MAY 1997 - Volume 8 - Number 2


Cerebral Resuscitation After Global Brain Ischemia: Linking Research to Practice
Therese S. Richmond, RN, PhD, CCRN, FAAN
During the past few decades tremendous technological advances in resuscitation medicine have occurred. Despite such
advances as early initiation of cardiopulmonary resuscitation (CPR). by bystanders and the use of advanced cardiac life
support in both prehospital and in-hospital settings, the survival rates for prehospital cardiac arrest to hospital discharge are
less than 20%. As if the high mortality were not dismal enough, more than half the survivors experience significant neurologic
deficits. Only 3% to 10% of resuscitated patients are finally able to resume their pre-cardiac-arrest lifestyles.2 It has become
well recognized that ischemic and postischemic events can cause significant neuronal damage. The focus of research today
is to further elucidate the pathophysiology of ischemic brain damage and to test strategies to successfully resuscitate the brain.
This article examines advances in resuscitation medicine, with a specific focus on cerebral resuscitation. Because of the rapid
changes in resuscitation research, clinicians can anticipate an ever-evolving change in practice into the next century as
scientific evidence serves either to support current practice or to radically alter it.

Extent of the Problem
The primary causes of cerebral ischemia commonly occur in acute care settings. The prototype of global brain ischemia is
cardiorespiratory arrest. Regardless of the initiating factors, cardiac arrest culminates in death to vital organs, most profoundly
the brain. Given the repercussions of ischemia on the brain, it is essential that clinicians extend their resuscitation focus beyond
CPR to include cardiopulmonary cerebral resuscitation. Approaching the patient from the perspective that death is not a
distinct moment in time, but rather a protracted physiologic process during which the person dies cell by cell by cell, will
assist clinicians in refocusing their resuscitation efforts.

Although global brain ischemia is the pro-totype and the focus of this article, it is important for clinicians to recognize that
incomplete cerebral ischemia occurs frequently. Evidence suggests that the lactate accumulation that occurs during
incomplete ischemia significantly hinders brain recovery.3 Shock, regardless of its cause, results in insufficient blood flow,
leading to acidosis. This acidosis is fed by an inflow of glucose at a time when the metabolic pathways cannot efficiently and
aerobically metabolize it.

Advanced practice nurses in all subspecialties of acute care have the opportunity to recognize the importance of cerebral
reperfusion techniques to their own specialty populations. It matters not whether the patient is hospitalized for renal, cardiac,
or gastrointestinal problems. Any patients who are at risk for or experience low-flow or no-flow states are at significant risk for
cerebral ischemia. Creating brain-friendly environments requires all personnel to be attuned to the implications of systemic
ischemia on the brain and to take steps to prevent and treat it.

Goals of Resuscitation
Clinicians must recognize that successful resuscitation outcomes are not limited to the restoration of normal cardiac rhythm and
hemodynamics. Rather, resuscitation must be viewed in the broader context. As defined in the dictionary, resuscitation is the
restoration of consciousness, vigor, and life.4 The true goal of resuscitation is the restoration of human mentations However,
necrologic recovery continues to be the major limiting factor in resuscitation medicine. By a conservative estimate, more
than 800,000 cardiac arrests occur annually in the United States. Survival to hospital discharge is less than 20% and may be
as low as 11%. 1,6 Data from the Brain Resuscitation Clinical Trial I showed that when arrest time was no longer than
6 minutes and resuscitation time was no longer than 30 minutes, only 50% of patients had a good necrologic recovery.7 When
resuscitation time exceeded 30 minutes, only 3% had good necrologic outcome. In those patients whose arrest time was longer
than 6 minutes but whose resuscitation efforts were less than 5 minutes, 50% of patients had good recovery. In all cases
where arrest time was longer than 15 minutes, 0% had good recovery.7 Given these rather dismal statistics, it should be clear
that CPR as currently practiced is inadequate at best and must be viewed as evolutionary. Cardiopulmonary re-suscitation is
not the gold standard but rather a rudimentary intervention that requires on-going researched-based refinement. It is
imperative that all health care providers be brain-oriented during episodes of cardiac arrest and low-flow states in order to
fully restore mentation and achieve maximal functional outcomes.

