Ebook Principles of critical care (4th edition): Part 2

(BQ) Part 2 book Principles of critical care presents the following contents: Neurologic disorders, hematologic and oncologic disorders, renal and metabolic disorders, gastrointestinal disorders, the surgical patient, special problems in critical care.

PART 6 Neurologic Disorders

Patients in the intensive care unit (ICU) who experience delirium are

exhibiting an under-recognized form of organ dysfunction Delirium is

extremely common in ICU patients as factors such as comorbidity, the

acute critical illness itself, and iatrogenesis intersect to create a high-risk

setting for delirium This neurologic complication is often hazardous,

being associated with death, prolonged hospital stays, and long-term

cognitive impairment and institutionalization Neurologic dysfunction

compromises patients’ ability to be removed from mechanical

ventila-tion or to fully recover and regain independence Unfortunately, health

care providers in the ICU are unaware of delirium in many

circum-stances, especially those in which the patient’s delirium is manifesting

predominantly as the hypoactive (quiet) subtype rather than the

hyper-active (agitated) subtype Despite being often overlooked clinically, ICU

delirium has increasingly been the subject of research during the past

decade, which has brought to light the scope of the problem in critically

ill patients and provided clinicians with tools for routinely monitoring

delirium at the bedside This chapter reviews the definition and salient

features of delirium, its primary risk factors, including drugs associated

with the development of delirium, proposed pathophysiologic

mecha-nisms, validated methods for bedside delirium assessment, and

nonphar-macologic and pharnonphar-macologic strategies for delirium management

DEFINITION AND TERMINOLOGY

The American Psychological Association’s (APA) Diagnostic and Statistical

Manual of Mental Disorders (DSM)-IV describes delirium as a

distur-bance in consciousness and cognition that develops over a short period

of time (eg, hours to days) and tends to fluctuate during the course of the

day.1 Specifically, there are four criteria required to diagnose delirium1:

1 Disturbance of consciousness, with reduced awareness of the

envi-ronment and impaired ability to focus, sustain or shift attention

2 Altered cognition (eg, memory impairment, disorientation, or

lan-guage disturbance) or the development of a perceptual disturbance

(eg, delusion, hallucination, or illusion) that is not better accounted

for by preexisting or evolving dementia

3 Disturbance develops over a short period of time (usually hours to

days) and tends to fluctuate during the course of the day

4 Evidence of an etiological cause, which the DSM-IV uses to classify

delirium as Delirium Due to a General Medical Condition,

Substance-Induced Delirium, Delirium Due to Multiple Etiologies, or Delirium

Not Otherwise Specified

Historically, two words were used to describe acutely confused patients

The Roman word delirium referred to an agitated and confused person

(ie, hyperactive delirium) The Greek word lethargus was used to describe

a quietly confused person (ie, hypoactive delirium) ICU patients

com-monly demonstrate both subtypes of delirium as they progress through

different stages of their illness and therapy In both subtypes, the patient’s

brain is not functioning normally It therefore makes sense that the

original derivation of delirium comes from the Latin word deliria, which

literally means to “be out of your furrow.” For greater clarity and to avoid

misuse of terms such as dementia and delirium, Table  82-1 lists basic

definitions and clinical characteristics of each syndrome

Delirium in the ICU has been referred to in the medical literature using

a multitude of terms, including ICU psychosis, ICU syndrome, brain

failure, encephalopathy, postoperative psychosis, acute organic syndrome,

82

C H A P T E R

subacute befuddlement, and toxic confusional state.2-5 Neurologists often use “encephalopathy” to refer to hypoactive delirium and “delirium” to describe only hyperactive delirium.6 Among ICU practitioners, “delirium”

is used inconsistently, as evidenced by a recent survey of Canadian sivists that found respondents were more likely to use the term “delirium”

inten-when no specific underlying etiology could be identified for a patient with fluctuating mental status with inattention, perceptual changes, and disor-ganized thinking, whereas alternative terms (eg, hepatic encephalopathy) were used when the etiology of delirium was obvious.5,7

Increasingly, however, the ICU community is seeking to standardize delirium terminology to conform to the APA definition, with the hope that use of “delirium” to describe this syndrome of acute brain dysfunction, regardless of etiology, will improve cross-talk between specialists with different medical backgrounds, collaborative research efforts, and ultimately management of this widely prevalent syndrome.4 Therefore, the unifying term “delirium” should be applied whenever patients meet DSM-IV diagnostic criteria for delirium, and the underlying etiology, when known, can be used as an associated term (eg, “delirium secondary

to sepsis” is preferred over “septic encephalopathy”)

PREVALENCE AND SUBTYPES

Delirium during critical illness occurs in 20% to 80% of ICU patients depending on the severity of illness of the population studied and meth-ods used to detect delirium.8-16 The prevalence is highest, for example, in mechanically ventilated ICU patients, with 60% to 80% developing delir-ium during their ICU stay,8,10,12,14,17 whereas lower prevalence rates are reported in nonventilated patients and in mixed ICU populations.9,11,18

In general, ICU patients have a higher prevalence of delirium compared with noncritically ill hospitalized patients.19,20 The prevalence of ICU delirium will likely increase as the U.S population ages

Delirium can be subtyped based on observed changes in motor ity, resulting in hypoactive, hyperactive, and mixed subtypes.21 Peterson

activ-et al reported these delirium subtypes in a cohort of 613 ventilated and nonventilated ICU patients in whom delirium was monitored for more

TABLE 82-1 Differentiating Delirium From Dementia

Diagnostic Features

• Impaired ability to focus, shift

or sustain attention

• Change in cognition (eg, memory impairment, disorientation

or language) or development in perceptual disturbances

• Impaired executive functioning

• Impairments must be severe enough to cause impairments

in social or occupational functioning and represent

a decline from baseline

Associated Features

• Sleep/wake disturbances

• Extremes in psychomotor activity

• Emotional disturbances (fear, anxiety, depression, irritability, euphoria, apathy)

Common Causes • Acute medical illness• Medication/substance/toxin

Data from American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 4th ed

Text Revision Washington, D.C.: American Psychiatric Association; 2000

CHAPTER 82: Delirium in the Intensive Care Unit 757

than 20,000 observations Among patients who developed delirium, pure

hyperactive delirium was rare (<5%), whereas hypoactive was present

in 45% and the mixed subtype—with alternating periods of hypoactive

and hyperactive delirium—was the predominant manifestation (54%)

Interestingly, hypoactive delirium was significantly more common in

patients over the age of 65 Similarly, in a cohort of 100 surgical and

trauma ICU patients, the prevalence of hypoactive delirium was greater

than 60%.22 The risk factors for, and clinical implications of, these

subtypes are the subject of ongoing investigations.23

Because sedation is commonly used in the ICU, the period

sur-rounding cessation of sedation represents a scenario in the ICU during

which delirium could be easily recognized but is often missed Delirious

patients emerging from the effects of sedation may do so peacefully or

in a combative manner The “peaceful” patients are often erroneously

assumed to be thinking clearly Delirium in this context is referred to

as hypoactive delirium and is characterized by lethargy, drowsiness, and

infrequent spontaneous movement,21 which contributes to delirium

being overlooked unless the patient is specifically screened for its

presence.24-28 Even in the absence of agitation, such delirium can lead

to adverse outcomes such as reintubation, which itself has been shown to

increase the risk of prolonging the ICU stay, transfer to a long-term care

or rehabilitation facility, and death.29 In addition, hypoactive delirium is

associated with immobility in the ICU,30 which itself places patients at

risk for adverse outcomes, including aspiration, pulmonary embolism,

and decubitus ulcers

In contrast to patients with hypoactive delirium are agitated or

combat-ive patients with hyperactcombat-ive delirium; these patients are at risk not only

for self-extubation and subsequent reintubation but also for pulling out

central venous catheters and even falling out of bed These hyperactive

patients are often given large doses of sedatives that lead to heavy

seda-tion and prevent timely liberaseda-tion from mechanical ventilaseda-tion, placing

patients at risk for remaining delirious or even comatose and on invasive

mechanical ventilation unnecessarily.31 To avoid this difficult and

danger-ous cycle, health care professionals should minimize use of psychoactive

medications and frequently assess patients for delirium, especially during

the transition from drug-induced or metabolic coma to wakefulness

RISK FACTORS

Nearly every ICU patient is exposed to one or more risk factors for

delirium; the average patient in one study, in fact, had 11 identifiable

risk factors for delirium.32 These risk factors may be divided into

predisposing (baseline) factors and precipitating (hospitalization-related)

factors.33 Patients who are highly vulnerable to developing delirium (ie, who have multiple predisposing risk factors) may become delirious with only minor insults, whereas those with low baseline vulnerability may require a greater insult to become delirious.33 Predisposing risk factors, those related to patient characteristics or underlying chronic pathology, are difficult to alter, whereas precipitating factors, such as those related to the acute illness or the ICU environment, represent areas

of risk that are modifiable or preventable (Table 82-2).

Baseline risk factors that have been identified in both ICU and non-ICU populations include older age, depression, vision impairment, hearing impairment, hypertension, history of smoking, history of alcohol use, living single at home, underlying cognitive impairment or dementia, and APOE4 polymorphism.9,10,13,34-37 Numerous features of the acute critical illness have been identified as delirium risk factors in studies specifically examining ICU patients; these include admission to an ICU for a medical illness, high severity of illness (indicated by high APACHE II and SAPS II scores), need for mechanical ventilation, receipt of sedative and/or anal-gesic medications (particularly when used to induce coma), respiratory disease, anemia, hypotension, hypocalcemia, hyponatremia, azotemia, transaminitis, hyperamylasemia, hyperbilirubinemia, acidosis, fever, infec-tion, sepsis, gastric tubes, bladder catheters, arterial lines, and more than three infusing medications.9,13,17,35-39 Risk factors related to the ICU envi-ronment include lack of daylight in the ICU, isolation, lack of visitors, and sleep disturbances.37,40

Though difficult to accurately measure in ICU patients, sleep tion is believed to be nearly universal in the ICU and has long been pro-posed as a risk factor for delirium The relationship, however, between sleep disturbance and delirium in the ICU remains controversial, and there is significant overlap in the symptoms of both syndromes such that either may present with inattention, fluctuating mental status and cognitive dysfunction, making it difficult to ascertain whether sleep deprivation causes delirium or vice versa.40,41 On average, ICU patients sleep between 2 and 8 hours in a 24-hour period, often with severe and frequent disruptions and only a small fraction of “restorative,” rapid eye movement (REM) sleep.42 In repeated studies, between one-third and one-half of patients’ sleep in the ICU occurs during daytime hours.42,43Reasons for poor sleep in this setting are multifactorial The ICU envi-ronment, with its continuous cycle of alarms, lights, and care-related interruptions interferes with a patient’s sleep cycle and may disrupt their circadian rhythm.41,43 Acute illness, with symptoms such as nausea, pain, and fever, may also disrupt sleep Mechanically ventilated patients may additionally suffer sleep disruptions due to anxiety, ventilator dyssynchrony, central apneas, and mode of mechanical ventilation.44

TABLE 82-2 Risk Factors for Delirium

Host Factors Factors Relating to Critical Illness Environmental and Iatrogenic

Not modifiable or preventable Age

HypertensionAPOE-4Preexisting cognitive impairmentAlcohol use

Tobacco useDepression

High severity of illnessRespiratory diseaseMedical illnessNeed for mechanical ventilationNumber of infusing medications

Lack of daylightIsolation

Potentially modifiable/preventable Hearing or vision impairment Anemia

AcidosisHypotensionInfection/sepsisMetabolic disturbances (eg, hypocalcemia, hyponatremia, azotemia, transaminitis, hyperamylasemia,

hyperbilirubinemia)Fever

Lack of visitorsSedatives/analgesics (eg, benzodiazepines and opiates)

ImmobilityBladder cathetersVascular cathetersGastric tubesSleep deprivationAPOE-4, apolipoprotein E polymorphism

Note: Risk factors for delirium can relate to the host, those relating to critical illness and those relating to the intensive care unit environment or treatment of critical illness Within each of these divisions, there are risk factors that are preventable or potentially modifiable and those that are not preventable or modifiable

PART 6: Neurologic Disorders

758

Finally, medications commonly given to ICU patients, such as

seda-tives, analgesics, vasopressors, β-agonists, and corticosteroids, disrupt

slow-wave and REM sleep.45 Further study of sleep in the ICU is

necessary to understand the underlying mechanisms for sleep

disrup-tion and the reladisrup-tionship between sleep and delirium Meanwhile,

clinicians should attend to modifiable risk factors by reducing noise

and light at night, minimizing other disruptions in the ICU

environ-ment, treating symptoms, and judiciously using sleep-disrupting

medications

The deliriogenic effects of medications given for sedation and/or

analgesia—drugs used to treat nearly all ICU patients at some time

during their ICU stay—have received specific attention in many

studies, as they represent a potent yet potentially modifiable risk

fac-tor for delirium Though sedative and analgesic medications are

pre-scribed to relieve pain and anxiety and to improve patient tolerance

of treatments during critical illness, these medications have important

side effects Continuous infusion of sedatives, for example, is

associ-ated with prolonged mechanical ventilation,31 whereas interruption

of sedative infusions expedites weaning from mechanical ventilation,

speeds discharge from the ICU and hospital, and improves long-term

survival.12,46

Multiple studies have now clearly demonstrated a link between

benzodiazepines and development of delirium Lorazepam dose was

found to be an independent risk factor for the delirium in medical ICU

patients, such that each day a patient was treated with the drug, the odds

of being delirious the next day increased by 20% In fact, patients treated

with greater than 20 mg of lorazepam in a day were nearly all delirious or

comatose the following day.13 Numerous other studies have consistently

found similar links between benzodiazepine administration (whether

lorazepam or midazolam) and delirium in patients in surgical, trauma,

burn, and mixed ICUs (Fig 82-1).14,15,17,36,38,39,47

Narcotic pain medications present a more complex picture in terms

of their relationship with delirium in the ICU, in that they have been

associated with development of delirium in some studies but not in

others This is likely due to the differing indications for (or dual effects

of) analgesics in the ICU Narcotic pain medications are associated with

the development of delirium in populations frequently sedated with

these drugs, such as medical and surgical ICU patients.9,17,37 In these

settings, narcotics are often co-administered with benzodiazepines; in

one study, elderly ICU patients treated with benzodiazepines and

opi-oids had a longer duration of delirium.39 When narcotic medications

are used to induce coma, the odds of developing delirium triple.36 Thus,

clinicians should seek to minimize the use of heavily sedating

medica-tions, whether benzodiazepines or narcotics, by using evidenced based

protocols to interrupt continuous sedative infusions12,46 and seek to use

nonbenzo diazepine sedative medications where possible.14,15,48 Patients

more often treated with narcotics because of pain, such as trauma ICU

patients, are found to have a lower risk of the development of delirium

when treated with fentanyl or morphine compared to patients who

were not exposed to these drugs.17 Intravenous opiates and exposure

to methadone was protective against development of delirium in burn

ICU patients.47

PATHOPHYSIOLOGY

The pathophysiology of delirium remains incompletely understood

Leading hypotheses, often drawn from research outside the ICU,

pro-pose that delirium results from neurotransmitter imbalances and/or

factors that affect neurotransmitter production, such as availability of

large neutral amino acids, or systemic and central nervous system (CNS)

inflammation Delirium during critical illness is most likely a

conse-quence of a complementary and interlinked series of events (Fig 82-2).

Delirium due to Atropa belladonna (a plant known as Deadly Nightshade,

which contains the anticholinergic atropine) and anticholinergic

drugs, such as scopolamine, has been recognized for centuries, an

obser-vation that led to the hypothesis that imbalances in the synthesis, release,

and inactivation of neurotransmitters—especially acetylcholine and dopamine—that control arousal and the sleep-wake cycle are the underly-ing mechanism leading to delirium.49,50 Studies measuring the amount

of anticholinergic activity in hospitalized patients found higher levels of serum anticholinergic activity (SAA) were associated with an increased risk of delirium, even in patients not exposed to medications with anti-cholinergic properties.51,52 Central cholinergic deficiency can theoretically result from derangements occurring anywhere along the continuum from acetylcholine production and release to its action on postsynaptic recep-tors In addition to cholinergic deficiency, dopamine excess is thought to

be associated with delirium, likely via its action on central dopamine tors that regulate acetylcholine production.50-54 Finally, imbalances in the production, release, and degradation of numerous other neurotransmitters, such as serotonin, norepinephrine, glutamate, melatonin, and gamma-aminobutyric acid (GABA), have also been suspected to play a role in the development of delirium.49-54

recep-Large neutral amino acids (LNAAs), including leucine, valine, tophan, tyrosine, and phenylalanine, are the precursors of several neurotransmitters that are involved in arousal, attention, and cognition and are therefore hypothesized to be involved in the pathogenesis of delirium.52 The synthesis of serotonin and melatonin depend on the availability of tryptophan, whereas the production of norepinephrine and dopamine require both tyrosine and phenylalanine The LNAAs compete for transfer across the blood-brain barrier, such that an increase in

tryp-100

A

9080706050

0-2.7Lorazepam dose (mg)

(A) Reproduced with permission from Girard TD, Pandharipande PP, Ely EW Delirium in the

intensive care unit Crit Care 2008;(12 suppl 3):S3 Similarly, daily midazolam use is associated

with an increase in the proportion of days with delirium in surgical and trauma ICU patients

(B) Reproduced with permission from Pandharipande P, Cotton BA, Shintani A Prevalence

and risk factors for development of delirium in surgical and trauma intensive care unit

patients J Trauma July 2008;65(1):34-41.

100

B

806040200

CHAPTER 82: Delirium in the Intensive Care Unit 759

one LNAA causes a decrease in the entry of other LNAAs into the brain.52

Thus, changes in serum levels of individual LNAAs may directly effect

CNS neurotransmitter concentrations With this in mind, Flacker and

collegues55 examined LNAA levels in acutely ill elderly medical patients

and found an association between delirium and an elevated plasma

phenylalanine/LNAA ratio Tryptophan/LNAA ratios are decreased

and phenylalanine/LNAA ratios increased in cardiac surgery patients

who developed delirium.56 Low plasma levels of tryptophan were also

observed in delirious postoperative patients.57 Finally, Pandharipande

and collaborators described both high and low tryptophan/LNAA ratios

and high and low tyrosine/LNAA ratios as independent risk factors for

delirium (with mid-range ratios being low-risk for delirium) in a cohort

of mechanically ventilated ICU patients.58 These studies suggest that

changes in LNAA concentrations with subsequent alterations in CNS

neurotransmitter levels are important in the pathogenesis of delirium

Delirium is also hypothesized to result from systemic inflammation,

which occurs frequently in critical illness as a result of infection, tissue

destruction, or surgery Proinflammatory cytokines, such as interleukin-1

beta, tumor necrosis factor-alpha, and interleukin-6, as  well as

prosta-glandins and bloodborne molecules, such as lipopolysaccharide,

commu-nicate with the brain via either direct autonomic neural pathways, active

transport of cytokines across the blood-brain barrier, second messenger

systems in the blood-brain barrier, or via disruption of the blood-brain

barrier.59-61 Recognition of these peripheral inflammatory stimuli initiates

a cascade resulting in astrocyte, microglial, and endothelial activation,

leading to production of additional inflammatory cytokines, reactive

oxygen species, and expansion of the microglia population, culminating

in neuroinflammation and ultimately neuronal damage.59,61 Advanced age,

underlying dementia, and states of chronic inflammation may “prime”

microglial cells, resulting in an exaggerated inflammatory response.59-61

In addition, systemic inflammation results in endothelial damage leading

to thrombin formation and vasoconstriction with resultant microvascular

compromise.62 The combination of neuroinflammation and disruption

of normal CNS perfusion may then impair neurotransmitter synthesis

and release (particularly acetylcholine),50 impair oxidative metabolism, and

deplete neuronal energy stores.52 These processes then may lead to

neuronal cell death, resulting in a functional disconnection between anatomical structures leading to the acute neurobehavioral changes observed in delirium.59 Indeed, recent data indicate that inflammatory biomarkers, such as procalcitonin, are associated with increased days of delirium or coma.63 Elevation of these inflammatory markers was not consistently associated with other organ failures, suggesting that systemic inflammation may modulate CNS inflammation and may be an impor-tant contributor to brain dysfunction in critically ill patients

MONITORING FOR DELIRIUM

Current Society of Critical Care Medicine (SCCM) guidelines recommend that all critically ill patients be monitored for delirium as well as changes

in level of consciousness.64 Bedside critical care nurses and the rest of the ICU team should use data obtained from well-validated, reliable but brief

assessment tools to monitor both level (which can change frequently ing critical illness) and content of consciousness, with changes in both

dur-components required before delirium is diagnosed Such neurologic monitoring can be streamlined in the ICU by using a two-step approach.The first step in the neurologic assessment of an ICU patient is

to assess that patient’s level of consciousness using an objective tool Though the available tools are typically referred to as sedation scales, they should be used to assess all critically ill patients—whether receiving sedation or not—and should be viewed as assessments of level of con-sciousness rather than solely level of sedation In addition to helping practitioners avoid oversedation, objective sedation scales provide a common language for the multidisciplinary team to use when discuss-ing goals and treatments for patients For decades, the Ramsay Scale was the instrument most widely used in clinical practice and the published literature.65,66 The Riker Sedation-Agitation Scale67 and Richmond Agitation-Sedation Scale,68 however, have been better validated67,69 and are also being widely used.16,66,70 Chapter 22 includes a thorough discus-sion of how to manage sedation in the ICU

The second step in the neurological assessment of an ICU patient—a step that can only be completed when a patient is not comatose—is to evaluate that patient for delirium using an objective tool Over the last

Cholinergicactivation

Cholinergicinhibition

ReducedGABA activity

GABAactivation

GlutamateactivationCortisol

excess

Delirium

Serotonindeficiency

Serotoninactivation

Cytokineexcess

Dopamineactivation

MedicationsStroke

MedicationsAlcohol withdrawal

MedicationsMedical illnessSurgical illness

Benzodiazepine andalcohol withdrawal

BenzodiazepinesHepatic failure

Hepatic failureAlcohol withdrawalGlucocorticoids

Cushings syndromeSurgery

Stroke

Tryptophan depletionPhenyalanine elevation

Surgical illnessMedical illness

Medicationssubstance withdrawal

FIGURE 82-2 Delirium pathophysiology represents a complex series of interrelated events Multiple pathways to delirium may be present in a single patient (Reproduced with permission

from Flacker JM, Lipsitz LA, et al Neural mechanisms of delirium: current hypotheses and evolving concepts J Gerontol A Biol Sci Med Sci June 1999;54(6):B239-B246.)

