Background

Despite our recognition of the brain’s dominant role in determin- ing the quality of life, modern
medicine’s ability to intervene and reverse neuronal injury remains limited. Consequently, modern
techniques of brain resuscitation are focused on restoring cerebral homeostasis and mitigating the
effects of secondary brain injuries. Hypoxic-ischemic injury following cardiac arrest can be seen as a
model of global ischemic disease, and recent advances in under- standing of its pathophysiologic
mechanisms have led to improve- ments in neurologic outcomes. Although hypoxic-ischemic injury
represents a so-called pure form of brain ischemia, its underlying pathology has significant overlap with
other cerebral injuries, such as stroke and traumatic brain injury. Thus, many of the physio- logic
principles of brain resuscitation following cardiac arrest are applicable to these conditions. This chapter,
therefore, reviews the pathophysiology of ischemic brain injury and discusses therapies for improving
neurologic recovery following cardiac arrest and other critical neurologic illnesses in which cerebral
ischemia may occur.

Anatomy, Physiology, and Pathophysiology

The human brain consists of 10 billion neurons, each with mul- tiple connections to other cells,
totaling an estimated 500 trillion synapses. Although the brain constitutes only 2% of body weight, it
receives 15% of the body’s cardiac output and accounts for 20% of the body’s overall oxygen use.
Although no mechanical or secretory work is performed by the brain, energy expenditures include the
synthesis of cellular constituents (eg, an estimated 2000 mitochondria are reproduced each day by each
cell) and neurotransmitter substances, axoplasmic transport of these sub- stances, and transmembrane
pumping of ions.
When the brain is deprived of adequate blood flow, the result- ing ischemia is characterized by a
bewildering array of interrelated physiologic and cellular responses that ultimately result in neuro- nal
cell death (Fig. 7-1).1 Although this complex cascade of events can be triggered by periods of ischemia
lasting only a few minutes, the resulting neuronal death is usually delayed by hours or days.
Furthermore, the biology of cerebral cell death after global cere- bral ischemia follows the pattern of
delayed cerebral cell death that follows stroke, traumatic brain injury, and other forms of hypoxic or
toxic brain injury, with slight variations. Increased understanding of the brain’s response to injury during
the period between insult and neuronal cell death will eventually allow more specific brain resuscitation
therapies.

Elevated Intracranial Pressure

Intracranial pressure (ICP) is an important consideration in isch- emic brain injury because
cerebral ischemia can directly result in ICP elevation. This occurs because the failure of oxidative phos-
phorylation depletes adenosine triphosphate (ATP) stores, which results in an inability to maintain
osmotic gradients actively. Increased intracellular osmolarity leads to water influx and the development
of cytotoxic edema, which usually peaks 48 to 72 hours after injury. By decreasing cerebral perfusion
pressure (CPP), elevated ICP is also an important contributor to secondary brain injury. This relationship
is discussed in further detail below; additional information on ICP management is contained in the
pharmacology, devices, and techniques sections.
To understand the pathophysiology of elevated ICP, it should be noted that the skull is a rigid
container whose relatively non- compressible contents include the brain (~80%), blood (~10%), and
cerebral spinal fluid (CSF; ~10%). According to the Monro- Kellie hypothesis, any addition to the volume
of one of these components—for example, increased brain volume due to cere- bral edema—must be
offset by a reduction in the volume of the other contents or the ICP will rise.
Typically, adaptation to increased intracranial volume is ini- tially accomplished by shifting CSF
from the intracranial to spinal subarachnoid compartment. Approximately two-thirds of cere- bral blood
volume is contained in the cerebral veins and dural sinuses, and this venous capacitance can be reduced
to accom- modate increased intracranial volume further. Unfortunately, these mechanisms are
sometimes quickly exhausted, resulting in decreased compliance and a significant increase in ICP. This
may occur rapidly with acute cerebral injury or slowly with mass lesions such as tumors.
In its final stages, uncontrolled intracranial hypertension will result in downward herniation of
the cerebellar tonsils through the foramen magnum, thereby compressing critical cardiorespira- tory
centers in the medulla. Prior to or concurrently with this, elevated ICP can exacerbate ischemic injury by
reducing cerebral blood flow. CPP is equal to the mean arterial pressure (MAP) minus ICP. As ICP
increases, CPP decreases, which is compen- sated for by cerebral arteriolar vasodilation. Unfortunately,
this vasodilation may increase cerebral blood volume, which can additionally increase ICP and further
reduce CPP. This vicious cycle is one of the primary inciting factors for the prolonged periods of
refractory ICP elevation known as plateau or Lundberg A waves.