Pathophysiology of Global Cerebral Ischemia
Although the brain is only 2% of body weight, it receives 20% of cardiac output. The brain requires a constant supply of
oxygen and glucose and consequently is dependent on a consistent cerebral blood flow (CBF). The brain is dependent
on the complete oxidation of glucose derived from the circulation for all of its energy requirements. 8

Two physiologic mechanisms are in place to protect the brain from an interruption of flow. Autoregulation, which maintains
constant cerebral perfusion in the face of fluctuating systemic blood pressure, is the primary mechanism in place to ensure
a constant supply of glucose and oxygen. In the normal brain, autoregulation maintains global CBF of about 50 mL/100 g
brain/min.9 The secondprotective mechanism is the cerebral metabolic requirement for oxygen (CMRO2), that tailors blood
flow to the specific metabolic needs of focal areas of the brain. The dependence of the brain on normal levels of CBF is
highlighted by its vulnerability to relatively brief ischemic periods.3

Consequences of Inadequate Blood Flow
A cascade of injurious events begins within minutes of ischemia. Within 6 to 8 minutes, permanent neuronal injury and death
occurs in the central ischemic area. However, there is a variable therapeutic window of opportunity that continues for several
hours after ischemia.10 It seems that global brain ischemia leads to the selective loss of subpopulations of neurons, while
neighboring neurons remain unaffected.8 Indeed, there is substantial experimental evidence that when adequately reperfused,
energy metabolism will recover after an arrest duration of as long as 1 hour of normothermic arrest.11

That this apparent resiliency of neurons does not translate into clinical recovery is evidenced by the grim outcomes. The
neuronal degeneration is not irreversibly determined by the ischemic period alone.8 Contributing to neuronal damage are the
numerous metabolic and hemodynamic disturbances that occur during and after arrest. It is difficult to firmly ascertain which of
the abnormalities are the key mediators of the pathophysiology of ischemic brain and attempts to elucidate key abnormalities
are the focus of current research.11

Impaired Perfusion
The induction of cerebral ischemia results in a rapid depletion of cerebral oxygen that culminates in unconsciousness in 10
seconds, followed by the depletion of glucose within 2 to 4 minutes.9 At this point, cells convert to anaerobic metabolism.
Adenosine triphosphate (ATP) concentration is initially maintained at the expense of phosphocreatine via the creatine kinase
reaction and anaerobic metabolism.8 However, cellular ATP is exhausted within 4 to 5 minutes from the onset of complete
ischemia.2 Maintenance of ionic gradients that normally consumes 50% to 75% of total energy metabometabolism fails,
resulting in ionic fluxes of sodium, potassium, and calcium (Table 1).

Abnormal cellular efflux of potassium and cellular influx of sodium result in both neuronal and interstitial swelling.8 Cellular
influx of calcium initiates a cascade of events including the cellular membrane breakdown that results in increased levels of
phospholipase and free fatty acids that trigger prostaglandin production and a biochemical cascade that leads to neuro-
cellular death.2 Calcium also causes the diversion of mitochondrial energy away from ATP production.

The loss of energy production and the alteration in ionic environment lead to a range of changes. Most notable is the extra-
cellular accumulation of glutamate, a neurotransmitter in the brain responsible for excitatory responses.8 Extracellular
glutamate increases with the length of ischemia to approximately fivefold after 10 minutes of ischemia and 10- to 15-fold by
20 minutes of ischemia and has been implicated in neuronal damage and death.8

Adenosine triphosphate does not immediately recover with the restitution of CBF. The extent of ATP depletion is dependent
on ischemia time and hence the recovery of normal ATP levels is a function of ischemia time as well.8 Once ATP production
recovers, ionic gradients are restored and the other metabolites are normalized.