PART 6: Neurologic Disorders

760

decade, the development of tools designed especially with the unique

characteristics of critically ill ICU patients in mind has allowed the

clinician to rapidly71 and reliably detect delirium at the bedside.8,11,72

Two assessment tools, the Intensive Care Delirium Screening Checklist

(ICDSC) and the Confusion Assessment Method for the ICU

(CAM-ICU), have been validated extensively against expert psychiatric raters

using DSM-IV criteria for delirium; these tools were widely tested in the

ICU setting on both mechanically ventilated and nonmechanically

venti-lated patients.8,11,72 Several other tools have been developed and assessed

in validation studies with varying results; these studies suggest the

Nursing Delirium Screening Scale (Nu-DESC) is a promising tool, though

more validation data are needed before it can be widely recommended.71

The ICDSC is an eight-item screening tool (Table 82-3) that is

com-pleted using clinical information collected during either the previous

eight or 24 hours (depending on how often the tool is used).11 For each of

the eight items on the checklist, patients are given one point for obvious

manifestations of the item or zero points if there is no manifestation or the

item is not assessable Before the checklist is completed, level of

conscious-ness is assessed, and the checklist is only completed if the patient is not

comatose or stuporous (ie, their level of consciousness is rated other than

A or B on the ICDSC scale) A score of 4 or more on the ICDSC identifies

delirium with 64% sensitivity and 99% specificity according to the

origi-nal validation study.11 More recently, studies have found the sensitivity to

range from 43% to 74% and the specificity to range from 75% to 95%.28,73

The CAM-ICU is a four-feature delirium-screening tool adapted from

the Confusion Assessment Method for use in nonverbal, mechanically

ventilated ICU patients.8,72 It has been translated into over 14 languages

and has been implemented across the world in medical, cardiovascular,

surgical, trauma, and burn intensive care units.8,16,18,28,74-76 The original

TABLE 82-3 The Intensive Care Unit Delirium Screening Checklist

Intensive Care Unit Delirium Screening Checklist (ICDSC)

Altered level of consciousness a

distracted

Hallucination-delusion-psychosis Clinical manifestation or suggestive behavior

Psychomotor agitation or retardation Agitation required use of drugs or restraints or

Total score (one point for obvious

aIf level of consciousness A or B no other features are assessed that day

The Intensive care delirium screening checklist This 8-item checklist should be completed using clinical

information gathered over the last 8 or 24 hours First assess level of consciousness If level of

conscious-ness is C, D, or E proceed with the remaining items Patients are given 1 point for having an obvious

manifestation of the item A score of 4 or greater is considered a positive delirium screen

Modified with permission from Bergeron N, Dubois MJ, Dumont M, et al Intensive Care Delirium

Screening Checklist: evaluation of a new screening tool Intensive Care Med May 2001;27(5):859-864.

validation studies found the CAM-ICU to have excellent sensitivity (89%-100%) and specificity (93%-100%) with high inter-rater reliability (κ = 0.79-0.96), and subsequent studies have found the sensitivity

to range from 47% to 100% and the specificity to range from 88% to 96%.8,18,28,72,75-78 As with the ICDSC, patients who are comatose cannot be assessed using the CAM-ICU but should be evaluated again frequently, since patients emerging from coma are high risk for delirium Patients who are moderately sedated (ie, have some response to verbal stimuli) or more alert may be assessed for delirium using the CAM-ICM The CAM-ICU assesses for four features of delirium According to the recently revised format, which was streamlined to improve efficiency, feature 1 is the acute onset of mental status changes or a fluctuation in mental status over the last 24 hours, feature 2 is inattention, feature 3 is altered level of consciousness, and feature 4 is disorganized thinking A patient is con-sidered delirious if features 1 and 2 and either feature 3 or feature 4 are

present (Fig 82-3).8,72 The CAM-ICU tool as well as an in-depth training manual are available for download at www.icudelirium.org

PROGNOSIS FOLLOWING ICU DELIRIUM

Numerous studies have now confirmed that ICU delirium is associated with multiple poor clinical outcomes, which can be divided into imme-diate, short-term, and long-term categories

Immediate complications associated with delirium include prolonged mechanical ventilation, use of physical restraints, self-extubation, and catheter removal.9,79,80 Indeed, in one recent study of 344 medical and sur-gical ICU patients, delirium independently predicted time to extubation

in a dose-dependent fashion, with additional days of delirium predicting more time on the ventilator; the number of days a patient was delirious, in fact, was the most significant predictor of time on mechanical ventilation.80Short-term outcomes associated with ICU delirium include prolonged ICU length of stay, prolonged hospitalizations, institutionalization after hospital discharge, increased hospital costs, and increased ICU and hospital mortality.32,36,80-82 After controlling for covariates, caring for patients with ICU delirium is associated with a 39% increase in ICU costs and a 31% increase in total hospital costs.83 Elderly postopera-tive patients who develop delirium in the ICU are 7 times more likely

to be discharged to a place other than home.84 Finally, patients with ICU delirium have a higher ICU mortality16 and at least double the in- hospital mortality rate of nondelirious patients.16,36,77,81,85,86 The risk

of death following delirium does not end at hospital discharge Indeed, delirious patients who survive hospitalization remain at a higher risk for death in the months after discharge.77,81,85,86 In one study of

275  mechanically ventilated medical ICU patients, those who oped delirium in the ICU were three times more likely to die in the

devel-6 months following hospitalization than those patients who were never delirious.81 The association between delirium and long-term mortality also increases the longer a patient is delirious, such that after adjusting for potential confounders, each additional day of delirium predicts a 10% increase in the hazard of dying in the 6 to 12 months following

hospitalization for critical illness (Fig 82-4).80,81,86Although often not observed by ICU clinicians caring for delirious patients, other long-term outcomes associated with ICU delirium are often as deleterious as the short-term outcomes Delirious patients are at high risk for long-term cognitive impairment, and the longer delirium persists in the ICU, the more severe these impairments are likely to be.87-89

In a prospective study of ICU survivors who underwent logical testing, nearly 7 in 10 patients demonstrated signs of cognitive impairment 1-year following critical illness After adjusting for covari-ates, the duration of delirium in the ICU was independently associated with cognitive impairment.89 These long-term cognitive impairments in ICU survivors manifest in numerous ways, including memory problems and executive dysfunction, which can cause difficulty with managing money, reading a map, and following detailed instructions, among other effects.87,89,90 These impairments have profound effects on patient’s lives Rothenhausler et al, for example, followed survivors of the acute

CHAPTER 82: Delirium in the Intensive Care Unit 761

STRATEGIES FOR PREVENTION OF DELIRIUM

Perhaps the most effective strategy to reduce the adverse outcomes associated with delirium is to prevent delirium in the first place In general, preventive strategies should focus on reducing risk factors for delirium To date, successful prevention strategies have utilized multi-component programs of non-pharmacologic interventions designed to ameliorate delirium risk factors in non-ICU populations at high risk for delirium.92 Modification of specific delirium risk factors, such as sleep deprivation, immobility, visual and hearing impairment, and dehydra-tion, was associated in one landmark trial with a 40% relative reduc-tion in the development of delirium in hospitalized (non-ICU) elderly patients.93 These interventions, however, were less effective if delirium was already present, indicating an important role for primary preven-tion A second trial explored the utility of early geriatrics consultation

in elderly hip fracture patients undergoing fracture repair The atricians followed a specific protocol and made targeted interventions aimed at specific risk factors, such as reducing potentially deliriogenic medications, ensuring adequate oxygenation and blood pressure control, providing adequate pain control as well as ensuring the presence of eye glasses and hearing aides Compared with the usual care group, who could have received a reactive geriatrics consultation, this proactive strategy was associated with an 18% absolute reduction in incident delir-ium during the hospitalization between groups (from 50% to 32%).94Overall rates of delirium in these non-ICU patient cohorts are much lower than those observed in critically ill patients, and ICU patients are exposed to many more risk factors than non-ICU patients, suggest-ing that delirium in the ICU is likely more complex than that outside the ICU Thus, the effectiveness of these nonpharmacologic strate-gies for preventing delirium observed in non-ICU studies may not be

geri-FIGURE 82-3 The CAM-ICU assesses for the four features of delirium Feature 1 is an acute change in mental status or a fluctuating mental status (first box), feature 2, is inattention, (second box), feature 3, is altered level of consciousness (third box) and feature 4, is disorganized thinking (fourth box) A patient screens positive for delirium if features 1 and 2 and either feature 3 or feature 4 are present (Used with permission of E Wesley Ely, MD and Vanderbilt University Copyright © 2002.)

Confusion assessment method for the ICU (CAM-ICU) Step

>2 Errors

>1 error

0-1error

0-2errors

No CAM-ICU negativeNo delirium

Command: “Hold up this many fingers” (Hold up 2 fingers)

“Now do the same thing with the other hand” (Do not demonstrate) “Add one more finger” (If patient unable to move both arms)

“Squeeze my hand when i say the letter ‘A’ ”

Read the following sequence of letters: SAVE A HAART

Errors: No squeeze with ‘A’ & squeeze on letter other than ‘A’

If unable to complete letters → pictures

Current RASS level (think back to sedation assessment in step 1)

1 Will a stone float on water?

2 Are there fish in the sea?

3 Does one pound weigh more than two?

4 Can you use a hammer to pound a nail?

Is there an acute change from mental status baseline? Or Has the patient’s mental status fluctuated during the past 24 hours?

Or

FIGURE 82-4 Survival probability and duration of delirium The hazard ratio for death

at 1 year is 1.10 (95% CI 1.02-1.18, p <.01), indicating a 10% increase in the risk of mortality

at 1-year for each day a patient is delirious (Reproduced with permission from Kong SY, Kasl

SV, et al Days of delirium are associated with 1-year mortality in an older intensive care unit

population Am J Respir Crit Care Med December 1, 2009;180(11):1092-1097.)

00.0

10 + Days

respiratory distress syndrome (ARDS) for a median of six years after

ICU discharge and found that 100% of patients with cognitive

impair-ment were unemployed compared with only 23% of those patients who

were not cognitively impaired.91

PART 6: Neurologic Disorders

762

generalizable to the ICU setting; further investigation of strategies for the

prevention and management of ICU delirium is needed Nevertheless, in

the ICU, where risk factors for delirium are nearly ubiquitous,

manage-ment and minimization of known risk factors should take precedent

Risk-factor management strategies may be easily implemented in the

ICU by frequently reorienting patients, removing restraints and catheters

as quickly as possible, minimizing sleep interruptions and noise during

nighttime hours, implementing early mobilization protocols, and

ensur-ing vision and hearensur-ing assist devices (eg, eyeglasses and hearensur-ing aides)

are present.44,93,95

Whereas most prevention strategies have focused on the use of

nonpharmacologic methods in non-ICU populations, a notable

excep-tion has been studies of the α2-agonist dexmedetomidine as a sedative

for mechanically ventilated ICU patients Two randomized trials have

compared the use of this novel sedative with benzodiazepine sedatives,

finding lower rates of delirium among patients sedated with

dexme-detomidine The MENDS (maximizing the efficacy of targeted sedation

and reducing neurologic dysfunction) trial randomized 106 patients to

sedation with either dexmedetomidine or lorazepam Patients who were

sedated with dexmedetomidine had a median of 4 more days alive

with-out delirium or coma than those sedated with lorazepam (7 vs 3 days).14

A second trial, the SEDCOM (safety and efficacy of dexmedetomidine

compared with midazolam) study randomized 375 patients in a 2 : 1

fashion to sedation with dexmedetomidine or midazolam.15 Patients

receiving dexmedetomidine demonstrated a 23% absolute reduction

in delirium prevalence compared with the midazolam group (delirium

prevalence 54% in dexmedetomidine group vs 76.6% in midazolam

group) Taken together, these studies provide evidence that choice of

sedation agent may be associated with a reduction in ICU delirium

Nevertheless, it remains unclear whether the reduction in ICU delirium

is due to treatment with dexmedetomidine or simply due to the

avoid-ance of benzodiazepines

DELIRIUM TREATMENT

When delirium is diagnosed, potential underlying causes should be

sought immediately, and treatment of suspected causes should be

under-taken Then, if the patient remains delirious and to prevent the harmful

sequelae of persistent delirium, current guidelines recommend

treat-ment with pharmacologic agents.64 To date, there have been only small,

preliminary trials examining pharmacologic treatments for delirium in

the ICU.96-98 Without large, well-designed, adequately powered,

placebo-controlled, randomized trials to guide drug use for the prevention or

treatment of delirium in critically ill patients, evidence must be

extrapo-lated from studies of non-ICU populations

Benzodiazepines are used commonly in the ICU for both sedation

and the treatment of delirium,66 but this class of drugs is not

recom-mended for the management of delirium because of the likelihood of

oversedation, exacerbation of delirium, and other adverse effects (eg,

respiratory suppression) As mentioned in the section on risk factors,

benzodiazepines actually increase the likelihood of developing delirium

for most patients.13,17,39 Benzodiazepines, however, remain the drugs of

choice for the treatment of delirium tremens (and other withdrawal

syndromes) and seizures

Though a number of medications are frequently used to treat delirium

in the ICU,66 there are currently no drugs approved by the U.S Food

and Drug Administration for this indication Expert guidelines from

the Society of Critical Care Medicine,64 the American Psychiatric

Association,99 and other authoritative bodies recommend haloperidol as

the drug of choice for the treatment of delirium, but it is acknowledged

that these recommendations are based on sparse data from

nonrandom-ized case series and anecdotal reports

Haloperidol, a butyrophenone, “typical” antipsychotic, is the most widely

used neuroleptic agent for delirium.66,100 It works primarily as a dopamine

receptor antagonist by blocking the D2 receptor, which is believed to

treat—borrowing terminology from the schizophrenia literature—positive

symptoms of delirium (eg, hallucinations, unstructured thought patterns, etc) Haloperidol can also have a sedative effect, though this is variable and, unlike most sedative agents, does not result in respiratory suppression In the non-ICU setting, the recommended starting dose of haloperidol

is 0.5 to 1.0 mg orally or parenterally, with doses repeated every 20 to

30 minutes until the desired effect, which is usually resolution of tion rather than complete resolution of delirium In the ICU, alternatively, higher doses are often recommended, eg, 2 to 5 mg intravenously with doses repeated every 20 to 30 minutes until the desired effect Some prac-titioners use scheduled haloperidol every 6 to 12 hours (intravenously or orally) No strong data exist indicating the ideal dose, but maximal effec-tive doses are believed to be approximately 20 mg/d based upon data that this dose is usually adequate to achieve the “theoretically optimal” 60% to 80% D2 receptor blockade while avoiding the complete D2 receptor satu-ration associated with the adverse effects described below.101,102 Because extreme agitation in the ICU is an urgent problem, due to the potential for inadvertent removal of catheters, endotracheal tubes, and other devices, much larger doses of haloperidol are sometimes used, but this approach

agita-is based upon anecdotal experience and expert opinion and should be considered unproven until more data are available

Neither haloperidol nor similar agents (eg, droperidol and promazine) have been extensively studied in the ICU In fact, the only placebo-controlled trial examining the effect of haloperidol on ICU delirium found no significant improvement with this agent.96 This pilot study was small, however, and cannot be taken to rule out a beneficial effect of haloperidol in delirium

chlor-Some observational studies of the use of antipsychotics in non-ICU patients with delirium have reported improvements in delirium in patients treated with antipsychotics Nevertheless, these conclusions are not supported by randomized controlled trials, therefore it is unknown

if this association is due to the natural history of the disease, treatment

of underlying medical conditions or antipsychotics themselves.103,104

In addition to using antipsychotics to treat delirium once present, one study explored the use of antipsychotic prophylaxis in elderly hip frac-ture patients at risk of developing postoperative delirium.105 Low-dose haloperidol did not reduce the incidence of delirium compared with placebo, but the duration of delirium was shorter in the haloperidol group These data suggest a potential role for antipsychotics in the treat-ment of delirium, but further studies are needed

In addition to haloperidol, “atypical” antipsychotic agents (eg, peridone, ziprasidone, quetiapine, and olanzapine) are also used to treat delirium in the ICU.96-98 The rationale behind the use of atypical anti-

ris-psychotics over haloperidol (especially in hypoactive/mixed subtypes of

delirium) is theoretical and arises from the atypical antipsychotics’ effect not only on dopamine but also on other potentially key neurotransmit-ters, such as serotonin, acetylcholine, and norepinephrine.106 Results

of prospective studies comparing atypical antipsychotics with placebo and/or typical antipsychotics in the treatment of delirium have been mixed.96-98 Though one very small randomized trial found quetiapine was effective in treating delirium compared with placebo,97 another small randomized trial found no differences in neurologic outcomes among patients treated with ziprasidone, haloperidol, or placebo.96 In aggregate, these trials do not provide strong evidence for use of atypical antipsychotics over typical antipsychotics

Adverse effects of both typical and atypical antipsychotics include hypotension, acute dystonia, extrapyramidal effects, thrombotic compli-cations, oversedation, laryngeal spasm, neuroleptic malignant syndrome, glucose and lipid dysregulation, and anticholinergic effects, such as dry mouth, constipation, and urinary retention One of the most imme-

diately life-threatening adverse effects of antipsychotics is torsades de pointes,107-109 so these agents should be given to patients with prolonged QTc intervals only with extreme caution Outpatients treated with either typical or atypical antipsychotics for schizophrenia are at an increased risk of sudden cardiac death,107,109 with this risk increasing as either dose

or duration of antipsychotic therapy increases.107,109 It remains unclear whether similar risk affects critically ill patients, who typically receive

CHAPTER 83: ICU-Acquired Weakness 763

these medications for much shorter periods of time Nevertheless, ICU

patients treated with antipsychotics should be monitored closely with

electrocardiography, and the medications should be avoided for patients

with a baseline QTc >450 to 500 ms or a prolongation of 25% or greater

from baseline

The role of novel agents, such as dexmedetomidine and rivastigmine,

in delirium treatment has recently been investigated As described in the

delirium prevention section above, use of the α2-agonist

dexmedetomi-dine as a sedative for mechanically ventilated ICU patients is associated

with lower rates of ICU delirium when compared with benzodiazepines

Dexmedetomidine has also been compared with haloperidol as a

treatment for agitated delirium in a small pilot study of mechanically

ventilated patients.110 Patients treated with dexmedetomidine were

more quickly extubated than those patients whose agitation was treated

with haloperidol Though delirium prevalence at baseline was similar

between the two groups, patients treated with dexmedetomidine may

have had more rapid resolution of delirium though these results were

not significantly different between groups Although further study is

required, this pilot study suggests dexmedetomidine may have a role not

only in preventing delirium among mechanically ventilated patients but

also treating delirium in this population

van Eijk explored the use of a cholinesterase inhibitor, rivastigmine,

as an adjuvant treatment for ICU delirium in a population of ICU

patients.111 The trial was stopped prematurely after differences in the

mortality rate between the rivastigmine group (22%) and placebo (8%)

met the predefined stopping criteria Further, the rivastigmine group

also demonstrated a trend toward longer duration of delirium compared

with placebo These results do not support the use of cholinesterase

inhibitors for the treatment of delirium in the ICU

SUMMARY OF KEY POINTS ON ICU DELIRIUM

Critically ill patients are at great risk for the development of delirium

in the ICU However, this form of brain dysfunction is grossly

under-recognized and undertreated Delirium is mistakenly thought to be a

transient and expected outcome in the ICU and of little consequence

(ie, part of the “ICU psychosis”) It is now recognized that delirium is

one of the most frequent complications experienced in the ICU; even

after adjusting for covariates such as age, sex, race, and severity of illness,

delirium is an independent risk factor for prolonged length of stay

and higher 6-month mortality rates In addition, many ICU survivors

demonstrate persistent cognitive deficits at follow-up testing months to

years later It is essential for health care professionals to be able to

recog-nize delirium readily at the bedside The CAM-ICU is a valid, reliable,

quick, and easy-to-use serial assessment tool for monitoring delirium in

ventilated and nonventilated ICU patients Delirium is a multifactorial

problem for ICU patients that demands an interdisciplinary approach

for assessment, management, and treatment Critical care nurses and

physicians should assume a position of leadership in the ICU with

regard to delirium monitoring because they are the best-suited members

of the ICU team to successfully implement this essential component of

patient management, which is recommended by the SCCM clinical

practice guidelines Although ongoing trials may elucidate the optimal

ways to treat delirium, standard pharmacologic and nonpharmacologic

management strategies have been reviewed

REFERENCES

Complete references available online at www.mhprofessional.com/hall

ICU-Acquired Weakness

William Schweickert John P Kress 83

C H A P T E R

KEY REFERENCES

• Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y Intensive

Care Delirium Screening Checklist: evaluation of a new screening

tool Intensive Care Med May 2001;27(5):859-864.

• Ely EW, Shintani A, Truman B, et al Delirium as a predictor of

mortality in mechanically ventilated patients in the intensive care

unit JAMA April 14, 2004;291(14):1753-1762.

• Girard TD, Jackson JC, Pandharipande PP, et al Delirium as a dictor of long-term cognitive impairment in survivors of critical

pre-illness Crit Care Med July 2010;38(7):1513-1520.

• Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C,

et al Preventive effects of ramelteon on delirium: a randomized

placebo-controlled trial JAMA Psychiatry 2014;71:397-403.

• Pandharipande P, Shintani A, Peterson J, et al Lorazepam is an independent risk factor for transitioning to delirium in intensive

care unit patients Anesthesiology Jan, 2006;104(1):21-26.

• Pandharipande PP, Pun BT, Herr DL, et al Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized con-

trolled trial JAMA December 12, 2007;298(22):2644-2653.

• Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP Rapidly ible, sedation-related delirium versus persistent delirium in the

revers-intensive care unit Am J Respir Crit Care Med 2014; 189:658-65.

• Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness

PH Days of delirium are associated with 1-year mortality in an

older intensive care unit population Am J Respir Crit Care Med

December 1, 2009;180(11):1092-1097

• Reade MC, O’Sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo

R Dexmedetomidine vs haloperidol in delirious, agitated, intubated

patients: a randomised open-label trial Crit Care 2009;13(3):R75.

• Riker RR, Shehabi Y, Bokesch PM, et al Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial

JAMA February 4, 2009;301(5):489-499.

• Skrobik YK, Bergeron N, Dumont M, Gottfried SB Olanzapine vs

haloperidol: treating delirium in a critical care setting Intensive Care Med March 2004;30(3):444-449.

• van Eijk MM, Roes KC, Honing ML, et al Effect of rivastigmine as

an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-

blind, placebo-controlled randomised trial Lancet November 27,

a suggestive history and when they can participate in a hensive bedside neuromuscular examination

• Electrophysiology testing, direct muscle stimulation, and biopsy may

be necessary to characterize neuromuscular injury in the patient who

PART 6: Neurologic Disorders

764

INTRODUCTION

Many patients admitted to the intensive care unit (ICU) develop a

syn-drome of neuromuscular dysfunction characterized by generalized muscle

weakness and an inability to be liberated from mechanical ventilation

Since this syndrome occurs in the absence of preexisting neuromuscular

disease, it is believed to reflect illnesses or treatments occurring in the ICU

Early reports described two categories of acute, acquired neuromuscular

dysfunction: polyneuropathy (during sepsis and multisystem organ

fail-ure)1,2 and myopathy (particularly in patients with acute respiratory failure

who received glucocorticoids and/or neuromuscular blocking agents).3,4

Decades of research on this acquired nerve and muscle injury has

char-acterized specific phenotypes via comprehensive physical examination,

electrophysiologic testing, and histopathology Overall, the spectrum of

neuromuscular disorders acquired in the ICU is now collectively referred

to as “ICU-acquired weakness” (ICUAW) (Fig 83-1).5

The rising incidence and societal burden of critical illness—such as

sepsis and the acute respiratory distress syndrome6-8—coupled with

declining case fatality rates and an aging population,9,10 suggests that

the number of patients with ICUAW and its sequelae may be substantial

and likely to grow Accordingly, intensivists must have familiarity with

the presentation of ICUAW, recognize when to conduct advanced

test-ing, and understand the diagnostic tests involved Although currently

limited in scope, measures designed to prevent or attenuate ICUAW

must be considered and implemented

CRITICAL CARE SURVIVORSHIP AND ICUAW

Critical care outcomes research has demonstrated substantial morbidity

in survivors Injuries include general deconditioning, muscle weakness,

dyspnea, depression, anxiety, and reduced health-related quality of life.11

One widely cited catalyst for attention to the burden of neuromuscular weakness was the comprehensive observations of a cohort of survivors

of acute respiratory distress syndrome (ARDS) published in 2003.12These 109 survivors were young (median age, 45 years), had few pre-existing comorbidities, and were severely ill (median APACHE II score, 23) Their critical illness was marked by prolonged mechanical ventilation (median duration, 21 days) and ICU and hospital lengths

of stay (median duration, 25 and 48 days, respectively) Despite severe acute lung injury, serial follow-up examination during the first year after ICU discharge demonstrated restoration of lung function Lung volumes and spirometry normalized by 6 months and carbon monoxide diffusion capacity improved to 72% predicted at 12 months In contrast, all 109 patients reported poor function attributed to the loss of muscle bulk, proximal weakness, and fatigue One year after ICU discharge, the median distance walked in 6 minutes was 66% of predicted and only 49% of patients had returned to work

More recently, the same cohort was characterized at 5 years after ICU discharge.13 All patients reported subjective weakness and decreased exercise capacity when compared to function before ICU admission

Although there was no evidence of clinical weakness on examination, the median distance walked in 6 minutes remained lower than expected based on age and sex (76% predicted) By the fifth year, 77% of patients had returned to work; however, patients often required a modified work schedule, gradual transition back to work, or job retraining In addition, patients were plagued with the psychological ramifications of their severe illness; more than half of survivors experienced at least one episode of physician-confirmed depression or anxiety

Others have reported similar findings of post-ARDS debilitation Specifically, an observational trial of 112 ARDS survivors without baseline impaired physical function noted a 66% cumulative incidence

of physical impairment during 2 year follow-up.14 This impairment, defined as the acquisition of two or more dependencies in instrumental activities of daily living, had greatest incidence by 3 months after discharge and was associated with longer ICU stay and prior depressive symptoms More recently, a comprehensive 1 year follow-up of patients enrolled in a randomized controlled trial of nutritional strategies

in patient with ARDS demonstrated that survivors, regardless of nutritional strategy, experienced substantial impairments in endurance (as defined by six minute walk test) and cognitive function.15

Acquired neuromuscular weakness and loss of function have been measured in other contexts of critical illness, including severe sepsis and mechanical ventilation in the elderly To determine the impact of a hospitalization for severe sepsis, Iwashyna and colleagues utilized The Health and Retirement Study, a cohort of Americans over age 50 under-going biennial surveys of physical and cognitive function.16 Participants were stratified into those surviving a hospitalization for severe sepsis

(n = 516) versus controls (survivors of a nonsepsis hospitalization,

n = 4517) Among patients with no functional limitations at baseline,

severe sepsis was associated with the development of 1.57 new tions (95% CI: 0.99-2.15), as well as a more rapid rate of development

limita-of functional limitations after hospitalization (0.51 new limitations per

year, p = 0.007 compared with baseline) The study also found that the

incidence of severe sepsis was highly associated with progression to moderate to severe cognitive impairment

In a similar design, Barnato et al used a longitudinal cohort study

of Medicare recipients to investigate the association of mechanical ventilation and disability.17 Community dwelling patients over age 65 completed quarterly interviews of physical function for four years Survivors of hospitalization with or without mechanical ventilation had similar levels of disability from each other, but significantly more than those who were never hospitalized There was a substantial increase in disability in both groups after hospitalization, greater among survivors

of mechanical ventilation than in those hospitalized without mechanical ventilation In adjusted analyses, mechanical ventilation was associated with a 30% greater disability in activities of daily living (ADLs) and a 14% greater disability in mobility

is unable to participate in a comprehensive neuromuscular

examina-tion, is failing to improve function despite weeks of therapy, or for the

patient with asymmetric weakness

• When conducted, advanced testing, particularly electrophysiology tests,

can characterize the specific phenotype of ICU-AW including critical

illness polyneuropathy, critical illness myopathy, a combination of the

two (polyneuromyopathy), or prolonged neuromuscular blockade

• The exact epidemiology of ICUAW is unknown Studies show that

46% of patients with sepsis, multiorgan failure, or prolonged

mechan-ical ventilation are diagnosed with ICUAW In patients undergoing

mechanical ventilation for 7 days or more, 25% develop ICUAW

• Factors associated with the diagnosis of ICUAW include the presence

of multisystem organ dysfunction, sepsis, SIRS, and hyperglycemia

and the duration of mechanical ventilation The only known therapy

to prevent ICUAW has been strict glycemic control with insulin;

how-ever, adverse events with this therapy have prevented its utilization

FIGURE 83-1 Classification of intensive care unit-acquired weakness CIM, critical illness

myopathy; CINM, critical illness polyneuromyopathy; CIP, critical illness polyneuropathy; NMJ,

neuromuscular junction

ICU-acquired weakness

ProlongedNMJblockade

CHAPTER 83: ICU-Acquired Weakness 765

TABLE 83-2 Diagnostic Features of ICUAW

1 Weakness is diffuse, symmetric, and often spares the cranial nerves

2 Causes of weakness other than those from the underlying illness have been excluded

3 Alert patient who can follow simple commands and participate in neuromuscular examination

4 MRC sumscore <48 or mean MRC <4 in all testable muscle groupsMRC, Medical research Council

Modified with permission from Stevens et al A framework for diagnosing and classifying intensive care

unit-acquired weakness Crit Care Med October 2009;37(suppl 10):S299-S308.