MANAGEMENT
Decision Making
Standard management of ischemic brain damage involves restor- ing cerebral blood flow (CBF)
and preventing secondary insult. Most treatments have not been studied in prospective, random- ized,
controlled trials, but have been supported by clinical expe- rience and limited experimental data.
Although proposed and experimental neuroprotectant therapies are generally aimed at specific
molecular interventions in the pathophysiology of isch- emic brain injuries, as yet none of these have
proven effective in clinical trials. In the case of ischemic injury following cardiac arrest, the most
comprehensive review and consensus guideline statement on care of patients with post–cardiac arrest
syndrome has come from the International Liaison Committee on Resus- citation and its constituent
bodies, with the endorsement of the American College of Emergency Physicians, Society for Academic
Emergency Medicine, Society of Critical Care Medicine, and Neurocritical Care Society.2 Improvements
in post–cardiac arrest care, through an inclusive multisystem approach, can increase the
likelihood of meaningful recovery in these patients. Implemen- tation of standardized protocols for
postresuscitation care that include many or all of the following components have demon- strated
increases in survival, with a favorable neurologic outcome of up to 30% in repeated (although poorly
controlled) before and after studies.

Pharmacology, Devices, and Techniques

Cardiopulmonary Resuscitation
In the event of cardiac arrest, return of spontaneous circulation is the first priority in cerebral
resuscitation. The degree of brain injury after cardiac arrest depends on the duration of complete
cerebral ischemia (the downtime, or time before the initiation of cardiopulmonary resuscitation [CPR])
and duration of relative ischemia that occurs during CPR and that may occur from car- diogenic shock
preceding or subsequent to the period of cardiac arrest. Events occurring after the restoration of flow
(eg, transient hypoxia, hypotension) also can exacerbate brain damage in this dynamic and important
early resuscitation time period. Extensive clinical evidence on hospital discharge rates and neurologic
recov- ery rates supports the concept that success in resuscitation is inversely proportional to the
duration of cardiac arrest. Although duration of arrest generally predicts outcome in the population of
patients with sudden cardiac death, it cannot be used reliably to predict the outcome of individual
patients. Modern brain resuscitation techniques focus on avoiding further secondary cerebral injury,
which also affects outcome. Neurologic outcome of survivors is influenced by patient age, comorbidity
and other individual characteristics.
The efficacy of closed chest CPR in generating adequate cere- bral perfusion is somewhat
controversial. Cardiac output during optimal standard closed chest CPR was previously estimated to be
only 20% to 30% of normal, but more recent studies have suggested that higher cardiac outputs are
possible in clinical prac- tice and, unquestionably, effective CPR is essential to neurologic recovery after
cardiac arrest.

Reperfusion
With cerebrovascular insults due to embolic or thrombotic mech- anisms, randomized clinical
trials have shown a benefit of revas- cularization in ischemic stroke. This is discussed in detail in Chapter
91).

Optimizing Perfusion and Oxygenation.

