [22.9] Brain CT 45 vs. 13 7 d
Torbey 200455 N/A 32 56 40.6 64 [16.5] Brain CT 45 vs. 13 Hospital discharge
Wijdicks 200156 Mixed 10 50 N/A 57 [14.1] Brain MRI 35 vs. 12 N/A
Wijman 200957 Mixed 10 N/A N/A 54 [15] Brain MRI 45 vs. 13 6 mo
Multimodal prognostication
Bassetti 199658 N/A 60 82 N/A 62 (1986) BR, GCS, MR, EEG,
SSEPs
45 vs. 13 12 mo
Berek 199559 OHCA 30 N/A 70 61 (1886) Brain MRI, SSEPs 35 vs. 12 1 mo
Edgren 198760 N/A 32 47 N/A 71 [8.5] BR, MR,EEG 35 vs. 12 6 mo
Topcuoglu 200961 Mixed 22 59 N/A 56 [16.9] GCS, FOUR score,
brain MRI
45 vs. 13 3 mo
Young 200562 Mixed 75 61 65 66 [13] PLR, CR, VOR, MR,myoclonus, SSEPs,
EEG
45 vs. 13 3 mo
Zandbergen 2006b63 N/A 407 67 68 63 [14] BR, MR, myoclonus,
NSE, S-100B, SSEPs,
EEG
45 vs. 13 6mo
Zingler 200364 Mixed 27 48 N/A 61 [17.3] NSE, S-100B, SSEPs 45 vs. 13 3 mo
Abbreviations: BAEPs = B rain stem Auditory Evoked Potentials; CPC = C erebral Performance Category; CR = C orneal Reflex; CT = C omputed 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-Specific Enolase; OCR= OculoCephalicReflex; 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 Reflex.a Defined by the reviewer.
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Table 2a
Summary of findings for predictors based on clinical examination.
Timing Index Reference Sensitivity % [95% CI] FPR % [95% CI] No. of patients Quality of evidence
CPC 45 vs. 13
On admission GCS4 Fisher, 198817 74 [5886] 40 [19 64] 62 Very low
Motor score = 13 Bertini, 198915 89 [6599] 81 [5496] 34 Very low
Myoclonus status Wijdicks, 199421 46 [3557] 0 [014] 107 Low
At 612 h PLR absent Bertini, 198915 33 [1262] 25 [752] 31 Very low
>1 BR absenta Bassetti, 199658 21 [1035] 0 [0 22] 60 Very low
Motor score = 13 Bertini, 198915 91 [7998] 62 [4180] 72 Very lowBassetti, 199658
At24h OVR absent Young, 200562 42 [2659] 0 [031] 44 Very low
PLRabsent Bertini, 198915 21 [1725] 9 [418] 496
Very lowYoung, 200562
Zandbergen, 200663
CR absent Young, 200562 38 [3343] 18 [1030] 465Very low
Zandbergen, 200663
PLR and CR absent Zandbergen, 200663 14 [1018] 5 [117] 386 Very low
Motor score =1 Young, 200562 63 [4876] 6 [030] 67 Low
Motor score = 12 Zandbergen, 200663 78 [7382] 45 [2962] 395 Very low
Motor score= 13 Bertini, 198915 84 [7293] 46 [2767] 83Very low
Bassetti, 199658
Myoclonus (status) Young, 200562 9 [713] 0 [03] 471Moderate
Zandbergen, 200663
At 48 h PLR absent Bertini, 198915 19 [1524] 4 [115] 375Very low
Zandbergen, 200663
PLR and CR absent Zandbergen, 200663 13 [917] 3 [018] 338 Very low
Motor score =12 Zandbergen, 200663 75 [7080] 41 [2461] 351 Very low
Motor score= 13 Bertini, 198915 92 [8098] 14 [433] 77Very low
Bassetti, 199658
CR absent Zandbergen, 200663 31 [2636] 10 [227] 341 Very low
At 3648 h Myoclonus status Krumholz, 198818 8 [511] 0 [05] 464Low
Zandbergen, 200663
At 72 h PLR absent Bertini, 198915 18 [1523] 0 [08] 382Low
Zandbergen, 200663
PLR and CR absent Zandbergen, 200663 14 [1018] 0 [015] 289 Very low
FOURscore
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Table 2b
GRADE summary of findings for predictors based on electrophysiology.
