Prognostication in hypothermia

Transcription

1 Prognostication in hypothermia PICO Among adults with ROSC who are treated with hypothermia, (P), does any clinical variable when normal (e.g. 1. Clinical Exam, 2. EEG, 3. SSEP, 4. Imaging, 5. Other) when present (I), compared with any clinical variable when abnormal (C), change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year (O)? Outcome Importance Survival with favourable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year 9-Critical 7-Critical Question type: Prognostic Task Force: ALS Question Owner: Clifton Callaway (COI # 214) Evidence Reviewers: Claudio Sandroni (COI #134); Eyal Golan (COI #61) Search Strategy PubMed Search Completed Nov 14, results ("Hypothermia, Induced"[Mesh] OR "targeted temperature management"[tiab] OR "therapeutic hypothermia"[tiab] OR "hypothermia therapy"[tiab] OR ((cool*[tiab] OR cold[tiab]) AND ("Brain Injuries/prevention and control"[mesh] OR neuroprotection[tiab] OR "Hypoxia-Ischemia, Brain/prevention and control"[mesh] OR hypoxic-ischemic encephalopathy [TIAB]))) AND ("Heart Arrest"[Mesh] OR "cardiac arrest"[tiab] OR "cardiac arrests"[tiab] OR "cardiovascular arrest"[tiab] OR "cardiovascular arrests"[tiab] OR "heart arrest"[tiab] OR "heart arrests"[tiab] OR "asystole"[tiab] OR "pulseless electrical activity"[tiab] OR "cardiopulmonary arrest"[tiab] OR "cardiopulmonary arrests"[tiab] OR "Advanced Cardiac Life Support"[Mesh] OR "Advanced Cardiac Life Support"[TIAB] OR "ACLS"[TIAB] OR "Ventricular Fibrillation"[Mesh] OR "cardiopulmonary resuscitation"[mesh] OR "cardiopulmonary resuscitation"[tiab] OR CPR[TIAB] OR "Heart Massage"[Mesh]) AND (clinical exam*[tiab] OR "Physical Examination"[Mesh] OR "Electroencephalography"[Mesh] OR EEG[TIAB] OR "Evoked Potentials, Somatosensory"[Mesh] OR "somatosensory evoked potential"[tiab] OR somatosensory evoked potentials"[tiab] OR Cardiac Imaging Techniques"[Mesh] OR cardiac endoscopy [TIAB] OR cardioscopy[tiab] OR radionuclide imaging [TIAB] OR Magnetic Resonance Imaging [TIAB] OR MRI[TIAB] OR tomography[tiab] OR ultrasonography[tiab] OR Angiocardiography[TIAB] OR Coronary Angiography [TIAB] OR Echocardiography[TIAB] OR Myocardial Perfusion Imaging [TIAB] OR Ventriculography[TIAB] OR "blood marker"[tiab] OR blood markers [TIAB] OR "S100 Proteins"[Mesh] OR S-100B[TIAB] OR "S-100 calcium-binding protein beta subunit" [Supplementary Concept] OR neuron specific enolase [TIAB] OR "Phosphopyruvate Hydratase"[Mesh] OR "Biological Markers"[Mesh] OR biomarker*[tiab]) AND (adult*[tiab] OR "Adult"[Mesh] OR "Aged"[Mesh] OR "Aged, 80