TABLE 1 Pathophysiologic Consequences of Impaired Cerebral Perfusion
Consequences	Timing
Depletion of oxygen	10 sec.
Depletion of glucose	2-4 min
Conversion to anaerobic metabolism	2-4 min
Exhaustion of cellular ATP	4-5 min
Consequences
Efflux of potassium
Influx of sodium
Influx of calcium

Postresuscitation Impaired Perfusior
Reperfusion and reoxygenation injury after reestablishment of systemic perfusion can last for 2 to 12 hours after cardiac
arrest and are typified by areas of hypoperfusion. Areas receiving trickle flow Gess than 10% CBF) and almost no CBF are
interspersed among regions of low, normal, or even high flow. Clinicians can consider this an ongoing "code" that is typified
by ongoing scattered ischemia. Clinicians cannot afford to congratulate themselves when patients at-tain a normal cardiac
rhythm and stable blood pressure, because these postarrest dynamics continue to contribute to cellular destruction and death
and worsen morbidity and mortality.

Impaired cerebral perfusion after cardiac arrest results in a period of no-reflow with multifocal ischemia followed by a short
period of global hyperemia, then prolonged hypoperfusion and finally the resolution phase.12,13 These changes in cerebral
perfusion during and after global brain ischemia are complex and not fully understood. However, it does seem that most of the
neuronal damage is incurred during reperfusion.2

Although there is a brief reactive hyperperfusion, there continue to be scattered areas not adequately perfused, resulting in a
mis-atch between oxygen supply and demand. Plausible mechanisms for areas of no-reflow include increased blood viscosity,
physiologic compression of the vascular lumen, endothelial microvillus formation, and inadequate perfusion pressure.3,11
No-reflow after ischemia is a major limiting factor in survival and quality of recovery after cardiac arrest.11

Reoxygenation Injury Cascades
Clinical evidence indicates that organ reperfusion exacerbates tissue injury.3 Blood derangements including polymorphonu-
clear leukocyte and macrophage aggregates may obstruct capillaries and release free radicals.9 It is now clear that
reperfusion of ischemic tissues stimulates a series of biochemical reactions that contribute to tissue injury.l4 Reoxygenation,
while essential for the restoration of cell function, appears to initiate chemical cascades involving iron, oxygen free radicals,
calcium, excitatory amino acids and catecholamines that result in cell membrane lipid peroxidation.9 The brain is especially
prone to oxidant damage.15 Since free radical-mediated damage was first demonstrated, it has become clear that although
partial injury occurs at the time of ischemia, much of it is sustained as reperfusion.l6 Substantial evidence exists that reactive
oxygen metabolites participate in the pathogenesis of brain damage after cerebral ischemia.l7,l8 Reactive oxygen metabolites
are compounds derived from molecular oxygen that have acquired less than four electrons.l4 The presence of iron in an acidic
environment or metal chelates seems to enhance the generation of free radicals.l4,l

During the reperfusion/reoxygenation injury after global brain ischemia, enhanced free radical production occurs with a burst
of superoxide production that initiates the infiltration of neutrophils by activation of the superoxide-dependent chemoattractant.
Oxygen free radicals attack the biochemical functioning of the cell, with the most likely targets being lipids, proteins, and
nucleic acids. The lipid component of the cellular membrane is the first structure encountered by oxygen free radicals and
hence is the most frequently damaged cellular compo-nent.l8 Not only are cells damaged or lysed, but more toxic oxidants
are generated. There follows an influx of neutrophils, referred to by McCord as the foot soldiers of the body's war for self-
preservation. Oxidant formation has been shown to contribute to the expression of adhesive structures on the surface of
neutrophils, promoting leukocyte adhesion to postischemic tissue.l4 Neutrophils have been shown to release enzymes that
contribute to the pathological catalytic oxide dynamics.l4 The tissue damage results in further release of oxygen free radicals
and a vicious cycle ensues.

