2269 Nervous System Disorders in Critical Care CHAPTER 307

CBF increases with hypercapnia and acidosis and decreases with

hypocapnia and alkalosis because of pH-related changes in cerebral

vascular resistance. This forms the basis for the use of hyperventilation

to lower ICP, and this effect on ICP is mediated through a decrease in

both CBF and intracranial blood volume. Cerebral autoregulation is a

complex process critical to the normal homeostatic functioning of the

brain, and this process may be disordered focally and unpredictably in

disease states such as traumatic brain injury and severe focal cerebral

ischemia.

Cerebrospinal Fluid (CSF) and ICP The cranial contents consist essentially of brain, CSF, and blood. CSF is produced principally

in the choroid plexus of each lateral ventricle, exits the brain via the

foramens of Luschka and Magendie, and flows over the cortex to be

absorbed into the venous system along the superior sagittal sinus.

In adults, ~150 mL of CSF are contained within the ventricles and

surrounding the brain and spinal cord; the cerebral blood volume is

also ~150 mL. The bony skull offers excellent protection for the brain

but allows little tolerance for additional volume. Significant increases

in volume eventually result in increased ICP. Obstruction of CSF

outflow, edema of cerebral tissue, or increases in volume from tumor

or hematoma may increase ICP. Elevated ICP diminishes cerebral

perfusion and can lead to tissue ischemia. Ischemia in turn may lead

to vasodilation via autoregulatory mechanisms designed to restore

cerebral perfusion. However, vasodilation also increases cerebral blood

volume, which in turn then increases ICP, lowers CPP, and provokes

further ischemia. This vicious cycle is commonly seen in traumatic

brain injury, massive intracerebral hemorrhage, and large hemispheric

infarcts with significant tissue shifts.

APPROACH TO THE PATIENT

Severe Brain Dysfunction

Critically ill patients with severe central nervous system (CNS) dysfunction require rapid evaluation and intervention in order to limit

primary and secondary brain injury. Initial neurologic evaluation

should be performed concurrent with stabilization of basic respiratory, cardiac, and hemodynamic parameters. Significant barriers

may exist to neurologic assessment in the critical care unit, including endotracheal intubation and the use of sedative or paralytic

agents to facilitate procedures.

An impaired level of consciousness is common in critically

ill patients. The essential first task in assessment is to determine

whether the cause of dysfunction is related to a diffuse, usually

metabolic, process or whether a focal, usually structural, process is

implicated. Examples of diffuse processes include metabolic encephalopathies related to organ failure, drug overdose, or hypoxiaischemia. Focal processes include ischemic and hemorrhagic stroke

and traumatic brain injury, especially with intracranial hematomas.

Because these two categories of disorders have fundamentally

different causes, treatments, and prognoses, the initial focus is on

making this distinction rapidly and accurately. The approach to the

comatose patient is discussed in Chap. 28; etiologies are listed in

Table 28-1.

Minor focal deficits may be present on the neurologic examination in patients with metabolic encephalopathies. However, the

finding of prominent focal signs such as pupillary asymmetry,

hemiparesis, gaze palsy, or visual field deficit should suggest the

possibility of a structural lesion. All patients with a decreased level

of consciousness associated with focal findings should undergo an

urgent neuroimaging procedure, as should all patients with coma

of unknown etiology. Computed tomography (CT) scanning is usually the most appropriate initial study because it can be performed

quickly in critically ill patients and demonstrates hemorrhage,

hydrocephalus, and intracranial tissue shifts well. Magnetic resonance imaging (MRI) may provide more specific information in

some situations, such as acute ischemic stroke (diffusion-weighted

imaging [DWI]). Any suggestion of trauma from the history or

examination should alert the examiner to the possibility of cervical

spine injury and prompt an imaging evaluation using CT or MRI.

Neurovascular imaging using CT or MRI angiography or venography is increasingly available and may suggest arterial occlusion or

cerebral venous thrombosis.

Acute brainstem ischemia due to basilar artery thrombosis may

cause brief episodes of spontaneous extensor posturing superficially

resembling generalized seizures. Coma of sudden onset, accompanied by these movements and cranial nerve abnormalities, necessitates emergency imaging. A noncontrast CT scan of the brain

may reveal a hyperdense basilar artery indicating thrombus in the

vessel, and subsequent CT or MR angiography can assess basilar

artery patency.