2 and over"[mesh] OR "Frail Elderly"[Mesh] OR "Middle Aged"[Mesh] OR "Young Adult"[Mesh]) AND ("Prognosis"[Mesh] OR prognos*[tiab] OR Predict*[TIAB] OR "Predictive Value of Tests"[Mesh] OR Sensitivity and Specificity [Mesh]) NOT ("animals"[mh] NOT (animals[mh] AND "humans"[mh])) NOT ("letter"[pt] OR "comment"[pt] OR "editorial"[pt] OR "Case Reports" [pt]) EMBASE Search Completed Nov 14, results ('induced hypothermia'/exp OR "targeted temperature management":ab,ti OR "therapeutic hypothermia":ab,ti OR "hypothermia therapy":ab,ti OR ((cool*:ab,ti OR cold:ab,ti) AND ('brain injury'/exp OR 'neuroprotection'/exp OR neuroprotection:ab,ti OR 'hypoxic ischemic encephalopathy'/exp OR hypoxic-ischemic encephalopathy :ab,ti))) AND ('heart arrest'/exp OR "cardiac arrest":ab,ti OR "cardiac arrests":ab,ti OR "cardiovascular arrest":ab,ti OR "cardiovascular arrests":ab,ti OR "heart arrest":ab,ti OR "heart arrests":ab,ti OR "asystole":ab,ti OR "pulseless electrical activity":ab,ti OR "cardiopulmonary arrest":ab,ti OR "cardiopulmonary arrests":ab,ti OR 'resuscitation'/exp OR "Advanced Cardiac Life Support":ab,ti OR "ACLS":ab,ti OR 'heart ventricle fibrillation'/exp OR "Ventricular Fibrillation":ab,ti OR "cardiopulmonary resuscitation":ab,ti OR CPR:ab,ti OR 'heart stimulation'/exp) AND (clinical exam*:ab,ti OR 'physical examination'/exp OR 'electroencephalography'/exp OR EEG OR 'evoked somatosensory response'/exp OR "somatosensory evoked potential":ab,ti OR somatosensory evoked potentials":ab,ti OR 'cardiac gated imaging'/exp OR 'cardiac imaging'/exp OR cardiac endoscopy :ab,ti OR cardioscopy:ab,ti OR 'scintiscanning'/exp OR radionuclide imaging :ab,ti OR 'nuclear magnetic resonance imaging'/exp OR Magnetic Resonance Imaging :ab,ti OR MRI:ab,ti OR tomography:ab,ti OR 'cardiography'/exp OR 'angiocardiography'/exp OR 'echography'/exp OR ultrasonography:ab,ti OR Angiocardiography:ab,ti OR Coronary Angiography :ab,ti OR 'echocardiography'/exp OR Echocardiography:ab,ti OR 'myocardial perfusion imaging'/exp OR Myocardial Perfusion Imaging :ab,ti OR 'heart ventriculography'/exp OR Ventriculography:ab,ti OR "blood marker":ab,ti OR blood markers :ab,ti OR 'protein S 100'/exp OR "S100 Proteins":ab,ti OR S-100B:ab,ti OR 'guanine nucleotide binding protein beta subunit'/exp OR "S-100 calcium-binding protein beta subunit":ab,ti OR 'neuron specific enolase'/exp OR neuron specific enolase :ab,ti OR 'enolase'/exp OR "Phosphopyruvate Hydratase":ab,ti OR 'biological marker'/exp OR biological marker :ab,ti OR biological markers :ab,ti OR biomarker*:ab,ti) AND (adult*:ab,ti OR 'adult'/exp OR 'aged'/exp OR 'middle aged'/exp) AND ('prognosis'/de OR prognos*:ab,ti OR Predict* OR 'predictive value'/exp OR 'sensitivity and specificity'/exp) NOT ('animal'/exp NOT 'human'/exp) NOT ([editorial]/lim OR [letter]/lim OR 'case report'/de) AND [embase]/lim Cochrane Search Completed Nov 14, results ([mh "Hypothermia, Induced"] OR "targeted temperature management":ab,ti OR "therapeutic hypothermia":ab,ti OR "hypothermia therapy":ab,ti OR ((cool*:ab,ti OR cold:ab,ti) AND ([mh "Brain Injuries/prevention and control"] OR neuroprotection:ab,ti OR [mh "Hypoxia-Ischemia, Brain/prevention and control"] OR hypoxicischemic encephalopathy :ab,ti))) AND ([mh "Heart Arrest"] OR "cardiac arrest":ab,ti OR "cardiac arrests":ab,ti OR "cardiovascular arrest":ab,ti OR "cardiovascular arrests":ab,ti OR "heart arrest":ab,ti OR "heart arrests":ab,ti OR "asystole":ab,ti OR "pulseless electrical activity":ab,ti OR "cardiopulmonary arrest":ab,ti OR "cardiopulmonary arrests":ab,ti OR [mh "Advanced Cardiac Life Support"] OR "Advanced Cardiac Life Support":ab,ti OR "ACLS":ab,ti OR [mh "Ventricular Fibrillation"] OR [mh "cardiopulmonary resuscitation"] OR "cardiopulmonary resuscitation":ab,ti OR CPR:ab,ti OR [mh "Heart Massage"]) AND (clinical exam*:ab,ti OR [mh "Physical Examination"] OR [mh "Electroencephalography"] OR EEG:ab,ti OR [mh "Evoked Potentials, Somatosensory"] OR "somatosensory evoked potential":ab,ti OR somatosensory evoked potentials":ab,ti OR [mh Cardiac Imaging Techniques"] OR cardiac endoscopy :ab,ti OR cardioscopy:ab,ti OR radionuclide imaging :ab,ti OR Magnetic Resonance Imaging :ab,ti OR MRI:ab,ti OR tomography:ab,ti OR ultrasonography:ab,ti OR Angiocardiography:ab,ti OR Coronary Angiography :ab,ti OR Echocardiography:ab,ti OR Myocardial Perfusion Imaging :ab,ti OR Ventriculography:ab,ti OR "blood marker":ab,ti OR blood markers :ab,ti OR [mh "S100 Proteins"] OR S-100B:ab,ti OR "S-100 calcium-binding protein beta subunit":ab,ti OR neuron specific enolase :ab,ti OR [mh "Phosphopyruvate Hydratase"] OR [mh "Biological Markers"] OR biomarker*:ab,ti) AND (adult*:ab,ti OR [mh "Adult"] OR [mh "Aged"] OR [mh "Aged, 80 and over"] OR [mh "Frail Elderly"] OR [mh "Middle Aged"] OR [mh "Young Adult"]) AND ([mh "Prognosis"] OR prognos*:ab,ti OR Predict*:ab,ti OR [mh "Predictive Value of Tests"] OR [mh Sensitivity and Specificity ]) NOT ([mh "animals"] NOT ([mh animals ] AND [mh "humans"]))

3 The reference lists of the following recent reviews were also screened: Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. Kamps MJ, Horn J, Oddo M, Fugate JE, Storm C, Cronberg T, Wijman CA, Wu O, Binnekade JM, Hoedemaekers CW. Intensive Care Med Oct;39(10): 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. Sandroni C, Cavallaro F, Callaway CW, Sanna T, D'Arrigo S, Kuiper M, Della Marca G, Nolan JP. Resuscitation Oct;84(10): Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 2: Patients treated with therapeutic hypothermia. Sandroni C, Cavallaro F, Callaway CW, D'Arrigo S, Sanna T, Kuiper MA, Biancone M, Della Marca G, Farcomeni A, Nolan JP. Resuscitation Oct;84(10): Predicting Neurologic Outcome After Targeted Temperature Management for Cardiac Arrest: Systematic Review and Meta-Analysis. Golan E, Barrett K, Alali AS, Duggal A, Jichici D, Pinto R, Morrison L, Scales DC. Crit Care Med Aug;42(8): Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. Sandroni C, Cariou A, Cavallaro F, Cronberg T, Friberg H, Hoedemaekers C, Horn J, Nolan JP, Rossetti AO, Soar J. Resuscitation Dec;85(12):

4 Flow-chart of included studies PubMed: 141 studies EMBASE: 113 studies Cochrane: 5 studies 52 additional studies identified through forward search 311 studies assessed for eligibility 267 studies excluded 44 studies included in final analysis

5 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 Al Thenayan N/A 37 N/A N/A N/A ( 1 ) PLR, CR, MR 4-5 vs days Bouwes 2012a 2 Mixed [±13] Myoclonus 3-5 vs days Okada OHCA PLR, MR 3-5 vs. 1-2 Discharge Schefold Mixed (47-69) GCS 3-5 vs. 1-2 Discharge Electrophysiology Bouwes N/A 77 71, (50-77) N vs days Cloostermans Mixed [± 11.5] EEG, SSEP 3-5 vs days Kawai Mixed [±17.5] EEG 4-5 vs days Leary Mixed [±16] BIS 3-5 vs 1-2 Discharge Leithner N/A SSEP 4-5 vs 1-3 Discharge Mani N/A (IQR 45-65) EEG 3-5 vs 1-2 Discharge Rittenberger Mixed [±15] EEG 3-5 vs 1-2 Discharge Rundgren Mixed (50-74) EEG 4-5 vs days Sakurai OHCA (22-68) BAEPs 3-5 vs days Seder N/A (48-72) BIS 3-5 vs 1-2 Discharge Stammet Mixed [±17] BIS 3-5 vs days Tiainen OHCA (23-75) N vs days Zanatta N/A [±13] SSEP, MLCEP 3-5 vs days