Although commonly referred to as oxygen free radicals, the more appropriate term is reactive oxygen metabolites, the release
of which is strongly correlated with the severity of ischemia. A vicious cycle ensues in which oxygen free radicals initially
released from damaged cells contribute to additional cellular damage, which consequently results in the release of more
oxygen free radicals.

The concept of reoxygenation injury provices hope for improving outcomes, because there is a therapeutic window of oppor-
tunity during which treatment of reperfusion injury can occur. It is during this critical post-cardiac arrest.global brain ischemia
that there is the most potential for preventing such processes that were once thought of as irreversible.l6

Assessment
Any event that leads to global brain is-chemia places patients at risk for cortical and whole-brain failure. Clinicians need to be
aware of this potential and incorporate necrologic assessment in any situations in which ischemia to the brain ensues. The
challenge is that during episodes of ischemia, performance of neurological examinations are difficult at best to perform and
challenging to interpret. Such classic resuscitation events as the injection of exogenous catecholamines, the use of paralytic
agents, and the use of sedatives all serve to cloud and alter the necrologic assessment. Serial neurologic examinations,
focusing on higher cortical function and brain stem function, assume increasing importance in the imme-diate postresuscitation
period.

Changes in neurologic findings are prognostically important. Duration of coma has been shown to be inversely related to
recovery. The Cerebral Resuscitation Study Group for the Belgian Society for Intensive Care reported that when post-
cardiac arrest Glasgow Coma Score value was more than 10 or less than 4, the ability to predict outcome at 2 days was 80%
correct. Unfortunately, when the value was between 5 and 9, accurate prediction of outcome could not be achieved until day 6.20

The ability to accurately assess patients and develop reliable prognoses is important for three reasons. Arriving at an accurate
assessment and realistic prognosis is central to informing families about probable outcome. Provision of information and advice
to families concerning the benefits and burdens of proposed treatments must be linked with realistic goals of treatment. The
ongoing dialogue that must occur between family members and the health care team is most useful when based on a firm
foundation of accurate assessment. Finally, the just deployment of resources within the health care system is assuming increas-
ing importance in today's environment. Limiting resource consumption by patients with little hope of recovery has become
increasingly important to prevent the inadvertent denial of resources to patients with better chances of recovery.

Neurodiagnostics
Unlike other body systems, there is not one gold standard marker that indicates the degree of cerebral insufficiency.
Potentially useful diagnostics include: the determination of cerebral perfusion pressure, calculation of CMRO2, measurement
of creatine kinase-BB (CK-BB), and electrophysiologic studies.

Cerebral perfusion pressure (CPP) provides the rough clinical evidence of adequacy of CBF. Cerebral perfusion pressure
(the difference between mean arterial pressure and intracranial pressure) is normally 60 to 90 mmHg. When CPP is less than
30mmHg, neurons are threatened. Normal CBF is 50 to 60 mL/100 g of brain/min, which in the average-sized adult converts
to a total flow of 700 to 840 mL/min. Because pressure is not synonymous with flow, it is important to examine the relationship
between CPP and CBF. When CPP decreases below 50 mmHg, CBF decreases. Critical CBF seems to be 20% of normal.
Although the brain has been shown to tolerate low flow (more than 10% of normal) better than no flow, it is important to
recognize that it tolerates no flow better than trickle flow (less than 10% normal). The clinician can calculate CPP when
intracranial pressure monitoring is in use. In this case, CPP is the difference between the mean arterial pressure and the
mean intracranial pressure.