Timing Index Reference Sensitivity % [95% CI] FPR% [95% CI] No. of patients Quality of evidence
CPC 45 vs. 13
At 8 h SSEPs N20 absent Brunko, 19872584 [7293] 0 [012]
80 Low
Nakabayashi,
200131
At 24 h SSEPs N20 absent Stelzl, 199535
46 [4053] 0 [05]
295 Moderate
Tiainen, 200536
Zandbergen,
200639
SS EPs N7 0 a bs ent Zan dber gen ,
20063930 [2337] 20 [1035] 212 Very low
At 48 h SSEPs N20 absent Rothstein, 200032
46 [4052] 0 [05]
328 Moderate
Zanatta, 201238
Zandbergen,
200639
Zingler, 200364
SSEPs N70 absent Zandbergen,
20063926 [1835] 17 [636] 148 Very low
At 48 h EEG malignant grade
(Synek)
Rothstein, 199133 42 [2363] 0 [019] 40 Very low
At 72 h SSEPs N20 absent Stelzl, 19953546 [4052] 0 [09]
293 Low
Zandbergen,
200639
SSEPs N20mono or
bilaterally absent
Berek, 199559 86 [42100] 0 [026] 17 Very low
EEG statu s e pile pticus Zan dber gen ,
2006399 [613] 8 [127] 283 Very low
At 72 h SSEPs N 20 a bsent Bauer, 200323
45 [3951] 1 [05]
408 Low
Bassetti, 199658
Young, 200562
SSEPs N20 absent Berkhoff, 200024 PPV 100 [48100] 5 Very low
SSEPs N70 absent Bauer, 200323
49 [4454] 8 [416]
470 Very low
Zandbergen,
200639
Young, 200562
EEG Grade IVV Bassetti, 199658 42 [2857] 0 [024] 59 Very low
EEG Burst-suppression Zandbergen,
200639 15 [1119] 2 [012]
349 Very low
Young, 200562
EEG voltage2021V Zandbergen,200639
28 [2334] 0 [06] 355 Low
Young, 200562
At 17d SSEPs N20 absent Zhang, 201140 70 [5780] 0 [024] 77 Low
Unfavourable EEG Zhang, 201140 97 [89100] 64 [3189] 77 Very low
Unreactive EEG Zhang, 201140 92 [8397] 45 [1777] 77 Very low
BAEP wave V absent Zhang, 201140 62 [4974] 9 [041] 77 Very low
At 13d EEG a lpha ( theta) c oma Berkhoff, 200024 PPV 100 [84100] 17 Very low
Vignaendra, 197437
At 16d EEG alpha coma Chokroverty,
197526PPV 88 [7596] 43 Very low
Grindal, 197728
Kaplan, 199929
CPC 35 vs. 12
At 24 h SSEPs N20 absent Madl, 200030 37 [2946] 0 [08] 159 Low
SSEPs N70>127ms or
absent
Gendo, 20012788 [8192]
2 [012] 187 Very low
Madl, 200030
EEG Grade IIIV Edgren, 198760 36 [1365] 0 [022] 26 Very low
At 48 h EEG Grade IIIV Edgren, 198760 36 [1169] 0 [024] 22 Very low
At 72 h EEG Grade IVV Scollo-Lavizzari,
19873450 [2971] 0 [078] 26 Very Low
At 24 h EEG alpha coma Edgren, 198760 PPV 100 [37100] 3 Very low
At 48 h EEG alpha coma Edgren, 198760 PPV 83 [36100] 6 Very low
Abbreviations:BAEP= Brainstem Auditory Evoked Potentials; CI= ConfidenceIntervals; CPC= Cerebral Performance Categories; EEG= Electroencephalogram;FPR = False Pos-
itive Rate; No= Number; SSEPs = Somatosensory Evoked Potentials.