6 Biomarkers Huntgeburth OHCA (26-86) NSE ( 2 ) 4-5 vs days Mortberg Mixed (22-84) S-100, NSE 3-5 vs days Oksanen OHCA (53-71) NSE 3-5 vs days Steffen Mixed (52-70) NSE 3-5 vs. 1-2 Discharge Storm Mixed (51-71) NSE 3-5 vs. 1-2 Discharge Tiainen OHCA (23-75) NSE, S-100B 3-5 vs days Zellner Mixed [±14] NSE, S-100B 3-5 vs days Neuroimaging Inamasu OHCA [±15] CT 3-5 vs days Kim J OHCA (42-72) MRI 3-5 vs days Kim S OHCA [± 16.8] CT 3-5 vs. 1-2 Discharge Mlynash Mixed 21 N/A N/A 57 [±17] MRI 4-5 vs days Wijman Mixed 22 N/A N/A 59 [±17] MRI 4-5 vs days Multimodal prognostication Bisschops N/A ( ) PLR, CR, MR, myoclonus, SSEP 3-5 vs days Bouwes 2012b 31 Mixed [±13.4] PLR, CR, MR, NSE, SSEP 3-5 vs days Choi OHCA [±13.3] SSEP, MRI 3-5 vs. 1-2 Discharge Crepeau OHCA N/A 61 (33-81) Myoclonus, EEG 3-5 vs. 1-2 Discharge Cronberg Mixed (51-76) PLR, CR, NSE, SSEP, EEG, MRI 3-5 vs days

7 Fugate Mixed ±[14] PLR, CR, MR, Myoclonus, EEG( 3 ), SSEP, NSE, CT 3-5 vs. 1-2 Discharge Kim J OHCA [±17.6] NSE, MRI 3-5 vs days Lee, Mixed (IQR 45-69) CT, NSE 3-5 vs. 1-2 Discharge Legriel Mixed (54-75) Myoclonus, EEG 3-5 vs days Oddo OHCA [±12.5] Rossetti OHCA (17-85) Rossetti N/A [±12.2] Samaniego Mixed (19-84) BR, Myoclonus, EEG, SSEP, NSE BR, MR, myoclonus, EEG, SSEP BR, MR, myoclonus, EEG, SSEP, NSE PLR, CR, MR, myoclonus, NSE, SSEP 3-5 vs days 3-5 vs days 3-5 vs days 4-5 vs days Stammet Mixed (29-83) BIS, S-100B 3-5 vs days Wennervirta OHCA (24-77) NSE, EEG 3-5 vs days Abbreviations BAEPs = Brain stem Auditory Evoked Potentials; BIS = Bispectral Index BR = Brain Reflexes; CPC = Cerebral Performance Category; CR = Corneal Reflex; EEG = electroencephalogram; GCS = Glasgow Coma Scale; IHCA/OHCA = In-Hospital/Out-of-Hospital Cardiac Arrest; MLCEP = Middle-Latency Cortical Somatosensory Evoked Potentials; MR = Motor Response; MRI = Magnetic Resonance Imaging; N/A = Not Available; NSE = Neuron-Specific Enolase; PLR = Pupillary Light Response; SSEP = Short-latency Somatosensory Evoked Potentials. VF/VT = Ventricular fibrillation/ventricular tachycardia. Notes ( 1 ) All patients were adults (>17 years) ( 2 ) Clinical examination, SSEP and BAEPs were also studied in a subset of 40 patients with persisting coma. ( 3 ) EEG studied only in a small subset of 21 patients.

8 Table 2 - Assessment of bias in included studies Author, year Index Blinding (treating team) Blinding (index or outcome evaluators) Excludes sedation or paralysis Best CPC reported Excludes previous neurological diseases Interobserver agreement assessed Length of follow-up Index test used for WLST Overall Al Thenayan, 2008 PLR, CR, MR no No No no no No 90 days Not reported Very serious Bisschops 2011 PLR+CR+MR, myoclonus, EEG no No Yes no no No 90 days Yes (BR) Very serious Bisschops 2011 SSEP no No N/A no no No 90 days Yes Very serious Bouwes 2009 SSEP (TH) limited Yes N/A no yes No 30 days No Serious Bouwes 2012 PLR, CR, M1-2, myoclonus no No uncertain no yes No 180 days Uncertain Serious Bouwes 2012 SSEP (TH) limited No N/A no no No 180 days No Serious Bouwes 2012 SSEP (after RW) no No N/A no no No 180 days Yes Very serious Bouwes, 2012 NSE yes No N/A no no N/A 180 days Uncertain Serious Choi 2012 SSSEP, CT, MRI no No N/A no no No Discharge Not reported Very serious Choi, 2012 PLR no No No no no No Discharge Not reported Very serious Cloostermans 2012 ceeg no Yes No no yes No 180 days No Serious Cloostermans 2012 SSEP no No N/A no yes No 180 days Yes Very serious Crepeau 2013 ceeg, myoclonus no Yes No no no No Discharge Yes Very serious Cronberg 2011 SSEP no No N/A yes no Yes 180 days Yes Very serious Cronberg 2011 EEG no Yes Yes yes no No 180 days No Serious Cronberg, 2011 PLR, CR, MR, myoclonus no No Yes yes no No 180 days Yes (PLR, MR) Very serious Cronberg, 2011 NSE no No N/A yes no N/A 180 days No Serious Cronberg, 2011 MRI DWI no Yes N/A yes no No 180 days No Serious

9 Fugate 2010 PLR, CR, MR, myoclonus no No No no no No Discharge Yes Very serious Fugate 2010 NSE, CT no No N/A no no No Discharge No Serious Huntgeburth 2014 NSE no No N/A no no No 60 days Not reported Very serious Inamasu 2010 CT no Yes N/A no no Yes 180 days Not reported Very serious Kawai 2011 EEG no No No no no No 180 days Not reported Very serious Kim, 2012 NSE, MRI no No N/A no no no (MRI) 180 days Not reported Very serious N/A (NSE) Kim 2013 MRI no No N/A no no No 180 days Uncertain Serious Kim S 2013 CT no Yes N/A no no No Discharge Not reported Very serious Leary 2010 BIS no No No no no N/A Discharge Not reported Very serious Lee 2013 NSE, CT no Yes N/A No No No Discharge No withdrawal Serious Legriel 2009 EEG no Yes No no no No Discharge Not reported Very serious Legriel 2013 Myoclonus no No No no no No 1 year Uncertain Serious Legriel 2013 EEG no No No no no No 1 year No Serious Leithner 2010 SSEP no No N/A no no No Discharge Not reported Very serious Mani 2012 EEG no Yes No no no Yes Discharge Uncertain Serious Mlynash, 2010 MRI no Yes N/A yes no Yes 180 days Not reported Very serious Mortberg, 2011 NSE, S-100B no No N/A no no N/A 180 days Not reported Very serious Oddo 2014 BR, Myoclonus no No Yes no no No 90 days Yes Very serious Oddo 2014 EEG no No No no no No 90 days Yes Very serious Oddo 2014 SSEP no No N/A no no Oddo 2014 NSE no No N/A no no no (SSSEP); N/A (NSE) no (SSEP); N/A (NSE) 90 days Yes Very serious 90 days No Serious

