postresuscitation encephalopathy 2005.pdf

ORIGINAL ARTICLE

Postresuscitation EncephalopathyCurrent Views, Management, and Prognostication

Boby Varkey Maramattom, MD, DM, and Eelco F.M. Wijdicks, MD

Background: Cardiac arrest has a high mortality rate. Postresusci-tation encephalopathy is commonly associated with significant mor-bidity.Review Summary: Among those patients who achieve a return tospontaneous circulation, more than half die during the subsequenthospital course. Few survivors recover without significant neuro-logic disability. Clinical examination is often used for predictingsubsequent neurologic outcome in these patients. The role of ancil-lary investigations and the judicious combination of these parame-ters with the findings on clinical examination to achieve accurateprognostication is discussed in this review. Only a few parametershave a strong predictive value in coma after cardiac arrest. Theseinclude pupillary light reflexes and motor responses at 3 days, absentsomatosensory evoked potential, and possibly diffuse magneticresonance imaging changes.Conclusion: The authors discuss the physiology, pathology, andconsequences of cardiac arrest to the central nervous system, and theuse of various parameters in prognostication. Induced hypothermiais a new therapeutic development.

Key Words: cardiopulmonary resuscitation, cardiac arrest, coma

(The Neurologist 2005;11: 234243)

Cardiac arrest leads to a sudden loss of cardiac output andcirculation. This is potentially reversible, with a success-ful restoration of spontaneous circulation (ROSC) and oxy-gen delivery. In contrast, sudden cardiac death (SCD) refersto death occurring within 1 hour from a primary cardiac causeand involves at least 2 to 5 minutes of absent pulses.1 In theUnited States in 1998 alone, there were around 450,000deaths attributed to SCD.2 Additionally 375,000 to 750,000patients undergo attempted resuscitation each year. When theheart stops, the lack of blood flow injures the brain. With 40%

of these patients attaining ROSC in the United States, almost100,000 to 200,000 cases present to intensive care units(ICUs) annually with brain injury after cardiac arrest.

The financial implications of this condition are stagger-ing. In 1999 alone, hospital costs averaged $160,000 to$180,0003 per patient discharged alive after cardiac arrest,and the mean hospital stay was 12 days.4 The emotionalburden of this devastating condition on the immediate familyis incalculable. As advance directives become prevalent,family members increasingly prefer withdrawing medicalsupport if the chances of a meaningful recovery are remote.Neurologists have to be able to predict reasonably the out-come of a particular patient. Important questions that ariseduring this period include the likelihood of severe disabilityor dependence and the ability to return to baseline function-ing. Currently neurologists and neurointensivists have alargely consulting role in the management of these patients.However, with the promise of new therapies such as hypo-thermia, neurointensivists should probably be closely in-volved in management to improve outcomes in these patients.This review summarizes current knowledge about the patho-physiology and consequences of cardiac arrest, and tools ofthe trade used in the prognostication and management of thisdevastating condition.

Strictly speaking, the term hypoxic-ischemic encepha-lopathy is not entirely correct in this setting because it impliesa common pathophysiologic mechanism for hypoxia andischemia (discussed later). The term postresuscitation en-cephalopathy (PRE) is preferred in the setting of brain injuryafter cardiac arrest and is used throughout this article.

PHYSIOLOGY OF CARDIAC ARRESTAND RESUSCITATION

Cardiac arrhythmias account for around 50% of casesof cardiac arrest. The remainder is associated with acuterespiratory failure or hypotension.5 In witnessed arrests, themost common arrhythmia is ventricular tachycardia (VT) orventricular fibrillation (VF) in a third of patients (33%).Respiratory causes (27%), asystole or bradyarrhythmias(18%), and electromechanical dissociation (18%) make upthe remainder.6 As rescuer arrival time lengthens, the

From the Division of Critical Care Neurology and Neurology, Mayo ClinicCollege of Medicine, Rochester, Minnesota.

Reprints: Eelco F.M. Wijdicks, MD, Mayo Clinic College of Medicine, 200First Street SW, Rochester, MN 55905. E-mail: [email protected].