Other diagnostic studies are best used in specific circumstances,

usually when neuroimaging studies fail to reveal a structural lesion

and the etiology of the altered mental state remains uncertain.

Electroencephalography (EEG) can be important in the evaluation

of critically ill patients with severe brain dysfunction. The EEG of

metabolic encephalopathy typically reveals generalized slowing.

One of the most important uses of EEG is to help exclude inapparent seizures, especially nonconvulsive status epilepticus. Untreated

continuous or frequently recurrent seizures may cause neuronal

injury, making the diagnosis and treatment of seizures crucial in

this patient group. Lumbar puncture (LP) may be necessary to

exclude infectious or inflammatory processes, and an elevated

opening pressure may be an important clue to cerebral venous sinus

thrombosis. In patients with coma or profound encephalopathy, it is

preferable to perform a neuroimaging study prior to LP. If bacterial

meningitis is suspected, an LP may be performed urgently, but most

often, it is prudent to administer antibiotics empirically before the

diagnostic studies are completed. Standard laboratory evaluation of

critically ill patients should include assessment of serum electrolytes (especially sodium and calcium), glucose, renal and hepatic

function, complete blood count, and coagulation. Serum or urine

toxicology screens should be performed in patients with encephalopathy of unknown cause. EEG and LP are most useful when

the mechanism of the altered level of consciousness is uncertain;

they are not routinely performed for diagnosis in clear-cut cases of

stroke or traumatic brain injury.

Monitoring of ICP can be an important tool in selected patients.

In general, patients who should be considered for ICP monitoring

are those with primary neurologic disorders, such as stroke or

traumatic brain injury, who are at significant risk for secondary

brain injury due to elevated ICP and decreased CPP. Included are

patients with the following: severe traumatic brain injury (Glasgow

Coma Scale [GCS] score ≤8 [see Table 443-1]); large tissue shifts

from supratentorial ischemic or hemorrhagic stroke; or hydrocephalus from subarachnoid hemorrhage (SAH), intraventricular

hemorrhage, or posterior fossa stroke. An additional disorder in

which ICP monitoring can add important information is fulminant

hepatic failure, in which elevated ICP may be treated with barbiturates or, eventually, liver transplantation. In general, ventriculostomy is preferable to ICP monitoring devices that are placed in the

brain parenchyma, because ventriculostomy allows CSF drainage

as a method of treating elevated ICP. However, parenchymal ICP

monitoring is most appropriate for patients with diffuse edema and

small ventricles (which may make ventriculostomy placement more

difficult) or any degree of coagulopathy (in which ventriculostomy

carries a higher risk of hemorrhagic complications) (Fig. 307-2).

TREATMENT OF ELEVATED ICP

Elevated ICP may occur in a wide range of disorders, including head

trauma, intracerebral hemorrhage, SAH with hydrocephalus, and

fulminant hepatic failure. Because CSF and blood volume can be

redistributed initially, by the time elevated ICP occurs, intracranial

compliance is severely impaired. At this point, any small increase

in the volume of CSF, intravascular blood, edema, or a mass lesion

may result in a significant increase in ICP and a decrease in cerebral

2270 PART 8 Critical Care Medicine

Ventriculostomy

Fiberoptic

intraparenchymal

ICP monitor

Brain tissue

oxygen probe

Lateral ventricle

FIGURE 307-2 Intracranial pressure (ICP) and brain tissue oxygen monitoring. A

ventriculostomy allows for drainage of cerebrospinal fluid to treat elevated ICP.

Fiberoptic ICP and brain tissue oxygen monitors are usually secured using a screwlike skull bolt. Cerebral blood flow and microdialysis probes (not shown) may be

placed in a manner similar to the brain tissue oxygen probe.

perfusion. This is a fundamental mechanism of secondary ischemic

brain injury and constitutes an emergency that requires immediate

attention. In general, ICP should be maintained at <20 mmHg and

CPP should be maintained at ≥60 mmHg.