10 Okada 2012 PLR, MR no No No no yes No Discharge Not reported Very serious Oksanen, 2009 NSE no No No no no N/A 180 days No Serious Rittenberger 2012 EEG, myoclonus no No No no no No Discharge Not reported Very serious Rossetti 2010 BR, MR, myoclonus, EEG no No Yes no no No 180 days Yes (BR, EEG) Very serious Rossetti 2010 SSEP no No N/A no no No 180 days Yes Very serious Rossetti 2012 BR, MR, myoclonus, EEG no No Yes no no No 90 days Yes (BR, myoclonus, EEG) Very serious Rossetti, 2012 SSEP, NSE yes No N/A no no no (SSEP); N/A (NSE) 90 days Yes (SSEP) Very serious Rundgren 2010 EEG no Yes No no no No 180 days No Serious Rundgren, 2009 NSE, S-100B no No N/A yes yes N/A 180 days No Serious Sakurai 2006 BAEP wave V absent no No N/A no yes No 60 days Not reported Very serious Samaniego 2011 BR, MR, myoclonus no No No no no No 90 days Yes Very serious Samaniego, 2011 SSEP no No N/A no no N/A 90 days Yes Very serious Samaniego, 2011 NSE no No N/A no no N/A 90 days No Serious Schefold 2009 GCS 4 no No No no no No Discharge Yes Very serious Seder 2010 BIS no No N/A no no N/A Discharge Not reported Very serious Stammet 2009 BIS limited Yes N/A yes no N/A 180 days No Serious Stammet 2013 BIS no No Yes no no N/A 180 days Not reported Very serious Stammet 2013 S-100B no No N/A no no N/A 180 days Not reported Very serious Steffen, 2010 NSE no No N/A no no N/A Discharge Yes Very serious Storm, 2012 NSE no No N/A no no N/A Discharge Yes Very serious

11 Tiainen 2005 SSEP limited No N/A no yes No 180 days No Serious Tiainen, 2003 NSE, S-100B no Yes N/A no no N/A 180 days Not reported Very serious Wennervirta 2009 EEG no Yes No no yes No 180 days Not reported Very serious Wennervirta, 2009 NSE, S-100B no No N/A no yes N/A 180 days Not reported Very serious Wijman, 2009 MRI (ADC) limited Yes N/A yes no No 180 days No Serious Zanatta 2012 SSEP, MLCEP no No N/A no no No 90 days Not reported Very serious Zellner 2013 NSE, S-100B No No No No No No 180 days Not reported Very serious Abbreviations ADC = Absolute Diffusion Coefficient; BAEPs = Brain stem Auditory Evoked Potentials; BIS = Bispectral Index BR = Brain Reflexes; ceeg = continuous EEG; CR = Corneal Reflex; CT = Computed Tomography; DWI = Diffusion Weighted Imaging; EEG = electroencephalogram; GCS = Glasgow Coma Scale; MLCEP = Middle-Latency Cortical Somatosensory Evoked Potentials; MR = Motor Response; MRI = Magnetic Resonance Imaging; N/A = Not Applicable; NSE = Neuron-Specific Enolase; PLR = Pupillary Light Response; SSEPs = Short-latency Somatosensory Evoked Potentials; WLST = withdrawal of life-sustaining treatment.. Tables 3 a-d Evidence Profiles See attached files.

12 Draft Consensus on Science with Treatment Recommendations Please note «Poor outcome» is intended as Death, Vegetative State or Severe Cerebral Disability (CPC 3 to 5), unless otherwise specified Timing is intended as time from recovery of spontaneous circulation (ROSC) unless otherwise specified Sensitivity and false positive rate (FPR) are reported as a percentage. Values in brackets are 95% confidence intervals [95%CIs] The term Targeted temperature management can be considered interchangeable with therapeutic hypothermia and it refers to achieving a core body temperature of either 33 C or 36 C. Clinical examination (Table 3a) For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified four studies on corneal reflex, pupillary reflex, motor response, Glasgow Coma Score, or myoclonus (295 patients, very low quality of evidence) (Crepeau 2013, Fugate 2010, Okada 2012, Schefold 2009). For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified five studies on corneal reflex, pupillary reflex, motor response, brainstem reflexes, or myoclonus (388 patients, very low quality of evidence) (Al Thenayan 2008, Bisschops 2011, Oddo 2014, Rossetti 2012, Samaniego 2011). For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified four studies on corneal reflex, pupillary reflex, motor response, brainstem reflexes, or myoclonus (642 patients, low or very low quality of evidence) (Bouwes 2012a, Cronberg 2011, Rossetti 2010, Legriel 2013). We synthesized these findings to estimate the performance of each individual predictor. Corneal reflex In patients who are comatose after resuscitation from cardiac arrest and are treated with targeted temperature management, bilaterally absent corneal reflexes at h from ROSC predicted poor outcome with 2[0-7]% FPR and 25[18-32]% sensitivity (4 studies, 301 pts; quality of evidence very low). Pupillary reflex Bilaterally absent pupillary light reflexes (PLR) on hospital admission predicted poor outcome with 32 [19-48]% FPR and 86[71-95]% sensitivity (2 studies, 86 pts; QOE very low). Bilaterally absent PLR at h from ROSC predicted poor outcome with 0[0-3]% FPR and 19[14-26]% sensitivity (5 studies, 383 pts; QOE low).