Copyright 2005 by Lippincott Williams & WilkinsISSN: 1074-7931/05/1104-0234DOI: 10.1097/01.nrl.0000159985.07242.22

The Neurologist Volume 11, Number 4, July 2005234

proportion of asystole increases as other arrhythmias convertinto asystole. The type of arrhythmia at rescuer arrival doesimpact survival rates. The best prognosis is seen with ven-tricular tachycardia (survival to discharge, 34%) and theworst prognosis with asystole (610%) or bradyarrhythmias.5

In a large cohort, pulselessness for more than 10 minutes wasincompatible with survival.7 In general, the shockablerhythms (VT and VF) have a better outcome than thenonshockable rhythms (asystole and bradyarrhythmias).Even with shockable rhythms, the time difference betweencollapse and defibrillation should not probably exceed 5 to 6minutes.8 Unfortunately, even in the best of circumstances,the combined time between onset of cardiac arrest, andrescuer arrival and defibrillation is on the order of 7 to 10minutes, by which time irreversible brain injury has oftenset in.

The American Heart Association divides cardiopulmo-nary resuscitation (CPR) into 2 phases: basic life support(BLS) and advanced cardiac life support (ACLS).9,10 BLSconsists of airway maintenance, breathing, and circulatorysupport. ACLS consists of drug administration and defibril-lation. Closed chest compression is a major component ofBLS. During BLS, compression of the chest wall maintainscardiac output via 2 mechanisms. Chest compression activelyforces blood out from the heart by compressing it between thesternum and the spine (cardiac pump theory). A primaryincrease in the intrathoracic pressure could also drive bloodpassively from the heart into the great vessels (thoracic pumptheory). Backflow is often minimal because venous valves are

intact. Both theories are likely valid; recent echocardio-graphic studies show valvular closure and forward flowanalogous to the normal cardiac physiology with closed chestmassage.11

Standard CPR generates 1.3 L/minute forward flow and25-mmHg systemic perfusion flow.12 Nevertheless, this isable to maintain only 30% of prearrest cerebral blood flow(CBF) and not even enough coronary flow to maintain thedemands of a fibrillating heart.13 This has spurred efforts tofind more effective ways of establishing adequate vital organperfusion pressure. Simultaneous interposed abdominal com-pression, when alternate chest and abdominal compressionare carried out (chest compressed/abdomen relaxed, chestrelaxed/abdomen compressed), improves forward flow tosome extent (2.4 L/minute).12 Open chest compression car-diac massage and active compression-decompression CPR(ACD CPR) devices have also been used.

ACD CPR uses a hand-held suction device that isapplied to the mid sternum and it actively decompresses andcompresses the chest. Although short-term survival im-proved, there was no significant difference when comparedwith standard CPR in any of the studies.1417 Life-stick CPRis a new 2-handled device that alternately compresses anddecompresses the chest and abdomen through adhesive padsand improves forward flow (3.1 L/minute), although clinicalbenefits are yet to be seen.12 (Fig. 1)

With successful CPR, patients either achieve ROSC ordevelop a low-output cardiac state requiring inotropic sup-port. Among the survivors, nearly 70% will succumb during

FIGURE 1. This drawing illustratesthe different methods of resuscita-tion (see text for details).

The Neurologist Volume 11, Number 4, July 2005 Postresuscitation Encephalopathy

2005 Lippincott Williams & Wilkins 235

the subsequent hospital course. Although cardiac electro-physiologic instability is common after resuscitation, recur-rent arrhythmias such as recalcitrant complex ventricularectopics are only responsible for 10% of subsequent deaths.The majority of subsequent deaths in hospital are due to PRE(38%) or continued low cardiac output states (31%).18 Fur-thermore, distant organ damage and systemic complicationscan develop and worsen the outcome (Table 1).19,20 Somepatients develop a postresuscitation syndrome as a result ofwhole-body ischemia and reperfusion injury. This resemblesthe sepsis response and manifests with a systemic inflamma-tory response (increase in cytokine levels), myocardial dys-function, coagulopathy, and adrenal dysfunction, and contrib-utes to vasoparalysis and electrophysiologic instability duringthe postresuscitative period.21