Interventions to lower ICP are ideally based on the underlying

mechanism responsible for the elevated ICP (Table 307-2). For

example, in hydrocephalus from SAH, the principal cause of elevated ICP is impairment of CSF drainage. In this setting, ventricular

drainage of CSF is likely to be sufficient and most appropriate. In

head trauma and stroke, cytotoxic edema may be most responsible,

and the use of osmotic agents such as mannitol or hypertonic saline

becomes an appropriate early step. As described above, elevated ICP

may cause tissue ischemia, and, if cerebral autoregulation is intact,

the resulting vasodilation can lead to a cycle of worsening ischemia.

Paradoxically, administration of vasopressor agents to increase

mean arterial pressure may actually lower ICP by improving perfusion, thereby allowing autoregulatory vasoconstriction as ischemia

is relieved and ultimately decreasing intracranial blood volume.

Early signs of elevated ICP include drowsiness and a diminished

level of consciousness. Neuroimaging studies may reveal evidence

of edema and mass effect. Hypotonic IV fluids should be avoided,

and elevation of the head of the bed is recommended. Patients

must be carefully observed for risk of aspiration and compromise

of the airway as the level of alertness declines. Coma and unilateral

pupillary changes are late signs and require immediate intervention.

Emergent treatment of elevated ICP is most quickly achieved by

intubation and hyperventilation, which causes vasoconstriction

and reduces cerebral blood volume. To avoid provoking or worsening cerebral ischemia, hyperventilation, if used at all, is best

administered only for short periods of time until a more definitive

treatment can be instituted. Furthermore, the effects of hyperventilation on ICP are short-lived, often lasting only for several hours

because of the buffering capacity of the cerebral interstitium, and

rebound elevations of ICP may accompany abrupt discontinuation

of hyperventilation. As the level of consciousness declines to coma,

the ability to follow the neurologic status of the patient by examination lessens and measurement of ICP assumes greater importance.

If a ventriculostomy device is in place, direct drainage of CSF to

reduce ICP is possible. Finally, high-dose barbiturates, decompressive hemicraniectomy, and hypothermia are sometimes used for

refractory elevations of ICP, although these have significant side

effects and only decompressive hemicraniectomy has been shown

to improve outcome in select patients.

SECONDARY BRAIN INSULTS

Patients with primary brain injuries, whether due to trauma or

stroke, are at risk for ongoing secondary ischemic brain injury.

Because secondary brain injury can be a major determinant of a

poor outcome, strategies for minimizing secondary brain insults

are an integral part of the critical care of all patients. Although elevated ICP may lead to secondary ischemia, most secondary brain

injury is mediated through other clinical events that exacerbate

the ischemic cascade already initiated by the primary brain injury.

Episodes of secondary brain insults are usually not associated with

apparent neurologic worsening. Rather, they lead to cumulative

injury limiting eventual recovery, which manifests as a higher

mortality rate or worsened long-term functional outcome. Thus,

close monitoring of vital signs is important, as is early intervention

to prevent secondary ischemia. Avoiding hypotension and hypoxia

is critical, as significant hypotensive events (systolic blood pressure

<90 mmHg) as short as 10 min in duration have been shown to

adversely influence outcome after traumatic brain injury. Even

in patients with stroke or head trauma who do not require ICP

monitoring, close attention to adequate cerebral perfusion is warranted. Hypoxia (pulse oximetry saturation <90%), particularly in

combination with hypotension, also leads to secondary brain injury.

Likewise, fever and hyperglycemia both worsen experimental ischemia and have been associated with worsened clinical outcome after

stroke and head trauma. Aggressive control of fever with a goal of

normothermia is warranted but may be difficult to achieve with

antipyretic medications and cooling blankets. The value of newer

surface or intravascular temperature control devices for the management of refractory fever is under investigation. The use of IV

insulin infusion is encouraged for control of hyperglycemia because

this allows better regulation of serum glucose levels than SC insulin. A reasonable goal is to maintain the serum glucose level at

<10.0 mmol/L (<180 mg/dL), although episodes of hypoglycemia appear equally detrimental and the optimal targets remain

uncertain. New cerebral monitoring tools that allow continuous

evaluation of brain tissue oxygen tension, CBF, cortical spreading

depolarizations, and cerebral metabolism (via microdialysis) may

further improve the management of secondary brain injury.

