1/12/2021

Cardiac Arrest Yara Mikhaeil-Demo, MD, FACNS Northwestern University Feinberg School of Medicine Comprehensive Epilepsy Center

[email protected] C- Slide 1

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Objectives

• Describe the current available guidelines for neuroprognostication after anoxic brain injury • Identify EEG findings associated with poor prognosis after anoxic injury • Identify EEG findings associated with good prognosis after anoxic injury • Present a clinical classification of postanoxic myoclonus • Discuss EEG classification system of postanoxic myoclonic status

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Outline

• Epidemiology of cardiac arrest • Current guidelines for neuroprognostication after anoxic brain injury • EEG findings in patients with anoxic brain injury  EEG findings associated with poor outcome after anoxic brain injury  EEG findings associated with good outcome after anoxic brain injury  Prognosis and management of seizures/status epilepticus after anoxic brain injury • Postanoxic myoclonic status  Prognosis in patients with postanoxic myoclonic status  Clinical classification  EEG classification

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Case

• 56 yo man with history of COPD and PE admitted to the MICU for acute on chronic hypercapnic/hypoxemic respiratory failure which was complicated by hypoxemia during trach change and subsequent cardiac arrest.

• ROSC was achieved after 10 minutes.

• Few hours after his arrest, he was noted to have rhythmic 2Hz mouth/tongue, asynchronous, asymmetric distal upper extremities myoclonus lasting > 30 minutes.

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EEG

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EEG: What is the prognosis?

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Epidemiology

• 300,000 out of hospital and 200,000 in hospital cardiopulmonary arrest annually in the United Stated. • 40-50% are witnessed. • 17-49% attain return of spontaneous circulation (ROSC). • Withdrawal of life-sustaining treatment remains the most common cause of death in patients who have poor outcome.

Mozaffarian et al. Circulation 2015; 131:434-41 Phung et al. Am J Hosp Palliat Care. 2018 ; 35(11):1446-1455

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Prognostication

• 4265 subjects hospitalized after out of hospital cardiac arrest  33% had withdrawal of life sustaining treatment in <72 hours after admission because of perceived poor neurological prognosis

• WLST for neurological reasons within 72 hours may be associated with mortality in ≈2300 patients/ year.  ≈ 1500 (65%) might have had a functional recovery if allowed to live longer

Elmer et al. Resuscitation 2016; 102:127–135 8

When to prognosticate? American Heart Association Guidelines (2015)

• TTM: 72 hours after return to normothermia (Class IIb, LOE C-EO).

• No TTM: 72 hours after cardiac arrest (Class I, LOE B-NR).

Callaway et al. Circulation; 132(18 Suppl 2): S465-82. 9

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Wijdicks et al. Neurology 2006; 67(2): 203-10 10

AAN practice parameter (2006)

Poor outcome (CPC 4-5) associated with: • Generalized attenuation to ≤20 μV • Burst-suppression pattern with generalized epileptiform activity • Generalized periodic complexes on a flat background

FPR for poor outcome was 3%

Recommendation: Insufficient prognostic accuracy (recommendation level C)

Wijdicks et al. Neurology 2006; 67(2): 203-10 11

European Resuscitation Council and the European Society of Intensive Care Medicine

Sandroni et al. Resuscitation 2014; 85: 1779–1789 12

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AAN guidelines vs. European Society of Intensive Care Medicine

Retrospective study: Prospective study: • AAN: • ERC/ESICM: • Discharge: FPR 8% • 3 months: FPR 0% • 6 month: FPR 15% • Predicted poor outcome in 57% of patients • ERC/ESICM: • Discharge: FPR 0% • 6 months: FPR 0% • Among 174 patients who had poor outcome, the algorithm predicted poor outcomes in 28%

Zhou et al. Resuscitation 2019. 139:343-350 Bongiovanni et al. Intensive Care Med 2020. 46:963–972 13

When to get an EEG

•Start cEEG monitoring (cEEG) during TH /TTM Provide prognostic information Monitor for subclinical seizures and nonconvulsive status epilepticus •Seizures and NCSE have been reported at a rate of 10%–12% •Independent risk factor for mortality