These studies show that decrements in physical function occur across

the spectrum of critical illness Although these outcomes may be

influ-enced by other factors—such as age, preexisting comorbidities, acquired

psychological and cognitive dysfunction, and social support—it is clear

that ICUAW needs to be recognized early to enable preventive

interven-tions However, the recognition of ICUAW has often been hindered

by challenges with various diagnostic testing approaches and complex

nomenclature

CLINICAL PRESENTATION OF ICUAW

The clinical approach is based on the recognition of generalized

weak-ness in the appropriate setting, the exclusion of causes extrinsic to

critical illness, and the measurement of muscle strength.5 The historian

should carefully review the time course of neuromuscular symptoms

as they relate to the underlying critical illness Potential risk factors for

ICUAW should be identified—including sepsis, multiple organ failure,

mechanical ventilation, hyperglycemia, and exposure to

pharmaco-logic agents like glucocorticoids and neuromuscular blocking agents

(NMBAs) Neurologic examination evaluates key functional domains

including consciousness, cognitive function, cranial nerves, motor and

sensory systems, deep tendon reflexes, and coordination Motor

assess-ment should include tone and bulk in addition to strength

Physical examination of patients for ICUAW is dependent on the

cooperation and maximal effort of the patient—an aspect of bedside

assessment that can be confounded by sedation and delirium When

a reliable motor examination is possible, affected patients will exhibit

diffuse, generally symmetrical motor deficits in all limbs, ranging from

paresis to true quadriplegia.18 Weakness affects the extremities and

diaphragm yet often spares the cranial nerves; accordingly, pupillary

and  oculomotor function and facial grimace are usually preserved

Patients often have concurrent respiratory failure with protracted

dependence on mechanical ventilation

An early clue for isolated myopathy (without neuropathy) is that

pain-ful stimulation—such as pressure upon the nail bed—results in a limited

to absent limb response, yet normal grimacing For patients with ability to

undergo a reliable sensory examination, deficits to light touch and pin

prick may implicate the presence of polyneuropathy Reflexes are usually

diminished to absent, but normal reflexes do not rule out the diagnosis

The most commonly reported test of muscle strength in critically

ill patients is manual muscle testing A standardized bedside muscle

exam can be utilized to evaluate individual muscle groups The Medical

Research Council (MRC) Score grades the strength of functional muscle

groups in each extremity on a scale from zero to five (Table 83-1).19

Individual MRC scores obtained from predefined muscle groups can be

combined into a sum score, yielding a global estimate of motor function

The usual standard is to combine three muscle group scores for each

limb; therefore, sum scores span from zero (complete paralysis) to 60 (full strength) This scoring has demonstrated excellent inter-rater reli-ability and can be utilized to document the extent of disease and track serial changes over time.20,21

To better characterize the incidence of acquired neuromuscular disorders in the ICU and to validate the bedside muscle strength exami-nation, De Jonghe and colleagues prospectively evaluated 95 patients without preexisting neuromuscular injury that had undergone mechani-cal ventilation for greater than 7 days.22 The first day a patient was awake and following commands was considered day 1 On the seventh day after awakening, patients underwent MRC muscle strength testing to determine a sum score A priori, they labeled patients with a sum score

of less than 48 to have “ICU-acquired paresis.” To confirm the peripheral neuromuscular origin of the clinical weakness, all patients underwent

an electrophysiologic examination exam at day 7 and persistently weak patients underwent muscle biopsy at day 14 All patients with ICU-acquired paresis demonstrated sensory-motor axonopathy Histological features of primary myopathic changes were observed in all patients with paresis persisting 1 week after the initial diagnosis

Since this landmark trial, leaders in the field have established use of the term “ICU-acquired weakness” to characterize clinically detected weak-ness in critically ill patients in whom there is no plausible etiology other than critical illness.5 ICUAW, synonymous with ICU-acquired paresis, is defined by the MRC muscle strength sum score <48 in a patient that

is awake and able to follow commands (Table 83-2) Since this

delinea-tion, this diagnosis has been repeatedly applied as a secondary end point

in prospective clinical trials to crudely assess for the presence of muscle injury and weakness.23,24

The intensivist should remain cognizant of the limitations of the MRC strength examination It requires a patient who is awake, cooperative, and capable of contracting muscle with maximal force Scores also can

be affected by patient positioning, the number of limbs available for assessment (pain, dressings, amputation), and, most importantly, timing Experts have lamented other limits including the omission of distal lower extremity function and poor ability to detect subtle changes over time

DIFFERENTIAL DIAGNOSIS

Generalized weakness may result from injury to the brain or brainstem, myelopathies, anterior horn cell disorders, polyneuropathies, neuro-

muscular junction disorders, and muscle disorders (Table 83-3) The

weakness may represent the exacerbation or unmasking of a chronic underlying neuromuscular disease Alternatively, the weakness may represent the acute neuromuscular condition In cases of uncertainty, additional tests should be performed, including neuroimaging of the brain, brainstem, or spinal cord; infectious and immunologic serologies, cerebrospinal fluid analysis, and electrophysiology (EP) studies

With a good history and physical examination, many of the tial diagnoses can be excluded with confidence Given that some of the other diagnoses are treatable, ICUAW should be regarded as a diagnosis

differen-of exclusion The weakness must follow the onset differen-of the critical illness; symptoms prior to admission should direct attention to other etiologies The inability to interview the patient, due either to intubation or delirium may limit historical detail and proper physical examination The pres-ence of delirium should not dissuade the search for a neuromuscular disorder, especially when cognition is improving and the weakness is not

TABLE 83-1 Medical Research Council (MRC) Neuromuscular Examination

Functions Assessed:

Upper extremity: Wrist flexion, forearm flexion, shoulder abduction

Lower extremity: Ankle dorsiflexion, knee extension, hip flexion

Score for Each Movement:

0—No visible contraction

1—Visible muscle contraction, but no limb movement

2—Active movement, but not against gravity

3—Active movement against gravity

4—Active movement against gravity and resistance

5—Active movement against full resistance

Maximum score: 60 (4 limbs, maximum 15 points per limb)—Normal

Minimum score: 0—Quadriplegia

PART 6: Neurologic Disorders

766

ADJUNCTIVE TESTING FOR NEUROMUSCULAR INJURY

Methods to confirm ICUAW and identify its subcategories include EP

studies, direct muscle stimulation, and morphologic analysis of muscle or

nerve tissue These tests help to exclude other differential diagnoses and

can help to characterize the specific subcategory of ICUAW: neuropathy,

myopathy, neuromyopathy, or prolonged neuromuscular junction

block-ade This section details the application of each test Figure 83-2 provides

an algorithm for the work-up of a patient exhibiting weakness or inactivity

Electrophysiologic studies used to evaluate the peripheral nervous

sys-tem include nerve conduction studies, needle EMG, and neuromuscular

junction testing Peripheral motor nerve stimulation elicits a compound muscle action potential (CMAP), which represents the summated response of all stimulated muscle fibers Alternatively, a sensory nerve may be stimulated at separate points to measure the sensory nerve action potential (SNAP), which represents the summated response of all stimulated sensory fibers Nerve conduction velocity is calculated by measuring the time between nerve stimulation and recording at two sites separated by a known distance Taken together, the information can diagnose an axonal sensory-motor polyneuropathy, such as CIP,

in which decreased CMAP and SNAP amplitudes are measured while nerve conduction velocity is normal In contrast, a demyelinating sensory-motor polyneuropathy, like Guillain-Barré syndrome, will exhibit preserved CMAP and SNAP amplitudes with markedly reduced conduction velocities

Awake and cooperative patients can undergo needle EMG Recordings are conducted during muscle rest, mild contraction, and with increasing

or maximal voluntary muscle contraction Fibrillation potentials and sharp waves at rest suggest recent denervation or muscle necrosis Motor unit potentials (MUPs) are recorded during voluntary contrac-tion Myopathy is suggested when MUPs are of short duration and low amplitude With maximal contraction, early recruitment of MUPs may occur In contrast, long-duration, polyphasic, high-amplitude MUPs may suggest neuropathy For the patient with persistent respiratory failure, phrenic nerve conduction studies and needle EMG of the dia-phragm can be performed

Assessment of the neuromuscular junction is accomplished via repetitive nerve stimulation and/or single-fiber EMG In repetitive nerve stimulation, a series of supramaximal stimuli are applied at 2 to 3 Hz Decreases in CMAP amplitude of greater than 10% between the first and fourth responses indicate a postsynaptic defect in neuromuscular transmission, such as myasthenia gravis or prolonged NMBA effect (see below) When the patient is able to contract muscle voluntarily, single-fiber EMG is possible This test records the time interval between action potentials in two muscle fibers that are parts of the same motor unit Variable inter-spike intervals, termed jitter, and absence of the second spike (blocking) are consistent with neuromuscular dysfunction

Limitations of EP testing include falsely dampened measurements from tissue edema, electrical interference from other ICU equipment, the inability for patients to voluntarily contract muscles, and the need for specialists well-versed in the complexities of interpretation Importantly, competing illnesses may cause preexisting axonal polyneuropathy, including diabetes and effects of chemotherapeutic agents

To overcome the challenges of patient cooperation, direct muscle stimulation can be conducted to distinguish polyneuropathy and myopathy.25,26 Theoretically, denervated muscle (as in CIP) should retain electrical excitability; therefore, direct muscle stimulation CMAP ampli-tude should be normal In contrast, patients with myopathy exhibit loss

of electrical excitability; therefore, both nerve and direct muscle lated CMAPs are diminished To accomplish this, a stimulating needle

stimu-or surface electrode is placed just proximal to the tendon insertion After obtaining a muscle twitch, a recording needle electrode is placed in the center of the muscle proximal to the site of stimulation, and the maxi-mal muscle-stimulated CMAP (mCMAP) is recorded Using the same recording electrode, the appropriate nerve undergoes surface stimula-tion to elicit a nerve-evoked CMAP (nCMAP) The nCMAP to mCMAP ratio is calculated; a value >0.5 suggests impaired muscle membrane excitability.27,28

■ BIOPSY

Nerve histology in patients with electrophysiologically defined CIP demonstrates distal axonal degeneration involving both sensory and motor fibers with no evidence of demyelination or inflammation Muscle biopsies have demonstrated denervation changes and commonly have myopathy In contrast, muscle biopsy in CIM demonstrates acute necrosis, regeneration, type II fiber atrophy, and selective loss

of thick filaments (myosin).29 This last feature is proven by the loss of

TABLE 83-3 Acute Generalized Weakness Syndromes in Critically Ill Patients

Bilateral or paramedian brain or brainstem lesionsa

6 Central pontine myelinolysis

Spinal cord disordersa

1 Trauma

2 Nontraumatic compressive myelopathies

3 Spinal cord infarction

4 Immune-mediated myelopathies (transverse myelitis, neuromyelitis optica)

5 Infective myelopathies (eg, HIV, West Nile virus)

Anterior horn cell disorders

1 Motor neuron disease

2 Poliomyelitis

3 West Nile virus infection

4 Hopkins syndrome (acute postasthmatic amyotrophy)

7 Critical illness polyneuropathy

Neuromuscular junction disorders

6 Drug-induced and toxic myopathies

7 Critical illness myopathy

8 Decompensation of congenital myopathies (eg, myotonic dystrophy, Duchenne

muscular dystrophy, adult onset acid maltase deficiency)

aUpper motor neuron signs (increased tone, hyperreflexia) may be absent in the acute setting

bIncludes acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy, acute

motor, and sensory axonal neuropathy

cIncludes polymyositis, dermatomyositis, pyomyositis

HIV, human immunodeficiency virus

CHAPTER 83: ICU-Acquired Weakness 767

TABLE 83-4 Major Diagnostic Features of CIP

1 Evidence for ICUAW

2 Abnormal sensory examination (when possible)

3 Electrophysiologic evidence of axonal motor and sensory polyneuropathy

• Sensory and motor nerve amplitudes <80% of the lower limit of normal in two or more nerves

• Normal or near normal conduction velocities without conduction block

• Absence of a decremental response on repetitive nerve stimulationOther supportive findings:

• Needle EMG with reduced recruitment of normal motor unit potentials (early finding)

• Needle EMG with fibrillation potentials and reduced recruitment of long-duration, high-amplitude MUPs (late finding)

• Normal CSF protein

• Normal serum creatine kinase

myofibrillar adenosine triphosphate staining on electron microscopic

imaging Although biopsies have provided valuable insight into the

mechanism of injury, the role of nerve and muscle biopsies in clinical

practice is controversial The prognostic value of histologic findings

remains poorly explored

■ OTHER DIAGNOSTIC TESTS: BIOMARKERS AND IMAGING

Increased serum creatine kinase has been reported in patients with

acquired myopathy, particularly those with necrotizing myopathy There

is simultaneous interest in the use of ultrasound to image muscle to

infer muscle bulk.29,30 Decrease in muscle thickness over time has been

documented in measurements of the anterior thigh, forearm, and biceps

For example, linear array, high frequency probes can be used to measure

quadriceps bulk at a specified point Validation studies of this tool as a

marker of muscle bulk and injury are ongoing

■ SUBCATEGORIES OF ICUAW: CIP, CIM, CIPNM AND PROLONGED

NEUROMUSCULAR JUNCTION BLOCKADE

Given the complex testing options, a comprehensive diagnostic

nomenclature and classification has been generated (Fig 83-1) As

described above, the term ICU-acquired weakness designates

clini-cally detected weakness in criticlini-cally ill patients in whom there is no

plausible etiology other than critical illness When advanced testing

is conducted, more specific phenotypes (or subcategories of ICUAW)

can be described Critical illness polyneuropathy refers to patients with

ICUAW who have electrophysiological evidence of an axonal

poly-neuropathy Critical illness myopathy indicates patients with ICUAW

who have electrophysiologic and/or histologic defined myopathy The

term critical illness neuromyopathy (CINM) is reserved for patients

who have electrophysiologic and/or histologic findings of coexisting

CIP and CIM Finally, a rare entity of prolonged neuromuscular

junc-tion blockade exists with overlapping clinical features of ICUAW and

distinct EP features

■ CRITICAL ILLNESS POLYNEUROPATHY (SEE TABlE 83-4)

Critical illness polyneuropathy (CIP) is a distal axonal sensory-motor polyneuropathy affecting both limb and respiratory muscles As in all cases of ICUAW, it is usually discovered in patients with prolonged criti-cal illness, particularly mechanical ventilation, and affected patients have limb muscle weakness—particularly distal weakness—with reduced or absent deep tendon reflexes.27 When measurable, patients have loss of peripheral sensation to light touch and pin prick, yet preserved cranial nerve function

Given the limitations of the sensory examination in critically ill patients, EP studies have generally been relied upon to establish the diagnosis EP studies show a reduction in amplitude of CMAPs and SNAPs reflecting the underlying axonal loss.31 Nerve conduction veloc-ity is normal or mildly reduced Over time, fibrillation potentials will

be evident on electromyography (EMG) needle examination In severe cases with ventilatory failure, phrenic motor amplitudes are commonly

FIGURE 83-2 Diagnostic algorithm for weakness in the ICU CIM, critical illness myopathy; CIP, critical illness polyneuropathy; DMS, direct muscle stimulation; EMG, electromyography;

EP, electrophysiology; ICUAW, intensive care unit-acquired weakness; MRC, Medical Research Council; NCS, nerve conduction studies; NMJ, neuromuscular junction

Critically ill patient exhibits weakness

No furthertesting

Fails toimproveOther

diagnosis

Confirmatorytest needed?

DMS, musclebiopsy

EMG, NCSRepetitive nerve stimulation

EP Studies

CIP, CIM NMJ blockade Prolonged

ICUAW

PART 6: Neurologic Disorders

768

reduced or absent In patients with CIP, direct needle stimulation of

muscle elicits a relatively higher amplitude response compared with the

response recorded from muscle after nerve stimulation

The serum CK level is normal, and, when performed, cerebrospinal

fluid protein levels are usually normal Muscle biopsy findings are those

of neurogenic atrophy Nerve histology in patients with

electrophysi-ologic-defined CIP demonstrates distal axonal degeneration involving

both sensory and motor fibers with no evidence of demyelination or

inflammation

Prior investigations have commonly associated CIP with severe

sepsis and experts suspect it represents a neurologic manifestation of

the systemic inflammatory response syndrome (SIRS).28,32,33 There is

some correlation with elevations in blood glucose and reductions in

serum albumin.34 The mechanism of axonal injury in CIP is unknown

However, injury to the microcirculation of distal nerves, causing

isch-emia and axonal degeneration, is speculated.33,35 During the early stages

of sepsis, electrical inexcitability due to sodium channel inactivation

may be present in otherwise intact nerves

■ CRITICAL ILLNESS MYOPATHY (SEE TABlE 83-5)

The most common form of intensive care unit (ICU)-acquired

myopa-thy is critical illness myopamyopa-thy (CIM).36 The most common presenting

features of CIM are flaccid quadriparesis that may have a different

pat-tern than CIP Whereas CIP exhibits a length-related patpat-tern (ie, distal

muscles are weakest), CIM usually affects proximal muscles either

equally or more pronounced than distal muscles Facial muscle

weak-ness can occur, but extraocular muscle weakweak-ness is rare Like other

entities, patients often repeatedly fail to wean from mechanical

ventila-tion Although not always assessable, sensation should be normal For

example, these patients often grimace to painful stimuli even during

periods of delirium

In retrospective series of patients with CIM, approximately one-half

had elevations in CK.37 In patients with appropriate clinical features, the

diagnosis of CIM can be confirmed by electrophysiologic testing with

nerve conduction studies (NCS) and electromyography (EMG) Muscle

biopsy establishes the diagnosis, but is rarely performed unless another

treatable condition, such as an inflammatory myopathy, is in the

dif-ferential diagnosis

The major nerve conduction findings of CIM are normal to low

motor amplitudes with occasional broadening of the CMAP.38,39 Phrenic

motor amplitudes may also be low Sensory responses are normal or

only mildly reduced, unless there is a coexisting polyneuropathy Needle

examination frequently demonstrates fibrillation potential activity

implicating recent denervation or muscle necrosis.31 Observation of the

recruitment of motor unit potentials (MUPs) may not be possible in

advanced weakness When feasible, recruitment tends to be early MUPs

are short in duration, low in amplitude, and may be polyphasic.40 In contrast, long-duration, polyphasic, high amplitude MUPs may suggest neuropathy

Direct muscle stimulation can be conducted to assess for electrical inexcitability and may help to differentiate CIM from motor axonopa-thy.26 However, this modality is often limited to those patients with a coexisting peripheral neuropathy

Alternatively, CIM may be established with muscle biopsy The major histopathologic finding is the selective loss of myosin, identified as a lack of reactivity to myosin ATPase in non-necrotic fibers This finding can be confirmed with immunohistochemic studies for myosin and by utilizing electron microscopy to identify loss of thick filaments There

is usually atrophy of myofibers (type 2 more than type 1), evidence of myofibrillar disorganization, and occasional necrosis.41,42

Several processes may be involved in the pathogenesis of CIM, ing upregulation of calpain, an increase in muscle apoptosis, activation

includ-of the proteasome ubiquitin-degradative system, and upregulation includ-of the transforming growth factor-beta/mitogen-activated protein kinase pathway.43 Oxidative stress may also play a role Observation of the loss

of sarcolemmal nitric oxide synthase isoform 1 may lead to muscle fiber inexcitability.44

A steroid-denervation animal model reproduces the histopathologic and electrophysiologic findings of CIM observed in humans.45 This model suggests that a deleterious interaction between glucocorticoids and denervation leads to depletion of the mRNA for myosin and results

in muscle atrophy.46 Finally, muscle sodium channel properties have also been implicated using a chronic sepsis animal model Patch clamp technique revealed decreased sodium current that could lead to muscle inexcitability.47

■ CRITICAL ILLNESS POLYNEUROMYOPATHY

More recent investigations have proven that a reasonable proportion of patients have features of combined CIM and CIP, termed critical illness polyneuromyopathy.48 The commonality of this entity was illustrated by

a prospective longitudinal cohort study of 48 patients who had baseline neurologic examinations and nerve conduction studies (NCS) within

72 hours of developing severe sepsis.49 Electromyography was performed

on patients who developed clinical weakness or had 30% or greater reduction in nerve conduction response amplitudes Clinical and elec-trophysiologic examinations were repeated weekly for the duration of the ICU stay Abnormal NCS were present at baseline in 63% of patients, and an abnormality on baseline NCS was significantly associated with hospital mortality compared with a normal baseline NCS (55% vs 0%, respectively) In 20 patients who remained in the ICU long enough to have serial NCS, neuromuscular dysfunction developed in 10 patients (50%) Electrophysiologic evidence of both CIM and CIP was present

in 8 of 10 patients with neuromuscular dysfunction The investigators hypothesized that sepsis may be a common pathologic mechanism underlying the development of both CIM and CIP

■ PROLONGED NEUROMUSCULAR JUNCTION BLOCKADE

Prolonged neuromuscular junction (NMJ) blockade is a rare disorder occurring in patients who receive non-depolarizing NMBAs who experi-ence persistent generalized weakness and respiratory failure despite drug cessation.50 These paralytic agents inhibit neuromuscular transmission via reversible binding to acetylcholine receptors on the motor end-plates

of NMJs However, specific drugs requiring end organ function for clearance may have persistent effects, particularly when infused for pro-longed periods For example, aminosteroid blocking agents, such as pan-curonium and vecuronium, undergo metabolism by the liver and result

in functionally active 3-hydroxy metabolites In situations of advanced liver or kidney injury ( creatinine clearance <30 mL/min), these drugs can accumulate for prolonged effect Other reported contexts include hypermagnesemia or metabolic acidosis

Examination is notable for flaccid quadriplegia, arreflexia, and involvement of the cranial nerves, including ptosis, ophthalmoparesis,

TABLE 83-5 Major Diagnostic Features of CIM

1 Evidence for ICUAW

2 Intact sensory examination (when possible)

3 Electrophysiologic evidence of myopathy without neuropathy

a Needle EMG with short-duration, low-amplitude MUPs with early or normal full

recruitment, with or without fibrillation potentials in 2 or more muscle groups

b Absence of other nerve injury

i Sensory nerve amplitudes >80% of the lower limit of normal in two or more

nerves on nerve conduction studies

ii Absence of a decremental response on repetitive nerve stimulation

4 Muscle inexcitability on direct muscle stimulation

a Muscle-stimulated CMAP/nerve-evoked CMAP ratio >0.5 in 2 or more muscles

5 Muscle histopathologic findings of myopathy with myosin loss

Other supportive findings:

1 Motor amplitudes <80% of the lower limit of normal in two or more nerves

2 Elevated serum creatine kinase

CHAPTER 83: ICU-Acquired Weakness 769

and facial weakness Train-of-four stimulation with a peripheral

nerve stimulator measures the decremental response

semiquantita-tively and may detect a major neuromuscular junction defect Formal

testing with repetitive nerve stimulation is the confirmatory test In

this test, a series of supramaximal stimuli are applied with a nerve

stimulator Decreases in CMAP amplitude greater than 10% from the

first to fourth response indicate a postsynaptic defect in

neuromus-cular transmission, such as myasthenia gravis or prolonged NMBA

effect Transient improvement in muscle strength after

administra-tion of an anticholinesterase reversing agent, such as pyridostigmine,

supports prolonged neuromuscular junction blockade as a cause

of weakness

The condition is reversible and recovery of motor function is

observed over a period of 2 to 10 days Weakness beyond this

dura-tion should prompt consideradura-tion for alternative diagnoses, especially

other neuromuscular junction diseases such as myasthenia gravis

Prolonged neuromuscular blockade can be prevented by avoiding

aminosteroid blocking drugs in favor of benzylisoquinoline agents,

such as cisatracurium, which has no dependence on end organ

function (metabolized by rapid nonenzymatic degradation in the

bloodstream, Hofmann elimination) Indeed, the routine use of

cisa-tracurium for neuromuscular blockade in the ICU has largely

elimi-nated this problem

■ ICUAW EPIDEMIOLOGY AND RISK FACTORS

Several studies have attempted to establish the prevalence of ICUAW

and its associated risk factors Given the history of reliance upon

advanced testing to delineate phenotypes, large-scale epidemiology

studies have not been conducted In this context, the best summary

data is a systematic review of 24 published studies that included both

clinical and electrophysiologic examination.51 Their end point was

abnormal EP test findings (including CIP, CIM, and CIPNM), which

they termed critical illness neuromuscular abnormalities (CINMAs), a

label now interchangeable with ICUAW Of the 1421 total patients with

sepsis, multiorgan failure, or prolonged mechanical ventilation, 46% had

ICUAW The risk of ICUAW was associated with hyperglycemia (and

inversely associated with tight glycemic control), the systemic

inflam-matory response syndrome (SIRS), sepsis, multiple organ dysfunction,

renal replacement therapy, and catecholamine administration Across

studies, there was no consistent relationship between ICUAW and

patient age, gender, severity of illness, or exposure to glucocorticoids,

neuromuscular blockers, aminoglycosides or midazolam Unadjusted

mortality was not increased in the majority of patients with ICUAW, but

mechanical ventilation and ICU LOS were prolonged

The cohort study that established the validity of the physical examination

for ICUAW had both complementary and different findings.18 For example,

in the 95 ICU patients who underwent mechanical ventilation for 7 days

or more, independent predictors of ICUAW included the number of days

with dysfunction of two or more organs (OR: 1.28, 95% CI: 1.11-1.49) and

the duration of mechanical ventilation (OR: 1.10, 95% CI: 1.00-1.22) In

contrast to the systematic review, female sex (OR: 4.66, 95% CI: 1.19-18.30)

and administration of corticosteroids (OR: 14.90, 95% CI: 3.20-69.80) were

strong predictors

In search of potentially modifiable risk factors for ICUAW, many

investigations have focused on exposure to corticosteroids and NMBAs

These agents have been both implicated in animal research and

observational trials in humans.52 Results have not been consistent or

conclusive, likely due to methodological limitations of these

inves-tigations More recently, randomized controlled trials have included

secondary analyses for evidence of ICUAW to bypass the problem of

confounding by indication.23

Although corticosteroids inhibit protein synthesis in type II muscle

fibers and contribute to severe protein catabolism, the relationship

between corticosteroids and ICUAW has been inconsistent In a

second-ary analysis of a multicenter study of patients with severe and persistent

ARDS randomized to methylprednisolone or placebo, 34% developed

ICUAW as detected by chart review.52 There was no statistically cant association of ICUAW with randomization to methylprednisolone; however, intervention patients were more likely to have evidence of ICUAW in the first 28 days of the study, and were more likely to be clinically diagnosed with myopathy It is plausible that some benefits

signifi-of corticosteroid treatment on lung function were signifi-offset by the adverse effects on strength

The association of neuromuscular weakness with prolonged effect

of neuromuscular blocking agents (NMBAs) has long been recognized and was the most prominent reason for a shift away from NMBA use

in the critically ill A typical scenario involves patients with severe acute asthma and ventilatory failure who undergo treatment with high-dose corticosteroids in combination with NMBAs These patients may exhibit severe and protracted myopathy.37,53,54 However, this relationship has not borne out in the general adult ICU population.36,42 Concerns about NMBA use have been reduced by a recent multicenter RCT test-ing the benefit of early neuromuscular blockade for severe ARDS.23Randomization to cisatracurium versus placebo significantly decreased 90-day mortality from 40.7% to 31.6% Investigators included ICUAW as

a secondary outcome At ICU discharge, there were neither differences

in average muscle strength among patients tested nor any difference in proportion of patients with ICUAW These findings are a substantial contribution, challenging the commonly held belief about the causal role

of neuromuscular blockers in ICUAW However, there are some tant limitations, including the use of manual muscle strength testing as the gold standard for investigating nerve and muscle function in the ICU and lack of follow-up testing to answer questions about lingering impairment

impor-PREVENTION AND TREATMENT

Data supporting specific approaches to prevent or treat ICUAW are limited A Cochrane review identified only one successful interven-tion: insulin therapy with strict glycemic control.55 This evidence for prevention comes from two trials studying “intensive” insulin therapy (defined as maintenance of a blood glucose level between 80 and

110 mg/dL) in critically ill patients who remain in the ICU for 7 or more days The first trial, focused on surgical patients, demonstrated

a mortality benefit and a secondary end point of fewer cases of CIP detected by routine electrophysiologic testing after day 7 (29% vs 52%,

p < 0.001).56 The same investigators studied the effect of intensive insulin therapy in medically critically ill patients The prospective subanalysis demonstrated a significant reduction in the incidence of

critical illness polyneuropathy and myopathy (51% vs 39%, p = 0.02)

when similarly screened by weekly EP studies Unfortunately, despite this protective effect on the development of ICUAW, intensive insulin therapy has been associated with an increased risk of severe hypogly-cemia and either increased mortality or had no effect on mortality when compared to more permissive blood glucose ranges (such as 140-180 mg/dL and 180-200 mg/dL).57,58 Furthermore, because more recent data suggest an increased mortality with aggressive insulin therapy,58 this treatment option cannot be recommended as a means

to prevent ICUAW

For all forms of ICUAW, care is supportive Measures to avoid ary injury must be undertaken These practices may span mechanical ventilation (low tidal volume ventilation for ARDS; protocols to guide ventilator readiness testing and liberation), stress ulcer and venous thrombosis prophylaxis, titrated sedation and analgesia therapy, and efforts to avoid nosocomial infection (head of bed elevation, early discontinuation of central venous and urinary catheters) Because prolonged immobilization and bed rest have been shown to acceler-ate muscle loss, which may exacerbate ICUAW, mobility therapy has emerged as a potential preventive measure.59

second-A new framework for early mobilization during critical illness has evolved Rather than delay rehabilitation until the patient has left the ICU, studies of progressively earlier exercise have repeatedly

PART 6: Neurologic Disorders

770

demonstrated safety and benefit.59 Specifically, early mobilization can be

safely implemented during mechanical ventilation via an endotracheal

tube, during infusions of vasopressors and relatively higher levels of

oxygen need, and in patients with multiple critical care devices.60-63 These

studies, spanning physical and occupation therapy services to bedside

cycle ergometer use, are detailed extensively in Chap 24 Overall, these

studies demonstrate improved patient physical function and shorter

durations of ICU and hospital lengths of stay.59

SUMMARY

ICUAW is a common morbidity of critical illness, represents an

important patient-centered outcome, and has substantial implications

on quality of life and patients’ ability to return to prior health and

life-style The ability to measure the presence of ICUAW in a reproducible

fashion via history and physical examination has yielded significant

improvements in global awareness of neuromuscular dysfunction The

practicing clinician needs to be aware when the presentation is atypical

and more advanced diagnostic testing is needed For the research

envi-ronment, longer term outcomes focusing on neuromuscular strength

and patient functional autonomy need to be considered when evaluating

the effect of new interventions Although it seems doubtful that a single

therapy might prevent weakness in varied populations, the meticulous

application of multidisciplinary care—including early patient

engage-ment and mobilization—may help to improve strength and function in

survivors of critical illness

KEY REFERENCES

• Batt J, dos Santos CC, Cameron JI, Herridge MS Intensive care

unit-acquired weakness: clinical phenotypes and molecular

mech-anisms Am J Respir Crit Care Med 2012;187:238-246.

• De Jonghe B, Sharshar T, Lefaucheur JP, et al Paresis acquired in

the intensive care unit: a prospective multicenter study JAMA

2002;288:2859-2867

• Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G

Interventions for preventing critical illness polyneuropathy and

critical illness myopathy Cochrane Database of Systematic Reviews

(Online) 2009:CD006832.

• Herridge MS, Batt J, Hopkins RO The pathophysiology of

long-term neuromuscular and cognitive outcomes following critical

illness Crit Care Clin 2008;24:179-199, x.

• Kress JP, Hall JB ICU-acquired weakness and recovery from

criti-cal illness N Engl J Med 2014; 370:1626-35.

• Lacomis D Electrophysiology of neuromuscular disorders in

criti-cal illness Muscle Nerve 2013;47:452-463.

• Latronico N, Peli E, Botteri M Critical illness myopathy and

neu-ropathy Curr Opin Crit Care 2005;11:126-132.

• Puthucheary ZA, Rawal J, McPhail M, et al Acute skeletal muscle

wasting in critical illness JAMA 2013;310:1591-1600.

• Stevens RD, Dowdy DW, Michaels RK, Mendez-Tellez PA,

Pronovost PJ, Needham DM Neuromuscular dysfunction

acquired in critical illness: a systematic review Intensive Care

Med 2007;33:1876-1891.

• Stevens RD, Marshall SA, Cornblath DR, et al A framework for

diagnosing and classifying intensive care unit-acquired weakness

Crit Care Med 2009;37:S299-S308.

• Stiller K Physiotherapy in intensive care: an updated systematic

KEY POINTS

• Etiology

• Cardioembolic and other nonarteriosclerotic causes of cerebral infarction occur more commonly in patients admitted to the ICU and should be carefully sought by appropriate diagnostic tests

• In hypertensive patients with hemispheric lobar hemorrhages and in patients without hypertension, causes for intracerebral hemorrhage such as coagulopathies, arteriovenous malforma-tions, or saccular aneurysms should be sought

• Nontraumatic spontaneous subarachnoid hemorrhage is almost always due to a ruptured saccular aneurysm and should be evaluated by arteriography

• Clinical and Laboratory Diagnosis

• X-ray computed tomography (CT) is the diagnostic ing test of choice for patients with acute stoke It is rapid, can be performed easily on acutely ill patients and acute intracerebral

neuroimag-or subarachnoid hemneuroimag-orrhage are easily identified

• Lumbar puncture is the most sensitive test for detection of SAH;

it should be performed when there is a strong clinical suspicion and a negative CT scan, or when CT is not available or feasible

• In suspected ischemic stroke, diffusion-weighted MRI can be helpful for improving diagnostic certainty when there is no clear history of an abrupt onset or the localization of the neuro-logical findings is confusing MRI has not been shown to be of value in selecting patients for thrombolytic therapy

• Early electrocardiographic (ECG) monitoring detects ously unsuspected atrial fibrillation in 3% to 5% of patients with acute cerebral ischemia

• Patients with transient ischemic attacks (TIAs) or mild stroke who are good surgical candidates for carotid endarterectomy should

be evaluated for symptomatic carotid stenosis immediately since the risk of stroke can be as high as 1 in 20 within the first 2 days

• Treatment of Cerebral Infarction

The following statements can be made based on good clinical trial data.

• Routine use of supplemental oxygen does not reduce mortality

• Early treatment of hyperglycemia to achieve levels <7 mmol/L does not improve outcome

• In patients with systolic blood pressures of 160 to 200 mm Hg, pharmacological reduction of systolic pressure by 20 to 25 mm Hg within the first 24 hours is safe, but does not improve outcome

• In hemiplegic patients, subcutaneous low-dose heparin or enoxaparin reduces deep venous thrombosis

• Intravenously administered t-PA improves outcome in carefully selected patients with acute ischemic stroke when instituted within 4.5 hours of onset

• The clinical value of any intra-arterial pharmacological or mechanical revascularization therapy for acute ischemic stroke has not been demonstrated

• Aspirin 160 or 300 mg/d of aspirin begun within 48 hours of the onset of ischemic stroke results in a net decrease in further stroke or death

• Full anticoagulation with heparin or similar drugs in patients with acute ischemic stroke provides no clinical benefit in general

CHAPTER 84: Cerebrovascular Disease 771

with hemispheric lobar hemorrhages and patients without hypertension, other causes should be sought, such as arteriovenous malformations

or saccular aneurysms.2 Amyloid angiopathy becomes increasingly important in patients in the seventh, eighth, and ninth decades These hemorrhages usually occur in the subcortical hemispheric white matter and may be multiple Previous microhemorrhages in parietal and occipi-tal lobes are often visible on magnetic resonance images Hemorrhage due to anticoagulant and thrombolytic drugs may affect any part of the brain Rarer causes of intracerebral hemorrhage occurring in patients with other systemic diseases include thrombocytopenia, hemophilia, and disseminated intravascular coagulation Primary or metastatic brain tumors will rarely present as ICH

Nontraumatic spontaneous subarachnoid hemorrhage (SAH) is almost always due to a ruptured saccular aneurysm Aneurysms may also rupture into the brain parenchyma, producing intracerebral hem-orrhage as well Saccular aneurysms are most commonly located on the large arteries at the base of the brain Both congenital and acquired factors appear to play a role in the postnatal development of aneu-rysms Acquired factors include atherosclerosis, hypertension, and hemodynamic stress In patients with infective endocarditis, mycotic aneurysms of more distal arteries may form and sometimes rupture Other causes of SAH include ruptured arteriovenous malformations (cerebral and spinal) and fistulae, cocaine abuse, pituitary apoplexy, and intracranial arterial dissection.3 In some cases, particularly SAH ventral to the midbrain or restricted to cortical sulci, the cause cannot

be determined

CLINICAL AND LABORATORY DIAGNOSIS

The initial diagnostic evaluation of the patient with suspected stroke serves (1) to determine whether neurologic symptoms are due to cere-brovascular disease or to some other condition, such as peripheral nerve injury, intracranial infection, tumor, subdural hematoma, multiple scle-rosis, epilepsy, or hypoglycemia; and (2) to distinguish among different types of cerebrovascular disease that require different treatments The clinical history and examination remains the cornerstone of this process Cerebrovascular disease typically produces focal brain dysfunction of sud-den onset in a single location The primary exception to this is aneurysmal SAH, which usually presents as a sudden onset of severe headache, with or without nausea, vomiting, or loss of consciousness In some cases, a less severe aneurysmal hemorrhage may present as a headache of moderate intensity, neck pain, and nonspecific symptoms A high index of suspicion

is needed in order to avoid missing the diagnosis of SAH Focal brain dysfunction may not always cause an obvious hemiparesis Neurologic deficits such as neglect, agnosia, aphasia, visual field defects, or amne-sia may be the only manifestations of brain infarction or hemorrhage Multiple small brain infarcts may produce impaired consciousness with minimal or no focal neurologic deficits, mimicking metabolic, or toxic encephalopathy The clinical distinction between cerebral infarction and intracerebral hemorrhage is unreliable as both produce sudden focal defi-cits Large hemorrhages may produce vomiting or unconsciousness, but

so may infarcts in the vertebrobasilar circulation The initial neurologic examination provides a baseline for monitoring the subsequent clinical course A thorough medical evaluation is necessary to detect systemic diseases that may be the cause of the cerebrovascular problem Careful evaluation of the heart is imperative to detect conditions that might pre-dispose to embolization, particularly atrial fibrillation, recent myocardial infarction, and more rarely, infective endocarditis

X-ray computed tomography (CT) is the diagnostic neuroimaging test

of choice for patients with acute stoke It is rapid and can be performed easily on acutely ill patients Acute intracerebral hemorrhage is easily identified by noncontrast CT Cerebral infarction may not be demon-strated by CT for several days If the infarct is small enough, it may never

be apparent Magnetic resonance diffusion weighted imaging is more sensitive than CT for lesion detection in the early period following isch-emic infarction Due to its higher resolution, magnetic resonance imag-ing (MRI) is also superior for detecting small infarcts (especially those in

or in any subgroup, including those with atrial fibrillation or

other cardioembolic sources

• Hemicraniectomy reduces mortality in patients with large

hemispheric infarcts and depressed level of consciousness who

are operated within 48 hours of stroke onset

• Treatment of Intracerebral Hemorrhage

The following statements can be made based on good clinical trial data

• Prophylaxis for deep venous thrombosis with low-dose

subcu-taneous heparin or heparinoids may be instituted safely on the second day after the hemorrhage and reduces subsequent deep venous thrombosis if begun before day 4

• In patients with systolic blood pressure of 150 to 220 mm Hg,

rapid pharmacological reduction of systolic pressure by 27 mm Hg

within the first hour is safe but does not improve outcome

• Craniotomy and clot evacuation in patients with supratentorial

ICH, either superficial or deep, is of no benefit

• Treatment of Subarachnoid Hemorrhage

The following statements can be made based on good clinical trial data

• Oral nimodipine at a dose 60 mg every 4 hours for 21 days after

hemorrhage reduces poor outcome

• Early definitive treatment reduces the risk of rebleeding

• For aneurysms amenable to both endovascular coiling and

surgical clipping, endovascular treatment is beneficial

• Intravascular volume contraction should be avoided

ETIOLOGY

Cerebrovascular diseases can be divided into three categories: cerebral

ischemia and infarction, intracerebral hemorrhage, and subarachnoid

hemorrhage Cerebral ischemia and infarction are caused by processes

that reduce cerebral blood flow Reductions in whole brain blood flow

due to systemic hypotension or increased intracranial pressure (ICP) may

produce infarction in the distal territories or border zones of the major

cerebral arteries More prolonged global reductions cause diffuse

hemi-spheric damage without localizing findings or, at its most severe, produce

brain death Prolonged regional reductions can lead to focal brain

infarc-tions Local arterial vascular disease accounts for approximately 65% to

70% of all focal brain infarctions In most cases, arterial disease serves

as a nidus for local thrombus formation with or without subsequent

distal embolization Focal arterial stenosis in combination with systemic

hypotension is a very rare cause of focal brain infarction Atherosclerosis

is the most common cause of local disease in the large arteries supplying

the brain Disease of smaller penetrating arteries may cause small deep

(lacunar) infarcts While emboli arising from the heart cause

approxi-mately 30% of all cerebral infarcts in a general population, they assume

more importance in ICU patients.1 Atrial fibrillation is the most common

of these causes Atherosclerotic emboli following heart surgery,

infec-tive endocarditis, nonbacterial thrombotic endocarditis, and ventricular

mural thrombus secondary to acute myocardial infarction or

cardio-myopathy should all be considered in the appropriate circumstances

More rare causes of cerebral infarction must also be considered in the

ICU These include dissections of the carotid or vertebral artery (after

direct neck trauma, “whiplash” injuries or forced hyperextension during

endotracheal intubation), intracranial arterial or venous thrombosis

secondary to meningeal or parameningeal infections, and paradoxical

embolization from venous thrombosis via a patent foramen ovale.1

Hemorrhage into the basal ganglia, thalamus, and cerebellum in

middle-aged patients with long-standing hypertension is the most

common type of intracerebral hemorrhage In hypertensive patients

PART 6: Neurologic Disorders

772

the posterior fossa) at any time However, MRI is more cumbersome to

perform in acutely ill patients because of longer imaging times, the need

for special nonferromagnetic life support equipment, and the necessity of

putting the entire body in the scanner Demonstration of cerebral

infarc-tion by neuroimaging is rarely necessary, since the diagnosis often can be

made reliably by the clinical presentation of the sudden onset of a focal

brain deficit together with a negative CT scan to exclude hemorrhage and

other conditions MRI can be helpful for improving diagnostic certainty

when there is no clear history of an abrupt onset or the localization of the

neurological findings is confusing Intravenous contrast administration

increases the sensitivity for detecting diseases that may mimic stroke,

such as tumor, chronic subdural hematoma, and abscess

Diagnosis of border zone infarction due to systemic arterial

hypoten-sion is almost entirely dependent on the pattern of infarction shown

by CT or MRI Border zone infarctions are often asymmetrical and

patchy; rarely is the entire border zone territory between the middle

cerebral artery and posterior or anterior cerebral artery involved

Furthermore, the actual location of the border zone varies from person

to person.4 When more than one area of acute infarction has occurred

and all infarcted areas are within the border zones, systemic hypotension

should be considered as a cause of infarction

MRI has no advantage over CT in the demonstration of acute

intra-cerebral hemorrhage, but it does have superior sensitivity for detecting

subacute or chronic hemorrhage MRI with contrast is the most sensitive

way to detect a tumor underlying an ICH Noncontrast CT has a

sensi-tivity of >90% for detecting SAH when performed within 24 hours of

hemorrhage There is no role for standard MRI in the initial diagnosis of

acute SAH since it is difficult to perform in an acutely ill agitated patient

and it does not increase the likelihood of detecting SAH

In the patient who is awake and alert with acute focal brain

dysfunc-tion and in whom noncerebrovascular causes can be excluded, the

imme-diate distinction between cerebral infarction and cerebral hemorrhage

may not be necessary if no emergent treatment of the stroke is planned

In certain situations, however, differentiation between infarction and

hemorrhage may be critical Patients with ischemic stroke whose time

of onset can be determined to be less than 4.5 hours earlier and whose

other medical problems do not preclude thrombolytic therapy, will

benefit from treatment with intravenous tissue plasminogen activator

(t-PA).5,6 In this circumstance, emergency CT to exclude cerebral

hemor-rhage is imperative (see the section on treatment below) In the patient

with decreased consciousness and a focal neurologic deficit, emergency

CT may be critically important in identifying an intracranial tumor or

subdural hematoma that requires emergency neurosurgical intervention

Except in patients with cerebral venous thrombosis, hematologic

evalu-ation of patients with ischemic stroke is rarely of value Antiphospholipid

antibodies are found in a high percentage of patients with arterial stroke,

but they confer neither a worse prognosis nor is there a benefit of

long-term anticoagulation.7 Acquired or hereditary hypercoagulable disorders

have not been clearly linked to arterial ischemic stroke, whereas they are

clearly of etiologic importance in cerebral venous thrombosis In patients

with intracranial hemorrhage, especially in the ICU, acquired

hemor-rhagic diatheses (eg, anticoagulant or thrombolytic drugs,

thrombocyto-penia) should always be considered and should be sought by appropriate

laboratory testing when clinical suspicion indicates

Lumbar puncture with cerebrospinal fluid (CSF) examination can

be an extremely important test in the evaluation of the patient with

apparent stroke, especially in patients with acquired immune deficiency

syndrome (AIDS) or when there is infection elsewhere Meningitis may

cause stroke by producing thrombosis of arteries or cortical veins CSF

pleocytosis is common following septic embolism from infective

endo-carditis and can serve as a valuable clue to its presence Lumbar puncture

is the most sensitive test for detection of SAH; it should be performed

when there is a strong clinical suspicion and a negative CT scan, or when

CT is not available or feasible CSF xanthochromia, which begins to

develop after 4 hours and is reliably present at 12 to 24 hours, can help

differentiate SAH from traumatic lumbar puncture.8,9

Early electrocardiographic (ECG) monitoring detects previously unsuspected atrial fibrillation in 3% to 5% of patients with acute cerebral ischemia.10-12 This information is clinically useful since the superiority of oral anticoagulation over aspirin for long-term secondary stroke preven-tion in this circumstance has been demonstrated.13 There is, however, no benefit for immediate anticoagulation in these patients.14 Transthoracic echocardiography can provide evidence of poor left ventricular function and, rarely, left ventricular thrombi In patients without clinical cardiac disease (no previous history or signs or symptoms of cardiac disease, no ECG abnormalities, and normal cardiac silhouette on chest x-ray), left ventricular thrombi are vanishingly rare Transesophageal echocardiog-raphy has made it possible to identify left atrial thrombi and atheroscle-rosis of the ascending aorta Large aortic arch lesions are associated with

an increased risk of stroke The most common lesion detected by cardiography in patients with stroke who have no other evidence of heart disease is patent foramen ovale with or without atrial septal aneurysm

echo-Treatment implications are problematic (see below) ECG ties are extremely common in patients with SAH However, the clinical relevance of these abnormalities is questionable since they often do not correlate with echocardiographic abnormalities, histopathologic abnor-malities, or serum markers of cardiac injury Approximately 20% of patients with SAH have elevated serum troponin-I levels Patients with elevated troponin-I levels should undergo echocardiography, as elevated troponin-I levels have been shown to be 100% sensitive and 86% specific for the detection of left ventricular dysfunction by echocardiography.15Cerebral arteriography provides high-resolution images of both extra-cranial and intracranial vessels, which may be useful occasionally in the identification of causes of cerebral infarction such as arterial dissection

abnormali-It is of little value for the diagnosis of isolated cerebral vasculitis due to the high prevalence of both false-positive and false-negative findings.16 Magnetic resonance arteriography (MRA), often overestimates the degree of stenosis, sometimes even portraying normal vessels as abnormal In addition, MRA lacks the high resolution of conventional arteriography and cannot be used to exclude small aneurysms or abnor-malities in distal arterial branches In contrast, magnetic resonance venography has supplanted conventional catheter angiography for the detection of sagittal and lateral sinus venous thrombosis In hypertensive patients with lobar intracerebral hemorrhage and in nonhypertensive patients with intracerebral hemorrhage in any location, arteriography may demonstrate vascular malformations or aneurysms.2 CT angiogra-phy is almost as sensitive as arteriography for detecting causes of intra-cerebral hemorrhage but will occasionally miss a small arteriovenous malformation or fistula.17-19 Cerebral arteriography plays an important role in the evaluation of the patient with SAH by confirming the exis-tence of an aneurysm and providing the necessary information to plan a surgical approach If CT or lumbar puncture demonstrates SAH, a four-vessel angiogram should be performed as soon as possible A complete study is necessary to look for multiple aneurysms If arteriography does not reveal a cause for SAH, it should be repeated in 1 to 2 weeks