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C. Sandroni et al. / Resuscitation 84 (2013) 13101323 1317
Table 2c
GRADE summary of findings for predictors based on biomarkers.
Timing Index Reference Cutoff (g l1) Sensitivity % [95% CI] FPR% [95% CI] No. of patients Quality of evidence
CPC 45 vs. 13
On admission S- 10 0B Ha chimi-I drissi , 2 00 241 0.7 67 [4882] 13 [334] 56 Very low
At 24 h NSE Zandbergen, 200663 33 48 [4255] 0 [08] 272 Moderate
NSE Zingler, 200364 47.6 53 [2877] 0 [026] 27 Very low
S-100B Rosen, 1 99844 0.2 77 [4695] 19 [542] 34 Very low
S- 10 0B Ha chimi-I drissi , 2 00 241
0.7 57 [5163] 10 [421]
330 Very low
Zandbergen, 200663
S-100B Zingler, 2 00364 5.2 35 [1462] 0 [026] 27 Very low
At 48 h NSE Zandbergen, 200663 33 61 [5468] 0 [08] 241 Low
NSE Reisinger, 200743 65 62 [4775] 0 [03] 156 Moderate
S-100B Rosen, 1 99844 0.2 79 [4995] 0 [012] 38 Very low
S-100B Zandbergen, 200663 0.7 51 [4458] 5 [118] 238 Very low
At 72 h NSE Samaniego, 20114633 55 [4863] 3 [014]
221 Very low
Zandbergen, 200663
NSE Reisinger, 200743 80 43 [2958] 0 [03] 152 Moderate
S-100B Zandbergen, 200663 0.7 42 [3450] 0 [08] 207 Low
CPC35 vs. 12
At 12-24h S-100B Tiainen, 200348 0.19 59 [3382] 0 [017] 33 Very low
S-100B Mussack, 2 00242 0.76 53 [2877] 0 [063] 20 Very low
At 24 h NSE Tiainen, 200348 13.3 59 [3382] 0 [017] 33 Very low
At 48 h NSE Tiainen, 200348 8.8 75 [4893] 0 [017] 32 Very low
NSE Rosen, 200145 25.0 37 [2254] 0 [012] 61 Very low
S-100B Tiainen, 200348 0.12 88 [6298] 0 [017] 32 Very low
S-100B Rosen, 2 00145 0.25 68 [5182] 0 [012] 61 Very low
At 72 h NSE Rosen, 200145 15.0 71 [5584] 0 [012] 65 Very low
NSE Steffen, 201047 22.4 86 [7892] 10 [227] 133 Very low
Abbreviations:CI= Confidence Interval; CPC= Cerebral Performance Categories; FPR= False Positive Rate; No= number; NSE= Neuron-Specific Enolase.
Presence ofmyoclonus or myoclonus status predicted death or
vegetative state with 0% [014] FPR when recorded on admission,
and remained predictive during the first 72h, with high precision
(95%CI 03 at 24h) but low sensitivity (89%; see Table 2a).
No value of eitherGCSor GCSmotor score consistently predicted
CPC 45 with zero FPR.
3.4. Electrophysiology
Bilateral absence of the N20 wave of short-latency somatosen-
sory 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 first 72h with a consistent sen-
sitivity (4546%). A single large study on 159 patients30 confirmed
bilateral absence of SSEP N20 at 24h 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 first 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 (seeTable 2b).
AGradeIIIVEEGaccordingto Edgrenet al60 at 24predicted poor
outcome (CPC 35) with 0% [022] FPR.EEGGrades IVVaccording
to Synek et al65 and Bassetti et al58 at 48 h and 72h respec-
tively, predictedpooroutcome (CPC 45) with 0%FPR (95% CIs019
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 (2021V)
at 24h72 h predicted poor outcome with 0% [08] FPR.