Although clinically of most interest, the CMRO2 (the amount of oxygen extracted by the brain to meet its requirements) is
not a variable that is easily measured. Normal CMRO2 (3.4 mL/100 g brain/min) is the quotient of CBF and arteriovenous
oxygen difference.21 A low CMRO2 indicates ischemia. To minimize extracerebral blood contamination, samples for
CMRO2 calculation are obtained from the superior bulb of the jugular vein. Alternatively, the clinician can measure jugular
bulb venous O2 saturation that reflects the ratio of global cerebral oxygen supply to demand and thus the status of cerebral
oxygen metabolism.22

In the near future the ability to measure CK-BB will be possible. This test shows promise of becoming an indicator of the
extent of necrologic damage after cardiac arrest. The majority of CK-BB is found in the brain, but does exist in other tissues
(gastrointestinal tract, bladder, uterus, vasculature, and prostate gland). When released from damaged cells, CK-BB is
degraded rapidly in the body and thus is at its highest levels immediately af-ter injury (the first 0.5 to 2 hours), but may
persist for several days if continuing injury occurs.23 Elevated CK-BB levels may not singularly demonstrate necrologic
damage, but may actually reflect release from the injured vasculature. Cerebrospinal fluid CK-BB level has been called the
brain's chemical biopsy and has been shown to correlate with the severity of neu-rologic damaged 24

Other diagnostic tests include the electroencephalogram and electrophysiologic studies. The electroencephalogram
has been used to predict neurologic outcome after cardiac arrest and to rule out the presence of subclinical seizure activity
in patients with cerebral ischemia. As a stand-alone diagnostic test, the evidence supporting the prognostic ability of the
electroencephalogram is conflicting.25 However, a recent study by Chen et al.26 suggests that the presence of a malignant
electroencephalogram coupled with abnormal motor responses is prognostic of a poor outcome. Other electrical diag-
nostic studies such as evoked potentials may also contribute to prognostic ability. The predictive ability of brainstem
auditory evoked responses has been examined and proven useful in children who have suffered cardiac arrest after
submersion in water.27 However, normative data are required before the wide application of this technology.27

Therapeutic Modalities
Because of the complex and multifaceted pathology of post-cardiac-arrest encephalopathy, there is not one treatment for
postis-chemic neuronal protection (Table 2). It is most likely that multiple therapies will be required and will be better than
a singular approach. 10Cardiopulmonary Resuscitation To date, the only known way to improve necrologic outcome is to
improve resuscitation response time, shorten the duration of cardiac arrest, and achieve early restitution of blood flow to
ischemic tissues.14 Current approaches to closed-chest CPR, even when performed in an exemplary manner, are
nsufficient to adequately perfuse the brainy Chibber et al.28 reported on a series of 32 patients in witnessed cardiac arrest,
and found that peak systolic artery pressure during CPR was only 59.8 (+4.3). Even with the addition of exogenous
catecholamines, closed-chest CPR does not provide adequate CBF. Despite its limitations, closed-chest CPR continues
to be the initial intervention for the treatment of cardiac arrests both inside and outside of the hospital. Because the longest
normothermic arrest period that is followed by complete cerebral recovery is still 4 to 5 minutes, educating the community in
basic CPR should be continued and increased.5

The limitations in current practice suggest the need to examine new modalities of CPR. There are currently two methods of
CPR proven to be superior to closed-chest CPR. New and promising methods, however, are logistically difficult to routinely
use. Open-chest CPR produces close to 100% normal CBF. Although commonly used in the post-cardiotomy and pen-
etrating trauma population, open-chest CPR is not widely accepted for routine arrest situations in prehospital or in-hospital
settings. As health care providers and the public become more comfortable with invasive modalities, open-chest CPR may
surface as a viable therapeutic intervention.