Doppler ultrasound of the carotid arteries is useful to screen for severe carotid stenosis at the cervical bifurcation in patients who are candidates for carotid endarterectomy It is important to remember that the reliabil-ity of this technique varies from center to center Patients with transient ischemic attacks (TIAs) or mild stroke who are good surgical candidates should be evaluated immediately since the risk of stroke following TIA can be as high as 1 in 20 within the first 2 days.20 On the other hand, in patients with a completed stroke, there is usually no urgency in obtain-ing this information since carotid endarterectomy does not play a role

in the management of acute stroke Transcranial Doppler (TCD) studies can detect stenosis of intracranial vessels, but the value of this informa-tion in management decisions remains to be demonstrated.21 TCD can also detect increases in flow velocity in most patients with arteriographic vasospasm following SAH (see below)

The value of regional cerebral blood flow (CBF) measurements with positron emission tomography (PET), single photon emission com-puted tomography (SPECT), CT, or MRI in the diagnosis and treatment

CHAPTER 84: Cerebrovascular Disease 773

TABLE 84-1 Inclusion and Exclusion Criteria From the NINDS t-PA Stroke Trial

Inclusion criteria

1 Age 18 through 80 years

2 Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit, defined as impairment of language, motor function, cognition, and/or gaze or vision, or neglect

Ischemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic deficit presumed to be due to cerebral ischemia after computed tomography (CT) has excluded hemorrhage

3 Time of onset well established to be less than 180 minutes before treatment would begin

4 Prior to treatment, the following must be known or obtained: complete blood cell count, platelet count, prothrombin time (if the patient has a history of oral anticoagulant therapy in the week prior to treatment initiation), partial thromboplastin time (if the patient has received heparin within 48 hours of treatment initiation), blood glucose, and CT scan (noncontrast)

Exclusion criteria

1 Minor stroke symptoms or major symptoms that are improving rapidly

2 Evidence of intracranial hemorrhage on CT scan

3 Clinical presentation that suggests subarachnoid hemorrhage even if initial CT scan is normal

4 Female patient who is lactating or known or suspected to be pregnant

5 Platelet count less than 100,000/µL; prothrombin time greater than 15 seconds;

heparin has been given within 48 hours and partial thromboplastin time is greater than the upper limit of normal for laboratory; anticoagulants currently being given

6 Major surgery or serious trauma, excluding head trauma, in the previous 14 days, or head trauma within the previous 3 months

7 History of gastrointestinal or urinary tract hemorrhage in the previous 21 days

8 Arterial puncture at a noncompressible site or a lumbar puncture within the previous 7 days

9 On repeated measurement, systolic blood pressure >185 mm Hg or diastolic blood pressure

>110 mm Hg at the time treatment is to begin, or patient requires aggressive treatment

to reduce blood pressure to within these limits

10 Patient has had a stroke in the previous 3 months or has ever had an intracranial hemorrhage considered to put the patient at an increased risk for intracranial hemorrhage

11 Serious medical illness likely to interfere with this trial

12 Abnormal blood glucose (<50 or >400 mg/dL)

13 Clinical presentation consistent with acute myocardial infarction or suggesting postmyocardial infarction pericarditis

14 Patient cannot, in the judgment of the investigator, be followed for 3 months

15 Seizure occurred at onset of stroke

of patients with cerebrovascular disease remains to be demonstrated

Since the diagnosis of cerebral infarction can be made reliably by means

of the clinical picture and a CT scan, it is rarely if ever necessary to

demonstrate a defect on a CBF study Furthermore, other conditions

also may produce focal regional reductions of CBF CBF measurement

as an adjunct in deciding the appropriate therapeutic intervention in

patients with stroke has not been shown to result in improved outcome

The combination of diffusion weighted imaging (DWI) and perfusion

weighted imaging (PWI) in patients with acute ischemic stroke often

reveals a central area of restricted diffusion surrounded by a larger area

of low perfusion The diffusion abnormality increases with time and its

final boundaries correspond closely to the eventual infarct These

obser-vations have led to the hypothesis that the area of perfusion-diffusion

mismatch indicates tissue destined for infarction that may be salvaged

by thrombolytic therapy As of 2012, several clinical trials all have failed

to demonstrate that treatment that decisions based on DWI-PWI

mag-netic resonance scans lead to better patient outcome.22

TREATMENT

■ CEREBRAL INFARCTION

Immediate supportive care of the patient with cerebral infarction requires

attention to the patient’s airway, breathing, and circulation Although

most patients have preserved pharyngeal reflexes, those with brain stem

infarction or depressed consciousness may require intubation for airway

protection Coexisting heart and lung disease are common Respiratory

and cardiac function should be assessed fully, and appropriate

interven-tions performed to maintain perfusion and oxygenation The use of

sup-plemental inspired oxygen is rational only if the arterial oxygen content of

the blood is decreased; routine use does not reduce mortality.23 At the time

of hospital admission, some patients may have mild intravascular volume

depletion In addition to normal maintenance requirements, careful fluid

supplementation may be required The composition of intravenous fluid

(normal saline solution, one-half normal saline solution, or 5% glucose)

makes no difference as long as serum electrolyte concentrations remain

normal Care should be taken to avoid hypo-osmolarity, which

poten-tially could exacerbate brain edema Early treatment of hyperglycemia to

achieve levels <7 mmol/L does not improve outcome.24 Systemic arterial

hypertension is common following acute ischemic stroke In most cases,

blood pressure returns to baseline levels without treatment in a few days

There are no known hazards to the brain from this spontaneous transient

elevation in systemic blood pressure The value of treatment, if any, is

unknown Case reports describe sudden neurological deterioration when

blood pressure is pharmacologically reduced.25 In patients with systolic

blood pressures of 160 to 200, a randomized trial has demonstrated that

pharmacological reduction of systolic pressure by 20 to 25 mm Hg within

the first 24 hours is safe as it did not cause more early neurological

dete-rioration when compared to the natural decrease of 10 to 15 mm Hg, but

neither did it improve death or dependency at 2 weeks.26 There are

insuf-ficient data to permit designation of any target blood pressure levels as

effective.27,28 Continuing or stopping preexisting antihypertensive therapy

for 2 weeks after acute ischemic stroke does not affect outcome.29 When

systemic hypertension causes organ damage elsewhere (eg, myocardial

ischemia, congestive heart failure, or dissecting aortic aneurysm), careful

and judicious lowering of the blood pressure with constant monitoring of

neurologic status is indicated

No clinical evidence or pathophysiologic rationale supports routine

restriction to bedrest for patients with acute brain infarction Prolonged

immobility carries an increased risk of iliofemoral venous thrombosis,

pulmonary embolism, and pneumonia Patients should be out of bed

and walking as soon as possible after a stroke Occasionally, orthostatic

hypotension with worsening of neurologic deficits will occur In these

cases, a more gradual program of ambulation should be instituted In

hemiplegic patients, subcutaneous low-dose heparin or enoxaparin

should be administered to prevent iliofemoral venous thrombosis.30

Alternating pressure antithrombotic stockings may provide benefit as well In the case of pulmonary embolism or deep venous thrombosis, full anticoagulation with heparin or heparin-like drugs may be instituted Fever may occur due to infection or other systemic causes Central fevers due to hypothalamic disease are an exceedingly uncommon event and the search for other causes should be vigorously pursued Animal studies have shown that even minor elevations in temperature of a few degrees poststroke can lead to worse brain damage Maintaining nor-mothermia through the use of antipyretics and cooling blankets makes good sense but is of unproven value Trials of induced hypothermia with both external and internal cooling are now underway It is important

to remember that dysphagia occurs commonly, even with unilateral hemispheric lesions Before oral feeding is instituted, each patient’s ability to swallow should be carefully checked Institutions with formal dysphagia screening protocols have a reduced incidence of pneumonia.31Incontinence is also common following acute stroke but the use of Foley catheters should be kept to a minimum because of the attendant increase

in urinary tract infections Careful attention must be given to the vention of decubitus ulcers in bedridden patients

pre-Intravenously administered t-PA improves outcome in carefully selected patients with acute ischemic stroke when instituted within 4.5 hours of onset.5,6 These findings were demonstrated in two separate studies: the NINDS Trial comprising patients within 0 to 3 hours of onset and the ECASS III Trial comprising patients within 3 to 4.5 hours

of onset Inclusion and exclusion criteria used in these trials were

dif-ferent and are listed in Tables 84-1 and 84-2 In both trials, patients

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774

received 0.9 mg/kg (90 mg maximum) of alteplase, 10% given as an

initial bolus over 1 minute, followed by a continuous intravenous

infu-sion of the remainder over 60 minutes The infuinfu-sion was discontinued

if intracranial hemorrhage was suspected In the NINDS 0- to 3-hour

trial, all patients were admitted to a neurology special care area or ICU

Anticoagulant or antiplatelet drugs were not allowed for 24 hours

Nasogastric tubes and Foley catheters were avoided for 24 hours if

possible Blood pressure was monitored every 15 minutes for 2 hours,

every 30 minutes for 6 hours, and then every 60 minutes for 16 hours

Blood pressure was kept below 180/105 mm Hg with labetalol or sodium

nitroprusside Symptomatic cerebral hemorrhage occurred more

com-monly in the group treated with t-PA (6%) than in the control group

(<1%) Recommended treatment of symptomatic intracerebral

hem-orrhage included cryoprecipitate and platelet transfusion.32 In spite of

this treatment, mortality at 3 months from ICH after t-PA was 75% in

the NINDS trial.33 Even taking into account the increased risk of

intra-cerebral hemorrhage, there was no difference in mortality, and more

t-PA-treated patients demonstrated an excellent neurologic outcome at

3 months by each of four separate outcome scales The odds ratio for

a favorable outcome due to treatment was 1.7 In the ECASS III 3- to

4.5-hour trial, anticoagulant or antiplatelet drugs were also not allowed

for 24 hours with the exception that subcutaneous heparin (≤10,000 IU)

or equivalent doses of low-molecular weight heparin was permitted for

prophylaxis against deep-vein thrombosis The odds ratio for a favorable

outcome due to treatment was 1.3 Supporting evidence for these two

pivotal trials is provided by retrospective analyses of small subgroups of

patients enrolled <4.5 hours postevent in other trials.34,35

Even though efficacy of IV t-PA has been demonstrated out to

4.5 hours, eligible patients should be treated as soon as possible since

the benefit is time-dependent.36 For patients who awaken from sleep

with a stroke, the time of onset must be taken to be the last time they

were awake and known to be in their premorbid state, not the time of

awakening If the time of stroke onset cannot accurately be established

to be less than 4.5 hours, intravenous t-PA should not be given Several

controlled clinical trials failed to demonstrate a benefit of intravenous t-PA after 4.5 hours, even when magnetic imaging criteria are used to select patients.37-40

The clinical value of any intra-arterial pharmacological or mechanical revascularization therapy for acute ischemic stroke has not been demon-strated A trial of intra-arterial pro-urokinase plus intravenous heparin within 0 to 6 hours after onset in patients with middle cerebral artery occlusion showed a barely statistically significant benefit over intravenous heparin alone These data were not sufficient proof for the drug to be approved for use in the United States.41 A trial of intra-arterial urokinase within 0 to 6 hours of onset in middle cerebral artery occlusion showed

no benefit.42 In neither of these studies was intravenous t-PA tered to any of the estimated 70% of the control groups who could have received it within 4.5 hours after onset.43 Consequently, the superiority of the intra-arterial to the intravenous approach in those who are eligible for

adminis-IV t-PA within 4.5 hours has not been shown Data to show efficacy for those who are ineligible for IV t-PA has not been published There are no controlled clinical trials of intra-arterial therapy with other thrombolytic drugs, including t-PA Several mechanical devices have been approved

by the United States Food and Drug Administration for intra-arterial use

in acute ischemic stroke based on trials that showed at least equivalent performance to previous devices in removing thrombus and restoring arterial patency Although these devices were tested in patients up to

8 hours after stroke onset, no trials included a medical control group so clinical benefit has never been demonstrated.44

Two large studies have shown that 160 or 300 mg/d of aspirin begun within 48 hours of the onset of ischemic stroke results in a net decrease

in further stroke or death of 9/1000.45 Data from many randomized controlled trials have shown that full anticoagulation with heparin, low-molecular-weight heparins, or heparinoids in patients with acute ischemic stroke provides no net short- or long-term benefit in general

or in any subgroup, including those with atrial fibrillation or other dioembolic sources.14,30,46-48 Ticlopidine, clopidogrel, and the combina-tion of low-dose aspirin and extended-release dipyridamole (Aggrenox) all have been demonstrated to be modestly effective in the long-term prevention of recurrent ischemic stroke, but there are no data regarding their value during the acute period.49 Many drugs aimed at ameliorating ischemic neuronal damage in patients with acute stroke have undergone clinical trials with none showing a benefit Physicians treating patients with acute ischemic stroke should be aware of the results of these trials

car-on an car-ongoing basis

Cerebral edema is the major cause of early mortality following bral infarction Mannitol and hyperventilation can temporarily reduce intracranial pressure They may be of value to the patient with brain stem compression from an edematous cerebellar infarct for which craniotomy and removal of the edematous tissue may be lifesaving Hyperosmolar therapy (mannitol or hypertonic saline), hypothermia, and hemicraniectomy are sometimes used to treat massive edema from hemispheric infarction The value of the first two treatments is unproven Recent studies have shown that hemicraniectomy can signifi-cantly reduce mortality in patients with large hemispheric infarcts and depressed level of consciousness who are operated on within 48 hours

cere-of stroke onset.50,51Specific causes of cerebral infarction may require specific definitive treatments, such as exchange transfusions for cerebral infarction due to sickle cell anemia Cerebral venous thrombosis can present a particularly difficult situation because of the presence of hemorrhage While two small controlled trials have demonstrated that anticoagulation is safe even in patients with hemorrhagic infarction, design issue preclude any conclusions about efficacy.52,53 Patent foramen ovale (PFO) is detected commonly in patients with ischemic stroke and is often the only abnor-mality found Based on this finding, it is often concluded that the cause

of stroke is paradoxical embolization from deep venous thrombosis However, in contrast to pulmonary embolization, it is unusual to find a deep venous source in these patients The risk of recurrent stroke is low and anticoagulation with warfarin does not reduce the risk of long-term

TABLE 84-2 Inclusion and Exclusion Criteria From ECASS III

Inclusion criteria

1 Acute ischemic stroke

2 Age 18 to 80 years

3 Onset of stroke symptoms 3 to 4.5 hours before initiation of study-drug administration

4 Stroke symptoms present for at least 30 minutes with no significant improvement

before treatment

Exclusion criteria

1 Intracranial hemorrhage

2 Time of symptom onset unknown

3 Symptoms rapidly improving or only minor before start of infusion

4 Severe stroke as assesses clinically (NIHSS >25) or by imaging (involving more than

one-third of middle cerebral artery territory)

5 Seizure at the onset of stroke

6 Stroke or serious head trauma, within the previous 3 months

7 Combination of previous stroke and diabetes mellitus

8 Administration of heparin within the 48 hours preceding the onset of stroke, with

activated partial thromboplastin time at presentation exceeding the upper limit of the

normal range

9 Platelet count of less than 100,000/mm3

10 Systolic pressure greater than 185 mm Hg or diastolic pressure greater than

110 mm Hg, or aggressive treatment (intravenous medication) necessary to reduce

blood pressure to these limits

11 Blood glucose less than <50 mg/dL or >400 mg/dL

12 Symptoms suggestive of subarachnoid hemorrhage even if CT scan was normal

13 Oral anticoagulant treatment

14 Major surgery or severe trauma within the previous 3 months

15 Other major disorders associated with an increased risk of bleeding

CHAPTER 84: Cerebrovascular Disease 775

recurrence.54,55 Studies of acute anticoagulation are not available Acute

anticoagulation of spontaneous or traumatic dissections of the carotid or

vertebral arteries is often recommended Data to support this approach

are derived only from small nonrandomized, nonblinded studies, and

even these data are weak.56

■ INTRACEREBRAL HEMORRHAGE

Supportive care of patients with primary intracerebral hemorrhage

(ICH) requires attention to the same basic factors as for patients

with cerebral infarction Any underlying coagulopathy should be

cor-rected as rapidly as possible No randomized trials on management of

warfarin-associated ICH have been carried out Prothrombin complex

concentrates, recombinant factor VIIa, and fresh frozen plasma alone

or in combination have all been recommended.57 Fresh frozen plasma

administration may cause pulmonary edema.58 Early use of Factor VIIa

in patients with normal hemostasis resulted in a small reduction in clot

expansion but no difference in clinical outcome.59 Prophylaxis for deep

venous thrombosis with low-dose subcutaneous heparin or heparinoids

may be instituted safely on or after the second day posthemorrhage and

reduces subsequent deep venous thrombosis if begun before day 4.60,61

Systemic blood pressure is often elevated acutely, sometimes to very

high levels In patients with systolic blood pressure of 150 to 220 mm Hg,

a randomized trial has demonstrated that rapid pharmacological

reduc-tion of systolic pressure by 27 mm Hg within the first hour was safe in

that it resulted in equivalent clinical outcomes when compared to a

lesser decrease of 13 mm Hg.62 There are insufficient data to permit

des-ignation of any target blood pressure levels as effective.27,63

Clinically evident seizures are more common with lobar ICH

com-pared to basal ganglia hemorrhage.64 Prolonged electroencephalographic

monitoring shows electrical epileptiform events without motor

convul-sions in 20% to 30% of patients with acute ICH.65,66 The value of treating

the electrographic events is under study Prophylactic anticonvulsant

treatment does not prevent seizures and may worsen outcome.67,68

The value of ICP monitoring and treatment remains unknown

Neither mannitol nor corticosteroids reduce morbidity and mortality.69

Although the area of perihematomal edema on CT or MRI increases in

the several weeks following ICH, this growth is not associated with early

clinical deterioration or worse eventual outcome.70-72 Ventriculostomy

is of unproven value as observational studies have shown no benefit.73,74

The efficacy of ventriculostomy in combination with instillation of

thrombolytic drugs is currently under study in patients with

intraven-tricular hemorrhage.75

The value of surgery is best accepted for cerebellar hemorrhages

resulting in brain stem compression, although no data other than

anec-dotal reports are available Ideally such surgical intervention should be

undertaken before brain stem damage occurs Patients with small

cere-bellar hematomas (<2 cm) may do well without surgical intervention, or

simply with ventricular drainage for hydrocephalus Those with larger

cerebellar hematomas usually undergo surgical evacuation, although

no prospectively validated criteria for the necessity and the timing of

cerebellar hematoma evacuation are available Multiple randomized

controlled trials of patients with supratentorial ICH, either superficial

or deep, have shown no benefit from craniotomy and clot evacuation.76

■ SUBARACHNOID HEMORRHAGE DUE TO RUPTURED

INTRACRANIAL ANEURYSM

Aneurysmal SAH remains a devastating neurologic problem, with a

mortality rate of up to 45% within the first 30 days Of those patients

that survive, more than half are left with neurologic deficits as a result

of the initial hemorrhage or delayed complications SAH presents the

intensivist with a unique and challenging series of management issues

SAH usually presents as an acute neurologic event that is frequently

followed by a series of processes leading to delayed central nervous

system and systemic complications Patients who are minimally

affected by the initial hemorrhage can, over the course of hours to

weeks, deteriorate due to rebleeding, hydrocephalus, or delayed emic deficits caused by vasospasm Management can be complicated

isch-by spontaneous volume contraction, cardiac and pulmonary tion, electrolyte abnormalities, infections, and a catabolic state The treatment team should include neurosurgeons, radiologists, anesthe-siologists, intensivists, and nurses experienced in the management of SAH patients Because of the complicated nature of their surgical and medical management, SAH patients are best cared for in centers that specialize in this care

dysfunc-The management of patients following rupture of intracranial rysms has changed significantly over the past decades The calcium channel blocker nimodipine is now routinely used to reduce the impact

aneu-of vasospasm Attempts at early obliteration aneu-of the ruptured aneurysm with surgical clipping or endovascular placement of detachable coils within the aneurysm have become routine Hemodynamic augmenta-tion is now the cornerstone of the management of vasospasm with adjunctive endovascular treatment employed in selected cases New and promising therapies that specifically target the underlying cause or direct effects of cerebral vasospasm are currently under investigation.77Initial Stabilization and Evaluation: Initial evaluation should assess air-way, breathing, circulation, and neurologic function Patients with a diminished level of consciousness often have impaired airway reflexes

In general, patients with a Glasgow Coma Scale score of 8 or less should

be intubated This should be performed under controlled conditions by experienced personnel using a rapid sequence protocol Premedication with short-acting agents such as propofol or etomidate should be used

to prevent elevations in blood pressure (BP) with tracheal stimulation in order to minimize the risk of rebleeding

As soon as the patient is stabilized, a complete neurologic tion, head CT, and, if indicated, lumbar puncture should be performed Patients are graded on the basis of clinical and radiographic criteria The two common clinical grading scales that are predictive of outcome are the Hunt-Hess scale and the World Federation of Neurological Surgeons

examina-scale (Table 84-3) The Fisher Scale is based on the amount of blood

visible on CT scan and is predictive of cerebral vasospasm.78

Fisher Scale (Based on Initial CT Appearance and Quantification of Subarachnoid Blood)

1 No subarachnoid hemorrhage on computed tomography

2 Broad diffusion of subarachnoid blood, no clots and no layers of blood greater than 1 mm thick

3 Either localized blood clots in the subarachnoid space or layers of blood greater than 1 mm thick

4 Intraventricular and intracerebral blood present, in absence of significant subarachnoid blood

World Federation of Neurologic Surgeons Scale Grade Glasgow Coma Scale Score Motor Deficits

TABLE 84-3 The Hunt-Hess, the World Federation of Neurologic Surgeons,

and the Fisher Scales Hunt-Hess Scale

Grade Criteria

I Asymptomatic or mild headache

II Moderate to severe headache, nuchal rigidity, with or without cranial nerve deficitsIII Confusion, lethargy, or mild focal symptoms

IV Stupor and/or hemiparesis

V Comatose and/or extensor posturing

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776

Routine management of SAH patients frequently include

anticonvul-sants and prophylaxis against deep vein thrombosis (DVT) in addition

to close neurologic and cardiopulmonary monitoring to detect the early

complications of hypertension, rebleeding, acute hydrocephalus,

pul-monary edema, cardiac arrhythmias, and left ventricular dysfunction

Seizures can be a presenting symptom of SAH; however, the incidence

of recurrent or new events after hospitalization is low.79 It remains

unclear as to the effect of seizures on the clinical course of patients with

aneurysmal subarachnoid hemorrhage although the use of prophylactic

anticonvulsants has been associated with poor neurological and

cogni-tive outcomes.80 The use of anticonvulsants in the perioperative period

or until definitive treatment of the aneurysm is supported albeit by

retrospective data.81,82 DVT is common in patients with SAH, therefore

prophylaxis is mandatory The use of pneumatic compression devices is

preferred initially because of the risk of intracranial bleeding, however,

once the aneurysm has been treated, prophylaxis with subcutaneous

heparin or low-molecular weight heparin is generally considered safe

Routine treatments aimed at reducing the risk of ischemic stroke

secondary to vasospasm include preventing hypovolemia and

admin-istering nimodipine Patients should be hydrated with isotonic saline

at 1.5 to 2 mL/kg/h and indicators of volume status should be

moni-tored closely (clinical exam, fluid balance, daily weights, laboratory

values, and in select cases invasive hemodynamic measurements)