Maintaining cerebral oxygen delivery is a mainstay of therapy after ischemic brain injury.
Oxygen delivery requires a sufficiently high CPP, sufficiently low cerebrovascular resistance (CVR), and
adequate blood oxygen saturation.
Hypotension can dangerously lower cerebral blood flow (CBF) and is associated with worse
outcome following cardiac arrest and traumatic brain injury (TBI). Normally, a change in systemic blood
pressure triggers corresponding changes in CVR, mediated by cerebral arterial vasodilation or
vasoconstriction. This capacity, termed cerebral autoregulation, functions to maintain a constant CBF
over a wide range of arterial blood pressures. Autoregulation is often lost in the injured brain and, as a
result, perfusion of ischemic tissue becomes passively dependent on CPP. Conse- quently, hypotension
can compromise CBF and result in signifi- cant additional brain damage. Therefore, low arterial
pressures should be rapidly normalized, with intravascular volume admin- istration and vasopressors
used as needed. In the absence of pro- spective clinical trial data to guide decision making, current
recommendations for cardiac arrest patients are to maintain a MAP of 65 to 100 mm Hg. Induced
hypertension, once believed to enhance CPP, is not currently a standard therapy due to con- cerns
related to disruption of the blood-brain barrier and worsen- ing of vasogenic edema.
Blood pressure goals fundamentally differ in intracerebral hemorrhage (ICH), in which elevated
blood pressure at presenta- tion is common due to a physiologic pressor response. Hyperten- sion is a
known risk factor for hematoma expansion, yet the targeted blood pressure goal in these patients
remains controver- sial due to uncertainty regarding perfusion to the brain tissue surrounding the
hematoma (ischemic penumbra). A large, mul- ticenter, randomized controlled trial has demonstrated
that rapid lowering of the systolic blood pressure (SBP) to less than 140 mm Hg is safe and may have a
small but meaningful benefit on neu- rologic outcome.5 Consequently, we endorse immediate manage-
ment with IV antihypertensives targeting an SBP less than 140 mm Hg. As in other conditions where
there is a risk of secondary ischemic injury, hypotension should be diligently avoided by not allowing the
MAP to drop below 65 mm Hg.
CVR is a critical determinant of CBF and may be affected by hyperventilation and microvascular
patency. Although the cere- bral circulation may lose its ability to adjust to blood pressure
changes after ischemia, attenuated responsiveness to carbon dioxide and oxygen levels in arterial blood
is generally present.3 Carbon dioxide is a potent vasoactive agent, and lowering the arterial carbon
dioxide partial pressure (Paco2) by hyperven- tilation results in a rapid reduction of CBF of 2% for every
1-mm Hg decrease in the Paco2. Because reductions in CBF reduce total cerebral blood volume,
hyperventilation quickly lowers ICP. Induced hyperventilation can transiently abort brain- stem
herniation in the presence of critically elevated ICP until an alternative therapy can be initiated.
However, the vasoconstric- tion and increased CVR caused by hyperventilation can lead to dangerous
reductions in CBF, with resulting cerebral ischemia.4 We recommend restricting the use of induced
hyperventilation to the short-term treatment of immediately life-threatening cere- bral herniation and
severe intracranial hypertension that is not responsive to other measures, such as osmotic therapy.
Chronic or prophylactic hyperventilation should not be used. Specific treatment for elevated ICP is
described in the next section. In general, ventilation to maintain a Paco2 of 35 to 40 mm Hg is safe and
appropriate, and inadvertent hyperventilation should be avoided.
Normal arterial oxygen saturation following resuscitation from ischemic brain injury is a primary
goal. The injured brain may not be able to compensate for hypoxia by augmenting CBF, and cerebral
oxygen delivery may diminish rapidly as the oxygen content of blood decreases. Hyperoxia secondary to
the use of high concentrations of oxygen, however, has also been shown to increase oxidative brain
injury in animal models of cardiac arrest and resuscitation and is associated with increased mortality in
stroke patients5 and in post–cardiac arrest patients.9 Normoxia or mild hyperoxia (arterial partial
pressure of oxygen, Pao2, of 80–120 mm Hg with oxyhemoglobin saturation percentage main- tained in
the high 90s) should be maintained through use of the lowest fraction of inspired oxygen (Fio2) possible.
Because hypoxia, hypocapnia, and hypercapnia must be avoided, con- trolled ventilation is appropriate
in the period after resuscitation, with sedation and muscle relaxation if needed. Continuous oxim- etry
and capnography, correlated with intermittent arterial blood gas determinations, will provide the
information necessary to optimize ventilation parameters.

Elevated Intracranial Pressure

The presence of intracranial hypertension is suggested by certain imaging findings and clinical
features. Relevant computed tomog- raphy (CT) findings include compressed basal cisterns, diffuse
sulcal effacement, and diffuse loss of differentiation between the gray and white matter, although ICP
can be elevated without any of these findings. Suggestive clinical features include papilledema, bilateral
sixth nerve palsies, and new third nerve palsy in a coma- tose patient. Definitive diagnosis requires
invasive ICP monitor- ing placement. The decision to place an ICP monitor should be guided by
neurosurgery whenever consultation is available. Most data on the management of elevated ICP is
derived from literature on TBI, a condition in which ICP elevation commonly occurs. Although support
from randomized controlled trials is lacking, the Brain Trauma Foundation has published guidelines for
ICP monitor placement, which we recommend following in TBI patients whenever possible. These call
for ICP monitor placement in all patients with an abnormal head CT scan and severe brain injury, defined
as a Glasgow Coma Score of 3 to 8. ICP monitoring is considered appropriate in the presence of a normal
head CT when two of the following are present: (1) age older than 40 years; (2) unilateral or bilateral
motor posturing; and (3) SBP less than 90 mm Hg.
Guidelines are not available for ICP monitoring in other con- ditions involving ischemic brain
injury, such as stroke, where it is generally not indicated. In particular, the clinical impact of intra- cranial
hypertension due to anoxic brain injury following cardiac arrest is unclear and has not been studied in
prospective trials. When cytoxic edema severe enough to cause ICP elevation devel- ops, it portends a
very poor prognosis. Consequently, invasive ICP monitoring is not recommended in the management of
global ischemic injury following cardiac arrest.