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Relevant EEG findings

• Background • Reactivity • Epileptiform discharges • Seizure/status

 EEG in the presence of Myoclonus

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EEG severity scale –Post anoxia in TH era Retrospective study: cEEG

cEEG started during TH and continued until NT

Crepeau et al. Neurology 2013; 80: 339-44

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Clinical Outcome

Crepeau et al. Neurology 2013; 80: 339-44

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Clinical Outcome

Crepeau et al. Neurology 2013; 80: 339-44

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Clinical Outcome

• There was a trend favoring an association between the evolution of the EEG background and prognosis.  9 patients had improvement in EEG grade 8 had good outcome  4 patients had worsening of EEG grade  3 had poor outcome

Crepeau et al. Neurology 2013; 80: 339-44

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Outcome

• Of patients with poor neurological outcome; 16/21 had a grade 3 EEG.

• Of patients who died; 16/19 had a grade 3 EEG.

• In this study, none of the patients with seizures or status epilepticus achieved good outcome despite treatment.  All 5 patients with seizures were treated by increasing the midazolam infusion to achieve seizure cessation.  Divalproex sodium in 2 pts, levetiracetam in 1, fosphenytoin in 1  In 4 patients, seizures abated after treatment.  In 1 patient, support was withdrawn before seizures could be controlled.

Crepeau et al. Neurology 2013; 80: 339-44

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Early EEG for Outcome Prediction: Prospective Study

• cEEG recordings started ASAP and continued up to 5 days • 850 patients 46% had a good outcome.

• Four EEG patterns:  Generalized suppression (<10 uV)  Synchronous patterns with ≥50% suppression • Generalized periodic discharges on a suppressed background • Burst suppression with generalized, abrupt-onset bursts  Continuous without periodic activity  Other

Ruijter et al. Ann Neurol 2019; 86:203-214 21

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Synchronous patterns with ≥50% suppression

Ruijter et al. Ann Neurol 2019; 86:203-214 22

Predictor of Poor outcome

 Generalized suppression  Synchronous patterns with ≥50% suppression  Specificity: • 1.0 at 12 and 24 hours

 Sensitivity: • 0.47 at 12 hours • 0.3 at 24 hours •≤0.22 at 36 hours or later

Ruijter et al. Ann Neurol 2019; 86:203-214 23

Predictor of Good Outcome:

Continuous EEG patterns • Specificity •0.91 at 12 hours •< 0.90 at 24 hours or later •Sensitivity •0.5 at 12 hours

Ruijter et al. Ann Neurol 2019; 86:203-214 24

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EEG classification using ACNS Terminology (routine EEGs after rewarming) Highly Malignant Malignant Benign Background suppression Periodic or rhythmic patterns: Absence of - Abundant Periodic discharges malignant features - Abundant rhythmic spike and wave - Unequivocal EEG Seizures Suppression with periodic Malignant background: discharges - Discontinuous (suppression >10%) - Low-voltage - Reversed anterior-posterior gradient Burst suppression Unreactive EEG (or only stimulus induced discharges)

Westhall et al. Neurology 2016; 86: 1482-90 25

EEG classification using ACNS Terminology

Westhall et al. Neurology 2016; 86: 1482-90 26

Clinical Outcome: Highly Malignant EEG

Sensitivity for poor prognosis using the highly malignant EEG pattern was 50% (exceeding that of SSEP and absent ocular reflexes)

Westhall et al. Neurology 2016; 86: 1482-90 27

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Clinical Outcome: Malignant EEG

Westhall et al. Neurology 2016; 86: 1482-90 28

Clinical Outcome: Malignant EEG

Westhall et al. Neurology 2016; 86: 1482-90 29

Clinical Outcome: Benign EEG

• 14 had a benign EEG • 13 (93%) had good outcome

• Benign EEG was found in:  1% of pts with poor outcome  48% of pts with good outcome

Westhall et al. Neurology 2016; 86: 1482-90 30

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European Resuscitation Council and the European Society of Intensive Care Medicine

Sandroni et al. Resuscitation 2014; 85: 1779–1789 31

EEG analysis increasing prediction?