Prophylactic hypervolemia should be avoided as it has not been

shown to be beneficial and may in fact lead to increased medical

complications.83,84 Several large, prospective, placebo-controlled

stud-ies have demonstrated that nimodipine reduces the incidence and

severity of delayed ischemic deficits and improves outcome in SAH.85

It remains uncertain whether this drug acts by causing vasodilation or

by exerting direct neuroprotective effects The recommended dose is

60 mg every 4 hours for 21 days from the time of hemorrhage At this

dose, nimodipine can sometimes reduce systemic BP, an effect that is

undesirable in patients with vasospasm (see below) This effect can

be ameliorated by increasing fluid administration and by altering the

dose to 30 mg every 2 hours; however, pharmacologic blood pressure

support is necessary in some patients

Early Complications

factors may contribute to an increase in BP, including headache, elevated

ICP in patients with hydrocephalus, increased sympathetic nervous

system activity, and preexisting hypertension The rationale for treating

hypertension is to reduce the risk of aneurysmal rebleeding There are

few compelling reasons not to treat the elevated BP before the onset of

vasospasm As definitive data on optimal BP are lacking, it seems

pru-dent to take the patient’s usual BP as a target When the patient’s usual

BP is not known, it is probably better to overtreat than to undertreat

There is one important exception—comatose patients in whom CT

shows marked hydrocephalus In such cases BP should be treated very

cautiously until the ICP is known, to avoid causing a critical reduction

in cerebral perfusion pressure In patients who present several days after

hemorrhage and are at risk for vasospasm, the appropriate management

of hypertension is less clear The benefit of preventing rebleeding must

be weighed against the risk of worsening neurologic symptoms by

low-ering BP in the presence of vasospasm

The first step in treating elevated BP is to administer a short-acting

analgesic such as fentanyl as pain can be the sole cause of BP elevation

Patients are routinely given nimodipine to prevent vasospasm, and it

alone may be adequate to control BP Otherwise, short-acting agents

are preferred, since BP may be labile Labetalol administered as

inter-mittent intravenous boluses is frequently used, since it appears to have

little effect on ICP and is easily titrated Other useful agents include

intravenous hydralazine and enalapril If frequent intravenous boluses

are required, one should consider starting a continuous intravenous

infusion of an antihypertensive agent Nicardipine is ideal as it is short

acting, can be titrated every 5 to 15 minutes, does not require

inva-sive hemodynamic monitoring, and has been shown to be safe in this

patient population.86 Sodium nitroprusside is usually avoided because

of its tendency to increase ICP and thus reduce the cerebral perfusion pressure

initial hemorrhage The cumulative risk after 1 week is ~20%, and the risk remains elevated for several weeks.87 About one-half of patients who rebleed will die Measures employed in the hope of preventing rebleeding include avoidance of hypertension, cough, the Valsalva maneuver, and excessive stimulation Treatment may involve the admin-istration of antitussives, stool softeners, and sedatives when indicated

Antifibrinolytic medications can reduce the risk of rebleeding, but do

so at the cost of an increased incidence of cerebral ischemia.88 With the increasingly wide use of early surgery, the use of antifibrinolytics has largely been abandoned

The timing of surgical obliteration of the aneurysm has changed considerably Up to the 1970s, surgery was routinely delayed because

of reluctance to operate on an edematous brain Several factors have resulted in a shift to early surgery (days 1-3) for patients who have a grade of I to III on the Hunt-Hess scale These include improved surgical techniques, better results with early surgery in North America,89 and the necessity that the aneurysm be clipped before hypertensive therapy for vasospasm is administered The timing of surgery in poor-grade patients (Hunt-Hess grades IV or V) remains controversial, but early surgery is routinely performed in some centers.90

In the past decade, the role of endovascular repair of amenable ruptured and unruptured aneurysms has become widespread and the standard of care at many institutions Electrolytically detachable coils can be placed directly in the aneurysm, where they induce thrombosis

In a recent multicenter randomized trial, 20% of all assessed patients had a ruptured aneurysm that was considered to be amenable to treat-ment with either surgical clipping or endovascular coiling Among this subgroup of patients (predominantly of good clinical grade with small ruptured aneurysms of the anterior circulation), the risk of death or dependency at 1 year was significantly lower with endovascular coiling.91Follow-up data for an average of 9 years have demonstrated the con-tinued efficacy in this patient population There was a small increased rerupture rate among the patients treated with coiling; however, the risk

of death remained significantly lower at 5 years.92

SAH It is most common in patients with a poor neurological grade on admission and higher Fisher Scale scores The hallmark of symptom-atic hydrocephalus is a diminished level of consciousness, sometimes accompanied by downward deviation of the eyes and poorly reactive pupils The diagnostic evaluation can be complicated if the patient has received sedative drugs; it is important that analgesics be adminis-tered in doses that provide adequate relief from pain, but not excessive sedation If sedatives are required for agitated patients, judicious admin-istration of short-acting agents is prudent

Hydrocephalus can be diagnosed reliably with CT and treated effectively with external ventricular drainage Since less than half of patients with CT evidence of hydrocephalus will deteriorate clinically, ventriculostomy is typically reserved for patients with a diminished level

of consciousness

abnor-malities are common in the first 24 to 48 hours after SAH Most mias are benign and include atrial fibrillation and atrial flutter More serious arrhythmias include supraventricular and rarely ventricular tachycardia and are associated with electrolyte abnormalities such as hypokalemia Mild elevations in cardiac enzymes also commonly occur however the significance of these elevations is not clear

arrhyth-A significant number of patients will have some degree of ventricular dysfunction; however, those at highest risk for neurogenic stunned myo-cardium are of a high clinical grade Neurogenic stunned myocardium

is characterized by diffuse T-wave inversions, moderate elevations in troponin-I, pulmonary edema, cardiogenic shock, and reversible left

CHAPTER 84: Cerebrovascular Disease 777

ventricular wall abnormalities The management of these patients

typi-cally requires invasive hemodynamic monitoring and treatment with

ionotropes such as dobutamine If clinical vasospasm develops in these

patients prior to the resolution of cardiogenic shock, management can

become very difficult

one-fourth of all patients with SAH.93 They include pneumonia (arising from

acute or subacute aspiration, commonly with nosocomial organisms),

cardiogenic pulmonary edema, neurogenic pulmonary edema, and

pulmonary embolism Management of severe pulmonary edema with

refractory hypoxia usually involves positive pressure ventilation and

diuretics; however, diuretics may not be appropriate for neurogenic

pulmonary edema if there is relative intravascular volume depletion.94 In

these cases, hemodynamic monitoring via a pulmonary artery catheter

or via transpulmonary thermodilution may be warranted

Postoperative Management: Knowledge of the intraoperative surgical

and anesthetic course facilitates the postoperative care of SAH patients

Large doses of mannitol may have been administered to shrink the

brain and facilitate retraction This measure can result in postoperative

hypovolemia If temporary clipping of cerebral vessels was required,

hypothermia and/or large doses of barbiturates may have been employed

and the risk of focal ischemia exists These maneuvers may also delay

emergence from anesthesia and add to the systemic complications of

hypothermia The decision to extubate a postoperative patient must

take these factors into consideration with the understanding that

keep-ing the patient on mechanical ventilation further increases their risk for

medical complications including ventilator-associated pneumonia If the

aneurysm is successfully treated, many practitioners will accept higher

blood pressures in the postoperative period in anticipation of vasospasm

(see below)

Hyponatremia and Intravascular Volume Contraction: A total of 30% to

50% of SAH patients develop intravascular volume contraction and a

negative sodium balance (referred to as cerebral salt wasting) when given

volumes of fluids intended to meet maintenance needs Low intravascular

volume is associated with symptomatic vasospasm and must be avoided

Hyponatremia develops in 10% to 34% of patients following SAH

Administration of large volumes (5-8 L/d) of isotonic saline prevents

hypovolemia, but patients may still develop hyponatremia The degree of

hyponatremia appears to be related to the tonicity rather than the volume

of fluids administered.95 Thus, administration of large volumes of isotonic

saline and restriction of free water are usually effective at limiting

hypona-tremia and preventing hypovolemia In SAH patients with hyponahypona-tremia,

the volume of fluids should never be restricted; instead only free water

intake should be limited Hypertonic saline solutions and fludrocortisone

may be required in severe or refractory cases

Vasospasm: The term vasospasm was originally used to refer to

segmen-tal or diffuse narrowing of large conducting cerebral vessels Recently,

this term has taken on multiple meanings It may refer to angiographic

findings, to increased transcranial Doppler velocities, or to delayed

ischemic deficits Angiographic and transcranial Doppler vasospasm

occurs in 60% to 80% of patients, whereas clinical vasospasm (or delayed

ischemic deficit) occurs in 20% to 40% of patients

The pathogenesis of vasospasm is complex Several molecular

mechanisms that are involved in the development of vasospasm have

been described in animal models and confirmed in human samples

including inflammation, the presence of degradation blood products,

nitric oxide signaling, and calcium signaling.96 All of these mechanisms

appear to be time-dependent as these pathological changes develop in

a delayed fashion after exposure to subarachnoid blood and are

self-limited In addition to changes in the large conducting cerebral vessels

that traverse the subarachnoid space, small-vessel reactivity may be

impaired as well

moni-toring for vasospasm These must be performed frequently by physicians

and nurses well-versed in the neurologic examination and recognition

of subtle deficits The patients with the highest incidence of vasospasm are those with Hunt-Hess grades III through V and Fisher Scale of 3 These patients are often monitored in the ICU (days 3-10) Clinically vasospasm presents as a decline in the global level of function or a focal neurologic deficit Patients may initially appear “less bright” and then become progressively less alert and finally comatose The focal deficits mimic those seen in ischemic stroke Middle cerebral artery vasospasm can produce hemiparesis, and if left-sided, aphasia or if right-sided, neglect Anterior cerebral artery vasospasm often manifests as abulia or lower extremity weakness The focal deficits wax and wane and there-fore are not reported by all observers The symptoms are exacerbated by hypovolemia or hypotension

Transcranial Doppler ultrasonography detects changes in the blood flow velocity in the proximal portion of the major cerebral vessels Very high flow velocities (>200 cm/s) in the middle cerebral and intracranial carotid arteries are closely correlated with angiographic vasospasm, while low flow velocities (<120 cm/s) suggest a low likelihood of vaso-spasm Furthermore, a Lindegaard ratio (MCA/extracranial ICA mean velocity ratio) which is greater than 6 is also highly predictive of severe vasospasm.97 Patients with rapidly rising velocities are considered to

be at highest risk for developing clinical vasospasm; therefore, a trend

is frequently more useful than isolated values Transcranial Doppler has several limitations High-flow velocities can be due to increased blood flow rather than narrowing of the blood vessel; however, this can

be corrected for by calculating the Lindegaard ratio instead of using velocities Distal segments of the major arteries cannot be evaluated The technique is also operator dependent and adequate “acoustic win-dows” are required Therefore, transcranial Doppler velocities should not be used in isolation as an indication for the initiation of aggressive treatments—the clinical course must be considered as well Given the limitations of transcranial Doppler, other imaging modalities have been explored and further developed These include CT angiography and CT perfusion as a recent meta-analysis suggests that these techniques offer

a high diagnostic accuracy.98 The major limitation though is the inability

to intervene which conventional angiography may provide (see below)

Treatment of Vasospasm

Hemodynamic Augmentation Hemodynamic augmentation for the treatment

of vasospasm has been referred to as hemodilution hypervolemic tensive therapy (“triple H therapy”) or as hypervolemic hypertensive therapy (HHT) The pathophysiologic rationale is based on the high

hyper-rate of spontaneous hypovolemia, the association of hypovolemia with delayed ischemic deficits, and the loss of autoregulation of cerebral blood flow in this population

Most centers continue aggressive hydration during the period of vasospasm risk Some will increase the rate of fluid administration if transcranial Doppler velocities are rising The indication for starting aggressive hemodynamic augmentation is usually the onset of clinical symptoms of delayed ischemic deficit Early descriptions of this therapy emphasized the role of volume expansion, as many of these patients had not been aggressively hydrated before the onset of symptoms However, if intravascular volume has been maintained before the onset of symptoms, further volume expansion may not be helpful.83 The optimal intravascular volume is unknown, and achieving cardiac filling pressures that optimize cardiac output has been advocated

When symptoms persist despite optimal intravascular volume, vasoactive drugs are administered, with a goal of either raising mean arterial pressure (MAP) or augmenting cardiac output in order to improve cerebral perfusion In most cases, patients will require moni-toring via an arterial line and with either pulmonary artery catheter or transpulmonary thermodilution hemodynamic monitoring The most commonly used agents to increase blood pressure are norepinephrine, dopamine, and phenylephrine Caution must be employed when using dopamine alone, because of a high incidence of tachyarrhythmias When using phenylephrine one must be aware that it tends to decrease cardiac output, especially in those patients with impaired cardiac

PART 6: Neurologic Disorders

778

function For augmentation of cardiac output dobutamine titrated to

a goal cardiac index (CI) can augment cerebral perfusion and reverse

neurological deficits.99

When therapy is initiated, the MAP should be raised to 15% to 20%

above baseline rather than to an arbitrary value If after 1 to 2 hours

the delayed ischemic deficit has not resolved, the MAP should be

raised further The MAP is increased progressively until the

neuro-logic deficit is completely resolved or the risk of systemic toxicity

becomes unacceptable Some patients may require a MAP of 150 to

160 mm Hg to completely reverse the neurologic symptoms For

car-diac output augmentation, dobutamine should be titrated to a goal CI

of at least 3.5 L/min/m2 and titrated further as needed to reverse the

neurological deficits.100 The neurologic status should be reevaluated

several times a day to determine MAP or CI goals Both approaches

are reported to produce neurologic improvement It has not yet been

determined whether the optimal therapy is to enhance cardiac output,

MAP, or both

Once instituted, the therapy is generally continued for 3 to 4 days

before attempts are made to wean the patient from it Weaning should

be done gradually, with very close monitoring of neurologic status If

the initial attempt at weaning is unsuccessful, a second attempt should

be made after 1 to 2 days The patient usually is weaned from vasoactive

drugs first, aggressive hydration being continued for several more days

Hemodynamic augmentation is not without complications Early

reports indicated high rates of fluid overload, heart failure, and

myo-cardial ischemia; however, when administered in a closely monitored

setting, even in patients with preexisting cardiac disease it can be done

safely.101 Cardiovascular monitoring should include continuous display

of the electrocardiogram, peripheral oxygen saturation, MAP, and

frequent measurements of cardiac filling pressures and cardiac output

In patients with a history of ischemic heart disease, daily

electrocar-diograms and cardiac enzyme measurements may be helpful Close

monitoring of potassium, magnesium, and phosphate levels is important

because of large losses in the urine

Endovascular Therapies: Percutaneous Transluminal Angioplasty and Direct Intra-Arterial

Vasodilators Balloon angioplasty can be used to dilate proximal segments

of intracranial vessels, but it is not well suited for use in the distal

vascula-ture The dilation achieved appears to be long-lasting Complications that

have been reported include artery rupture and displacement of aneurysm

clips In most cases there is clear-cut angiographic improvement, but the

clinical efficacy of angioplasty has not been clearly established

Direct intra-arterial injection of vasodilators into the vessel affected

by vasospasm has become routine in many centers The most commonly

used agents currently used include verapamil and nicardipine While

the radiographic improvement is usually evident, the clinical effect has

been less clear There have not been any randomized controlled trials

demonstrating a benefit on patient outcome These therapies are usually

reserved for patients who do not tolerate or do not respond to

hemody-namic augmentation

Other Potential Therapies Prevention rather than treatment of the

conse-quences of vasospasm would significantly reduce the morbidity,

mortal-ity, and cost of SAH Intracisternal instillation of thrombolytic agents

has been employed in an attempt to dissolve clots around the circle of

Willis and thereby decrease vasospasm A multicenter, randomized,

blinded, placebo-controlled study found trends toward reduction of

angiographic vasospasm, reduced delayed neurologic worsening, lower

14-day mortality, and improved 3-month outcome that did not achieve

statistical significance in patients treated with intracisternal t-PA

Patients with thick subarachnoid clots had a significant reduction in the

incidence of severe vasospasm with intracisternal t-PA.102

The degradation of blood deposited during an SAH involves the

conversion of oxyhemoglobin to methemoglobin, which releases an

acti-vated form of oxygen that catalyzes free radical reactions, including lipid

peroxide formation The 21-aminosteroid, tirilazad mesylate, a potent

scavenger of oxygen free radicals, inhibits lipid peroxidation and reduces

vasospasm in animal models A European-Australian multicenter study

showed that tirilazad was associated with better outcomes compared

to control patients, but this was not confirmed in a subsequent North American study.103,104 In a multicenter, randomized, double-blind, placebo-controlled trial, nicaraven, a hydroxyl radical scavenger, sig-nificantly reduced the incidence of severe vasospasm and poor outcome

at 1 month but not at 3 months.105 Ebselen, another lipid peroxidation inhibitor, did not lower the incidence of symptomatic vasospasm in a controlled study.106 Clazosentan, an endothelin receptor antagonist, is one of the more promising medical treatment options currently in phase

3 clinical trials A phase 2 study demonstrated a reduction in moderate

to severe vasospasm and clazosentan appeared safe.107 Other potential therapies being studied include statins, magnesium infusions, nitric oxide donors, and albumin infusions.108

KEY REFERENCES

• Anderson CS, Huang Y, Arima H, et al Effects of early intensive blood pressure-lowering treatment on the growth of hema-toma and perihematomal edema in acute intracerebral hemor-rhage: the Intensive Blood Pressure Reduction in Acute Cerebral

Haemorrhage Trial (INTERACT) Stroke 2010;41:307-312.

• Dorhout Mees SM, Rinkel GJE, Feigin VL, et al Calcium

antag-onists for aneurysmal subarachnoid haemorrhage Cochrane Database Syst Rev 2007:CD000277.

• Fisher CM, Kistler JP, Davis JM Relation of cerebral vasospasm

to subarachnoid hemorrhage visualized by computerized

tomo-graphic scanning Neurosurgery 1980;6:1-9.

• Hacke W, Kaste M, Bluhmki E, et al Thrombolysis with alteplase

3 to 4.5 hours after acute ischemic stroke N Engl J Med

2008;359:1317-1329

• Jüttler E, Unterberg A, Woitzik J, et al Hemicraniectomy in older

patients with extensive middle-cerebral-artery stroke N Engl J Med 2014;370:1091-1100.

• Molyneux A, Kerr R, Stratton I, et al International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovas-cular coiling in 2143 patients with ruptured intracranial aneu-

rysms: a randomised trial Lancet 2002;360:1267-1274.

• Potter JF, Robinson TG, Ford GA, et al Controlling sion and hypotension immediately post-stroke (CHHIPS): a

hyperten-randomised, placebo-controlled, double-blind pilot trial Lancet Neurol 2009;8:48-56.

• Robinson TG, Potter JF, Ford GA, et al Effects of antihypertensive treatment after acute stroke in the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospec-

tive, randomised, open, blinded-endpoint trial Lancet Neurol

emic stroke N Engl J Med 1995;333:1581-1587.

• Vahedi K, Hofmeijer J, Juettler E, et al Early decompressive surgery in malignant infarction of the middle cerebral artery:

a pooled analysis of three randomised controlled trials Lancet Neurol 2007;6:215-222.

REFERENCES

Complete references available online at www.mhprofessional.com/hall

CHAPTER 85: Seizures in the Intensive Care Unit 779

TABLE 85-1 Causes of Status Epilepticus Presenting From the Community

Prior Seizures No Prior Seizures Prior Seizures No Prior Seizures Common causes

Subtherapeutic anticonvulsant

Ethanol-related Subtherapeutic

anticonvulsant

Febrile seizuresEthanol-related Drug toxicity Intractable epilepsy CNS infection

Head traumaCNS tumor

less common causes

CNS infection Metabolic aberration Anoxic brain injury CNS infectionMetabolic aberration Stroke Head trauma Intractable epilepsyDrug toxicity Metabolic aberration Metabolic aberrationStroke

CNS tumorHead traumaCNS, central nervous system

Adapted with permission from Bleck TP, Dunatov CJ Seizures in critically ill patients In: Shoemaker WC, Ayres

SM, Grenvik A, Holbrook PR, eds Textbook of Critical Care 4th ed Philadelphia, PA: WB Saunders; 2000.

Seizures are a relatively common occurrence in the ICU, complicating

the course of about 3% of adult ICU patients admitted for nonneurologic

conditions.1 Status epilepticus (SE) may be the primary indication for

admission, or it may occur in any ICU patient during a critical illness

Seizures are second to metabolic encephalopathy as a cause of

neuro-logical complications (28.1%).1 A seizure may be the first indication of a

central nervous system (CNS) complication or the result of

overwhelm-ing systemic disease Seizures in the settoverwhelm-ing of critical illness are often

difficult to recognize and require a complex diagnostic and management

strategy Delay in recognition and treatment of seizures is associated

with increased mortality,2 thus the rapid diagnosis of this disorder is

mandatory Conventionally, status epilepticus referred to a protracted

seizure episode or multiple frequent seizures lasting 30 minutes or

longer However more recently, revised definitions have suggested to

consider seizures lasting for 5 minutes or longer as status epilepticus,3-5

and newer guidelines define status epilepticus as five minutes or more

of either continuous clinical and/or electrographic seizure activity, or

recurrent seizure activity without recovery between seizures.6

While most seizures will terminate spontaneously within a few

minutes,5 only half of seizure episodes lasting 10 to 29 minutes will

stop spontaneously7 and aggressive treatment should be administered to

prevent ongoing SE.8

EPIDEMIOLOGY AND OUTCOME

Limited data are available on the epidemiology of seizures in the ICU A

10-year retrospective study of all ICU patients with seizures at the Mayo

Clinic revealed that 7 patients had seizures per 1000 ICU admissions.8

Our 2-year prospective study of medical ICU patients identified 35 with

seizures per 1000 admissions.1 The incidence of generalized convulsive

SE (GCSE) in the United States is estimated to be up to 195,000 episodes

per year,9 but it is unknown how many of these patients require care in

an ICU The incidence of SE in the elderly is almost twice that of the

general population.10 Nonconvulsive seizures and NCSE are present

in a large proportion of comatose patients with traumatic brain injury,

intracranial hemorrhage, sepsis, cardiac arrest, or CNS infection.11-15 In one series, 8% of hospitalized comatose patients were found to be in electrographic status epilepticus,15 up to 34% of patients in neurological ICUs,15 and other series of patients with altered mental status found 37%

to have nonconvulsive seizures.16 Of all patients with status epilepticus, about 80% have nonconvulsive status epilepticus.17 Seizures are probably even more frequent in the pediatric ICU, as children in the first year of life have the highest incidence of SE of any age group studied.8

Table 85-1 summarizes the most common causes of SE in adults and

children in the community An analysis of 204 cases of SE in Virginia revealed that the primary etiology in children was infection with fever, followed by remote symptomatic epilepsy, and subtherapeutic levels of anticonvulsant drugs In adults, cerebrovascular disease and low anti-epileptic drug levels were the most prevalent causes.8 A recent study from Brazil found anticonvulsant noncompliance to be the main cause

of SE in patients with a prior history of epilepsy, and CNS infection, stroke, and metabolic disturbances predominated in the group without previous seizures.18 A prospective study of neurologic complications in medical ICU patients determined that two-thirds of patients had a vascular, infectious, or neoplastic explanation for their seizures1; meta-bolic and toxic etiologies are common in the ICU as well A review of

100 cases of nonconvulsive SE (NCSE) demonstrated that 14% were due

to acute neurologic events, 28% due to acute systemic causes, and 31% due

to epilepsy, with the remainder due to multiple causes or a cryptogenic etiology,19 and among patients with NCSE in a comatose state, hypoxia (42%) and stroke (22%) were the most common etiologies.15 In medical ICU patients, electrographic seizures or periodic epileptiform discharges were detected in 22% of patients, with the predominant underlying disease state being sepsis.13 It is important to realize that the frequency of diagnos-ing NCSE will rise with implementation of continuous EEG monitoring by 6% to 8% accounting for the increment of investigations.20

A prospective study of neurologic complications in medical ICU patients showed that having one seizure in the ICU doubled mortal-ity.1 At least 20% of patients with status epilepticus die,21,22 and up to 61% of patients developing SE during hospitalization do not survive.23