CENTRAL NERVOUS SYSTEMPATHOPHYSIOLOGY

Within 20 seconds of cardiac arrest, the neuronal oxy-gen stores are depleted and the patient becomes unconscious.The central nervous system (CNS) is able to tolerate onlyvery brief periods of circulatory arrest, and glucose and ATPstores are depleted in 5 minutes. This is the critical periodduring which vulnerable tissue can be salvaged. During theimmediate postresuscitation period, global CBF and cerebral

metabolic rate of oxygen (CMRo2) transiently increase (tran-sient hyperemia) for 15 to 30 minutes. Subsequently CBFdecreases along with decreased CMRo2 (delayed hypoperfu-sion phase). The CBF is decreased to 50% of baseline valuesbetween 90 minutes and 12 hours after arrest. This decreaseis heterogenous and patchy. During this phase the cerebralautoregulation curve is often shifted to the right,22 which hasimportant implications for blood pressure management.

The underlying mechanism of cerebral necrosis isischemia. Pure hypoxia alone does not result in cerebralnecrosis23 even with extreme hypoxia (PaO2 20 mmHg).

24

Pure hypoxia results in a marked increase in CBF25 thatwashes out metabolic waste products. Consequently, neuro-nal damage is ameliorated even though oxygen delivery iscompromised. In this situation, GABA-ergic deficiency andsynaptic dysfunction are often readily reversible.26 Conse-quently, respiratory arrest alone has a better prognosis thanwhen associated with cardiac arrest.

In ischemia there is a massive outpouring of excitotoxicglutamate. This activates NMDA and AMPA receptors,opens calcium and sodium channels, and initiates cata-strophic enzymatic processes, leading to neuronal death.Unfortunately, although tissue perfusion is restored, neuronaldamage continues. Vulnerable neuronal populations (such ashippocampal CA1 neurons) briefly recover from the ischemicprocess before delayed neuronal death sets in.27 The neuriticprocesses (axons and dendrites) of these cells seem particu-larly susceptible to subcellular organelle disruption. Eventhough the cell body is relatively resistant to ischemia anddemonstrates regenerative changes after restoration of CBF,cell death eventually ensues via a die-back phenomenon. Anexciting new discovery is the role of unfolded protein re-sponses (UPR) in the endoplasmic reticulum. These pathwaysare abnormally activated during ischemia and increase apo-ptosis in vulnerable neurons.28

Two patterns of neuronal death are seen. Neuronal necro-sis and reactive astrocytes are seen in vulnerable areas. Inaddition, multifocal microinfarcts or confluent pan-cellular ne-crosis are seen in laminar and border zone arterial areas second-ary to postresuscitation microcirculatory disturbances.29

Preferential areas of involvement in the CNS includethe frontoparietal cortex, hippocampus, basal ganglia, cere-bellum, and spinal cord. Laminar necrosis of the cortex (withinvolvement of layers 3, 4, and 5) is often noted. The CA1

TABLE 1. Systemic Complications After SuccessfulRestoration of Spontaneous Circulation

Acute tubular necrosisTraumatic liver damage (due to CPR)Shock liverIschemic colon and sepsisPneumothoraxBone marrow embolusRib fracturesVentilator-associated pneumoniaSepsisPostresuscitation syndrome

Adapted with permission from Wijdicks EF. Neurologic Complicationsof Critical Illness. 2nd ed.20

The central nervous system (CNS) is able to

tolerate only very brief periods of circulatory

arrest, and glucose and ATP stores are depleted

in 5 minutes.The underlying mechanism of cerebral necrosis

is ischemia.

Maramattom and Wijdicks The Neurologist Volume 11, Number 4, July 2005

2005 Lippincott Williams & Wilkins236

area of the hippocampus (Sommers sector) is particularlyaffected by ischemia. Damage to the hippocampus can evenincrease with time and produce crippling amnesia.30 Withincreasing ischemia the mid brain and deep gray matter arealso involved. Ischemic myelopathy is found at autopsy inapproximately 46% of patients; however, it is often unrecog-nized during life. Involvement predominates at the lumbar orlumbosacral spinal cord whereas other areas are involved lessfrequently.31 Mild degrees of ischemia involve the lumbosa-cral spinal cord (69%), intermediate degrees affect the lum-bosacral and cervical spinal cord in a patchy manner (9%),and severe ischemia results in holo-cord necrosis (17%).Large neurons in the anterior and paramedian groups of theanterior horns and Clarkes column of the low thoracic andlumbar levels are preferentially involved. With severe cases,the gray matter is completely infarcted. The location oflesions in the CNS reflects the selective vulnerability oftissues to global ischemia, high metabolic demand, and thepresence of receptors for excitatory neurotransmitters in sus-ceptible areas. In contrast, other areas of more resistantneurons can withstand the same injury.