Presence ofalpha coma was not consistently associated with
poor outcome.24,37,60
3.5. Biomarkers
The highest threshold of NSE or S-100B serum concentrations
associated with a 0% FPR varied with studies, timing and definition
of poor outcome.
For poor outcome defined as CPC 45, this threshold for NSE
was 47.6g l1, 65g l1 and 80g l1 at 24 h, 48 h, and 72 h,respectively (see Table 2c).43,64 For S-100B, single studies reported
a threshold of 5.2g l1 at 24 h64 andof 0.7g l1 at72h.63
For poor outcome defined as CPC 35, this threshold for NSE
was 13.3g l1 at24hand25g l1 at48 h while for S-100B itwas
0.76 and0.25g l1, respectively. At 72h, a single study45 reported
an NSE threshold of 15g l1 for 0% FPR, but in a larger study47 a
NSE level of 22.4g l1 was associated with a 10% [227] FPR. All
studies in which poor outcome was defined as CPC 35 had a very
low quality of evidence.
3.6. Imaging
The number of patients studied with imaging techniques wasrelatively small, except for CT scan.
In 3 studies on a total of 113 patients, diffuse brain swelling on
brain CT scanwithin 72h predicted an almost invariably poor out-
come (FPR 5% [025]) with 54% [4364] sensitivity (see Table 2d).
In two small studies (total 22 patients), presence of extensive
brain abnormalities at 432h52 or reduction of absolute diffusion
coefficient (ADC) below 650106 mm2/s in more than 10% of
brain volume at 49108h57 on diffusion weighted (DWI) MRIpre-
dicted poor outcome with 0% FPR but wide 95% CI (045 and 078,
respectively).
Elevated lactate on MRI spectroscopy within 96h predicted a
poor outcome (CPC 35) with 71% [4292] sensitivityand 0%[035]
FPR in a study including 21 patients.59 Reduction of either cere-
bral blood flow (CBF) below 30ml/100g/min or cerebral oxygen
http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013http://dx.doi.org/10.1016/j.resuscitation.2013.05.013 -
8/14/2019 Pronostico Neurologico Paro Cardiaco
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1318 C.Sandroni et al./ Resuscitation 84 (2013) 13101323
Table 2d
GRADE summary of findings forpredictors based on imaging.
Timing Index Reference Sensitivity % [95% CI] FPR% [95% CI] No. of patients Quality of evidence
CPC 45 vs. 13
At 432 h Extensive DWI alterations ( MRI) Els, 2 00452 100 [65100] 0 [045] 12 Very low
At 72 h Brain swelling (CT) Choi, 200849 54 [4364] 5 [025] 113 Very low
Morimoto, 199354
Torbey, 200455
Median 80h (IQR
55117)
Abnormalities in basal ganglia
(MR-DWI)
Mlynash, 201053 100 [55100] 43 [1082] 12 Very low
Diffuse moderate to severe cortical
FLAIR-DWI alterations (MRI)
Mlynash, 201053 80 [2899] 0 [035] 12 Very low
At 49108 h > 10% Brain volume with ADC 2021V at
2472 h, and absence ofPLR at72 h each predicted death orvegeta-
tive state with zero FPRand narrowCIs,and (b)absence of SSEP N20
wave at 24h predicted death, vegetative state or severe disability
with zero FPR and narrow CIs. In addition, a serum NSE65g l1
at48hor80g l1 at 72h also predicteddeathor 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 confirmed in a prospective validation
study.
6. Conflict of interest statement
Claudio Sandroni, Fabio Cavallaro, Clifton Callaway, Tommaso
Sanna,SoniaDArrigoand Michael Kuiperhave no conflicts of inter-
est to declare.
Jerry Nolan is Editor-in-Chief of Resuscitation.
Acknowledgements
We gratefully thank the following investigators for having pro-
vided 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. KyuNam Park, Department of EmergencyMedicine, 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.
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8/14/2019 Pronostico Neurologico Paro Cardiaco
13/14
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