Medical Treatment.
Medical treatment for elevated ICP has similarly not been proven effective in randomized
controlled trials, and treatment protocols are primarily based on clinical experience and expert opinion.
To ensure adequate cerebral perfu- sion, the MAP should be maintained above 65 mm Hg in all patients
at risk for ICP elevation, and a CPP of 50 to 70 mm Hg should be targeted when ICP monitoring is
available. Although the exact threshold for ICP treatment is unclear and may vary between individual
patients, an ICP over 20 mm Hg has been associated with worse neurologic outcomes and should trigger
treatment. Although there are many and somewhat diverse rec- ommendations for the initial medical
management of patients with elevated ICP, we suggest the following:
1. Position the patient with the head up by elevating the upper half of the bed or gurney to 30 degrees.
2. Maintain a neutral head and neck position to avoid jugular venous compression.
3. Treat fever. Administer antipyretics agents (eg, acetaminophen suppositories, 1000 mg every 6 hours)
and use mist cooling as necessary, targeting a temperature at or below 37°C.
4. Minimize triggers of ICP increases.
This is accomplished by treating and avoiding pain. We recom-
mend titrated doses of a hemodynamically stable opioid medica- tion, such as fentanyl 25 to 50 μg every
5 minutes, as needed. Cough or bucking of the ventilator also should be avoided; this is best
accomplished by achieving adequate sedation and analgesia to permit mechanical ventilation, as
described in Chapters 1 and 2. Propofol is our sedative agent of choice for this purpose because it
decreases cerebral metabolic activity and thereby CBF, and rapidly clears for neurologic assessment, as
needed. Propofol can cause or contribute to hypotension, which generally is avoided by dosage
adjustment.
5. Initiate osmolar therapy.
Osmolar therapy with mannitol or hypertonic saline can draw
water across an intact blood-brain barrier and thereby lower ICP. Mannitol, 0.5 to 1 g/kg is given every 6
hours, up to a serum osmolality of 320 mOsm/kg. Treating with 30 mL of 23.4% normal saline appears to
be at least as effective as mannitol at rapidly lowering ICP and reversing herniation, although a central
line is necessary for safe administration; 30 to 60 mL can be given every 6 hours, up to a maximum
serum sodium level of 160 meq/L. Because it is a potent diuretic, mannitol is preferred in cases of fluid
overload, whereas hypertonic saline can be used as a resuscitative fluid.
6. Treat cases of refractory ICP elevation not amenable to the previous therapies.
Induced coma with a barbiturate will further decrease CBF and
lower ICP. Pentobarbital is started with a 10-mg/kg loading dose over 1 hour, followed by a continuous
infusion of 0.5 to 5 mg/ kg/h, titrated to achieve electroencephalographic burst suppres- sion.
Barbiturate administration is frequently accompanied by hypotension, which often requires
vasopressors to maintain ade- quate CPP.
7. Mild induced hypothermia is an additional option in highly refractory cases.
Endovascular or surface cooling devices should be used to
target a temperature of 32° to 36°C, titrated to achieve ICP control. Once cooled, rapid rewarming
should be avoided because this may precipitate a significant ICP elevation.

Surgical Treatment.
Surgical options for the management of refractory ICP include decompressive craniectomy and
evacu- ation of intracranial hematoma, when present, and should be guided by neurosurgical
consultation. In the event of severe cyto- toxic edema following middle cerebral artery stroke, there is a
benefit of early (<36 hours) decompressive hemicraniectomy in patients younger than 60 years.6 A
bifrontal craniectomy is typi- cally used to treat refractory ICP in TBI. Based on a recent ran- domized
controlled trial that noted worse outcomes in TBI patients treated with very early craniectomy, we
recommend reserving craniectomy for patients that have failed medical man- agement, or as an urgent
life-saving procedure when cerebral herniation is present in this population.