SE in and of itself confers a mortality rate of 26% to adults older than

16 years and 38% to those 60 years and older.8 Multiple reports rate an especially poor outcome in the elderly.15,24 The mortality rate of

corrobo-SE in children is 3% in the general population and 6% in the ICU,25 and

85

C H A P T E R Seizures in the Intensive

Care Unit

Katharina M Busl Thomas P Bleck

KEY POINTS

• Seizures are a relatively common occurrence in the intensive care

unit (ICU), but may be difficult to recognize

• Seizures that persist longer than 5 to 7 minutes should be treated

to prevent progression to status epilepticus

• Three major factors determine outcome in status epilepticus: type

of seizure, cause, and duration

• Electroencephalographic (EEG) monitoring to titrate therapy

should be implemented in seizing patients who do not awaken

promptly after institution of antiepileptics, even if tonic-clonic

motor activity resolves

• Lorazepam is a preferred agent for initial treatment, followed by

consideration of additional agents for long-term management or

to “break” status epilepticus

• Patients with refractory status epilepticus require intubation,

mechanical ventilation, and aggressive treatment with

antiepilep-tics titrated to the EEG

• The underlying cause of the seizure disorder must be sought in

tandem with treatment of the seizure disorder itself

PART 6: Neurologic Disorders

780

much higher if a preexisting significant neurological deficit is present.26

Factors determining outcome in SE include the type of SE, the cause,

and the duration In a 90-day follow-up study after convulsive SE, longer

seizure duration, presence of cerebral insult, and progression to

refrac-tory SE were associated with a worse outcome, only 8% of all patients

whose SE was characterized by those three factors had a good outcome,

as opposed to 65% of patients who had SE but none of those factors.21

Based on the combined assessment of previous history of seizures,

seizure type, extent of impairment of consciousness, and age, a prognostic

score has been recently suggested for outcome prediction (STESS, status

epilepticus severity score).27 Better outcomes are observed if the status

is convulsive or focal, as opposed to nonconvulsive, and if the

underly-ing etiology is epileptic or toxic.28 Anoxic SE, including myoclonic SE

following an anoxic episode carries a very poor prognosis for survival

Survivors of SE may experience impaired cognitive function, motor

deficits, and worsening of preexisting epilepsy.29 Particularly, complex

partial SE (CPSE) can produce limbic system damage, usually

mani-fested as a memory disturbance

The mortality of patients with NCSE has been reported between

17% and 57%,2 and correlates with the underlying etiology, severity of

impairment of mental status, and the development of acute

complica-tions (especially respiratory failure and infection) Older age had a

positive influence on outcome in one series.17 Causes associated with

increased mortality included anoxia, intracranial hemorrhage, tumor,

infection, and trauma Status epilepticus in the setting of acute

isch-emic stroke has a very high mortality, approaching 35%.30 Prolonged

seizure duration is a negative prognostic factor.31 A study of 253 adult

SE patients showed a greater than tenfold increase in mortality rate

associated with seizures lasting ≥60 minutes compared with those

lasting 30 to 59 minutes.32

In children who are treated for SE in an ICU, the mortality is reported

close to 10% Etiology of SE and prior neurologic abnormalities are

predictors of mortality; younger age, etiology, and duration of SE were

associated with morbidity.33

CLASSIFICATION

The International League Against Epilepsy’s (ILAE) classification of

seizures is generally accepted The system allows classification on the

basis of clinical criteria without inferring cause Knowledge of interictal

or ictal electroencephalographic (EEG) findings is not necessary to

classify seizures except for absence seizures, which are not likely to be a

problem in the ICU The classification system divides seizures into two

types: partial, which have a focal or localized onset, and generalized, in

which the cortex of both cerebral hemispheres is involved

simultane-ously at onset Partial seizures can further be categorized as simple, in

which consciousness remains intact throughout the event, or complex,

in which consciousness is disrupted or altered (but not lost), often

resulting in amnesia for the event Seizures that start locally and then

spread to involve the entire cortex are termed secondary generalized

Generalized seizures are of two types: convulsive, in which tonic, clonic,

or myoclonic movements are prominent, and nonconvulsive, in which a

patient has an altered level of consciousness with or without very subtle

motor manifestations

The clinical manifestation of partial seizures varies with the location

of their onset Motor seizures are usually due to a lesion in the

contra-lateral frontal lobe Deviation of eyes and head toward the irritative

focus is often seen at the onset of seizure activity and is termed versive

movement Careful observation of the direction of this initial

move-ment provides important diagnostic information regarding the location

of brain pathology Muscle contractions may be localized to a small

region, such as the face or fingers, or be more extensive, involving the

entire hemibody Movements are usually tonic or clonic, but dystonic

posturing is also common Sensory seizures can be primarily auditory,

somatosensory, visual, or consist of vague visceral sensations Patients

with complex partial seizures may demonstrate any combination of the

above symptoms and have associated motor automatisms, such as lip smacking or swallowing

Generalized convulsive seizures are usually of the tonic-clonic type

During the tonic phase, initial extension of the trunk is followed by extension of the arms, legs, neck, and back The respiratory muscles may be involved in the tonic spasm, resulting in cyanosis and decreased oxygen saturation if the tonic phase is long enough, although this is rare

The clonic phase follows and is manifest by repetitive muscle tions Fixed and dilated pupils, tachycardia, and hypertension are well described during tonic-clonic seizures Incontinence usually follows termination of the seizure The frequency of the clonus eventually wanes and respiration commences when the seizure stops Patients may initially be deeply comatose but should begin to regain consciousness within 15 to 20 minutes

contrac-Status epilepticus refers to prolonged or serial seizures without ictal resumption of baseline mental status Refractory SE refers to SE

inter-that is resistant to treatment with first-line measures and requires more aggressive therapy Super-refractory status epilepticus is refractory SE which is unresponsive to initial anesthetic therapy as it continues or recurs 24 hours or more after the onset of anesthesia, or on the reduction

or withdrawal of anesthesia Description of specific treatment modalities

will be reviewed below Epilepsia partialis continua is a special type of

focal motor epilepsy that consists of near constant muscle contractions

of a specific muscle group These movements can last for months or years without generalizing

There are theoretically as many different types of SE as there are zures, since SE is a prolonged seizure However, SE cannot be classified

sei-in exactly the same manner as sei-individual seizures, because seizures are discrete time-limited events with symptomatology restricted to the brief duration of their occurrence SE, on the other hand, can evolve over time and therefore can have a symptomatology that may encompass more than one seizure type Furthermore, NCSE can have similar signs and symptoms with different EEG signatures and etiologies The simplest classification divides SE into generalized convulsive SE and nonconvul-sive SE, depending on whether convulsive movements are present Since NCSE includes everything that is not convulsive, it describes a wide variety of clinical entities and scenarios

The conventional method of subcategorizing NCSE is to divide it into absence SE and complex partial SE This works well for patients with a previous history of epilepsy In this context, absence SE denotes confu-sion, typically mild, in a patient with generalized, approximately 3-Hz spike-wave discharges on EEG and a history of generalized epilepsy Complex partial SE denotes confusion, typically waxing and waning,

or recurrent complex partial seizures associated with focal seizures in a patient with focal epilepsy As defined herein, both types of NCSE imply that the encephalopathy is due to seizure activity Historically, NCSE was labeled “absence” type if generalized EEG changes were found and “com-plex partial” if focal EEG changes were found, regardless of whether a history of epilepsy was present

Many patients with NCSE do not have a history of epilepsy and

do not fit into the conventional categorization elaborated above For example, in a retrospective study of NCSE, we did not find any asso-ciation between EEG findings and mortality,19 emphasizing that this categorization is not very useful This is particularly a problem in ICU patients in whom there are typically numerous factors contributing to encephalopathy This nosologic uncertainty has given rise to several terms to describe NCSE arising in the ICU, including ICU status, subtle generalized convulsive status epilepticus, EEG status, and status in the critically ill An important aspect of ICU status is that encephalopathy often has other causes in addition to the seizure activity

NCSE is of particular importance to the intensivist when it occurs

as a sequela of inadequately treated GCSE After prolonged generalized convulsions, visible motor activity may stop, but the electrochemical seizure continues Patients who do not start to awaken after 20 minutes should be assumed to have entered NCSE NCSE following GCSE is a dangerous problem because the destructive effects of SE continue even

CHAPTER 85: Seizures in the Intensive Care Unit 781

without obvious motor activity NCSE in this setting demands emergent

treatment guided by electroencephalographic monitoring to prevent

further cerebral damage since there are no clear clinical criteria to

indi-cate whether therapy is effective

NCSE can occur as a late stage of convulsive SE from any etiology, or

as an initial form of SE from another cause Failure to recognize NCSE

is common in patients presenting with nonspecific neurobehavioral

abnormalities, such as delirium, lethargy, bizarre behavior, cataplexy,

or mutism.34 A high level of suspicion for this disorder should be

main-tained in patients with unexplained alteration in level of consciousness

or cognition who are admitted to the ICU

Two special circumstances with which the intensivist should be

famil-iar are myoclonus and febrile seizures Brief, shock-like, involuntary

muscle contractions constitute myoclonus Myoclonic jerks are

arrhyth-mic, of variable amplitude, and involve both small and large muscles In

patients with postanoxic coma, myoclonus may be continuous or evoked

by stimuli such a noise or touch While this disorder has been associated

with epileptiform discharges in the EEG,35 not all episodes of myoclonus

are epileptic; an EEG can clarify whether it is epileptic in individual

cases Postanoxic myoclonus also occurs in patients who have regained

consciousness (the Lance-Adams syndrome); in this setting the

myoclo-nus is probably of cerebellar origin and is not a seizure Febrile seizures

are specific to young children and are usually generalized motor

convul-sions that occur in association with fever, typically as the temperature is

rising These seizures should not be confused with those that transpire

in the setting of fever secondary to infection of the nervous system

Febrile seizures are usually brief, but can be prolonged and recurrent,

prompting admission to an ICU

Clinical judgment is required to classify seizures in the ICU Patients

in whom consciousness has already been altered by drugs,

hypoten-sion, sepsis, or intracranial pathology may be difficult to classify using

only the ILAE classification because it depends heavily on whether the

seizure activity has altered consciousness However, focal seizure

activ-ity on EEG or focal neurologic deficits often helps determine whether

the seizure is focal or generalized in onset The ILAE continues to work

toward revising and updating the current classification system The goal

is a multi-axis diagnostic scheme that incorporates anatomic, etiologic,

therapeutic, and prognostic implications For the most recent

informa-tion regarding this ongoing project, refer to www.epilepsy.org.36

PATHOGENESIS AND PATHOPHYSIOLOGY

The systemic and cerebral pathophysiology of GCSE can be divided into

early and late phases.37 The early phase of systemic manifestations results

from an adrenergic surge and excessive muscle activity.38 The

adrener-gic surge causes tachycardia, hypertension, and hyperglycemia These

are augmented by extreme muscle activity that causes hyperthermia

and acidosis and can lead to muscle breakdown, rhabdomyolysis, and

secondary acute renal failure This stage is generally well compensated

by homeostatic mechanisms so that the excessive demands are met with

increased supply or other compensatory mechanisms

Most facets of GCSE begin to slow down late in GCSE, so only a

rare patient continues to have continuous convulsive motor activity for

more than 1 hour Cessation of continuous motor activity would seem

to be a beneficial turn of events, but this is actually coincident with a

sharp increase in mortality and in complications Although systemic

factors such as heart rate and blood pressure normalize, they may be

inadequate to meet increased demands of intermittent convulsions or

electrographic seizure activity, even in the absence of convulsions Thus

mortality increases dramatically for SE lasting longer than an hour.31

Death may result from a number of causes, but in a prospective study

of cardiovascular changes during GCSE, 58% of patients had potentially

fatal arrhythmias.39 Patients with atherosclerotic cardiovascular risk

factors may have a gradual deterioration in hemodynamic parameters

as their cardiovascular reserve is expended, while other patients decline

acutely, presumably from arrhythmias.40

SE may cause neuronal injury in surviving patients Some neuronal injury is caused by systemic factors; for example, hyperthermia causes cerebellar neuronal injury However, neuronal injury continues during electrographic SE, even without motor manifestations or when physi-ologic parameters are held in the normal range This is illustrated most clearly in experimental GCSE Neuronal injury is prominent in the hip-pocampus and temporal lobe in primates with experimental GCSE The injury persisted even when muscle activity was eliminated by paralysis, and pulse, blood pressure, temperature, and oxygenation were kept normal

Neuronal injury during SE is due in part to the excitotoxic effects of glutamate-mediated neuronal seizure activity.37 Glutamate is the most common excitatory neurotransmitter in the brain It mediates transfer

of information between neurons under normal conditions via several

receptors However, glutamate excessively activates the

N-methyl-d-aspartate (NMDA) subtype of receptor in the robust conditions of SE NMDA receptors have a limited normal function, but during SE they cause very prolonged depolarization of neurons This results in intracel-lular accumulation of calcium and other cellular changes that result in both immediate and delayed cell death.37

There are two important clinical implications of the pathophysiology

of SE First, neuronal injury continues during electrical SE even after control of motor manifestations Therefore it is imperative to exclude ongoing seizure activity if patients are pharmacologically paralyzed after GCSE or do not awaken soon after motor activity stops These cir-cumstances require EEG monitoring to exclude ongoing seizure activity Second, pharmacologic treatment is aimed at augmenting inhibition, via drugs that act on γ-aminobutyric acid (GABA), such as barbiturates and benzodiazepines There will probably also be a role for NMDA antago-nists Ketamine is the only currently available NMDA antagonist, but others are likely to be helpful in the future

CLINICAL MANIFESTATIONS

Three problems complicate seizure recognition in the ICU: (1) occurrence

of complex partial or nonconvulsive seizures in the setting of depressed consciousness, (2) masking of seizures by pharmacologically induced paralysis or sedation, and (3) misinterpretation of other abnormal move-ments as seizures ICU patients often have decreased levels of conscious-ness in the absence of seizures that are ascribable to the underlying disease and its complications.1 An encephalopathic patient may be unable to appreciate or report symptoms of seizure Fluctuations in mental status are frequently subtle and may go unrecognized by staff A decline in base-line alertness may reflect a seizure; an EEG may be required to confirm that one has occurred

Patients receiving neuromuscular junction blocking agents do not manifest the motor signs of seizures Patients with refractory intracra-nial hypertension, severe pulmonary disease, or other critical illnesses may be both paralyzed and sedated, making identification of seizures particularly challenging Tachycardia and hypertension are signs of seizure that can be misinterpreted as evidence of inadequate sedation Continuous EEG monitoring is warranted in this population if seizures are suspected

Patients with metabolic disturbances, anoxia, and other types of vous system injury may demonstrate abnormal movements that can be confused with seizure Asterixis, or flapping tremor, is a brief arrhythmic loss of tone that can appear in the setting of hepatic encephalopathy, hypercarbia, drug intoxication, or CNS pathology.41 Myoclonus in post-anoxic coma has been reported in the presence34 and absence42 of epilep-tiform discharges Therefore, EEG is absolutely indicated in this setting to evaluate for ongoing seizures Action myoclonus in a patient recovering from hypoxic encephalopathy is evoked during movements directed at a target, such as an examiner’s finger It is frequently associated with cer-ebellar ataxia and postural lapses, which when combined with myoclonus can severely impair ambulation Myoclonus associated with  etomidate

ner-is described,43 but whether it is cortically mediated remains unclear

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782

Brain-injured patients may suffer from so-called “hypothalamic seizures.”

Tetanus patients do not lose consciousness during their spasms, and

describe excruciating pain associated with the sustained whole-body

contractions Psychiatric disturbances in the ICU occasionally resemble

complex partial seizures If doubt about the nature of abnormal

move-ments persists, an EEG should be performed

DIAGNOSTIC APPROACH

The initial approach to seizure management is the same as that for any

other acute medical problem: circulation, airway, and breathing As

described above, generalized convulsive status epilepticus often causes

apnea and/or poor oxygen saturation Hypertension and tachycardia

may be marked However, respiratory and hemodynamic dysfunction

is transient, and with seizure termination rapidly returns to normal

Padded tongue blades or similar items should not be placed inside the

mouth; they are more likely to obstruct the airway than to preserve it

Medication to treat tachycardia and hypertension before the seizure

activity stops is not warranted

When a patient has a seizure, one has a natural tendency to try to stop

the event This leads to both diagnostic confusion and iatrogenic

com-plications Beyond protecting the patient from harm, very little can be

done rapidly to influence the course of the seizure The seizures of most

patients stop before any medication can reach the brain in an effective

concentration Observation is the most important activity to perform

when a patient has a single seizure This is the time to collect evidence

of a partial onset in order to implicate structural brain disease The

postictal examination is similarly valuable; language, motor, sensory, or

reflex abnormalities after an apparently generalized seizure are evidence

of focal pathology

Seizures in ICU patients have many potential causes that must be

investigated Medical conditions such as hepatic encephalopathy or

acute hypothyroidism have been associated with seizures,

particu-larly nonconvulsive status epilepticus.44,45 Drugs are a major cause of

seizures in critically ill patients, especially in the setting of renal or

hepatic dysfunction Imipenem-cilastatin46 and fluoroquinolones47 have

the potential to lower the seizure threshold, particularly in patients

with impaired renal function Similarly, cephalosporins, particularly

cefepime, have been associated with NCSE, especially in adult patients

with impaired renal function.48 Theophylline can provoke seizures or SE

if it has been rapidly loaded or if high concentrations of the drug occur;

however, these complications can also arise with normal serum drug

levels.49 Immunosuppressant agents such as cyclosporine or tacrolimus

are known culprits for seizures, and as etiology for posterior

revers-ible leucoencephalopathy, which may manifest primarily with seizures,

but status epilepticus seems to arise only rarely.50,51 Accumulation of

a metabolite of meperidine, normeperidine, causes seizures, even in

patients with normal renal function Sevoflurane, a volatile anesthetic

agent, also causes electrographic and clinical seizures without a

his-tory of epilepsy or CNS pathology.52 Other, less conventional etiologies

include the use of tranexamic acid in cardiac surgery, which was found

to be associated with postoperative seizures in patients with renal

dysfunction.53

Recreational drugs are frequently-overlooked offenders in patients

presenting to the ICU Acute cocaine or methamphetamine

intoxica-tion is characterized by a state of hypersympathetic activity followed by

seizures.54 Ethanol withdrawal is a common cause of seizures between

6 and 96 hours after the patient’s last drink, but concomitant causes

must not be overlooked Narcotic withdrawal may produce seizures in

the critically ill8 and in newborns of opioid-dependent mothers.55 Both

bupropion hydrochloride56 and tricyclic antidepressants are associated

with seizure in overdose and occasionally at therapeutic doses In the

absence of other clear causes for seizure, a complete toxicology screen

should be performed upon admission

Serum glucose, electrolyte concentrations, and serum osmolality

should also be measured Nonketotic hyperglycemia can precipitate both

focal and generalized seizures57,58; epilepsia partialis continua was the most common type seen in a recent series.59 Seizure activity infrequently may be the first presenting sign of diabetes mellitus Both severe, rapidly developing hyponatremia and hypoglycemia can cause seizures The patient’s blood glucose concentration should be measured immedi-ately upon presentation, and dextrose and thiamine administered if hypoglycemia is present Hypocalcemia rarely causes seizures beyond the neonatal period; identifying even moderate hypocalcemia must

not signal the end of the diagnostic work-up Hypomagnesemia has an

equally unwarranted reputation as the cause of seizures in malnourished alcoholic patients

In recent years, the importance of autoimmune and paraneoplastic disorders has become clearer.60 Empiric immunologic therapy may be necessary when these conditions are suspected, as diagnosis may require weeks of specialized testing.61

The physical examination should emphasize assessment for both global and focal abnormalities of the CNS Evidence of cardiovascular disease or systemic infection should be sought and the skin and fundi examined closely Particular attention should be given to the fundu-scopic examination of infants presenting from the community with sei-zures, as retinal hemorrhages may be the only evidence of brain trauma induced by child abuse (the “shaken baby syndrome”)

New-onset seizures almost always warrant brain imaging Considering the large number of critically ill patients with neurologic pathology as a primary or contributing cause for seizures, acute brain processes must be ruled out Computed tomography (CT) scanning is a rapid modality with which the trained clinician can detect acute blood, swelling, large tumors

or abscesses, and subacute or remote ischemic strokes With current technology, there are exceptionally few patients who cannot undergo CT scanning Magnetic resonance imaging (MRI) is particularly helpful in detecting evidence of acute ischemic stroke, encephalitis, small tumors, subdural empyemas, and cerebral edema Most cardiac pacemakers are

a contraindication to MRI, but many other medical devices, such as inferior vena cava filters, intracranial pressure monitors, and cerebral aneurysm clips, are now manufactured using MRI-compatible material

Patients with altered mental status who need cerebrospinal fluid analysis require imaging of the brain first, to rule out a mass, swelling, or other cause of impending brain herniation When CNS infection is suspected, empiric antibiotic treatment should be started while imaging studies are being obtained

In contrast to the patient with a single or a few seizures, the SE patient requires simultaneous diagnostic and therapeutic efforts Most seizures

in critically ill patients stop within 2 to 3 minutes However, if the opment of SE is suspected based on a seizure duration of greater than

devel-5 minutes, or absence of recovery in between seizures episodes, one should not wait, but rather initiate immediate treatment

■ THE ELECTROENCEPHALOGRAM

Treatment for recognized SE should not be delayed to obtain an EEG, but such recognition is not always straightforward A prospective evalu-ation of 164 patients demonstrated that nearly half manifested persistent electrographic seizures in the 24 hours after clinical control of convul-sive SE, and 14% went into electrographic status epilepticus.62 Therefore, continuous EEG monitoring should be initiated within 1 hour of SE onset if ongoing seizures are suspected.6 Subclinical seizures have been observed during aggressive treatment for SE, even in patients treated with high-dose barbiturates to produce a burst-suppression pattern on EEG These data suggest that EEG monitoring after control of convul-sive SE can be essential in directing the course of treatment Emergent EEG is necessary to exclude NCSE in those patients who do not begin

to awaken soon after visible seizure activity has stopped Patients who develop refractory SE or receive neuromuscular junction blockade require continuous EEG monitoring, since ongoing seizure activity can cause neuronal injury via excitotoxic mechanisms as outlined above

A variety of findings may be present in the EEG, depending on the seizure type, duration, and level of pharmacologic intervention

CHAPTER 85: Seizures in the Intensive Care Unit 783

TABLE 85-2 Drugs for the Treatment of Acute Convulsive Status Epilepticus

Fosphenytoin 20 mg/kg <150 mg/min Easy transition to chronic administration Delay to onset of action; prolonged loading time; hypotension

Lorazepam 0.1 mg/kg IV push diluted 1 : 1 Quick onset of action; may prevent early recurrence Respiratory depression

Midazolam 0.2 mg/kg IV/IM push Can be given IM; quick onset of action Respiratory depression

Phenobarbital 10-20 mg/kg 50-100 mg/min Readily available Prolonged loading time; hypotension

Phenytoin 20 mg/kg <50 mg/min Readily available Prolonged loading time; cardiac arrhythmias; necrosis if extravasation

occurs; hypotension; incompatible with dextrose-containing solutionsValproate 25 mg/kg 12-200 mg/min diluted 2 : 1 Appears safe in children Not well studied in status epilepticus

Prospective data indicate that EEG patterns may also be helpful in

determining prognosis One study found that the presence of burst

sup-pression, post-SE ictal discharges, and periodic lateralized epileptiform

discharges during the initial 24 hours after control of SE were

statisti-cally significantly correlated with mortality and poor outcome.63 Burst

suppression secondary to pharmacologic coma for treatment of SE must

be differentiated from burst suppression due to widespread cortical

injury, or that seen as the last stage of the EEG evolution of SE The

availability of continuous paperless electroencephalographic monitoring

allows for detection of seizure activity over a long period In critically

ill patients with an otherwise unexplained decrease in mental status,

electrographic seizures were captured on continuous EEG monitoring

in 93% by 48 hours, and only 7% after 48 hours11; therefore, continuous

EEG monitoring should at least be continued for 48 hours in comatose

patients.6

The EEG can also provide information that is very useful in the

diagnosis and management of other neurologic conditions.64,65

MANAGEMENT APPROACH

■ ISOLATED SEIZURES

Not all patients who have seizures require anticonvulsant therapy

Making the decision to administer anticonvulsants to a hospitalized

patient who experiences one or a few seizures mandates consideration of

a provisional cause, estimation of the likelihood of recurrence, and

rec-ognition of the utility and limitations of anticonvulsants For example,

seizures due to ethanol or other hypnosedative withdrawal do not need

chronic treatment, but short-term therapy with benzodiazepines for

repeated or prolonged seizures may be warranted (Table 85-2) Seizures

caused by metabolic disturbances such as hyponatremia are often

refractory to conventional anticonvulsant medications such as

phe-nytoin, and are best treated with correction of the underlying disorder

( benzodiazepines may be useful for seizure suppression if needed while

the metabolic problem is being corrected) Seizures related to nonketotic

hyperglycemia respond best to correction of hyperglycemia with insulin

and rehydration.57

A patient with CNS disease who has even one seizure should receive

anticonvulsant therapy because the risk of seizure recurrence is very

high However, this treatment should be reviewed before discharge

Initiating this treatment after the first unprovoked seizure may help delay

the appearance of subsequent seizures,66 but probably does not

influ-ence whether epilepsy subsequently develops.67 Prophylactic therapy

in patients at high risk for seizure, especially if the condition was

seri-ously complicated by a convulsion, is not unreasonable Patients with

traumatic brain injury, intracerebral hemorrhages, and subarachnoid

hemorrhages are frequently placed on anticonvulsants immediately

upon admission, although no prospective randomized trials have proven

a positive effect on outcome

In the ICU setting, phenytoin is often the first drug selected due to

ease of administration and rapid assessment of blood levels While the

efficacy of phenytoin in the control of seizures is well established, several inherent properties of the drug limit its tolerability In order to improve aqueous solubility, phenytoin is suspended in a highly alkaline solution that is comprised of 40% propylene glycol.68 The propylene glycol vehicle has been linked to hypotension and cardiac arrhythmias during phe-nytoin infusion; however, phenytoin itself may be partly responsible for hemodynamic instability The caustic pH of the parenteral formulation can cause injection site reactions that can range from burning at the IV site to necrosis in the event of extravasation

