Neurological Prognostication Post Cardiac Arrest

Neurological Prognostication Post Cardiac Arrest

Anoxic Auguring: Neurological Prognostication After Cardiopulmonary Resuscitation Where do we stand in 2011? Robert Altman PGY 4, Neurology Resident McGill University Division of Neurology, McGill University Health Center May 18th 2011 Prognosis Fore-knowing

Phronesis Practical wisdom Case 1 55 M collapses while jogging CPR immediately initiated by bystander

V-fib arrest; circulation restored after 6 minutes Exam (day 1): comatose, absent pupillary and corneal reflexes, extensor posturing to pain, myoclonic status epilepticus CT head (day 2): Normal study SSEP (day 3): Absent N20 responses Exam (day 3): Unchanged Case 2

35 M collapses while playing basketball CPR immediately initiated by bystander PEA arrest; circulation restored after 20 minutes Induced hypothermia x 24 hours (32 degrees C) Exam (day 1): Comatose, pupils fixed, triggers ventilator but otherwise no evidence of intact brainstem function, no spontaneous movements or motor response to noxious stimuli EEG (day 2): Severe diffuse slowing of cerebral activity Exam (day 3): Comatose, pupils reactive, oculocephalic,

corneal, and gag reflexes intact, triggers ventilator, flexor posturing of upper limbs to pain, no spontaneous movements Case 3 71M with HTN, CAD (previous CABG), collapsed at home No CPR administered PEA arrest; circulation restored after 20 minutes Exam (day 1): Comatose, R pupil reactive/L pupil fixed, corneal reflex present but sluggish, no ocular response to cold calorics, no spontaneous movements, left arm and leg withdraw to painful stimuli, bilateral Babinski signs MRI brain (day 2): Cerebral infarctions in superficial and deep

watershed territories bilaterally (L > R) SSEP (day 3): N20 response present on right, absent on left Exam (day 3): Unchanged Why does neurology get called to evaluate these cases? Outcome? Poor or favourable? Why? What do you base your judgement on?

Outline Cases Historical Perspective Prognostication Guidelines

The Era of Hypothermia Approaching the Family Return to Cases Take Home Points Mission (im)possible? The neurologists role: To predict with perfect accuracy the likelihood of awakening and (if the patient survives) future morbidity. Self-fulfilling prophecy? A physicians negative expectation or overreliance on laboratory tests affects

management decisions and thus outcome. Therefore paramount that studies adhere strictly to independent assessment of prognostic indicators and outcomes Poor Prognosis Glasgow Outcome Scale (GOS) 3 Cerebral Performance Scale (CPC) 3 Emphasis on the poor because may facilitate decision for withdrawal of life-sustaining therapies Tests ideally have a 0% FPR for determining poor prognosis, narrow CIs

N.B. No postarrest physical examination finding or diagnostic study has as yet predicted poor outcome of comatose cardiac arrest survivors during the first 24 hours after ROSC N Engl J Med 2009;361:605-11 C. Booth JAMA, February 18, 2004Vol 291, No. 7 Outcomes Severe Disability Vegetative (GOS3)

State (GOS2) Moderate Disability (GOS4) Good (GOS5) Dead (GOS 1)

Bernat. Neurology Clinical Practice 2010;75(Suppl 1):S33S38 History of Prognostication Levy et al (1985) establishes algorithms for neurological prognosis Determinations derived from a single cohort study, 211 patients Not without limitations Statistical uncertainty Since (late 70s); revolution in critical care since this era How many patients suffered from a cardiac arrest in the Levy cohort? How many were cooled? Only 71% suffered cardiac arrest

TH only introduced in 2002 Levy DE, et al. JAMA 1985;253:1420-1426 Meta-analysis of relevant literature from 1966-2006; 391 papers reviewed and rated. E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203 AAN Recommendations E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203

The Tools Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) The Tools

Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) ct Dire sment s asse

Brainstem Clinical Exam Physical exam, clinical findings Present vs. Absent (day 1 to 3) Pupils (CN II,III) Corneal reflex (CN V, VII) Cold calorics (CN VIII, VI, III, MLF) Motor responses (day 1 to 3) Flexion vs. extension / none

0 % FPR for poor outcome, narrow CIs, 10 studies. Clinical Exam Since Levy et al. Prospective, class I studies. Zandbergen, et al. Neurology 2006;66:6268. Point in fact Clinical Exam The brainstem is more resistant to anoxia than the cortex, thus if abolished BS reflex, this

generally implies a severely damage cortex Preserved BS reflexes by no means imply intact cortical function No direct way of evaluating cortical activity in an unconscious patients Related to Poor Outcome but Insufficient Predictive Value