Maintenance of Body Temperature

Hyperthermia (or fever) exacerbates brain injury and worsens neurologic outcome.17 Elevated
body temperature increases cere- bral metabolic demand by 8% to 13%/°C, escalates glutamate release,
increases oxygen free radical production, and increases cytoskeletal and blood-brain barrier breakdown,
with increased vasogenic edema. The core body temperature should be moni- tored in patients
resuscitated from cerebral ischemia and mea- sures should be initiated to prevent temperature
increases in the postischemic period. In general, all temperature higher than 38°C should be treated
aggressively with acetaminophen and surface cooling. Inducing therapeutic hypothermia has emerged
as a therapy for comatose survivors of hypoxic-ischemic injury fol- lowing cardiac arrest.

Resuscitative Mild Hypothermia

More than 50 years ago, hypothermia was first claimed to have a protective effect in global and
focal brain ischemia. The neuro- protective mechanism is linked to a reduction of glutamate release,
metabolic demand, free radical formation, and production of inflammatory cytokines. Cell signaling and
genetic responses to cellular injury are also affected, and hypothermia may protect the brain from
programmed neuronal cell death.
Mild hypothermia (32°–34°C) is easier to achieve and has fewer adverse effects than lower
temperatures and has consistently been found to be neuroprotective in experimental models of cerebral
ischemia. Two multicenter prospective, randomized controlled trials of mild hypothermia have shown
marked improvements in neurologic outcome in comatose survivors of out-of-hospital cardiac arrest
(Table 7.1).18,19 In these trials, the number needed to treat to have one additional patient with a good
neurologic outcome was only about seven. Evidence-based guidelines recommend cooling unconscious
adult patients after cardiac arrest to 33°C for 12 to 24 hours.7 Recent investiga- tions in adults and
children have compared therapeutic hypo- thermia of 33°C to targeted temperature management”
(TTM) of 36°C.8,9 The safety and efficacy of TTM versus therapeutic hypothermia were no different.
There is strong biologic evidence from earlier clinical trials and animal models that 33°C provides better
neuroprotection. The TTM trial did not provide evidence that one target was easier or safer than the
other. Most patients included in these trials had immediate bystander CPR and, by extension, were likely
to have less severe neurologic insults than cardiac arrest patient resuscitated in routine practice outside
Europe. Given the evolving nature of the evidence in this area, we recommend protocols that cool to a
target of 33°C; however, practicing emergency clinicians should work with their inten- sive care
colleagues to develop local protocols. A definitive tem- perature control device, surface or endovascular,
with a feedback loop temperature sensor is required, regardless of the target chosen.
The optimal method of cooling patients resuscitated from cardiac arrest has not been
established (see Chapter 8). Animal experimentation and consensus recommendations have suggested
that cooling should be initiated as early and rapidly as possible. Cooling may begin during the out-of-
hospital phase of resuscita- tion and may even be initiated before return of spontaneous cir- culation. In
the positive clinical trials, hypothermia at 33° ± 1°C was achieved by 2 or 8 hours after return of
spontaneous circula- tion and was maintained for 12 or 24 hours. Patients are allowed to rewarm
passively or with a combination of passive and active rewarming. Rebound hyperthermia is common
with passive rewarming and should be avoided.
Clinical trials of mild hypothermia in adults and children with traumatic brain injury have
generally been small and have shown variable results, but large multicenter trials evaluating the use of
mild hypothermia as a neuroprotectant or treatment for elevated ICP are ongoing. Therapeutic
hypothermia following ischemic stroke is not of proven benefit, and we do not recommend its use (Box
7.1).

Avoidance of Hyperglycemia
Postischemic hyperglycemia has detrimental effects on CBF, metabolism, edema formation, and
neurologic outcome. Hyper- glycemia after brain ischemia is strongly associated with worse outcomes in
diabetics and nondiabetics. Because the brain is an obligate glucose consumer, brain resuscitation must
balance hyperglycemia prevention with adequate cerebral glucose availability. Cerebral microdialysis
studies in humans have shown that tight glucose control (<120 mg/dL) is associated with low cerebral
glucose and elevated lactate levels, which in turn are associated with increased mortality.20 Current
recommendations for glucose control following cardiac arrest are to avoid hypogly- cemia and target a
blood glucose level of less than 180 mg/dL. This can typically be achieved by the administration of
subcutaneous insulin, although a continuous intravenous insulin infusion is sometimes necessary. A
multicenter clinical trial of intensive insulin therapy in acute ischemic stroke is currently underway.