TABLE 307-2 Stepwise Approach to Treatment of Elevated Intracranial

Pressure (ICP)a

Insert ICP monitor—ventriculostomy versus parenchymal device

General goals: maintain ICP <20 mmHg and CPP ≥60 mmHg. For ICP >20–25 mmHg

for >5 min:

1. Elevate head of the bed; midline head position

2. Drain CSF via ventriculostomy (if in place)

3. Osmotherapy—mannitol 25–100 g q4h as needed (maintain serum osmolality

<320 mosmol) or hypertonic saline (30 mL, 23.4% NaCl bolus)

4. Glucocorticoids—dexamethasone 4 mg q6h for vasogenic edema from tumor,

abscess (avoid glucocorticoids in head trauma, ischemic and hemorrhagic

stroke)

5. Sedation (e.g., morphine, propofol, or midazolam); add neuromuscular

paralysis if necessary (patient will require endotracheal intubation and

mechanical ventilation at this point, if not before)

6. Hyperventilation—to Paco2

 30–35 mmHg (short-term use or skip this step)

7. Pressor therapy—phenylephrine, dopamine, or norepinephrine to maintain

adequate MAP to ensure CPP ≥60 mmHg (maintain euvolemia to minimize

deleterious systemic effects of pressors). May adjust target CPP in individual

patients based on autoregulation status.

8. Consider second-tier therapies for refractory elevated ICP

a. Decompressive craniectomy

b. High-dose barbiturate therapy (“pentobarb coma”)

c. Hypothermia to 33°C

a

Throughout ICP treatment algorithm, consider repeat head computed tomography

to identify mass lesions amenable to surgical evacuation. May alter order of steps

based on directed treatment to specific cause of elevated ICP.

Abbreviations: CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; MAP,

mean arterial pressure; Paco2

, arterial partial pressure of carbon dioxide.

2271 Nervous System Disorders in Critical Care CHAPTER 307

CRITICAL CARE DISORDERS OF THE CNS

■ HYPOXIC-ISCHEMIC ENCEPHALOPATHY

This occurs from lack of delivery of oxygen to the brain because of

extreme hypotension (hypoxia-ischemia) or hypoxia due to respiratory

failure. Causes include myocardial infarction, cardiac arrest, shock,

asphyxiation, paralysis of respiration, and carbon monoxide or cyanide

poisoning. In some circumstances, hypoxia may predominate. Carbon

monoxide and cyanide poisoning are sometimes termed histotoxic

hypoxia because they cause a direct impairment of the respiratory

chain.

Clinical Manifestations Mild degrees of pure hypoxia, such as

occur at high altitudes, cause impaired judgment, inattentiveness,

motor incoordination, and, at times, euphoria. However, with hypoxiaischemia, such as occurs with circulatory arrest, consciousness is lost

within seconds. If circulation is restored within 3–5 min, full recovery

may occur, but if hypoxia-ischemia lasts beyond 3–5 min, some degree

of permanent cerebral damage often results. Except in extreme cases, it

may be difficult to judge the precise degree of hypoxia-ischemia, and

some patients make a relatively full recovery after even 10 min or more

of global cerebral ischemia. The brain is more tolerant to pure hypoxia

than it is to hypoxia-ischemia. For example, a Pao2

 as low as 20 mmHg

(2.7 kPa) can be well tolerated if it develops gradually, and normal

blood pressure is maintained, whereas short durations of very low or

absent cerebral circulation may result in permanent impairment.

Clinical examination at different time points after a hypoxicischemic insult (especially cardiac arrest) is useful in assessing prognosis for long-term neurologic outcome. The prognosis is better

for patients with intact brainstem function, as indicated by normal

pupillary light responses and intact oculocephalic (doll’s eyes), oculovestibular (caloric), and corneal reflexes. Absence of these reflexes and

the presence of persistently dilated pupils that do not react to light are

concerning prognostic signs. A low likelihood of a favorable outcome

from hypoxic-ischemic coma is suggested by an absent pupillary

light reflex or extensor or absent motor response to pain on day 3

following the injury, excluding patients with metabolic disturbances

and those treated with high-dose barbiturates or hypothermia, which

confound interpretation of these signs. Electrophysiologically, the

bilateral absence of the N20 component of the somatosensory evoked

potential (SSEP) in the first several days also conveys a poor prognosis.