Age Sex Cause of arrest Type of arrhythmia (vfib or asystole) Total time of arrest Duration of CPR Based in 2 large prospective studies involving 774 patients E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203 The Tools

Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) Blood work Biochemical Signs

NSE (neuron-specific enolase) S100 (glial protein) BB fraction of creatine kinase (serum or csf) Neurofilament protein Combination panels Blood work Biochemical Signs

NSE (neuron-specific enolase) S100 (glial protein) BB fraction of creatine kinase (serum or csf) Neurofilament protein Combination panels Blood work Biochemical Signs NSE (neuron-specific enolase) 33g/L, b/w 1-3d post arrest

Reflects diffuse CNS injury Only validated use in carcinoid & other tumors Not commonly available in N. America Not at MUHC, CHUM, Ontario Variability in assays and cut-off values Class B 0 % FPR for poor

outcome, CI 0-3; One class I study The Tools Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP)

The Tools Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) Neuroimaging

Findings correlate poorly with functional prognosis Performed to rule out primary neurological catastrophe, as aetiology of cardiovascular event However, CT often normal on day 1 Technical barriers may preclude neuroimaging i.e. Hemodynamic instability, inability to transfer Class U Diagnostic value not prognostic The Tools

Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) The Tools

Physical exam, clinical findings Blood work Biochemical Signs Neuroimaging (CT, MRI) Electrophysiology (EEG, SSEP) Cortical and subcortical GM indir ectly

EEG , SSEP EEG Early myoclonic status correlates with poor outcome At 24hrs, 0% FP Bilaterally synchronous twitches of limb, trunk or facial muscles Supported by autopsy and multiple trials Status epilepticus, GTC seizures, multifocal asynchronous myoclonus Represent nonspecific indicator of metabolic

encephalopathy without real prognostic value E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203 EEG FPR for poor outcome 3% (95% CI: 0.9% to 11%) with malignant EEG patterns Malignant categories include suppression, burstsuppression, alpha and theta pattern coma, and generalized periodic complexes combined; (malignant EEG group)...therefore strongly but not invariably associated with poor outcome E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203

Status Epilepticus Burst Suppression Myoclonic Status 86 F, post cardiac rest Etiology unclear Duration of downtime unknown 18 hours after resuscitation, patient was in coma with intact

brainstem reflexes Clinical movements q3-5 Video of myoclonic status epilepticus What is SSEP? SSEP = Somatosensory Evoked Potential N20 response primary somatosensory cortex 200 consecutive rapid stimulations are given to the median nerve Recorded at

brachial plexus cervical spinal cord At 20 msec, contralateral somatosensory cortex N Engl J Med 2009;361:605-11 SSEP and Prognosis Bilateral absence of the N20 component of the SSEP with median nerve stimulation recorded on days 1 to 3 after CPR accurately predicts a poor outcome Zandbergen, et al. Neurology 2006;66:6268.

Pros/Cons of SSEP +: not influenced by medications, able to be performed when brainstem testing limited mechanical or metabolic reasons; including hypothermia - : confounded in many ways any interruption in somatosensory pathways invalidates test Tiainen M, et al. Crit Care Med 2005; 33: 17361740 SSEPs: Clinical Practice

Physicians use of SSEP fuel decisions about withdrawal of life support. 58 comatose CPR survivors referred for neurologic consultation SSEP testing correlated best with waiting time to withdrawal of life-sustaining therapies. 40 patients whose life support was eventually withdrawn, the median waiting time was 7 days for patients with preserved SSEPs and only 1 day in patients with bilaterally absent N20 SSEP components. Geocadin RG et al. Neurologic prognosis and withdrawal of life support after resuscitation from cardiac arrest. Neurology 2006 Jul 11; 67:105-8.

AAN 2006 Practice Parameter Confounders Hypothermia NM blocking agents

Large dose sedatives Organ failure Shock Absent pupils/corneal and extensor/no motor response. Outline

Cases Historical Perspective Prognostication Guidelines The Era of Hypothermia Approaching the Family Return to Cases Take Home Points History of Prognostication

Levy et al (1985) establishes algorithms for neurological prognosis determinations derived from a single cohort study Not without limitations Levy DE, et al. JAMA 1985;253:1420-1426 Therapeutic hypothermia early 2000s, 2 major publications in the NEJM 2002 TH Increased the rate of a favourable neurologic outcome and reduced mortality. N Engl J Med 2002;346:549-56

N Engl J Med 2002;346:557-63 The Conundrum TH now used for neurological protection for a multitude of other life-threatening catastrophes Worldwide 25% - 75% of all admitted resuscitated patients Prognostication tools thus need revalidation Life-sustaining therapies outpacing our capacity for accurately predicting outcomes Era of Therapeutic Hypothermia (TH)