Seizure Management
Although the prevention of seizures has not been demonstrated to improve neurologic
recovery, seizures are clearly not desirable in the postischemic period. Seizures can result from global
cere- bral ischemia and may exacerbate underlying brain injury. Seizure activity can increase brain
metabolism by 300% to 400%, worsen- ing the mismatch between oxygen delivery and demand, with
greater metabolic failure and neuronal loss and worsened neuro- logic outcome. When present,
prolonged seizures or status epilep- ticus following cardiac arrest are strongly, although not invariably,
associated with a poor neurologic outcome. Nonconvulsive status epilepticus has been reported after
cardiac arrest; consequently, continuous electroencephalographic monitoring is frequently used in
comatose survivors, and we recommend its use for patients who are paralyzed while receiving
therapeutic hypothermia.21 Electroencephalographic findings have been shown to predict neurologic
outcome after cardiac arrest reliably and, in the future, electroencephalographic monitoring may be a
core component in prognostication algorithms.
We do not recommend the prophylactic use of anticonvulsant drugs in patients resuscitated
from cardiac arrest, but seizures should be quickly and effectively treated. Lorazepam, 0.1 mg/kg, with a
maximum rate of 2 mg/min, is the preferred first-line agent to abort seizures and should be followed by
longer term treatment with an antiepileptic drug. Phenytoin, levetiracetam, or valproic acid are equally
efficacious options based on current data. These are all available in IV formulations. Treatment is
initiated with identical 20-mg/kg loading doses. In intracerebral hemorrhage, the prophylactic use of
anticonvulsants has been associated with worse neurologic outcomes, and we concur with current
guide- lines that do not recommend their routine use.12 In TBI, prophy- laxis with phenytoin reduces
seizures during the first 7 days, but not beyond, and has not been shown to improve outcome. There are
limited data suggesting that prophylaxis with levetiracetam may be better tolerated than phenytoin, so
7 days of levetiracetam, 500 mg bid ,is our preferred regimen for prophylaxis in TBI patients.

OUTCOMES
Cerebral ischemia is a frequently fatal and highly morbid condi- tion, but the prognosis for its
victims is not universally poor. An increasing body of data is providing more complete and precise
estimates of the functional outcomes and quality of life of survi- vors, and the results are better than
many emergency clinicians assume.
However, identification of reliable prognostic indicators of severe brain injury is hampered by
the self-fulfilling prophecy, in which counseling provided to families of patients with a pre- sumed poor
prognosis leads to withdrawal of life-sustaining treat- ments, thereby seeming to confirm the poor
prognosis. There is significant individual and institutional variation in the implemen- tation of “Do not
resuscitate” (DNR) orders and early withdrawal of life support, and these variations can profoundly
affect our understanding of outcomes. In an important study using a large data set of patients with ICH,
institution of DNR orders within 24 hours was strongly associated with mortality, independently of other
known risk factors.14 Consequently, recent ICH guidelines have emphasized the importance of avoiding
assigning new DNR status within the first day of hospital presentation.15 Prognostica- tion in TBI, which
disproportionately affects young adults, can be particularly difficult, and there are examples of good
outcomes in spite of a prolonged hospital course and numerous poor prognos- tic indicators.
On the other hand, prolonged survival with significant dis- ability also may be a tragic outcome,
and consideration of this may lead emergency clinicians and families to consider with- drawal of life
support. This may account, in part, for the nihilism common among emergency clinicians treating
patients with cardiac arrest. This may arise in part from the fact that most survivors of cardiac arrest are
comatose at the time of admission and without early prognostic findings suggesting which patients will
have a favorable outcome. The most recent American Academy of Neurology (AAN) guidelines (2006)
for prognostication after cardiac arrest are driven by data from the pretherapeutic hypo- thermia era.
These guidelines identified six factors that reliably predict poor outcome—absent pupillary response,
corneal reflex, or motor response at 72 hours; neuron-specific enolase (NSE) level higher than 33 μm/L;
myoclonic status epilepticus within 24 hours; and bilateral, absent, somatosensory evoked potentials.
More recent data from patients undergoing therapeutic mild hypothermia have cast doubt on the
reliability of several of these factors. In particular, NSE levels and motor responses at 72 hours have had
poor predictive value in these patients. Additionally, a higher false-positive rate has been associated
with absent corneal reflexes at 72 hours and early myoclonic status epilepticus. Further clinical studies
and meta-analyses are needed to clarify reliable prognostic indicators.
Despite continued work to identify an imaging biomarker for outcome after cardiac arrest, there
is no established role for early magnetic resonance imaging or CT in prognostication in survi- vors of
cardiac arrest. In the near future, serum biomarkers of brain injury may identify the potential for
neurologic recovery early in a patient’s course and help guide therapy. Until early predictions of
outcome can be made accurately, the emergency clinician should consider most survivors of cardiac
arrest as having a significant chance of full recovery (14%–55%); however, patients with severe coma
(motor plus brainstem four score below 4 in the absence of sedatives and paralytics) within 6 hours of
resuscitation have a lower likelihood of recovery (5%–10%).