CLINICAL FEATURESPatients who are resuscitated from cardiac arrest dis-

play a wide variety of manifestations of PRE. A few patientsawaken or have purposeful motor movements almost imme-diately after CPR. These patients progress from an amnesic,confused state to gradual alertness within a few hours. Thisgroup has the best prognosis. Others are comatose, and manypatients are found to be spontaneously hypothermic. In gen-eral, the outcome of PRE worsens with the duration of coma.

If the duration of coma exceeds 6 hours, the proportionof patients who will regain independence during the firstpostarrest year drops to 10%. Within 3 days most comatosepatients who are destined to awaken will do so,32,33 andearlier awakening is associated with lesser impairment.

The initial degree of motor responsiveness is a goodindicator of outcome. A motor response consisting of local-ization or better at the initial assessment has a good progno-sis. The lack of motor response to pain at initial assessmentsuggests a poor recovery; less than 22% of patients recover toindependence. However, one must rule out a man-in-the-barrel syndrome before categorizing the upper limb motorresponse.34 This syndrome appears with bilateral border zoneinfarctions in the prerolandic areas at the ACA-MCA water-

shed region, which subserves proximal upper limb motorfunction. The syndrome presents with severe bilateral prox-imal upper limb weakness with preservation of lower limband distal upper limb power.

After ROSC, brainstem reflexes such as pupillary,oculocephalic, and corneal responses are often abnormal.Pupillary dilatation starts within 1 to 2 minutes of cardiacarrest. However, if dynamic pupillary changes are seenduring CPR (such as progressive decreases in pupil size orthe presence of light reactivity) a better prognosis isimplied than if the pupils are fixed and dilated throughoutthe procedure.35 In survivors, the pupillary reflexes returnquickly by 6 hours.36 Administration of atropine duringresuscitation can produce dilated pupils, which persist forseveral days, and this drug effect must be considered.Sustained upgaze is seen almost immediately after arrest inpatients who have sustained severe ischemia. Pathologicstudies show diffuse cerebral and cerebellar damage inthese patients with sparing of the mid brain.37 Thesepatients have a poor prognosis. Occasionally patients showjerky upward movements of the eyeballs along with myo-clonic facial jerking. Sustained downgaze has also beenreported, appearing a few days after arrest. Patients withthis sign often develop a persistent vegetative state (PVS)but have a better outcome than those with sustained up-gaze.38 Other eye movements such as ping-pong gaze orperiodic lateral gaze are associated with a poor prognosis,although some reports question their prognostic value.39

Generalized tonic-clonic seizures are uncommon andmay be related to lidocaine administration during CPR. Amore portentous development is the appearance of myoclonicstatus epilepticus (MSE). Intermittent or continuous, synchro-nous or asynchronous jerky movements affect the face, trunk,and limbs. The prognosis is uniformly poor and MSE isconsidered to be an agonal phenomenon.40 The Lance-Adamssyndrome, which occurs after hypoxia-induced cardiac arrest,is seen in awake patients, has a better outcome and mayrespond favorably to sodium valproate,41 baclofen,42 or leve-tiracetam.43 Rarer types of seizures seen in these patientsinclude area-specific stimulus-provoked seizures such ashemiclonic seizures provoked by stimulation of the trigemi-nal areas.44

Within 3 days most comatose patients who are

destined to awaken will do so.

The lack of motor response to pain at initial

assessment suggests a poor recovery; less than

22% of patients recover to independence.