Studies ongoing and constantly emerging Single studies show cooling: 1. Delayed motor response up to 6 days; 3 of 37 regained awareness E. Thenayan, M. Savard et al. Neurology 2008;71:15351537 2. Hypothermia to 32C or above increases latency of SSEPs by approximately 15%, reductions of temperature below 30C can decrease the N20 amplitude by up to 20% 3. Decreases NSE levels May reflect neuroprotection? M.Tiainen, Risto O. Roine. et al. Stroke 2003;34;2881-2886

Dr. Bryan Young It is highly likely that the factors that have been shown to be reliable predictors in the past such as loss of pupillary and corneal reflexes and of somatosensory-evoked responses will be validated. However, the timing of the testing of some variables may require adjustment 192 patients (103 TH vs 89 NT) Primary outcome = in hospital death (GOS 1) The absence of pupillary light responses, corneal reflexes, and extensor or absent motor response at 72h remained accurate

predictors (p < 0.0001 for all) Myoclonic status epilepticus (p < 0.0002) NSE > 33 ng/ml has a high false-positive rate in patients treated with hypothermia and should be interpreted with caution J Fugate, E F.M. Wijdicks et al ANN NEUROL 2010;68:907914 Nov 2010 Outline

Cases Historical Perspective Prognostication Guidelines The Era of Hypothermia Approaching the Family Return to Cases Take Home Points

Discussion with family Uncertainty furthers emotional distress of a grieving and anxious family Respect decision made by the patients lawful surrogate decision-maker who attempts to faithfully represent the treatment preferences of the patient Compassionate communication Encouragement of emotions Appreciation of personal values and religious preferences Define poor outcome PVS E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203

Poor outcome Terms Severely disabled state, requiring long-lasting or indefinite comprehensive nursing care Hope for significant recovery is unrealistic Chances of meaningful recovery extremely negligible Fully dependent state of living Some possible reasonable options Extubation Discontinuation of ionotropes, vasopressors Discontinuation of ivf, nutrition Turn off monitor

E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203 Persistent Vegetative State (PVS) Wakefulness without awareness Observation Sleeps with eyes closed, open during the day Blinking, roving, pursuit (brief and unsustained) Nystagmus Vocalizations Swallowing saliva

Exam Nonpurposeful limb movements, posturing Flexion withdrawal from noxious stimulation Brief movements of head or eyes towards stimulus without localization or fixation Startle (auditory, or myoclonus) ANS function intact (neuro-vegetative) Bernat JLAnnu Rev Med 2009;60:381392. PVS Pathophysiology

Extreme reductions in cerebral blood flow and metabolism, measured with positron emission tomography (PET) CT and MRI scans show progressive and profound cerebral atrophy in cases of vegetative state Terry Schiavo

Brain at autopsy weighed 615g Normal adult brain 1300-1500g Terri Schiavo; cardiorespiratory arrest 1990 1996 2002 Food for Thought Recent fMRI has thrown into question our understanding of disordered consciousness Case reports

2006, Owen and colleagues; Science 23 yo TBI victim in PVS for 5 months able to wilfully modulate brain regions required for volleying a tennis ball and looking at objects in her home while navigating room to room 2010, Monti and colleagues; NEJM 4/23 subjects in PVS able to activate appropriate brain regions Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the vegetative state. Science 2006;313:1402

Prognosis in PVS Major grey area depends mostly on the cause and extent of the brain damage producing the syndrome Certain patients that modulate brain activity (fMRI; Owen, Monti et al.) may have better prognoses / predictors of recovery. Need validation studies, larger cohorts Not available outside select centers Still very far from clinical practice guidelines Bernat JL. Chronic consciousness disorders. Annu Rev Med 2009;60:381392.

Costs of maintaining PVS Psychological Was the test a false positive? Will recovery occur? Emotional Family / loved-ones Financial Hospital Caregiver

Outline Cases Historical Perspective Prognostication Guidelines The Era of Hypothermia

Approaching the Family Return to Cases Take Home Points Case 1 55 M collapsed while jogging CPR immediately initiated by bystander V-fib

arrest; circulation restored after 6 minutes *Final outcome: Exam (day 1):secondary comatose, absent pupillary and corneal 1) Death to sepsis from reflexes, extensor posturing to pain, myoclonic status

pneumonia <30d. epilepticus Glasgow Outcome CT2)head (day 2): Normal study Scale 1. SSEP (day 3): Absent N20 responses Exam (day 3): Unchanged Case 2

35 M collapses while playing basketball CPR immediately initiated by bystander PEA arrest; circulation restored after 20 minutes *Final outcome: Induced hypothermia x 24 hours (32 degrees C) 1) Probable HOCM. Exam (day 1): Comatose, pupils fixed, triggers ventilator but