SUMMARY
Rapidly expanding knowledge about the pathophysiology of post- ischemic brain injury has
stimulated the search for effective cere- bral resuscitation therapies. Newly proven therapies such as
resuscitative hypothermia will continue to be studied and will improve the outcomes of patients with
ischemic brain injury in future years. Although experimental work has suggested many potentially
promising brain resuscitation therapies, attention should also be paid to determining the benefits of
existing stan- dard therapies. Because of the complexity and interconnectedness of the pathophysiologic
cascades that occur after cerebral isch- emia, it is likely that a multifaceted therapeutic approach
targeting mediators of secondary brain injury, rather than a single pharma- cologic agent, is needed to
reduce neurologic damage after cardiac arrest.
It is crucial that the emergency clinician recognize that the patient resuscitated from ischemic
injury is, contrary to his or her outward appearance, in a dynamic stage of brain injury. At present,
patients should be protected from further brain injury caused by hypotension, hypoperfusion, ICP
elevation, hypoxia, hyperthermia, hypoglycemia. hyperglycemia, and seizures. Coma- tose survivors of
out-of-hospital cardiac arrest should now also undergo resuscitative hypothermia or targeted
temperature
management. In the future, cerebral resuscitation may also involve other specific pharmacologic
interventions to derail the process whereby brain cells slowly die after ischemic brain injury.

KEY CONCEPTS
• Neuronal injury is a dynamic process that continues for hours or days after an ischemic insult to the
brain.
• Hypotension and hypoperfusion should be avoided by maintaining MAP > 65 mm Hg and CPP of 50–70
mm Hg.
• Normoxia or mild hyperoxia, with PaO2 of 80–120 mm Hg and
 oxyhemoglobin saturations in the high 90s, should be maintained. Hypoxia and significant
hyperoxia should be avoided.
• ICP elevation can further exacerbate ischemic brain injury. Initial management should include
optimizing patient positioning while providing adequate analgesia and sedation. Management
should then be escalated in a stepwise fashion to include hypertonic therapy, deep sedation
with barbiturates, hypothermia, and surgery as needed.
• Hyperventilation decreases cerebral blood flow and should be avoided by targeting a PaCO2 of
35–40 mm Hg. In the event of life-threatening cerebral herniation or significant ICP elevation,
therapeutic hyperventilation is appropriate only as a short-term intervention bridging to more
definitive therapy (ie, craniectomy). • Hyperglycemia worsens neurologic outcome.
Subcutaneous or IV insulin should be used to maintain a glucose level <180 mg/dL.
• When present, seizures should be promptly aborted using IV lorazepam, followed by
treatment with IV phenytoin, valproic acid, or levetiracetam, with an initial 20-mg/kg loading
dose. The prophylactic administration of antiepileptic drugs is not recommended, except for 7
days immediately following TBI. Levetiracetam, 500 mg bid, is a preferred agent.
• Fever is an important mediator of secondary brain injury and all temperatures >38°C should be
treated promptly with acetaminophen and surface cooling.
• Comatose survivors of out-of-hospital cardiac arrest should be rapidly cooled in the ED, maintained at
a constant target of 33°–36°C in an ICU setting for 24 hours after resuscitation, and receive targeted
temperature management to prevent hyperthermia after this period.