Researchers have tried to identify variables that help inprognostication in PRE. A seminal paper by Levy et al32

presented rules to differentiate patients who had almost nochance of regaining independence from those who had thebest chance, based on clinical examination at specified inter-vals (Table 2). However, these rules still had a poor speci-ficity. Other authors used predictive models based on 4parametersmotor response, pupillary light reaction, spon-taneous eye movements, and the blood glucose level onadmissionfrom which a composite score from 0 to 9 pointswas generated.33 These scores had a high error rate inidentifying poor-prognosis patients. A more recent meta-analysis of predictive studies suggested only 4 variables hada high specificity: absent pupillary light reactions on day 3,absent motor response to pain on day 3, bilaterally absentmedian somatosensory evoked potentials (SSEPs) withinweek 1, and burst suppression or isoelectric EEGs withinweek 1.45 Evaluation for outcome prediction may thus be bestundertaken at 72 hours after the onset of coma. However, the

sensitivity of these predictors is still very low. Absent pupilreactions are seen in less than 20% of patients, and absentmotor responses or SSEPs are seen in only about a third ofthese patients. Obviously, more robust predictors of outcomeneed to be developed.

Prognosis is also influenced by other factors such asage, comorbidities, and circumstances of cardiac arrest. El-derly patients (75 years) with organ failure and unwitnessedor out-of-hospital arrest have the worst prognosis (2%chance of ROSC). Better outcomes are seen with youngerpatients and witnessed or in-hospital cardiac arrest. In wit-nessed arrests, the availability of automated external defibril-lators and increased prevalence of bystander CPR haveimproved survival rates. Indeed, in earlier studies, it was seenthat bystander CPR improved survival rates by prolonging theduration of shockable rhythms until emergency medicalservices (EMS) arrived for defibrillation.46 There is also a

TABLE 2. Levys Rules for Prognostication of Patients After Cardiac Arrest

Time of Examination Poor Prognosis Good Prognosis

Initial exam No pupillary light reflex Pupillary light reflex presentMotor response flexor or extensorRoving or orienting conjugate eye movements

1 day Motor response no better than flexor Withdrawal motor response or betterDisconjugate or nonorienting eye movements Spontaneous eye opening

3 days Motor response not better than flexor Normal spontaneous eye movementsWithdrawal motor response or better

1 week Not obeying commands Obeying commandsDisconjugate or nonorienting eye movementsNo spontaneous eye opening at 3 days

2 weeks Abnormal oculocephalic reflexes Normal oculocephalic reflexesNo spontaneous eye opening at 3 daysNot obeying commands at 3 days

TABLE 3. Poor Prognostic Factors in PostresuscitationEncephalopathy

Asystole or bradycardia at rescuer arrival (nonshockablerhythm)

ICU setting, critical illness, multiorgan dysfunction syndromeOut-of-hospital or unwitnessed arrestSustained upward and downward gazeAbsent pupil light response by day 3Absent motor response to pain by day 3Myoclonic status epilepticusBilaterally absent median somatosensory evoked potential within

week 1Burst suppression with epileptiform activity within week 1Diffuse cortical MRI abnormalities

A more recent meta-analysis of predictive

studies suggested only 4 variables had a high

specificity: absent pupillary light reactions on

day 3, absent motor response to pain on day

3, bilaterally absent median SSEPs within

week 1, and burst suppression or isoelectric

EEGs within week 1.



large difference in survival between those patients who arrestin-hospital or out-of-hospital. Of patients who arrest in-hospital, 44% attain ROSC5 and 15 to 17% survive todischarge. Out-of-hospital arrests have a poorer survival rateof 2 to 5% at 1 month.47,48 Two thirds of all survivors suffervarying degrees of neurologic impairment, and a third areable to return to work.6,49

Poor prognosis is also seen with ICU patients who oftenhave a critical illness, chronic underlying medical disease, ormultiorgan dysfunction syndrome in whom the survival todischarge approaches zero.50 Table 3 details all poor prog-nostic features collected from the previously mentioned lit-erature.

Once the recovery phase begins, it follows characteris-tic patterns during the first postresuscitation year. In theinitial phase, cranial nerve reactivity, miosis, and spontane-ous respiration return. Patients then develop motor respon-siveness with decerebrate posturing followed by decorticateposturing. The EEG shows only intermittent electrocorticalactivity at this time. Subsequently the EEG shows continuouscortical activity along with stereotypic motor reactivity andspontaneous eye opening. After awakening, recovery withvariable degrees of disability is seen.51 The spectrum ofrecovery ranges from severely affected patients with demen-tia and total dependency to those with minimal involvementand return to normal functioning.