2) Postnoanoxic otherwise evidence encephalopathy. of intact brainstem function, no spontaneous movements or motor response to noxious stimuli Persistent Vegetative State. EEGGlasgow

(day 2): Severe diffuse slowing of cerebral 3) Outcome Scale 2 at activity 6 months. Exam (day 3): Comatose, pupils reactive, oculocephalic, corneal, and gag reflexes intact, triggers ventilator, flexor posturing of upper limbs to pain, no spontaneous movements

Case 3 71M with HTN, CAD (previous CABG), collapsed at home No CPR administered PEA arrest; circulation restored after 20 minutes *Final outcome: Exam (day 1): Comatose, R pupil reactive/L pupil fixed, corneal 1) Mild ischemic cortical subcortical damage.

reflex present but sluggish, no ocular&response to cold calorics, no 2) Residual R hemiparesis. spontaneous movements, left arm and leg withdraw to painful stimuli, bilateral Babinski

signs 3) Post-anoxic myoclonus (Lance-Adams). MRI 4) Glasgow Scale 4inat 6 months. brain (dayOutcome 2): Cerebral infarction superficial and deep watershed territories bilaterally (L > R)

SSEP (day 3): N20 response present on right, absent on left Exam (day 3): Unchanged Take-Home Points Neurologic Prognostication 1. Our tools allow for an accurate prediction of poor neurologic outcome Indeterminate largely equals = 2. Timing of exam

3. Clinical exam remains the most reliable method for determining poor outcomes 4. Current prognostication evidence predates TH era; and thus need to interpret with caution 5. Structured, compassionate approach to family; define what poor outcome means in appropriate terms 3 Key References N Engl J Med 2009;361:605-11 Neurology 2006;67;203

JAMA. 2004;291:870-879 References Cited

Young B. N Engl J Med 2009;361:605-11 E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203 Mayo Clin Proc. 2005;80(8):1037-1046 Bernat. Neurology Clinical Practice 2010;75(Suppl 1):S33S38 Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557563 Circulation 2010;122;S768-S786 Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549556 Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the

vegetative state. Science 2006;313:1402 Thenayan EA, et al. Electroencephalogram for prognosis after cardiac arrest. J Crit Care. 2010 Jun;25(2):300-4. Monti et al. Willful Modulation of Brain Activity in Disorders of Consciousness. N Engl J Med 2010;362:579-89 Neuroopthalmology review manual: Kline MedLink: myoclonic status epilepticus NDD (neurological determination of death) Aetiology established that can cause irreversible death Deep coma

Absence of motor responses to stimuli, no spontaneous or abnormal mvmts (dyskinesia, posturing) or seizures Absence of BS reflexes No spontaneous breathing during apnea test No confounders 2 exams, 2 independent MDs

Infants (30d and <1yr); rpt exam recommended In case of cardiac arrest, clinical evaluation of NDD delayed 24hrs subsequent to CPR N.b. spinal reflexes may exist Date and time of death = first NDD Brain Death Exam Brainstem Pupils 4mm, unresponsive to light

Corneals Movement of jaw or lids excludes NDD OCR Ignore if trauma Calorics 30 degrees 50cc ICE water quickly. If no eye movement, wait 5 min and try contralateral side

Pharyngeal Stimulate posterior pharynx Suction the ETT Depress larynx, swallow reflex Apnea test VOR: vestibulo-ocular reflex Cold Caloric Testing Vestibulo-Ocular Reflex (VOR)

Slow phase Pearl: COWS mneumonic implies intact cortex (frontal eye fields). If on coma / sedated, will not get corrective nystagmus.

Attenuates resting state vestibular tone Warm Caloric Testing Vestibulo-Ocular Reflex (VOR) Increases resting state vestibular tone

Rarely done in neurology Apnea Test Pre-oxygenate with 100% FiO2 for 10-15 min Baseline ABG PH 7.35-7.40 PC02 40+/- 5 mmHg Disconnect ventilator T piece with CPAP at 10 CM H20, deliver FiO2 at 10L/min or insert

catheter into ETT and deliver FiO2 at 6L/min (at carina) Observe for resp. effort x 10 min Repeat ABG and reconnect ventilator Test + if PaCO2 >60mmHg and rise in 2mmHg/min PH <7.28 No respiratory efforts demonstrated

Stop if HD instability or desaturation occurs Ancillary test Cerebral angiography or radio-isotope scan Absence of intracranial blood + LR (CI) - LR (CI) Pooled Clinical Signs in the Prognosis of Post Cardiac Arrest Coma

LR for poor neurological outcome demonstrated. JAMA. 2004;291:870-879 Rational Clinical Exam JAMA 2004 Pooled Clinical Signs in the Prognosis of PostCardiac Arrest Coma + LR (CI) - LR (CI)

JAMA. 2004;291:870-879

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