Also, the presence of a burst-suppression pattern of myoclonic status

epilepticus on EEG (Fig. 307-3) or a nonreactive EEG is associated

with a low likelihood of good functional outcome. A very elevated

serum level (>33 μg/L) of the biochemical marker neuron-specific

enolase (NSE) within the first 3–5 days is indicative of brain damage

after resuscitation from cardiac arrest and predicts a poor outcome.

Current approaches to prognostication after cardiac arrest encourage

the use of a multimodal approach that includes these diagnostic tests,

along with CT or MRI neuroimaging, in conjunction with clinical

neurologic assessment. Recent studies suggest that the administration

of mild hypothermia after cardiac arrest (see “Treatment”) may affect

the time points when these clinical and electrophysiologic predictors

become reliable in identifying patients with a very low likelihood of

clinically meaningful recovery. For example, the false-positive rate for

incorrect prediction of poor neurologic outcome may be as high as

21% (95% confidence interval [CI] 8–43%) for patients treated with

mild hypothermia who exhibit 3-day motor function no better than

extensor posturing. Thus, sufficient time from injury is important to

ensure accuracy of prognostic assessment. The minimum observation

period to ensure accuracy of prognostication remains unclarified.

Long-term consequences of hypoxic-ischemic encephalopathy include

persistent coma or an unresponsive wakeful state (Chap. 28), dementia

(Chap. 29), visual agnosia (Chap. 30), parkinsonism, choreoathetosis,

cerebellar ataxia, myoclonus, seizures, and an amnestic state, which

may be a consequence of selective damage to the hippocampus.

Pathology Principal histologic findings are extensive multifocal or

diffuse laminar cortical injury (Fig. 307-4), with frequent involvement

of the deep gray nuclei and hippocampus. The hippocampal CA1

FIGURE 307-3 Electroencephalography (EEG) after cardiac arrest. A burst-suppression pattern is seen in a comatose patient with severe hypoxic-ischemic encephalopathy

after cardiac arrest. In this patient, each burst on EEG was associated with a whole-body jerking movement leading to the clinical and electrophysiologic diagnosis of

myoclonic status epilepticus.

2272 PART 8 Critical Care Medicine

FIGURE 307-4 Hypoxic-ischemic brain injury after cardiac arrest. Diffusionweighted magnetic resonance imaging shows reduced diffusion (bright signal)

throughout the cerebral cortex as well as in the caudate, globus pallidus, and

thalamus bilaterally.

neurons are vulnerable to even brief episodes of hypoxia-ischemia,

perhaps explaining why selective persistent memory deficits may occur

after brief cardiac arrest. Scattered small areas of infarction or neuronal

loss may be present in the basal ganglia, hypothalamus, or brainstem.

In some cases, extensive bilateral thalamic scarring may affect pathways

that mediate arousal, and this pathology may be responsible for the

unresponsive wakeful state (previously known as the vegetative state).

A specific form of hypoxic-ischemic encephalopathy, so-called watershed infarcts, occurs at the distal territories between the major cerebral

arteries and can cause cognitive deficits, including visual agnosia, and

weakness that is greater in proximal than in distal muscle groups.

Diagnosis Diagnosis is based on the history of a hypoxic-ischemic

event such as cardiac arrest. Blood pressure <70 mmHg systolic or

Pao2

 <40 mmHg is usually necessary, although both absolute levels

and duration of exposure are important determinants of cellular injury.

Carbon monoxide intoxication can be confirmed by measurement

of carboxyhemoglobin and is suggested by a cherry red color of the

venous blood and skin, although the latter is an inconsistent clinical

finding.

TREATMENT

Hypoxic-Ischemic Encephalopathy

Treatment should be directed at restoration of normal cardiorespiratory function. This includes securing a clear airway, ensuring adequate oxygenation and ventilation, and restoring cerebral perfusion,

whether by cardiopulmonary resuscitation, fluid, pressors, or cardiac pacing. Hypothermia may target the neuronal cell injury cascade and has substantial neuroprotective properties in experimental

models of brain injury. In three trials, mild hypothermia (33°C)

improved functional outcome in patients who remained comatose

after resuscitation from an out-of-hospital cardiac arrest. Treatment

was initiated within minutes of cardiac resuscitation and continued

for 12 h in one study and 24 h in the other two. In another study,

targeted temperature management (TTM) to 33 or 36°C resulted in

similar outcomes. Potential complications of hypothermia include

coagulopathy and an increased risk of infection. Current guidelines

recommend TTM for cardiac arrest patients who have no meaningful response to verbal commands after return of spontaneous

circulation, with temperature maintained constant between 32 and

36°C for at least 24 h.