Closed-chest venoarterial cardiopulmonary bypass using the groin vessels is an alternative to open-chest CPR. This
procedure allows control of circulation, oxygenation, blood composition, and temperature. Series of animal experiments
show that cardiopulmonary bypass produces a reliable circulatory resuscitation while concurrently decreasing the work of
a stunned myocardium, thus facilitating recovery.l.9 Portable emergency cardiopulmonary bypass allows for control over
cerebral resuscitation during prolonged life support, but before full-scale implementation, cardiopulmonary bypass would
have to undergo well-controlled human studies to ex-amine its effects on necrologic outcomes5

TABLE 2 Brain-Oriented Therapeutic Modalities

Cardiopulmonary cerebral resuscitation

Promotion of reflow

Ventilatory support

Hypothermia

Pharmacologic support

Hemodilution

Metabolic manipulation

Prevention/control of seizure activity

Control of free radical-mediated injury

Promotion of Reflow
Cerebral resuscitation is impossible without the ability to restore spontaneous and stable normotension.9 Given the
pathophysiologic consequences of a no-flow state that occurs during cardiac arrest, the promotion of re-flow is a priority in
the early postresuscitation phase. Critical to meeting this goal is the understanding that reperfusion pressure must be high
enough to overcome the resistance built up by increased blood viscosity and the reduction of the microvascular lumen.ll

Induced hypertension has been shown to improve neurological outcome in animal studies29 and can be considered in the
post-cardiac-arrest population if cardiac status can tolerate it. Safar9 suggests giving a brief hypertensive bout on restoration
of systemic circulation, followed by controlled normotension using fluids and vasoactive drugs as necessary. Increasing the
systolic pressure to 150 to 200 mmHg serves to start reperfusion, but may have the consequence of increasing the cardiac
burden, requiring constant hemodynamic monitoring of the post-cardiac-arrest patient.

Ventilatory Support
Maximizing oxygen delivery, necessary to reestablish cellular processes dependent on ATP, using controlled ventilation
for at least the first 12 hours after cardiac arrest is preferred.9 Current thought is to maintain normocarbia throughout the
duration of coma.9 Hyperventilation may serve to vasoconstrict normal vessels yet exert little to no effect on damaged
vessels, thus increasing the possibility of ischemia.

Hypothermia
Reduction of CMRO2 is central to intra- and postresuscitation neuronal protection. Induced hypothermia has been shown to
decrease CMRO2, decrease the rate of enzymatic reac-tions, and decrease the rate of ATP depletion. Although it has been
shown that the brain is capable of withstanding extended ischemia when intrinsic temperature is lowered before cardiac
arrest, this is not particularly useful for the unexpected cardiac arrest. The use of post-cardiac-arrest hypothermia has been
shown to protect the brain from reperfusion injury although not to the degree achievable when hypothermia is instituted in the
pre-cardiac-arrest state.3,8 Moderate hypothermia (28°C to 32°C) may be more protective of the neurons, but is more likely
to induce ventricular fibrillation. Mild hypothermia (34°C) has been shown in animal studies to protect the brain without
cardiac side effects.30 Although findings are mixed on the effect of mild hypothermia on CBF and cerebral metabolism, it
does consistently improve neurologic outcome.30 Thus the effects of hypothermia on cerebral resuscitation efforts seem
to be multifactorial.l2 Some mechanisms by which this improved outcome is achieved are by the suppression of free
radical, enzyme, excitotoxic, and inflammatory reactions in addition to the direct physical protec-tion of membranes.31

The goal, then, is to rapidly decrease brain temperature without incurring cardiovascular side effects. Intracarotid iced saline
slush is the most effective but least feasible method of achieving a rapid drop in brain temperature. A feasible alternative
tested in dogs is the use of an iced hood that encapsulates the head and creates a localized hypothermia. Further research
is required before widespread human use.

In summary, hypothermia used alone and in combination with other therapies shows promise in the protection of the brain in
the post-cardiac-arrest state. Induction of mild brain hypothermia as early and rapidly as possible is recommended, but the
optimal duration of hypothermia is unknown.9 Although there is not currently a recommended mechanism by which cerebral
hypothermia can be induced in the human population, clinicians can institute conven-tional means to prevent elevated body
temperature and to create a mild hypothermia.