LABORATORY INVESTIGATIONSDrugs, sepsis, and metabolic abnormalities could

hamper the interpretation of the EEG and make it lessuseful than evoked potentials. Immediately following re-suscitation, the EEG may show electrographic silence, anddistinct patterns tend to evolve only after 24 hours. Thusthe EEG is most useful after 24 hours. Certain patterns areassociated with a poor prognosis, including the generalizedsuppression and the burst suppression patterns.52,53 Gen-eralized suppression patterns may even evolve after 2 to 3days and are associated with a grave prognosis. Burstsuppression patterns may be compatible with an outcomeequivalent with a PVS. Drug-induced changes (propofol,

midazolam) can mimic all these patterns and should beexcluded as influences on the EEG. Generalized epilepti-form discharges can be seen in a periodic or pseudoperi-odic pattern, associated with myoclonic jerks or eyeblinks.54 These discharges are usually associated with afatal outcome. -, -/-, or -pattern coma may be tran-siently seen and by itself is not associated with a pooroutcome. They tend to evolve over 5 days into a moredefinitive pattern, and subsequent EEG reactivity is abetter predictor of outcome.55

Evoked potentials are less susceptible to sedative drugs,metabolic changes, or artifactual interference. Median N20SSEPs are conventionally used in the prediction of recoveryafter cardiac arrest. Absence of potentials has more valuethan their presence. If the N20 potential is absent in thepresence of preserved lower potentials (Erbs point, neck),there is a specificity of 100% for mortality, provided con-founding focal lesions affecting the cortical potential havebeen ruled out. If the N20 potential is present, there is noprognostic value in PRE. SSEP has the disadvantage of lowsensitivity (5567%). Due to variations in SSEP with time indifferent studies,56,57 this modality is more accurate if used24 hours or more after the event.

Computed tomographic (CT) scans are normal imme-diately after resuscitation. Changes are seen after a few days.Diffuse cerebral swelling with effacement of basal cisternsand sulci or diffuse hemispheric hypodensities from edemaare seen. Basal ganglia, cerebellar, and watershed area in-farcts can be seen. These areas are particularly involved dueto their large metabolic demand and consequent need for ahigh blood supply.58 A reversal sign is sometimes seenwhen the gray matter becomes hypodense with a diffuserelative white matter hyperdensity.59 Elevated intracranialpressure (ICP) leading to partial obstruction of cerebral ve-nous drainage and consequent distension of the deep medul-lary veins may underlie this phenomenon. This sign is amarker of poor prognosis.60

Magnetic resonance imaging (MRI) could play a role inthe prediction of outcome. In the first week following cardiacarrest, the presence of widespread diffusion or FLAIR abnor-malities in the cortex, thalamus, and cerebellum could por-tend poor outcome. Other areas that are typically involved inPRE are the striatum and hippocampus. Cortical abnormali-ties are thought to be more important than changes in otherlocations. Diffuse abnormalities suggest devastating PRE incontrast to restricted abnormalities.61,62 Reperfusion can alsocause microhemorrhages in the basal ganglia, which can bedetected by MRI.63 Conventional MRI can be normal; how-ever, diffusion-weighted MRI (DW MRI) will likely showsome changes (Fig. 2). DW MRI also helps to date the injuryby showing gray matter changes in the acute and earlysubacute stages, and white matter changes in the late subacutestage. In the chronic stage, DW MRI is normal.64 The

In the first week following cardiac arrest, the

presence of widespread diffusion or FLAIR

abnormalities in the cortex, thalamus, and

cerebellum portends irreversibility could portend

poor outcome.



disadvantages of MRI lie in the logistic difficulties of trans-porting patients on multimodality support, ventilators, andinotropic agents to the MRI scanner. The need for closemonitoring for recurrent arrhythmias or hemodynamic sup-port may also preclude MRI. Nevertheless, the costs ofunnecessary medical support may be offset by the importantinformation afforded by this modality.

Positron emission tomographic (PET) scans provideadditional information. Globally decreased CBF and oxygenextraction is seen with devastating PRE.65 Patients destinedto remain in a prolonged coma demonstrate progressivereductions in CMRo2 over the first week following resusci-tation.66 However, as yet PET cannot differentiate good-outcome from poor-outcome patients or add to prognosticinformation derived from other variables.67 Moreover, cur-rently it is a cumbersome technique.