13 Motor response to pain On hospital admission, bilaterally absent or extensor motor responses, corresponding to a motor score 1 or 2 (M1-2) of the Glasgow Coma Scale (GCS), predicted a poor outcome with 53 [36-68]% FPR and 92[75-99]% sensitivity (1 study, 66 pts; QOE very low). At h from ROSC, a M1-2 predicted a poor outcome with 70 [65-74]% sensitivity and 10 [7-15]% FPR (6 studies, 635 pts; QOE very low). One study 42 indicated that both absent corneal reflexes and motor response to pain at 72h predicted poor outcome (CPC = 4-5) more accurately in patients who did not receive any sedative drugs 12 h prior of neurological assessment than in those who did. Combination of clinical signs Bilateral absence of one or more brainstem reflexes (pupillary, corneal, or oculocephalic) at 36-72h from arrest predicted a poor outcome with 8 [4-14]% FPR and 56 [48-63]% sensitivity (3 studies, 304 pts; QOE very low). In one study (103 patients; quality of evidence very low), the combined absence of corneal reflex, PLR and M1-2 at 72h from ROSC predicted poor outcome with 0 [0-8]% FPR and 15[7-26]% sensitivity. In that study, the index test was used as a criterion for WLST. A Glasgow Coma Score equal or less than 4 at 96h from ROSC predicted poor outcome with 5 [1-15]% FPR and 46 [28-66]% sensitivity (1 study, 72 pts; QOE very low). Myoclonus and status myoclonus Presence of myoclonus within 72h from ROSC predicted a poor outcome with 5[3-8]% FPR and 39[35-44]% sensitivity (6 studies, 845 pts; QOE very low). In one study (103 patients; quality of evidence very low), presence of myoclonus within 7 days after ROSC predicted poor outcome with 11[3-26]% FPR and 54 [41-66]% sensitivity. In 3 studies (215 patients; QOE low) presence of status myoclonus (defined as a continuous prolonged and generalised myoclonus) within 72 from ROSC predicted poor outcome with 0[0-4]% FPR and 16 [11-22]% sensitivity. However, reports of good neurological recovery despite an early-onset, prolonged and generalised myoclonus have been published 38, In some of these cases 38, 45, myoclonus persisted after awakening and evolved into a chronic action myoclonus (Lance-Adams syndrome). No study on clinical examination reported blinding of the treating team to the results of the index test (see Table 2). DRAFT CONSENSUS ON SCIENCE In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management, bilaterally absent pupillary reflexes to light at 72h or later from ROSC predict a poor neurological outcome with very high precision (FPR 0[0-3]%). Bilaterally absent corneal reflexes at 72h or later from ROSC is also an accurate

14 predictor of poor outcome, but it is less specific (FPR 2[0-7]%). Both these predictors have a low sensitivity ( 25%). Bilaterally absent or extensor motor response to pain at 36h or later from ROSC has a relatively high sensitivity for prediction of poor outcome (70[65-74]%). However, its false positive rate is also high (10[7-15]%). There are little data at present on combination of clinical signs for prediction of poor outcome. Presence of myoclonus within 72h from cardiac arrest is inconsistently associated with poor outcome (FPR 6%; 95%CIs 3-9). A prolonged, continuous and generalised myoclonus (status myoclonus) within 72h from cardiac arrest predicts poor outcome with high precision (FPR 0 [0-4[%) but low sensitivity (16%; 95%CIs 11-22). Rare cases of good outcome in patients with an early-onset status myoclonus have been reported. Predictors based on clinical examination, especially corneal reflex and motor response to pain, may be affected by sedation or paralysis. Blinding of the treating team is very difficult to achieve for predictors based on clinical examination, which implies a risk of self-fulfilling prophecy. DRAFT TREATMENT RECOMMENDATIONS In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management, we recommend using bilaterally absent pupillary light reflexes or the combined absence of both pupillary and corneal reflexes at 72 h from ROSC to predict poor outcome. We suggest against using an absent or extensor motor response to pain (M 2) alone to predict poor outcome, given its high false positive rate. However, due to its high sensitivity, this sign may be used to identify the population with poor neurological status needing prognostication or to predict poor outcome in combination with other more robust predictors. We suggest using the presence of a status myoclonus within 72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome. We suggest prolonging the observation of clinical signs when interference from residual sedation or paralysis is suspected, so that the possibility of obtaining false positive results is minimized. We recommend that the earliest time to prognosticate a poor neurological outcome is 72hrs after ROSC, and should be extended longer if the residual effect of sedation and/or paralysis confounds the clinical examination. KNOWLEDGE GAPS Prospective studies are needed to investigate the pharmacokinetics of sedative drugs and neuromuscular blocking drugs in post-cardiac arrest patients, especially those treated with controlled temperature. Studies are needed to investigate the reproducibility of clinical signs used to predict outcome in comatose post-arrest patients.

15 There is no universally accepted definition of status myoclonus. A recently proposed definition 48 suggests using the term status myoclonus to indicate a continuous and generalised myoclonus persisting for 30 minutes in comatose survivors of cardiac arrest. Electrophysiology (Table 3b) For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified eight studies on short-latency somatosensory evoked potentials (SSEP), EEG or BIS (571 patients, very low quality of evidence) (Leary 2010, Leithner 2010, Mani 2012, Rittenberger 2012, Seder 2010, Choi 2012, Crepeau 2013, Fugate 2010). For the critical outcome of survival with unfavorable neurological status or death at 30 days, we identified one study on SSEP (77 patients, very low quality of evidence) (Bouwes 2009). For the critical outcome of survival with unfavorable neurological status or death at 60 days we identified one study on BAEPs (26 patients, very low quality of evidence) (Sakurai 2006). For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified five studies on SSEP or EEG (362 patients, low or very low quality of evidence) (Zanatta 2012, Bisschops 2011, Oddo 2014, Rossetti 2012, Samaniego 2011). For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified ten studies on SSEP, EEG or BIS (921patients, moderate, low, or very low quality of evidence) (Cloostermans 2012, Kawai 2011, Rundgren 2011, Stammet 2009, Tiainen 2005, Bouwes 2012b, Cronberg 2011, Rossetti 2010, Stammet 2013, Wennervirta 2009). For the critical outcome of survival with unfavorable neurological status or death at 1 year, we identified one study on EEG (106 patients very low quality of evidence) (Legriel 2013). We synthesized these findings to estimate the performance of each individual predictor. Short-latency somatosensory evoked potentials (SSEPs) In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management, a bilaterally absent N20 SSEP wave during TTM predicted poor outcome with 2[0-4]% FPR and 28 [22-34]% sensitivity (4 studies, 421 pts; quality of evidence very low). A bilaterally absent N20 SSEP wave after rewarming (at 2-5 days after ROSC) predicted poor outcome with 1 [0-3]% FPR (9 studies, 629 pts; quality of evidence low) and 45 [41-50%] sensitivity. SSEP recording is prone to electrical interference. In one study 31, three patients with a bilaterally absent N20 during TTM rapidly recovered consciousness after rewarming and ultimately had a good outcome. In a post-hoc assessment, two experienced neurophysiologists reviewed blindly the original tracings and concluded that the SSEP recordings were undeterminable because of excessive noise. In most prognostication studies, absence of the N20 wave after rewarming has been used alone or in combination as a criterion for deciding on WLST, with a consequent risk of self-fulfilling prophecy.