Pharmacologic Interventions
To date, there are no clinically effective pharmacologic agents for amelioration of brain damage from ischemia and
reperfusion injury.2 Epinephrine, currently a part of ad-vanced cardiac life support protocols, is an effective agent to
increase perfusion pres-sures of the heart and brain. Epinephrine remains superior to other alpha receptor agonists in
achieving this goal, yet optimal dosing has not yet been achieved.9 Timely correction of metabolic acidemia is important
and has been shown to improve resuscitability and cerebral recovery in animal models.9 The clinician must continually
assess acid-base status in order to normalize metabolic acidemia, but take care not to overshoot and create an alkalotic
state.

In addition to its edema-reducing properties, mannitol has been shown to increase cortical CBF and is a good free-radical
scavenger. In a series of 35 patients, mannitol was found to cause a significant increase in CBF when autoregulation was
defective, even in the absence of an effect on cardiac output.32 To date, optimal dosing of osmotherapy for its neuro-
protective properties has not yet been established.9

Etomidate is a carboxylated imidazole that depresses cerebral metabolism without the cardiotoxic effects found in high-
dosebarbiturates.33 Although there are promising animal studies, there are no well-controlled human clinical trials that can
currently support the use of etomidate as a cerebral protective agent in the post-cardiac-arrest state. However, it is highly
likely that etomidate prolongs the brain's ischemic tolerance by decreasing neuronal electrical activity and metabolic
demand.33

Hemodilution
Normovolemic hemodilution with the goal of achieving a hematocrit level of 30% to 35% increases flow by decreasing
viscosity and resistance to flow in the microvasculature. Coupled with induced hypertension, normovolemic hemodilution
has been shown to result in a more homogenous cerebral perfusion and improved oxygen delivery after cardiac arrest in
animal models.9

Metabolic Manipulation
The age-old practice of empirically administering D50W has undergone reevaluation. Although it is true the hypoglycemia
of less than 50 mg/dL is deleterious to the brain, the opposite is also true.9 An elevated blood glucose level at the onset of
ischemia exaggerates neuronal damage, impairs recovery of high-energy phosphate, and causes greater hypoperfusion,
but the mechanisms by which this is accomplished are not fully understood.l7,34 Hyperglycemia feeds the glycolytic path-
way and is associated with increased lactic acidosis and more severe tissue damage.8 A trickle of blood flow with high
glucose is worse than no flow at all. Unfortunately, at the onset of arrest, because of the stress response, glucose rises.

Control of blood glucose is critical in the immediate postischemic period. The optimal range of blood glucose is unclear,
but it is safest to keep it within normal range at ap-proximately 100 to 200 mg/dL.9 Interestingly, the role of insulin in pre-
vention of postis-chemic brain injury seems to be independent of its hypoglycemic effect.2 Duration of postischemic control
of glucose remains unclear.9

Prevention and Control of Seizure Activity
The post-cardiac-arrest patient is at high risk for seizure activity secondary to the residual mass of injured neuronal and
glial tissue called the ischemic penumbra. This evolving ischemic zone is highly irritable.l Seizure activity is deleterious to
neuronal survival, because seizures increase the CMRO2 by 300% to 400%. This increase in oxygen demand occurs at a
time when oxygen delivery is impeded.

Phenytoin is the drug of choice to prevent seizure activity. The rapidity with which therapeutic levels can be accomplished
with the relative safety of phenytoin makes it an optimal treatment. Furthermore, phenytoin has been shown to provide addi-
tional neuronal protection by decreasing cellular permeability and facilitating the sodium potassium pump.

Therapy to Minimize Free Radical-Mediated Injury
Therapy aimed at minimizing free radical-mediated injury focuses on prevention and scavenging of free radicals, augmen-
tation of host antioxidant defenses, and prevention of tissue damage amplified by neutrophils. Most research focuses on
agents that directly scavenge free radicals. The most notable of this group are the Lazaroids (21-aminosteroids), however
there are several aminosteroids under study. All aminosteroids have the common steroid-like structure, but are devoid of
glucocorticoid or mineralocorticoid action.15 Interest in the Lazaroids rests in their ability to scavenge superoxide anions
and lipid hydroperoxides.