TREATMENTEvidence-based guidelines have not been developed for

the management of the postresuscitation phase. The primary

goals of treatment at this stage are hemodynamic stability,maintenance of adequate oxygenation, and prevention ofsecondary brain damage. The patient is typically intu-bated and ventilated in the field. PaO2 goals are 100 to150 mmHg, and PCO2 goals are 40 to 45 mmHg. Rat modelsdemonstrate a reduction in volume of necrotic tissue if PaO2levels are maintained at more than 200 mmHg.23 This hasbeen achieved at normobaric levels and may be applicable inhumans, although randomized, controlled trials are needed tosettle this issue.

Midazolam and fentanyl are used to decrease the stressassociated with invasive procedures and to facilitate ventila-tion. Neuromuscular blockers are helpful in preventing shiv-ering. Head position is optimally maintained at 30. Twistingof the neck can increase jugular venous pressure and theo-retically may increase ICP. Ideally, the head should bemaintained straight without turning it from side to side.

The blood pressure temporarily increases in some pa-tients, partly due to the effect of epinephrine administeredduring resuscitative measures. In other patients, a sepsislikestate (the postresuscitation syndrome) develops, requiringintravenous (IV) fluids and pressors to maintain the bloodpressure.21 Because the cerebral autoregulation curve isshifted to the right and microcirculatory disturbances arepresent, it is advantageous to maintain normotension orinduced hypertension to increase tissue perfusion. Mean ar-terial pressure (MAP) is raised with crystalloid infusionsanalogous to the management of subarachnoid hemorrhage.Vasopressors such as epinephrine, norepinephrine, dopamine,dobutamine, or vasopressin can be used if these measures fail.It must be stated that although induced hypertension withepinephrine has not demonstrated improved outcomes aftercardiac arrest, MAPs are typically maintained at more than 60mmHg to ensure adequate CBF.68

Blood sugar management is also controversial. Hyper-glycemia has been associated with decreased regional CBF69

and worse outcome.70 However, it is undetermined whetherhyperglycemia is an epiphenomenon or a primary factor.Currently, administration of small amounts of glucose solu-tions during the postresuscitation phase does not seem toworsen outcome even when 5% dextrose is used.71 In thelong term, physicians should probably avoid the use ofdextrose-containing solutions to attenuate cerebral swellingas well as to prevent chronic hyperglycemia and hyperinsu-linemia.

Myoclonic jerks prove troublesome in some patients.MSE can interfere with mechanical ventilation and be asource of distress for family members. The jerks do notrespond to conventional antiepileptics such as phenytoin orbarbiturates. In these circumstances, propofol or neuromus-cular-blocking agents can prove very useful.72 Lamotriginehas the potential to be useful in MSE, especially as it hasshown promise in rat models by decreasing hippocampal cell

FIGURE 2. DW MRI shows restricted diffusion in the thalamusbilaterally and in the frontal cortices. Corresponding FLAIRimages are normal.

Hypothermia is postulated to improve outcome

by reducing CMR, ICP, glutamate release, and

production of reactive oxygen species.



loss after cardiac arrest (via inhibition of glutamate release).73

Again, human trials are lacking for this indication.Although ICP elevations are expected in these patients,

this is not often the case. In one study of 7 patients whounderwent ICP monitoring, 6 had an ICP of less than20 mmHg, and the only patient with raised ICP had concur-rent seizures.74 ICP is often normal in these patients becauselesions are small and patchy. Currently, there is no goodevidence to suggest that ICP monitoring is helpful in themanagement of patients with PRE. The use of jugular venousoxygen saturation or other invasive modalities has likewisenot been demonstrated to improve outcome.