16 Electroencephalogram (EEG) Absence of background reactivity Absence of background reactivity on the EEG recorded during TTM predicted poor outcome with 2[1-7]% FPR and 63[54-72]% sensitivity (3 studies, 249 pts; quality of evidence very low). Absence of background reactivity on the EEG recorded after rewarming predicted poor outcome with 0[0-3]% FPR and 62[53-70]% sensitivity (3 studies, 223 pts; quality of evidence low). Among four prognostication studies on absent EEG reactivity after cardiac arrest included in this evidence review, three were made by the same group of investigators. Burst-suppression Presence of burst-suppression on initial EEG immediately after induction of TTM predicted poor outcome with 0[0-5]% FPR and 31[19-44]% sensitivity (2 studies, 119 pts; quality of evidence low). Presence of burst-suppression on EEG during TTM predicted poor outcome with 6[1-15]% FPR and 70[56-82]% sensitivity (2 studies, 226 pts; quality of evidence very low). In one study (95 pts) presence of burst-suppression on EEG after rewarming predicted poor outcome with 0[0-5]% FPR and 18[8-34]% sensitivity (quality of evidence very low). Definitions of burst-suppression were inconsistent among studies. Epileptiform activity Presence of epileptiform discharges on EEG during TTM (one study, 38 pts) or after rewarming (one study, 138 pts) predicted poor outcome with 8 [0-38] and 12 [3-31] FPR, respectively. Quality of evidence was very low in both studies. Presence of electrographic seizures with nonreactive EEG background during TTM (one study, 61 pts), electrographic seizures during TTM (one study, 38 pts), or electrographic seizures both during TTM and after rewarming (one study, 54 pts) predicted poor outcome with 0% FPR (95%CIs 0-10, 0-22 and 0-9 respectively). Quality of evidence was very low for all studies. Presence of status epilepticus (SE) during TTM (one study, 51 pts) or after rewarming (one study, 30 pts) predicted poor outcome with 0% FPR (95%CIs 0-22 and 0-13 respectively). However, in another study the presence of a SE within 72h from ROSC was associated with good outcome in two cases (FPR 6[1-20]%). In both those patients, SE was first recorded at 40 h from ROSC (shortly after rewarming) and the EEG was reactive. The quality of evidence was very low for all these studies. In one study (95 pts) presence of electrographic status epilepticus (ESE) on a burstsuppression pattern was associated with an invariably poor outcome (CPC 4-5; FPR 0[0-5]%), while an ESE on a continuous background was still compatible with recovery of consciousness (FPR 4[0-12]; quality of evidence very low).

17 Definitions of epileptiform activity, electrographic seizures, and status epilepticus were inconsistent among studies. Flat or low-amplitude EEG, BIS In one study (46 pts), a flat or low-amplitude (<20 µv) EEG during TTM at 24h from cardiac arrest predicted poor outcome with 0% [0-11] FPR and 40 [19-64] sensitivity. In another study (95 pts), however, a flat (<10 µv) EEG recorded during TTM at a median of 8h from cardiac arrest or immediately after rewarming was followed by recovery of consciousness (FPR 46% [32-59] and 5% [1-15] respectively). Quality of evidence was very low for both studies. In one study (45 pts) a lowest bispectral index (BIS) value of 0 during TTM, corresponding to a flat or low-amplitude EEG, predicted a poor outcome with 0 [0-6]% FPR and 50[31-69]% sensitivity. However, in another study (75 pts), a lowest BIS value of 0 during TTM predicted poor outcome with 10[3-23]% FPR. The quality of evidence was very low for both studies. EEG grades In one study (54 pts; quality of evidence very low) a Grade 3 EEG, corresponding to one pattern among unreactive, burst-suppression, focal or generalised seizures, generalised periodic epileptiform discharged (GPED), status epilepticus, low amplitude ( 10 µv), or alpha-theta coma, predicted poor outcome with 6[1-20]% FPR during TH and 0[0-9]% FPR after rewarming. Other tests In one study (26 patients; quality of evidence very low) absence of brain-stem auditory evoked potentials (BAEP) wave V during induction of TTM predicted poor outcome with 0[0-31]% FPR and 56[31-78]% sensitivity. In one pilot study (17 patients; quality of evidence very low) the bilateral absence of painrelated middle-latency cortical evoked potentials (MLCEP) predicted poor outcome with 0[0-53]% FPR and 85[55-98]% sensitivity. DRAFT CONSENSUS ON SCIENCE In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management a bilaterally absent N20 wave accurately predicts a poor neurological outcome after rewarming (at 2-5 days from ROSC) (FPR 1[0-3]%) while prediction during TTM is less reliable (FPR 2[0-4]%). Absence of EEG background reactivity during TTM is inconsistently associated with a poor neurological outcome (FPR 2 [1-7]%) while after rewarming at 72 h from ROSC it predicts a poor outcome with 0[0-3]% FPR. Limitations of EEG reactivity include being operatordependent and non-quantitative, and lacking standardization. Presence of epileptiform discharges on EEG, both during TH or after rewarming is inconsistently associated with poor neurological outcome. Presence of electrographic seizures or status epilepticus, either during TTM or after rewarming is almost invariably

18 associated with poor outcome. The definition of epileptiform activity and status epilepticus is inconsistent among studies. Limited evidence shows that prognosis is worse when status epilepticus is associated to a non-continuous background or absence of reactivity. A flat or low-voltage EEG was inconsistently associated with poor outcome. Timing and definitions of low voltage were inconsistent among studies. A lowest BIS value =0 during TTM, corresponding to a flat or very low voltage EEG during TH is inconsistently associated with poor outcome (FPR from 0% to 10%). BIS is affected by interference from muscular artefacts, which restricts its use in patients who are sedated and paralysed during TTM treatment. The amplitude of the EEG signal may be affected 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 filters adopted. 49 Use of EEG grading, brainstem auditory evoked potentials and pain-related somatosensory evoked potentials has been documented only in single studies and their predictive value needs confirmation from other studies. DRAFT TREATMENT RECOMMENDATIONS In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management we recommend using bilateral absence of N20 SSEP wave at 72h after ROSC to predict poor outcome. SSEP recording requires appropriate skills and experience, and utmost care should be taken to avoid electrical interference from muscle artefacts or from the ICU environment. In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management we suggest using EEG-based predictors such as absence of EEG reactivity to external stimuli, presence of burst-suppression after rewarming or status epilepticus 72h after ROSC in combination with other predictors for prognosticating a poor neurological outcome. We suggest against using BIS to predict poor outcome during TTM in patients who are comatose after resuscitation from cardiac arrest and are treated with targeted temperature management. KNOWLEDGE GAPS In most prognostication studies, results of SSEPs were not blinded and were used as a criterion for limitation or suspension of life-sustaining treatment. Blinded studies on SSEPs are needed to assess the relevance of self-fulfilling prophecies for SSEPs. Definitions of EEG-based predictors are inconsistent among prognostication studies. Future studies should comply with recently recommended definitions 50. The stimulation modalities for eliciting EEG reactivity have not been standardised.

