BRAIN RESUSCITATION

NEURONAL SURVIVAL AND SALVAGE

Nabil El Sanadi, MD, MBA, Marc Plotkin, MD

Broward General Medical Center

Fort Lauderdale, Florida, USA
CARDIOPULMONARY-
CEREBRAL RESUSCITATION
CPR / BLS IMPORTANCE AND EFFICACY
17-40%
PROLONGED ARREST
CHAIN OF SURVIVAL BROKEN
EARLY ACCESS
EARLY CPR
EARLY DEFIB
EARLY ACLS
IRREVERSIBLE CEREBRAL CORTEX
INJURY
CARDIOPULMONARY-
CEREBRAL RESUSCITATION
BLS/ACLS EFECTIVE WITHIN 8-10
MINUTES
CENTRAL EMS OBJECTIVE
NEUROLOGICAL DAMAGE BEYOND
8-10 MIN
UNACCEPTABLY HIGH
DEATH / DYSFUNCTION
HEALTHY BRAIN / FUNCTIONAL
PATIENT IS PRIMARY GOAL
STROKE - BRAIN ATTACK

ISCHEMIA IS FOCAL
FOLLOWS SUDDEN OCCLUSION OF
ARTERY
NEURONAL SURVIVAL DEPENDS ON
COLLATERAL FLOW
AT 40% NORMAL FLOW,
NEUROTRANSMITTER FLOW
CEASES AND NEURONS BECOME
SILENT
INFARCT or SURVIVE?
STROKE - BRAIN ATTACK
THERAPEUTIC CHALLENGE

REVERSE
ISCHEMIA
THROUGH
PHARMACOLOGIC
AND NON-
PHARMACOLOGIC
METHODS
BRAIN RESUSCITATION

HISTORY
PATHOPHYSIOLOGY
GOALS OF TREATMENT
CARDIAC ARREST
ISCHEMIC STROKE
NEW HORIZONS IN 2000 -
NEUROPROTECTIVE AGENTS
HISTORY

INITIAL WORK IN CARDIAC ARREST

HYPOTHERMIA
BARBITUATE INTOXICATION
NEUROPROTECTIVE EFFECTS
DURING RESUSCITATION
MULTIPLE HUMAN AND ANIMAL
STUDIES
NO DEFINITIVE RESULTS ACHIEVED
PATHOPHYSIOLOGY

LACK OF CIRCULATION
10 SECONDS: UNCONSCIOUSNESS
2-4 MINUTES: GLUCOSE / GLYCOGEN
DEPLETED
4-5 MINUTES ATP EXHAUSTED
AUTOREGULATION LOST AFTER
EXTENDED HYPOXEMIA / HYPERCARBIA
PATHOPHYSIOLOGY

FOLLOWING ROSC/REPERFUSION
INITIAL HYPEREMIA
NO-REFLOW PHENOMENON
CEREBRAL BLOOD FLOW IS REDUCED
MICROVASCUALTURE DYSFUNCTION
REGARDLESS OF CPP
CEREBRAL BLOOD FLOW DEPENDENT
ON CPP ( CPP = MAP - ICP )
PATHOPYSIOLOGY

NEURONAL SURVIVAL DEPENDS ON:

PERFUSION PRESSURE
DURATION OF ISCHEMIA
ONSET
REPERFUSION
PROGNOSIS

REALISTIC OUTCOMES
DIRECTLY CORRELATED TO
TIME UNTIL ROSC / REPERFUSION
INITIAL SEVERITY OF DEFICIT
AGE OF PATIENT
CO-MORBID DISEASES
EARLY REHABILITATION / PHYSICAL
THERAPY
GOALS OF THERAPY

OPTIMIZE CPP
TEMPERATURE REGULATION
SEIZURE CONTROL
OTHER MODALITIES
EXPERIMENTAL: THE ISCHEMIC
PENUMBRA
OPTIMIZE CPP

NORMAL - > SLIGHT ELEVATED

MAP
NO REFLOW PHENOMENON
DELIVER NUTRIENTS
REDUCE ICP ( IF INCREASED )
CRANIOTOMY
GLYCEROL / MANNITOL
MILD HYPERVENTILLATION
TEMPERATURE REGULATION

 CEREBRAL METABOLIC RATE

INCREASES 8% PER DEGREE CELCIUS
IMBALANCE BETWEEN O2 SUPPLY AND
DEMAND
IMPAIRS BRAIN RECOVERY
TREAT FEVER AGGRESSIVELY (IIa)
ACETOMINOPHEN
COOL BLANKETS
TEMPERATURE REGULATION

HYPOTHERMIA HYPOTHERMIA
SUPPRESSES CEREBRAL MAY BE DETRIMENTAL
METABOLIC ACTVITY POST CARDIAC ARREST
REDUCES INCREASED
EXCITOTOXICITY VISCOSITY
REDUCES FREE RADICALS DYSRHYTHMIAS
PROTECTS BLOOD DECREASED CARDIAC
VESSELS OUTPUT
MEMBRANE COAGULOPATHY
STABILIZATION
INCREASED SUSCEPT
INHIBIT HYPERTHERMIA TO INFECTION
EXTEND THERAPEUTIC
WINDOW
TEMPERATURE REGULATION

HYPOTHERMIA (cont)

DEEP HYPOTHERMIA STUDIES 40 YRS

AGO
LATE 1980’S (MILD HYPO)
NEUROPROTECTIVE
LEONOV et al: STROKE 1990
MODERATE HYPOTHERMIA AFTER
CARDIAC ARREST
CANINE STUDY
REDUCED HISTOLOGICAL DAMAGE
TEMPERATURE REGULATION