• 68% of patients fall in the indeterminate category • 64% of those showed good recovery • Absence of a highly malignant EEG by day 3 had 99.5% sensitivity for good recovery (CPC 1-2 at 3 months)

Bongiovanni et al. Intensive Care Med 2020. 46:963–972 32

EEG Pattern Within 5 Days After Cardiac Arrest

Benign EEG RSE GPDs Malignant nonepileptiform Continuous and/or RSE at any time point, GPDs <2.5 Hz at any time Discontinuous and reactive background at without any GPDs <2.5 Hz* point independently of unreactive EEG any time point EEG background background activity, activity or RSE with no episodes of status epilepticus or GPDs at any time

• * Myoclonic status at <2.5 Hz was • EEG pattern within 5 days after cardiac arrest not included in the RSE group • 4 channel cEEG • Only 18.7% of pts with RSE were in • 18 channel EEG at least twice in the first 5 days myoclonic status • Multimodal prognostic approach • Status myoclonus was the most • Primary outcome: survival and CPC at 6 months common type of clinical seizure manifestation in GPDs (62.5%) Beretta et al. Neurology 2018; 91(23):e2153-e2162 33

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Beretta et al. Neurology 2018; 91(23):e2153-e2162 34

EEG patterns

Beretta et al. Neurology 2018; 91(23):e2153-e2162 35

Clinical Outcome

Beretta et al. Neurology 2018; 91(23):e2153-e2162 36

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Postanoxic Refractory Status Epilepticus

• Seen in 9-35% of patients • Can be associated with clinical motor seizures (myoclonic, clonic, or tonic clonic).

Beretta et al. Neurology 2018; 91(23):e2153-e2162 Hofmeijer et al. Font Neuro 2014; 31; 5:39

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Postanoxic Refractory Status Epilepticus

• Status epilepticus: 25.9% (43 pts) • Refractory Status epilepticus: 21.7% (36 pts) • 7 pts -> evolved from RSE to GPDs (classified as GPDs)

• Super refractory in 21 pts

• Onset 3 ± 2.3 days after cardiac arrest • Lasted 4.7 ± 4.3 days

Beretta et al. Neurology 2018; 91(23):e2153-e2162 38

Aggressive standardized treatment of postanoxic status epilepticus

• IV benzodiazepines and IV valproate, levetiracetam, and/or phenytoin • If refractory within 60 minutes  a first anesthetic-with propofol and/ or midazolam for 48 hours

If continues to be refractory: • Other AEDs; lacosamide, topiramate, perampanel and/or • Other anesthetics (propofol, midazolam, thiopental, ketamine)

• Mean number of AEDs: 3.2 (1-7); mean number of anesthetic cycles: 2.4 (1-5)

Beretta et al. Neurology 2018; 91(23):e2153-e2162 39

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Clinical outcome with Aggressive treatment of RSE

• In this study pts with RSE who had aggressive treatment: • 52.8% survival • 44.4% good neurological outcome

• In literature: • 10% good neurological outcome of RSE after anoxic injury • 75% from all causes of nonanoxic RSE

• Myoclonic status at <2.5 Hz was not included in the RSE group • Only 18.7% of pts with RSE were in myoclonic status • Background activity of pts in RSE was not described

Beretta et al. Neurology 2018; 91(23):e2153-e2162 Lee. Epilepsy Currents 2019; 19(3):168-170 40

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In the future…

• Treatment of Electroencephalographic Status Epilepticus After Cardiopulmonary Resuscitation [TELSTAR]

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Anti-Seizure Drugs and EEG

• Patterns on the ictal-interictal continuum is seen in ~ 1 in 3 comatose post-arrest patients Superimposed Activity Generalized suppression Background Activity Seizures Suppressed (<10uV) Polyspike-burst with myoclonus Burst Suppression Polyspike-wave discharges without myoclonus Continuous with periods of attenuation / nearly Generalized periodic discharges <2.5 Hz continuous Generalized periodic discharges >2.5 Hz continuous Non generalized periodic patterns Non periodic epileptiform discharges Non-epileptiform activity

Solanki et al. Resuscitation 2019; 142:82-90 43

Anti-Seizure Drugs and EEG

EEG Patterns • Patients with epileptiform discharges: Suppressed 50% transitioned to a non- Discontinuous with superimposed epileptiform activity epileptiform, non-suppressed state Discontinuous without epileptiform features • Patients with non-epileptiform Continuous with superimposed epileptiform activity activity: 19% transitioned to an Continuous without epileptiform features epileptiform state