19 Biomarkers (Table 3c) For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified four studies on NSE (354 patients, moderate, low or very low quality of evidence) (Steffen, 2010, Storm 2012, Fugate 2010, Lee 2013). For the critical outcome of survival with unfavorable neurological status or death at 60 days, we identified one study on NSE (73 patients, very low quality of evidence) (Huntgeburth, 2014). For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified three studies on NSE (248 patients, very low quality of evidence) (Oddo, 2014, Rossetti 2012 Samaniego 2011). For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified eight studies on NSE or S-100B (810 patients, moderate, low, or very low quality of evidence) (Bouwes 2012b, Cronberg 2011, Mortberg 2011, Oksanen 2009, Stammet 2013, Tiainen 2003, Wennervirta 2009, Zellner 2013). We synthesized these findings to estimate the performance of each individual predictor. Neuron-specific enolase (NSE) In comatose resuscitated patients who are treated with TTM, the threshold for prediction of poor outcome with 0% FPR varied between 49.6 mcg L -1 and mcg L -1 at 24 h from ROSC (4 studies, 309 pts; quality of evidence from moderate to very low), between 25 mcg L -1 and mcg L -1 at 48 h (7 studies, 743 pts; quality of evidence from moderate to very low), and between 57.2 mcg L -1 and 78.9 mcg L -1 at 72 h (3 studies,, 193 pts; quality of evidence low or very low). Limited evidence 18, 20, 51 suggests that not only the NSE absolute concentrations but also their trends over time may have predictive value. Limited evidence 18, 20, 37 suggests that the discriminative value of NSE levels at 48h 72h is higher than at 24h. S-100B For S-100B, the documented thresholds for a 0% FPR were 0.18 and 0.21 mcg L -1 at 24 h after ROSC (2 studies, total 66 patients; quality of evidence very low) and 0.3 mcg L -1 at 48 h (one study, 75 patients; quality of evidence very low). Major reasons for the observed variability in biomarker thresholds include the use of heterogeneous measurement techniques 52-54, the presence of extra-neuronal sources of biomarkers (haemolysis and neuroendocrine tumors for NSE 55, muscle and adipose tissue breakdown for S-100B 56 ), and the incomplete knowledge of the kinetics of their blood concentrations in the first few days after ROSC. DRAFT CONSENSUS ON SCIENCE In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management, high and increasing concentrations of biomarkers are associated with poor outcome. However, the biomarkers thresholds which predict a poor neurological outcome with 0% FPR vary between studies.

20 Advantages of biomarkers over other predictors such as EEG and clinical examination include quantitative results and likely independence from the effects of sedatives. Moreover, in most prognostication studies biomarkers have not been used as a criterion for WLST (see Table 2). S-100B is less well documented than NSE. DRAFT TREATMENT RECOMMENDATIONS In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management we suggest using high serum values of NSE at 48 h- 72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome. However, no threshold enabling prediction with zero FPR can be recommended. We also suggest using utmost care and preferably sampling at multiple time-points when assessing NSE, to avoid false positive results due to haemolysis. KNOWLEDGE GAPS There is a need for standardisation of the measuring techniques for NSE and S-100 in cardiac arrest patients. Little information is available on the kinetics of the blood concentrations of biomarkers in the first few days after cardiac arrest. Imaging (Table 3d) For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified three studies on CT (273 patients, low or very low quality of evidence) (Kim S 2013, Lee 2013, Fugate 2010). For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified six studies on CT or MRI (246 patients, very low quality of evidence) (Cronberg 2011, Inamasu 2010, Kim J 2012, Kim J 2013, Mlynash 2010, Wijman 2009). We synthesized these findings to estimate the performance of each individual predictor. CT The main CT finding of global anoxic-ischaemic cerebral insult following cardiac arrest is cerebral oedema 57, which appears as a reduction in the depth of cerebral sulci (sulcal effacement) and an attenuation of the grey matter/white matter (GM/ WM) interface, due to a decreased density of the GM. This attenuation has been quantitatively measured as the ratio (GWR) between the GM and the WM densities. In four studies (total 276 patients; quality of evidence low or very low) a reduced GWR at the level of the basal ganglia on brain CT performed within 2h from ROSC predicted an almost invariably poor outcome (FPR from 0% to 8%). Measurement techniques and thresholds for GWR varied among studies.

21 In one study (102 patients; quality of evidence low) a global cerebral oedema on brain CT at a median of 1 day after cardiac arrest predicted poor outcome with 0[0-5]% FPR. MRI The main MRI finding of anoxic-ischaemic cerebral injury is a hyperintensity in diffusion weighted imaging (DWI) sequences due to cytotoxic oedema. Presence of DWI abnormalities in cortex or basal ganglia (1 study, 21 patients; quality of evidence very low) or both (2 studies, 30 patients; quality of evidence very low) between 2 and 6 days from ROSC was associated with poor outcome (FPRs from 0% to 9%). Precision of prediction was very low, due to the small size of these studies. Post-ischaemic DWI abnormalities can be quantified using absolute diffusion coefficient (ADC). ADC values between 700 and 800 x 10-6 mm 2 sec -1 are considered to be normal 58. In one study (22 patients; quality of evidence very low) presence of more than 10% of brain volume with ADC < 650 x 10-6 mm 2 sec -1 predicted poor outcome with 0[0-28]% specificity. In another study, a low ADC at the level of putamen, thalamus or occipital cortex also predicted poor outcome with 0% FPR (95%CIs from 0-24 and 0-63). The ADC thresholds varied according to the brain area studied. All prognostication studies on imaging have a small sample size and in all of them imaging was performed at discretion of treating physician. DRAFT CONSENSUS ON SCIENCE In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management the presence of global cerebral oedema or a reduction of the grey/white matter interface measured as the GWR within 2 hours from ROSC predicted poor outcome with 0% FPR, but the GWR thresholds for 0% FPR varied among studies, according to the area studied and the measurement technique. In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management the presence of diffuse hypoxic-ischemic injury detected by DWI changes and quantified by ADC from 2 to 6 days from ROSC predicted poor outcome with 0% FPR. The ADC thresholds for 0% FPR varied among studies, according to the cerebral area studied and the measurement technique. All studies on prognostication after cardiac arrest using imaging have a small sample size with a consequent low precision, and are prone to selection bias, since the imaging studies were performed at discretion of treating physician, which may have caused a selection bias and overestimated their performance. Imaging studies depend partly on subjective human decision in identifying the region of interest to be studied and in the interpretation of results. DRAFT TREATMENT RECOMMENDATIONS In patients who are comatose after resuscitation from cardiac arrest and who are treated with targeted temperature management we suggest using the presence of a marked reduction of the GM/WM ratio on brain CT within 2 h after ROSC or the presence of