Severe carbon monoxide intoxication may be treated with hyperbaric oxygen. Anticonvulsants may be needed to control seizures,

although these are not usually given prophylactically. Posthypoxic

myoclonus may respond to oral administration of clonazepam at

doses of 1.5–10 mg daily or valproate at doses of 300–1200 mg daily

in divided doses. Myoclonic status epilepticus within 24 h after a

primary circulatory arrest generally portends a poor prognosis,

even if seizures are controlled.

Carbon monoxide and cyanide intoxication can also cause a

delayed encephalopathy. Little clinical impairment is evident when

the patient first regains consciousness, but a parkinsonian syndrome characterized by akinesia and rigidity without tremor may

develop. Symptoms can worsen over months, accompanied by

increasing evidence of damage in the basal ganglia as seen on both

CT and MRI.

■ POSTCARDIAC BYPASS BRAIN INJURY

CNS injuries following open heart or coronary artery bypass grafting

(CABG) surgery are common and include acute encephalopathy,

stroke, and a chronic syndrome of cognitive impairment. Hypoperfusion and embolic disease are frequently involved in the pathogenesis

of these syndromes, although multiple mechanisms may be involved

in these critically ill patients who are at risk for various metabolic and

polypharmaceutical complications.

The frequency of hypoxic injury secondary to inadequate blood flow

intraoperatively has been markedly decreased by modern surgical and

anesthetic techniques. Despite these advances, some patients still experience neurologic complications from cerebral hypoperfusion or suffer

focal ischemia from carotid or focal intracranial stenoses in the setting

of regional hypoperfusion. Postoperative infarcts in the border zones

between vascular territories are often attributed to systemic hypotension, although these infarcts can also result from embolic disease.

Embolic disease is likely the predominant mechanism of cerebral

injury during cardiac surgery as evidenced by diffusion-weighted

MRI and intraoperative transcranial Doppler ultrasound studies.

Thrombus in the heart itself as well as atheromas in the aortic arch

can become dislodged during cardiac surgeries, releasing a shower of

particulate matter into the cerebral circulation. Cross-clamping of the

aorta, manipulation of the heart, extracorporeal circulation techniques

(“bypass”), arrhythmias such as atrial fibrillation, and introduction of

air through suctioning have all been implicated as potential sources of

emboli.

This shower of microemboli results in a number of clinical syndromes. Occasionally, a single large embolus leads to an isolated

large-vessel stroke that presents with obvious clinical focal deficits.

When there is a high burden of very small emboli, an acute encephalopathy can occur postoperatively, presenting as either a hyperactive

or hypoactive confusional state, the latter of which is frequently and

incorrectly ascribed to depression or a sedative-induced delirium.

When the burden of microemboli is lower, no acute syndrome is recognized, but the patient may suffer a chronic cognitive deficit.

■ METABOLIC ENCEPHALOPATHIES

Altered mental states, variously described as confusion, delirium,

disorientation, and encephalopathy, are present in many patients with

severe illness in an intensive care unit (ICU). Older patients are particularly vulnerable to delirium (Chap. 27), a confusional state characterized by disordered perception, frequent hallucinations, delusions, and

sleep disturbance. This is often attributed to medication effects, sleep

deprivation, pain, and anxiety. The presence of delirium is associated

with a worse outcome in critically ill patients, even in those without

an identifiable CNS pathology such as stroke or brain trauma. In these

patients, the cause of delirium is often multifactorial, resulting from

organ dysfunction, sepsis, and especially the use of medications given

to treat pain, agitation, or anxiety. Critically ill patients are often treated

with a variety of sedative and analgesic medications, including opiates,

benzodiazepines, neuroleptics, and sedative-anesthetic medications,

such as propofol. In critically ill patients requiring sedation, use of the