HYPOTHERMIA (cont)
MARION et al: CRITICAL CARE MEDICINE
1996
RESUSCITATIVE HYPOTHERMIA
RANDOMIZED CONTROLED TRIAL
82 SEVERE CLOSED HEAD INJURY
PATIENTS
MODERATE HYPTHERMIA (32-33C / 89-
91.5F) 24hrs
IMPROVED NEUROLOGIC OUTCOMES
TEMPERATURE REGULATION
HYPOTHERMIA (cont)
DEBATE OF MILD HYPOTHERMIA
(34C/93F)
BENEFIT
DETRIMENTAL
NO CHANGE
(DURATION/TIMING)
• PROLONGED DURATION OF ISCHEMIA
• PROLONGED HYPOTHERMIA
• LITTLE EFFECT / NO EFFECT / HARM
TEMPERATURE REGULATION

CONCLUSIONS:
POST CARDIAC ARREST
HEMODYNAMICALLY STABLE PATIENTS
MILD HYPOTHERMIA ( >33C / 91.5F )
DO NOT ACTIVELY REWARM
IIb
HYPOTHERMIA SHOULD NOT BE
INDUCED POST CARDIAC ARREST
(INDETERMINATE)
TEMPERATURE REGULATION
POST ISCHEMIC STROKE
POSSIBLE POTENT THERAPEUTIC
APPROACH
MULTICENTER EUROPEAN TRIALS ( 500
PTS )
DIRECT BRAIN COOLING
• BRAIN COOLING HELMETS
• INFUSIONS
• LIMIT SYSTEMIC EFFECTS
• MORE RAPID
NO RECOMMENDATIONS OR GUIDELINES
EXIST
SEIZURE CONTROL

INCREASED OXYGEN / NUTRIENT

DEMAND
MEDICATIONS
DILANTIN
PHENOBARBITOL
DIAZEPAM (ACUTE)
OTHER MODALITIES

ELEVATE HEAD OF BED 30’

MIDLINE POSITIONING OF HEAD/NECK
PREOXYGENATE SUCTIONING
AVOID UNNECCESSARY STIMULATION
SUCTION
FOLEY CATH (PROLONGS HOSPITAL STAY)
VISITORS
PRESERVING NEURO FUNCTION
(POST CARDIAC ARREST)

MULTIPLE EXPERIMENTAL PROTOCOLS

AND DRUGS
EXCITING EXPERIMENTAL DATA
EXISTS
NONE SUFFICIENT IN SCOPE OR
EFFICACY TO CURRENTLY WARRANT
CLASS I OR II RECOMMENDATIONS
EXCEPT POST RESUSCITATION
HYPOTHERMIA
DO NOT REWARM (IIb)
 PRESERVING NEURO FUNCTION
(POST ISCHEMIC STROKE)

6 hr WINDOW FOR ACUTE

INTERVENTION
TYPE I AHA RECOMMENDATION
PERIPHERAL LYTIC THERAPY WITHIN 3
HOURS
TYPE IIb RECOMMENDATION
INTRA-ARTERIAL LYTIC THERAPY WITHIN 6
HOURS
SAME GENERAL SUPPORTIVE
MEASURES
TEMPERATURE / MAINTAIN CPP
PRESERVING NEURO FUNCTION
(POST ISCHEMIC STROKE)

DRUGS OF THE FUTURE

KEY CONCEPTS
ISCHEMIC PENUMBRA
THERAPEUTIC WINDOW
PATHOPHYSIOLOGY OF INJURY
NEUROPROTECTIVE AGENTS
KEY CONCEPTS

WHAT ISCHEMIC TISSUES ARE THE

THERAPEUTIC TARGET?
WHEN IS THE TISSUE LIKELY TO
RESPOND?
ISCHEMIC PENUMBRA

PENUMBRA: SHADOW ZONE

REGION OF REDUCED CEREBRAL BLOOD
FLOW
ABSCENT SPONTANEOUS OR INDUCED
ELECTRICAL POTENTIALS
MAINTAINS IONIC HOMEOSTASIS
MAINTAINS TRANSMEMBRANE
POTENTIALS
“POTENTIALLY REVERSIBLE” ISCHEMIC
TISSUE
THERAPEUTIC TIME WINDOW

EXISTANCE OF PENUMBRA IMPLIES

IRREVERSIBLE INJURY OVER TIME
THERAPEUTIC INTERVENTION
SPONTANEOUS IMPROVED FLOW
EVOLUTION OF PENUMBRA
EVOLUTION OF PENUMBRA
PATHOPHYSIOLOGY
THE REPERFUSION CASCADE
REPERFUSION O2 SUPPLY
TO MITOCHONRICALLY
INJURED CELLS

FORMATION OF
SUPEROXIDE O2 AND
HYDROXYL IONS

GENERATION OF
LIPID PEROXIDES

MEMBRANE DEGRADATION

IRREVERSIBLE CELL INJURY

NEUROPROTECTIVE CONCEPTS

PRESYNAPTIC INHIBITION OF
GLUTAMATE RELEASE
INHIBITORS OF NMDA
CALCIUM CHANNEL ANTAGONISTS
INHIBITION OF FREE RADICALS
GABA AGONISTS
CONCLUSIONS:
VIGILANT ATTENTION TO THE
DETAILS OF OXYGENATION AND
PERFUSION OF THE BRAIN AFTER
RESUSCITATION
TEMPERATURE MANAGEMENT
DECREASE METABOLIC DEMAND
SEDATION
TIME IS OF THE ESSENCE
ROSC / LYTICS
SAVE THE PENUMBRA