Solanki et al. Resuscitation 2019; 142:82-90 44

Anti-Seizure Drugs and EEG

• Continuous EEG and epileptiform activity:  Valproate and levetiracetam were associated with resolution of epileptiform activity  Warmer body temperature was associated with a decrease in the probability of resolution of epileptiform activity

• Discontinuous EEG and epileptiform activity:  No ASD was associated with resolution of epileptiform activity  Core body temperature was not associated either

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EEG Reactivity

• Reproducible change in EEG frequency or amplitude in response to an external stimulus (not including SIRPDs)  When ?  How long does it need to last? • Standardized protocol for stimulation • IRA is not great  QEEG algorithm

Admiraal et al. An Neurol 2019; 86:17-27 46

EEG Reactivity

high pass filter = 0.53Hz, low pass filter = 70Hz, scaling = 50μV/cm. Admiraal et al. An Neurol 2019; 86:17-27 47

EEG Reactivity

high pass filter = 0.53Hz, low pass filter = 70Hz, scaling = 30μV/cm. Admiraal et al. An Neurol 2019; 86:17-27 48

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EEG Reactivity

high pass filter = 0.53Hz, low pass filter = 70Hz, scaling = 70μV/cm

Admiraal et al. An Neurol 2019; 86:17-27 49

EEG Reactivity

• Reactive EEG:  Specificity: 73% for good outcome  Sensitivity: 82% for good outcome • Absent reactivity:  Specificity of 82% for poor outcome  Sensitivity 73% for poor outcome

AHA: Absence of EEG reactivity is a poor prognostic marker

• Dose of propofol or midazolam did not differ between reactive and unreactive patients.

Admiraal et al. An Neurol 2019; 86:17-27 50

EEG Reactivity

Admiraal et al. An Neurol 2019; 86:17-27 51

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Postanoxic Myoclonic Status

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Post anoxic myoclonus

• Post anoxic myoclonus occurs in 16-20% of patients

Kusztos et al. Resuscitation. 2020;S0300-9572(20)30537-2 53

Wijdicks et al. Neurology 2006; 67(2): 203-10 54

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Myoclonic Status = Bad Outcome

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What is Myoclonic Status?

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Postanoxic Myoclonic Status: Clinical Classification

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Clinical classification

Mikhaeil-Demo et al. Resuscitation 2017; 119:76-80 60

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OUTCOME 30

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Total 20 Followed Commands 15

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0 Type 1 Type 2 Type 3 p value Number of patients (%) 3 (6.9%) 27 (62.7%) 13 (30.2%) Outcome 0.03 Following commands(%) 2 (66.6%) 2 (7.4%) 0 All Other 1 25 13 Mikhaeil-Demo et al. Resuscitation 2017; 119:76-80 61

Characteristics of patients with good outcome

Patient 1 Patient 2 Patient 3 Patient 4 Age 55 22 65 29 Sex F M M M Type of myoclonus 1 1 2 2 Type of arrest Respiratory Respiratory Cardiac Cardiac Initial rhythm PEA PEA PEA Vfib Duration of arrest 15 minutes 2 x 2 minutes 9 minutes 15 minutes Location of arrest Out of hospital In hospital In hospital Out of hospital Timing to myoclonus > 24 hours < 12 hours < 12 hours < 12 hours Temperature management HT none TTM HT MRB Unremarkable Unremarkable Unremarkable Anoxic injury Time followed commands Day 2 Day 7 Day 3 > 14 days

Mikhaeil-Demo et al. Resuscitation 2017; 119:76-80 62

Myoclonic Status = Bad Outcome

• 9% of our cohort had good neurological outcome.