Chelating agents, specifically those aimed at iron metabolism, augment host antioxidant defenses. It is theorized that free
iron in the acidic environment facilitates the generation of free radicals, with the subsequent damage to cellular membranes.
Deferoxamine is a chelating agent that effectively sequesters iron from participation in the formation of oxygen free radicals.
There is also research on the use of nonsteroidal anti-inflammatory agents because of their role in blocking the tissue
damage resulting from the nonspecific neutrophil amplification. All of the agents targeting free radical-mediated injury
require additional clinical trials before the routine application to clinical practice.

Excitatory Amino Acid Antagonists
Early in clinical trials, N-methyl-D-aspartate and other excitatory amino acid antagonists are being examined for their
potential in reducing ischemic damage. It is hypothesized that there is a toxic build-up of excitatory neurotransmitters as a
result of cellular ischemia that produces further neuronal injury.l There are currently ongoing clinical trials examining safety,
pharmacokinetics, and efficacy of this group of drugs. Various drugs known to effectively deplete glutathione also are
hoped to improve neurologic outcomes.l8

Interventions Not Supported by Research
Corticosteroids have long been used for a variety of neurological diseases. Although corti-costeroids have been shown
to stabilize vascular membranes, prevent astrocyte swelling, and improve intracranial compliance, there has been no
clinical benefit shown from the postischemic administration of steroids.l Two hundred and sixty-two patients entered in the
Brain Resuscitation Clinical Trial I were retrospectively placed in one of four treatments groups (no, low, medium, and high
steroids) in the first 6 hours after cardiac arrest. No difference in Glasgow Outcome Score was found among the four groups.

Calcium channel blockers have received increasing attention for their potential role in neuronal protection after cardiac
arrest. By inhibiting calcium entry into the injured neurons, they inhibit the metabolic distur-bances associated with ischemia.
In addition, they may inhibit calcium-induced vascular smooth muscle contraction and stabilize erythrocyte membrane.
In animal studies, calcium channel blockers have been shown to increase cortical CBF, increase electrical activ-ity, and
improve cellular metabolism in the post-cardiac-arrest state. However, research has shown inconsistent improvement in
outcomes in dog, primate, and human trials. The Brain Resuscitation Clinical TrialII, performed in 24 hospitals in eight
countries, reported no significant difference in outcome at 6 months when comparing 520 patients, half of whom had re-
ceived lidoflazine versus placebo within the first 30 minutes after arrest.36 Additionally,the lidoflazine group had increased
incidence of hypotension and re-current ventricular fibrillation. Although there are additional ongoing clinical trials, based on
the results of this clinical trial, there is no support for the use of calcium channel blockers at this time outside of a clinical trial
protocol.

High-dose barbiturate coma was viewed as a hopeful therapy because of its ability to reduce CMRO2. Clinical trials of
barbiturate induced coma have been disappointing and high-dose barbiturate coma has only been shown to be effective
in certain subgroups of the post-cardiac-arrest population.37 Barbiturate therapy for cerebral protection is currently viewed
as optional9 and if used should be accompanied by appropriate he-modynamic assessment and support.

Summary
The challenge of cerebral resuscitation after no-flow and low-flow states has assumed increasing importance as ever-
improving technology increases the number of survivors. Gone are the days when death was synonymous with a moment
in time. Research has shown that patients die cell by cell by cell and that the therapeutic window of opportunity extends well
beyond the period of systemic instability. Given our increasing understanding of the pathophysiology of global brain is
chemia, clinicians can tailor their care to incorporate both intra-cardiac-arrest and post-cardiac arrest interventions aimed
at improving neurologic outcome.

References

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