Anoxic Auguring:Neurological Prognostication After

Cardiopulmonary Resuscitation

Where do we stand in 2011?

Robert AltmanPGY 4, Neurology Resident

McGill University

Division of Neurology, McGill University Health Center

May 18th 2011

πρόγνωση • Prognosis • “Fore-knowing”

Φρόνησις• 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

Outcome?

Poor or favourable?Why? What do you base your

judgement on?

Why does neurology get called to evaluate

these cases?

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 physician’s 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 CI’s

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, 2004—Vol 291, No. 7

Dead (GOS 1)

Vegetative State (GOS2)

Severe Disability (GOS3)

Moderate Disability (GOS4)

Good (GOS5)

Outcomes

Bernat. Neurology® Clinical Practice 2010;75(Suppl 1):S33–S38

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 70’s); 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

E.F.M. Wijdicks, A. Hijdra, G. B. Young, et al. Neurology 2006;67;203

Meta-analysis of relevant literature from 1966-2006; 391 papers reviewed and rated.

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)

Brainstem

Clinical ExamDirect

assessment

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 CI’s, 10 studies.

Zandbergen, et al. Neurology 2006;66:62–68.

Clinical Exam

• Since Levy et al.– Prospective, class I studies.

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)– ≥33µg/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

EEG , SSEP

indirectly

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, burst-

suppression, 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 restEtiology unclearDuration 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;66:62–68.

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: 1736–1740

SSEP’s: 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.

Confounders• Hypothermia• NM blocking agents• Large dose sedatives• Organ failure• Shock

Absent pupils/corneal and extensor/no motor response.

AAN 2006 Practice

Parameter

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

• Therapeutic hypothermia early 2000’s, 2 major publications in the NEJM 2002– TH Increased the rate of a favourable neurologic outcome and

reduced mortality.

Levy DE, et al. JAMA 1985;253:1420-1426

N Engl J Med 2002;346:549-56N 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;71:1535–1537

2. Hypothermia to 32°C or above increases latency of SSEP’s by approximately 15%, reductions of temperature below 30°C 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;68:907–914

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 patient’s 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 Exam

Sleeps with eyes closed, open during the day

Nonpurposeful limb movements, posturing

Blinking, roving, pursuit (brief and unsustained)

Flexion withdrawal from noxious stimulation

Nystagmus Brief movements of head or eyes towards stimulus without localization or fixation

Vocalizations Startle (auditory, or myoclonus)

Swallowing saliva ANS function intact (neuro-vegetative)

Bernat JLAnnu Rev Med 2009;60:381–392.

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

1996 2002

Terri Schiavo; cardiorespiratory arrest 1990

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 RevMed 2009;60:381–392.

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• 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

*Final outcome: 1) Death secondary to sepsis from

pneumonia <30d.2) Glasgow Outcome Scale 1.

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

*Final outcome: 1) Probable HOCM.2) Post anoxic encephalopathy.

Persistent Vegetative State.3) Glasgow Outcome Scale 2 at 6 months.

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 infarction in superficial and deep watershed territories bilaterally (L > R)

• SSEP (day 3): N20 response present on right, absent on left• Exam (day 3): Unchanged

*Final outcome: 1) Mild ischemic cortical & subcortical damage.2) Residual R hemiparesis.3) Post-anoxic myoclonus (Lance-Adams).4) Glasgow Outcome Scale 4 at 6 months.

Take-Home PointsNeurologic Prognostication

1. Our tools allow for an accurate prediction of poor neurologic outcome

– “Indeterminate” largely equals =

2. Timing of exam3. Clinical exam remains the most reliable method for

determining poor outcomes4. Current prognostication evidence predates TH era;

and thus need to interpret with caution5. Structured, compassionate approach to family; define

what ‘poor’ outcome means in appropriate terms

3 Key References

N Engl J Med 2009;361:605-11

JAMA. 2004;291:870-879

Neurology 2006;67;203

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):S33–S38• 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; 346:557–563• Circulation 2010;122;S768-S786• Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl

J Med 2002; 346:549–556• 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 MD’s• 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 TestingVestibulo-Ocular Reflex (VOR)

Attenuates resting state vestibular tone

Slow phase

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

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

Pooled Clinical Signs in the Prognosis of Post–Cardiac Arrest Coma

+ LR (CI) - LR (CI)

LR for poor neurological outcome demonstrated.

JAMA. 2004;291:870-879

Rational Clinical Exam – JAMA 2004

Pooled Clinical Signs in the Prognosis of Post–Cardiac Arrest Coma

+ LR (CI) - LR (CI)

JAMA. 2004;291:870-879