• This is similar to a recently published papers with similar outcome rate (9-14%)

Seder et al. Crit Care Med 2015; 43(5): 965-72 Mikhaeil-Demo et al. Resuscitation 2017; 119:76-80 Dhakar et al. Resuscitation 2018;131:114-120 63

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Postanoxic Myoclonic Status: EEG Classification

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• Two experts reviewed the EEGs of patients with post anoxic myoclonic status

• Identified two major categories: 1. Suppression-burst background with high- amplitude polyspikes in lockstep with myoclonic jerks 2. Continuous background with narrow, vertex spike-wave discharges in lockstep with myoclonic jerks 3. Subcortical myoclonus 4. Unclassifiable Elmer et al. Ann Neurol 2016; 80(2): 175-84 65

Pattern 1

Post arrest day 0 Post arrest day 1

Elmer et al. Ann Neurol 2016; 80(2): 175-84 66

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Pattern 1

Post arrest day 2 Post arrest day 3 Elmer et al. Ann Neurol 2016; 80(2): 175-84 67

Pattern 2

Post arrest day 0 Post arrest day 30 Elmer et al. Ann Neurol 2016; 80(2): 175-84 68

Pattern 2

Post arrest day 0 Post arrest day 4 Elmer et al. Ann Neurol 2016; 80(2): 175-84 69

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Clinical outcome

401 post anoxic patients

69 with early myoclonus

Pattern 1: 48 Unclassifiable: pts (74%) Pattern 2: 8 Subcortical: 2 7 pts (11%) pts (12%) pts (3%)

4 pts survived Elmer et al. Ann Neurol 2016; 80(2): 175-84 70

Postanoxic Myoclonic Status: Clinical and EEG

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• 11.9% (7/59) of patients with post anoxic myoclonus regained consciousness • In a subset of those that recovered with video EEG available: • 5/5 had “multifocal myoclonus” • 4/5 had midline maximal spikes with a continuous background

Dhakar et al. Resuscitation 2018;131:114-120 72

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Dhakar et al. Resuscitation 2018;131:114-120 73

Outcomes

• No patient with suppression burst or low voltage background (N=52) at any point regained consciousness • Median time to recovery of consciousness was 11 days

Dhakar et al. Resuscitation 2018;131:114-120 74

Predicting Favorable Prognosis

• Overall, 14% of patients with post anoxic myoclonus recovered to follow commands

• 7.7 % achieved CPC 1-2 at 3 months

• Continuous background on BEST EEG + No anoxic changes on MRI

• Coma recovery:  Sensitivity 91%  Specificity 99%  Positive predictive value 91%  Negative predictive value 99%

Beuchat et al. Neurology 2020. 95(4):e335-e341

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Burst Suppression with Identical Bursts

• If they have associated myoclonus, most common motor manifestations:  Axial muscle jerks  With or without eye opening and upward gaze deviation

• EEG source localization: bursts begin bilaterally synchronously

• Patients who have myoclonus have more prominent activation in the motor cortex

“myoclonus in this population may not have particular prognostic significance in and of itself”

Kusztos et al. Resuscitation. 2020;S0300-9572(20)30537-2 76

Post anoxic myoclonus - Conclusion

• Prognostic factors that may suggest a “better” outcome:  Semiology: Multifocal, distal myoclonus  EEG: Continuous EEG with midline central spikes; normal voltage EEG

• Continuous background on BEST EEG + No anoxic changes on MRI: predict better outcomes

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Back to the case

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Case:

• 56 yo man with history of COPD, PE, on anticoagulation c/b retroperitoneal bleed admitted to the MICU for acute on chronic hypercapnic/hypoxemic respiratory failure which was complicated by hypoxemia during trach change and subsequent cardiac arrest. • ROSC was achieved after 10 minutes. • Few hours after his arrest, he was noted to have rhythmic tongue movement and asynchronous, asymmetric distal upper extremities myoclonus.

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What is the prognosis?

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EEG: What is the prognosis?

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A month later…

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EEG one month later

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EEG one month later

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Take-home points

• No single parameter predicts poor neurological outcome with absolute certainty (studies biased with self fulfilling prophecy).

• Prognostic evaluation should start not earlier than 72 h after ROSC (if no TTM) / rewarming (if TTM) and only after major confounders have been excluded.

• Multimodality appears to be the most reasonable approach for prognostication after cardiac arrest.

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Take-home points

• EEG findings associated with poor outcome:  Background suppression <10uV  Burst suppression (>50%)  GPDs on a suppressed background

• EEG findings associated with good outcome:  Continuous and reactive EEG

• Postanoxic myoclonic status is not all the same  Postanoxic myoclonic status is not incompatible with return of consciousness

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Thank you • Questions?

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