New and exciting developments have taken place inresuscitation physiology with the introduction of inducedhypothermia. Two controlled trials have demonstrated a mod-est improvement in outcome with this therapy.75,76 Hypother-mia is postulated to improve outcome by reducing CMR, ICP,glutamate release, and production of reactive oxygen spe-cies.77 Various techniques have been used to reduce coretemperatures, including cooled helmets, ice packs, rapid in-fusion of cold IV fluids (30 mL/kg ice-cold crystalloids),external cooling devices, and water-cooled mattresses. Addi-tional measures include gastric lavage hourly with ice-coldsaline, axillary ice packs, and air-cooled blankets. Hypother-mia has been used only in comatose or stuporous patientsbecause it is extremely uncomfortable for awake patients.Nevertheless even comatose patients required neuromuscu-lar-blocking agents to control compensatory shivering. Inthese 2 trials, hypothermia was initiated within 2 to 3 hoursafter cardiac arrest, and core temperatures were reduced to 32to 34C (measured by bladder probes). The optimum durationof induced hypothermia is currently unclear, although thesetrials used durations of 12 to 24 hours with gradual rewarm-ing thereafter. In the 2 trials, hypothermia has been achievedover a 2- to 8-hour period, although it is likely that fastercooling rates could result in better outcomes. Potentiallythese can be achieved by rapid IV infusion of cold saline viaa central venous catheter (with a reduction of 23C within30 minutes).78

Limitations of these studies include poor documenta-tion of neurologic findings after resuscitation and inadequateoutcome determination. Additionally, we do not yet knowhow soon after resuscitation hypothermia needs to be inducedor the duration of treatment necessary. Other practical limi-tations of hypothermia include complications such as pneu-monia, sepsis, coagulopathy, electrolyte shifts, and cardiacarrhythmias. Fortunately, brief hypothermia (1224 hours)seems to produce few complications and is relatively safe.Most patients with PRE are encountered in the cardiac ICUs,where the neurologist plays a consulting role. Cardiologistsare unlikely to initiate induction of hypothermia, and areconcerned about electrophysiologic instability and medicalcomplications. Hence, unless neurologists take an active part

in the management of these patients, this aspect of therapy islikely to be neglected. A word of caution is necessary.Although the results of the trials look promising, large,randomized, controlled trials are needed before this mode oftherapy becomes the standard of care. For the interestedreader, comprehensive reviews of hypothermia are availablethat provide more information on this subject.79,80

Elevated body temperature has been shown to worsenoutcome in these patients,81,82 and acetaminophen is used ifbody temperature exceeds 38C. If induced hypothermia isnot achievable, at least normothermia should be maintainedfor neuronal integrity.

Another new development has been the use of throm-bolytics after cardiac arrest. A pilot placebo-controlled, ran-domized trial using tenecteplase showed a modest benefit inROSC (36% difference compared with placebo), althoughsurvival to discharge was not affected.83 However, patients inthe treatment arm were younger (P 0.04) and more likelyto have VF as the rhythm at rescuer arrival (44%). It ispossible that the benefit seen with this drug is likely due to theinfluence of age and shockable rhythms. Again, a largerrandomized study is necessary to shed more light on theeffectiveness of this therapy.

CONCLUSIONAs the patient arrives in the ER, the physician should

obtain information regarding circumstances, location, dura-tion of CPR, and type of arrhythmia encountered at arrest. Atadmission, findings suggestive of a poor outcome are sus-tained upgaze and MSE. Serial clinical examination is man-datory, although neurologic findings have the strongest pre-dictive value after 3 days. Investigations including SSEP,EEG, and neuroimaging provide corroborative information.An SSEP is ideally obtained after 24 hours. Although an EEGis often obtained urgently, a repeat EEG after 4 to 5 days willmore likely display patterns with a higher predictive value.Neuroimaging should be delayed for a few days becauseradiologic changes evolve slowly. MRI is more sensitive thanCT. It should be realized that, ultimately, clinical findings arestill the best predictors of neurologic outcome.

With the increasing use of antiarrhythmic agents and-blockers, increasing numbers of patients are presenting toERs with cardiac arrest due to asystole rather than VF or VT.This is balanced by an increase in public awareness, by-stander CPR, automated external defibrillators, faster EMSresponse times, and the advent of therapies such as inducedhypothermia. Hence, it is likely that the numbers of patientswith PRE will increase over time.

To reduce neurologic morbidity and disability amongsurvivors, aggressive intervention is necessary to ameliorateprimary and secondary neuronal injury. There is promise forneuroprotective agents84 and therapies such as hypothermiaand thrombolysis during this critical juncture, and these



modalities represent a vast area of potential research. Fur-thermore, the elucidation of subcellular mechanisms of braininjury is likely to provide the key to the management of PRE.

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