22 extensive reduction in diffusion on brain MRI at 2-6 days after ROSC in combination with other predictors for prognosticating a poor neurological outcome. We suggest using brain imaging studies for prognostication only in centres where specific experience is available. KNOWLEDGE GAPS Prospective studies in unselected patient populations are needed for evaluating the prognostic accuracy of imaging studies in comatose patients resuscitated from cardiac arrest. References 1. Al Thenayan ES, M.; Sharpe, M.; Norton, L.; Young, B. Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest. Neurology 2008; 71 (19): Bouwes AvP, D.; Koelman, J. H.; Kuiper, M. A.; Zandstra, D. F.; Weinstein, H. C.; Tromp, S. C.; Zandbergen, E. G.; Tijssen, M. A.; Horn, J. Acute posthypoxic myoclonus after cardiopulmonary resuscitation. BMC Neurol 2012; Okada KO, S.; Otani, N.; Sera, T.; Mochizuki, T.; Aoki, M.; Ishimatsu, S. Prediction protocol for neurological outcome for survivors of out-of-hospital cardiac arrest treated with targeted temperature management. Resuscitation 2012; 83 (6): Schefold JCS, C.; Kruger, A.; Ploner, C. J.; Hasper, D. The Glasgow Coma Score is a predictor of good outcome in cardiac arrest patients treated with therapeutic hypothermia. Resuscitation 2009; 80 (6): Bouwes A, Binnekade JM, Zandstra DF, et al. Somatosensory evoked potentials during mild hypothermia after cardiopulmonary resuscitation. Neurology 2009; 73 (18): Cloostermans MC, van Meulen FB, Eertman CJ, et al. Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: a prospective cohort study. Crit Care Med 2012; 40 (10): Kawai M, Thapalia U and Verma A. Outcome from therapeutic hypothermia and EEG. J Clin Neurophysiol 2011; 28 (5): Leary M, Fried DA, Gaieski DF, et al. Neurologic prognostication and bispectral index monitoring after resuscitation from cardiac arrest. Resuscitation 2010; 81 (9): Leithner C, Ploner CJ, Hasper D, et al. Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest? Neurology 2010; 74 (12): Mani R, Schmitt SE, Mazer M, et al. The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation 2012; 83 (7): Rittenberger JC, Popescu A, Brenner RP, et al. Frequency and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest subjects treated with hypothermia. Neurocrit Care 2012; 16 (1): Rundgren M, Westhall E, Cronberg T, et al. Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients. Crit Care Med 2010; 38 (9):

23 13. Sakurai A, Kinoshita K, Moriya T, et al. Reduced effectiveness of hypothermia in patients lacking the wave V in auditory brainstem responses immediately following resuscitation from cardiac arrest. Resuscitation 2006; 70 (1): Seder DB, Fraser GL, Robbins T, et al. The bispectral index and suppression ratio are very early predictors of neurological outcome during therapeutic hypothermia after cardiac arrest. Intensive Care Med 2010; 36 (2): Stammet P, Collignon O, Werer C, et al. Bispectral index to predict neurological outcome early after cardiac arrest. Resuscitation 2014; 85 (12): Tiainen M, Kovala TT, Takkunen OS, et al. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med 2005; 33 (8): Zanatta P, Messerotti Benvenuti S, Baldanzi F, et al. Pain-related middle-latency somatosensory evoked potentials in the prognosis of post anoxic coma: a preliminary report. Minerva Anestesiol 2012; 78 (7): Huntgeburth M, Adler C, Rosenkranz S, et al. Changes in neuron-specific enolase are more suitable than its absolute serum levels for the prediction of neurologic outcome in hypothermia-treated patients with out-of-hospital cardiac arrest. Neurocrit Care 2014; 20 (3): Mortberg E, Zetterberg H, Nordmark J, et al. S-100B is superior to NSE, BDNF and GFAP in predicting outcome of resuscitation from cardiac arrest with hypothermia treatment. Resuscitation 2011; 82 (1): Oksanen T, Tiainen M, Skrifvars MB, et al. Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia. Resuscitation 2009; 80 (2): Steffen IG, Hasper D, Ploner CJ, et al. Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care 2010; 14 (2): R Storm C, Nee J, Jorres A, et al. Serial measurement of neuron specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: a prospective study. Scand J Trauma Resusc Emerg Med 2012; Tiainen M, Roine RO, Pettila V, et al. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 2003; 34 (12): Zellner T, Gartner R, Schopohl J, et al. NSE and S-100B are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest. Resuscitation 2013; 84 (10): Inamasu J, Miyatake S, Suzuki M, et al. Early CT signs in out-of-hospital cardiac arrest survivors: Temporal profile and prognostic significance. Resuscitation 2010; 81 (5): Kim J, Kim K, Hong S, et al. Low apparent diffusion coefficient cluster-based analysis of diffusion-weighted MRI for prognostication of out-of-hospital cardiac arrest survivors. Resuscitation 2013; 84 (10): Kim SH, Choi SP, Park KN, et al. Early brain computed tomography findings are associated with outcome in patients treated with therapeutic hypothermia after out-ofhospital cardiac arrest. Scand J Trauma Resusc Emerg Med 2013; Mlynash M, Campbell DM, Leproust EM, et al. Temporal and spatial profile of brain diffusion-weighted MRI after cardiac arrest. Stroke 2010; 41 (8): Wijman CA, Mlynash M, Caulfield AF, et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann Neurol 2009; 65 (4):