The phenytoin prodrug fosphenytoin is water soluble; therefore the parenteral formulation is more neutral than that of phenytoin and contains no organic solvents Cardiovascular side effects were initially thought to be less common with fosphenytoin, but subsequent experi-ence suggests that hypotension and arrhythmias may follow its infusion Pain at the infusion site is significantly less common with fosphenytoin than with phenytoin.69 In patients without IV access, fosphenytoin can be safely administered intramuscularly IM doses of fosphenytoin are well tolerated, require no cardiac monitoring, and are completely absorbed Fosphenytoin is rapidly converted to phenytoin in vivo and free phenytoin levels after fosphenytoin administration are not markedly different compared to phenytoin, although the time to reach the peak level after IM administration is several hours

A 20-mg/kg loading dose of phenytoin brings most patients to the desired concentration of 20 µg/mL (corresponding to an unbound or free concentration of 2 µg/mL) Fosphenytoin is dosed by phenytoin-equivalent units (PE); therefore no dosage adjustments are needed when converting patients from phenytoin to fosphenytoin Fosphenytoin can

be administered via intravenous infusion at rates of up to 150 mg PE/min, compared with a maximum rate of 50 mg/min for phenytoin Both of these drug infusions should be started at a lower rate and increased

as tolerated When loading doses of fosphenytoin are given IM, two divided doses of 10 mg/kg each are recommended After fosphenytoin administration, phenytoin concentrations should not be measured until the biologic conversion to phenytoin is complete and the drug has equilibrated throughout the body, about 2 hours after an intravenous infusion or 4 hours after an intramuscular injection of fosphenytoin Phenytoin is approximately 90% protein bound in normal hosts, but the unbound fraction is the active component Patients with renal or hepatic dysfunction or those taking drugs that compete for protein binding may benefit from measuring the free (unbound) serum phenytoin concentra-tion before increasing phenytoin doses due to apparently subtherapeutic total phenytoin concentrations

The maintenance dose for phenytoin is typically in the range of 5

to 7 mg/kg per day, but is highly variable because of individual ences in metabolism and interactions with other drugs metabolized via the cytochrome P450 system Maintenance doses can be given either enterally or parenterally Maintenance doses of IV or enteral liquid suspension phenytoin must be given in twice-daily divided doses since their half-life is less than 24 hours Extended-release capsules can be given once a day However, patients often do not tolerate more than 300

differ-or 400 mg of phenytoin enterally in any one dose secondary to nausea

PART 6: Neurologic Disorders

784

Therefore, patients requiring more than this amount in capsules should

usually receive divided doses

Hypersensitivity is the major adverse effect of concern to the

inten-sivist This may manifest itself solely as fever, but commonly includes

rash, eosinophilia, and elevated liver enzymes Adverse reactions to

phenytoin and other anticonvulsants have been reviewed elsewhere.70

Over the recent years, levetiracetam has become increasingly popular as

antiepileptic drug in the inpatient setting Levetiracetam was originally

approved in 1999 as add-on therapy for the treatment of partial-onset

seizures in adults; by now, labeled use additionally includes

myo-clonic, and/or primary generalized tonic-clonic seizures While the

precise mechanism of action is unknown, inhibition of

high-voltage-activated Ca2+ channels and enhanced activity of potassium channels

that maintain the resting membrane potential seem to be involved.71

Levetiracetam can be administered as infusion or as oral solution or

tablet Its half-life is 6 to 8 hours The bioavailability of levetiracetam

is not dependent on food, it does not affect the protein binding of

other drugs, and its distribution volume is close to that of total body

water.72 It is primarily metabolized by enzymatic hydrolysis, and renally

excreted Dose adjustment is needed in decreased renal function, and

approximately half of the drug is removed during hemodialysis, so that

extra dosing is required after dialysis.73,74 Furthermore, lack of hepatic

metabolism or interactions with other medications and few cardiac or

peripheral venous effects are advantageous to levetiracetam, especially

when compared with phenytoin.75 Its low incidence of serious adverse

reactions (as low as 1% for acute drug reactions76) and the lack of

drug-drug interactions make levetiracetam a safe medication in the elderly or

multimorbid patient population.77 Patients treated with levetiracetam

monotherapy in a neurological intensive care setting had lower

compli-cation rates78 when compared to other antiepileptic drugs When used

for prophylaxis after neurological injury, patients treated with

levetirace-tam had better outcomes at 3 months compared to patients treated with

phenytoin.79 Levetiracetam is found at least as effective as phenytoin in

the prevention of seizures after neurological injury or neurosurgery76,79,80

In the adult patient, effective doses of levetiracetam range from 500 to

3000 mg/d

Phenobarbital remains a useful anticonvulsant for those intolerant

to phenytoin or those who have persistent seizures after adequate

phe-nytoin administration The loading IV dose is 15 to 20 mg/kg, and the

target serum concentration is 20 to 40 µg/mL The serum concentration

may be altered by hepatic and renal dysfunction Furthermore,

pheno-barbital can also induce P450-related metabolism, thereby affecting the

metabolism of other drugs that undergo hepatic clearance Since the

usual clearance half-life of phenobarbital is about 96 hours, maintenance

doses of this agent should be given once a day A steady-state level takes

about 3 weeks to become established Sedation is the major adverse

effect; allergy to the drug occurs rarely

Carbamazepine is rarely initiated in the ICU because it is not available

in parenteral form and absorption from the gastrointestinal tract is

rela-tively slow Carbamazepine has significant interactions with many drugs

that are used in hospitalized patients, such as corticosteroids,

theophyl-line, warfarin, and cimetidine Adjusting blood levels of carbamazepine

in the setting of polypharmacy can be unpredictable Carbamazepine

and the newer anticonvulsant oxcarbazepine can both cause

hyponatre-mia with chronic use, probably due to a combination of the syndrome

of inappropriate secretion of antidiuretic hormone (SIADH) and

salt-wasting nephropathy

■ STATUS EPILEPTICUS

Status epilepticus is a medical emergency While proper diagnosis of the

cause is critical, the most important initial goal is to expeditiously stop

the clinical and electrographic seizures The likelihood of successfully

treating SE is inversely related to the duration of seizures; the longer

seizures last, the more difficult they are to terminate Administration of

antiepileptic drugs within 5 to 10 minutes has been shown essential to

limit the emergence of status epilepticus and related neuronal damage

and permanent cerebral injury,81 as well as further systemic tions Aggressive and rapid management is warranted, particularly when considering that only two-thirds of patients in SE respond to the first treatment.82

complica-The preferred agents used for first-line treatment of SE are azepines (especially lorazepam, diazepam, and midazolam), phenytoin, phenobarbital, levetiracetam, and valproate sodium The Veterans Affairs Status Epilepticus Cooperative Study Group trial compared four regimens for the initial treatment of GCSE and demonstrated that lorazepam was more efficacious than phenytoin, and easier to use than phenobarbital or phenytoin plus diazepam.82 Lorazepam has been our agent of first choice for terminating SE for many years and remains so with support from this study

benzodi-The major advantage of lorazepam over diazepam is its longer tion of action, thereby limiting seizure recurrence Lorazepam has traditionally been given in 2-mg doses repeated at 5-minute intervals

dura-if seizures do not terminate Since this is often an inadequate dose and valuable time passes before definitive treatment is instituted, we recom-mend instead a single IV dose of 0.1 mg/kg of lorazepam If lorazepam

is not available, a single IV dose of 0.15 mg/kg of diazepam is an tive However, another agent such as phenytoin or phenobarbital should

alterna-be started immediately, as the duration of action of diazepam against

SE is only about 20 minutes In the event that IV access is unattainable, 0.2 mg/kg of midazolam administered IM will be rapidly and reliably absorbed The use of midazolam in refractory SE will be discussed below All benzodiazepines carry a risk of hypotension and respiratory depression However, these are also sequelae of prolonged or inad-equately treated SE The intensivist should be prepared to intubate or use vasopressors if necessary

RAMPART, a recently published double-blind, randomized trial comparing intramuscular midazolam with intravenous lorazepam in the prehospital treatment of SE, found that intramuscular midazolam was at least equally safe as intravenous lorazepam, particularly regard-ing the need for endotracheal intubation Seizure termination was at least as effective with intramuscular midazolam, the time-to-treatment being significantly shorter for the intramuscular treatment likely playing

a significant role.83 Phenytoin is an effective anti-SE agent; however, the constraint on the rate of intravenous administration is of concern when treating SE Fosphenytoin may be a better drug for use in SE since it can

be loaded up to three times faster, although its 7-minute conversion life means that the serum phenytoin level does not reach its target much faster Phenytoin has a long duration of action when an adequate dose

half-is given (a 20-mg/kg dose produces a serum level above 20 mg/mL for

24 hours) Adding an additional 5 mg/kg if the initial load fails to stop

SE may be useful Intramuscular injection of fosphenytoin in SE patients may be supported by the known pharmacokinetics of this route, but it should not be considered to be acceptable therapy for SE and should be reserved for only those rare circumstances in which IV access cannot

2000 to 3000 mg daily maintenance dose The efficacy to abort SE has been found to be higher when loading with a bolus, and when initiated earlier during the course of SE.85 Several smaller series found intravenous leveti-racetam highly effective in patients with SE refractory to benzodiazepines

or other initial therapy.73,75Phenobarbital in the management of acute SE is not routinely rec-ommended, except when phenytoin is contraindicated However, the Veterans Affairs study showed no difference in efficacy between loraz-epam and phenobarbital as first-line agents in SE, but phenobarbital took longer to administer.82 Furthermore, in the patients that did not respond to lorazepam or phenytoin, the response rate to phenobarbital was only 2.1% (unpublished data) We therefore recommend pursuing a

CHAPTER 85: Seizures in the Intensive Care Unit 785

TABLE 85-3 Drugs for the Treatment of Refractory Status Epilepticus

Drug IV loading Dose Maintenance Dose Advantages Disadvantages

Ketamine 4-5 mg/kg over

2-4 minutes 1-5 mg/kg per hour Unlikely to cause hemodynamic instability Not well studied for status epilepticusMidazolam 0.2 mg/kg IV bolus 0.05-2 mg/kg per hour Fast onset of action Tachyphylaxis

Pentobarbital 5-12 mg/kg at 50 mg/min 1-10 mg/kg per hour Readily available Hypotension; immune suppression

Propofol 1-2 mg/kg IV bolus 1-15 mg/kg per hour Easy to adjust High lipid and calorie content; “propofol infusion syndrome” (metabolic acidosis, and

on occasion rhabdomyolysis, with doses greater than 5 mg/kg per hour)Thiopental sodium 75-125 mg IV bolus 1-5 mg/kg per hour Fast onset of action Can have prolonged effects after extended infusions due to absorption into adipose tissue

leukocytes The intensivist must be vigilant in monitoring for infection since barbiturate-induced poikilothermia may mask fever Despite these side effects, barbiturate anesthesia should not be rapidly discontinued

if it is successful in terminating refractory SE Continuing therapy for

at least 48 hours, gradual tapering of the infusion dose, and the istration of phenobarbital during the drug taper are recommended.93Pentobarbital is loaded at 5 to 12 mg/kg followed by an infusion of 1 to

admin-10 mg/kg per hour As an alternative, thiopental sodium may be given in 75- to 125-mg IV boluses followed by infusion rates of 1 to 5 mg/kg per hour Both medications rapidly redistribute into adipose tissue; recovery

of consciousness usually takes much longer after thiopental infusions than after pentobarbital Elimination times can be greatly increased in obese patients after prolonged infusions.90-100

The efficacy of alternative regimens needs further evaluation to define their role in the treatment of seizure emergencies While there are many case reports, no convincing evidence or randomized trials are available

to support early initiation of these interventions.6

In brain tumor patients with RSE, the use of phenytoin, levetiracetam, and pregabalin to abort RSE has been found safe and highly effective.102Lacosamide, a modulator of voltage-gated sodium channels,103 has also gained attention for the use in refractory SE It has been reported effective as an adjunct in refractory NCSE, especially focal SE104; how-ever, other series have not been able to confirm its efficacy in RSE.105

It is available intravenously, and is easy to administer.103 Common dosing is a loading dose of 200 to 300 mg IV, followed by 100 to 200 mg maintenance every 12 hours Success in the termination of RSE has also been reported for isoflurane, intravenous valproate, ketamine, and topiramate Ketamine in particular is often described, probably at least partly due to its lack of cardiosuppressive side effects, and its potential neuroprotective capacity given its structure as NMDA antagonist.106Emerging insight into antibody-induced seizures and SE, mainly NMDA-receptor antibodies, has also triggered exploration of emergency treatment of SE with immunosuppressants in selected cases, with high dose methylprednisolone and/or intravenous immunoglobulin.106The application of therapeutic hypothermia, the use of which in RSE has anecdotally been reported successful,107 lacks data on a larger scale Once SE is addressed, one must manage the major systemic complica-tions of SE Patients with GCSE should be screened for rhabdomyolysis with urine myoglobin and serum creatin kinase (CK) determination

If myoglobinuria is present or if the CK concentration is more than

10 times the upper limit of normal, rehydration and urinary tion should be instituted.81 Prolonged or severe hyperthermia should be aggressively treated with cooling blankets, ice packs, or other cooling modalities

alkaliniza-■ SPECIAL CONSIDERATIONS FOR CHILDREN

Treatment of seizures or SE in critically ill children generally parallels that for adults Intravenous access is often more difficult to achieve in children Lorazepam and diazepam can both be administered by the rec-

tal route (usually 0.5 mg/kg per rectum for both agents) and midazolam

(0.2 mg/kg) via the IM, nasal, or buccal routes Lorazepam is probably the first-line drug of choice for terminating SE in children as for adults

more definitive treatment strategy for patients who have entered

refrac-tory SE (RSE)

■ REFRACTORY STATUS EPILEPTICUS

Refractory status epilepticus evolves in 31% to 44% of patients in

SE.86 Failure of a first-line anticonvulsant drug to terminate SE usually

requires the use of a definitive therapy in anesthetic doses that are highly

likely to cause significant respiratory suppression and hypotension

Therefore, mechanical ventilation is necessary, and invasive

hemody-namic monitoring is frequently required Concomitant continuous EEG

monitoring is also mandatory to confirm treatment success and monitor

depth of sedation The traditional goal of therapy is burst-suppression

pattern on EEG for 12 to 24 hours prior to any attempts to wean

medi-cation Since the available data suggest that successful treatment and

improved outcome probably required seizure suppression regardless of

background EEG activity,87 we recommend cessation of electrographic

seizures as the goal instead

The agents used most frequently include propofol, midazolam, and

barbiturates.88 Propofol is an intravenous anesthetic agent that acts

primarily on the GABAA receptor Smaller series and case reports

documenting its efficacy in RSE are abundant,89 but studies examining

direct comparisons with other agents have had mixed results.90-92 An

initial bolus of 1 to 2 mg/kg should be followed with a maintenance

infusion at 1 to 15 mg/kg per hour Propofol is fast acting, highly lipid

soluble, and has little propensity to accumulate even with prolonged

infusions.93 Because of its rapid clearance, propofol should not be

abruptly discontinued, but instead tapered gradually Respiratory

depression and hypotension are extremely common, especially after

the initial bolus Nutritional support must be adjusted in the setting of

propofol infusion due to the high lipid and calorie content of the

solu-tion Acidosis and rhabdomyolysis have been reported in both adults94

and children.95 Careful monitoring of creatine kinase and blood pH

are prudent

Midazolam is a water-soluble benzodiazepine that has demonstrated

high efficacy in refractory SE in adults and children.96-98 Midazolam is

loaded at 0.2 mg/kg followed by continuous infusion of 0.05 to 2.0 mg/kg

per hour Respiratory depression may be encountered less frequently

than with other hypnosedatives, but should be anticipated Since most

patients with RSE are already intubated, concern for respiratory effects

should not limit use Clinically significant hypotension is rare even at

the very high doses that are often required to address tachyphylaxis.99

Sedation is quickly reversed after short-term infusions are discontinued

However, terminal half-lives of three to eight times normal have

been reported with extended administration.100 In addition, prolonged

elimination times have been associated with critical illness and

hepa-torenal dysfunction High-dose barbiturates, most commonly

pentobar-bital, are extremely useful in RSE when used as third-line therapeutic

choice,101 but side effects can be severe and may limit use (Table 85-3)

Hypotension can be refractory to initial resuscitative efforts, and the

patient may benefit from pulmonary artery catheterization to plan fluid

and vasopressor management Pulmonary infection is common due to

prolonged intubation and impaired function of both respiratory cilia and

PART 6: Neurologic Disorders

786

One study of 86 children presenting with seizure found that those who

received lorazepam had a higher incidence of termination of seizure

activity and less frequent respiratory depression than those treated with

diazepam.108

Midazolam administered by continuous infusion appears effective

in RSE in children.97,109,110 Although all eight patients in one study were

mechanically ventilated, none demonstrated cardiovascular instability

despite midazolam doses resulting in burst suppression.108

As with adults, rapid control of SE in children achieved with

benzodi-azepines should be followed by administration of a longer-acting agent

such as phenytoin (20 mg/kg IV), fosphenytoin (20 mg PE/kg IV), or

phe-nobarbital (10-20 mg/kg IV).111 The rate of conversion of fosphenytoin

to phenytoin is probably the same in children as in adults Intramuscular

injection of fosphenytoin may be particularly advantageous for

preven-tion of recurrent seizures in children without IV access The use of IV

fosphenytoin over IV phenytoin is prudent in infants and neonates,

whose small limbs are at especially high risk of extensive necrosis and

amputation in the event of a phenytoin extravasation

Similarly to the treatment of seizures and SE in adults, there is

growing evidence to support the use of levetiracetam In the neonatal

period, intravenous levetiracetam has been found useful and safe as

monotherapy or as an adjunct in acute seizure management.112 When

administered within half an hour of seizure onset in children at a dose of

29.4 ± 13.5 mg/kg, 89% of patients were seizure free at 1 hour.113 When

given with a bolus dose of 25 to 50 mg/kg followed by maintenance as

adjunct or monotherapy for status epilepticus or exacerbation of seizure

disorder, response rates were as well favorable.114

Intravenous valproate appears to be safe and effective in children.115

Several retrospective and prospective series have reported seizure

ter-mination after infusion of valproate in loading doses between 25 and

30 mg/kg, with response rates between 65% and 100% and without

occurrence of serious adverse events.115-117

• Towne AR, Waterhouse EJ, Boggs JG, et al Prevalence of

non-convulsive status epilepticus in comatose patients Neurology

2000;54:340-345

• Waterhouse EJ, Vaughan JK, Barnes TY, et al Synergistic effect of

status epilepticus and ischemic brain injury on mortality Epilepsy Res 1998;29:175-183.

KEY REFERENCES

• Bleck TP Status epilepticus and the use of continuous

electroen-cephalographic monitoring in the intensive care unit Continuum

Neurology 2012;18:560-578.

• Brophy GM, Bell R, Claasen J, et al Guidelines for the evaluation

and management of status epilepticus Neurocritical Care 2012;16.

• Fountain NB, Lothman EW Pathophysiology of status epilepticus

J Clin Neurophysiol 1995;12:326-342.

• Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ Continuous

electroencephalography in the medical intensive care unit Crit

Care Med 2009;37:2051-2056.

• Sharma V, Katznelson R, Jerath A, et al The association between

tranexamic acid and convulsive seizures after cardiac

sur-gery: a multivariate analysis in 11 529 patients Anaesthesia

2014;69(2):124-130

• Shneker BF, Fountain NB Assessment of acute morbidity

and mortality in nonconvulsive status epilepticus Neurology

2003;61:1066-1073

• Shorvon S Super-refractory status epilepticus: an approach to

therapy in this difficult clinical situation Epilepsia 2011;52(suppl

8):53-56

• Silbergleit R, Durkalski V, Lowenstein D, et al Intramuscular

versus intravenous therapy for prehospital status epilepticus

N Engl J Med 2012;366:591-600.

• Swisher CB, Doreswamy M, Gingrich KJ, Vredenburgh JJ, Kolls

BJ Phenytoin, levetiracetam, and pregabalin in the acute

manage-ment of refractory status epilepticus in patients with brain tumors

Geraldine Siena L Mariano Matthew E Fink

Caitlin Hoffman Axel Rosengart

KEY POINTS

• To gain an understanding of the mechanisms and anticipatory agement of brain tissue displacement (herniation) and intracranial hypertension

• To understand available brain monitoring devices in measuring ICP and to appreciate their role in guiding early interventions to avoid secondary brain injury as hesitation to monitor intracranial pressure dynamics, and to aggressively pursue ICP management likely accounts for the vast majority of secondary brain injury in patients with reduced level of consciousness

• To foster an individualized patient approach in addressing mal ICP and flow dynamics within the practice of neurocritical care Understanding the indications for brain monitoring via real-time parenchymal blood flow, oxygen tension, and chemistry surveillance, as well as mastering the current recommendations

abnor-in aggressive management approaches toward elevated ICP such

as induced hypothermia, suppression of abnormal electrical charges, and early surgical decompression are necessary tools for the neurocritical care clinician

dis-CONSIDERATION OF CEREBRAL PRESSURE AND FLOW DYNAMICS

■ COMPARTMENTS AND MONRO-KELLIE DOCTRINE

In adults, the cranial vault represents a closed, noncompliant structure

Two important exceptions exist in which intracranial compliance is increased These are at the foramen magnum and craniectomy sites Craniectomy refers to surgical bone removal to treat refractory intra-cranial hypertension or as a by-product of neurosurgical decompression for an alternate indication This removal of bone leaves a palpable, soft, cranial defect covered only by dura, galea, and skin The brain is distin-guished from other organs by the unique challenge of monitoring brain function and intracranial dynamics in a structure enclosed by a bony vault The noncompliant surrounding bone of the calvarium does not allow for significant volume change of the brain or adjustment of intra-

cranial pressure (ICP) (Fig 86-1A) As a result, the pressure within the

CHAPTER 86: Intracranial Pressure: Monitoring and Management 787

Falx cerebri

PCA

ACATentorium

cerebelli

A

FIGURE 86-1 A Anatomical relationship of key intracranial structures The two hemispheres within the supratentorial compartment are separated and stabilized by rigid dura duplications,

known as the falx and the tentorium, respectively These structures become clinically important in the setting of brain herniations; for example, as a late complication of subfalcine herniation the anterior cerebral artery (ACA) is compressed against the free edge of the falx, leading to ACA infarction Whereas in lateral or descending transtentorial herniation, the posterior cerebral artery

(PCA) is displaced inferiorly over the free edge of the tentorium, leading to herniation-induced occipital lobe infarction B Tentorial opening and its contents The tentorial opening that separated

the supratentorial from the infratentorial space consists of the midbrain and important structures, that is, circle of Willis and cranial nerves Due to the location of the oculomotor nerve, it is the most commonly affected nerve secondary to herniation of the medial temporal lobe and aneurysm of the posterior communicating artery

Optic nerve

PosteriorcommunicatingarteryOculomotornerve

Tentoriumcerebelli

Superiorcerebralartery

Posteriorcerebralartery

Petroclinoidligament

Internalcarotidartery

Anteriorcerebralartery

B

fixed space of the calvarium must be carefully regulated by many

mecha-nisms in order to be maintained within a physiologic range Disruption

of these mechanisms through trauma, space-occupying lesions, or

edema leads to dysregulation of the delicate balance required to

main-tain normal pressure that results in significant neurologic and systemic

dysfunction For instance, the tentorial opening, which separates the

supratentorial and infratentorial compartments, encloses, among other

structures, the midbrain, posterior cerebral arteries, posterior

commu-nicating arteries, oculomotor, and sixth cranial nerves These structures

are frequently damaged during transtentorial herniation, leading to a

chain of often irreversible, secondary injuries (Fig 86-1B).

The structures between the brain surface and the inner skull, the meningeal layers, are important in identifying and maintaining normal ICP The most important of these is the subarachnoid space where the arachnoid villi conduct cerebrospinal fluid (CSF) from the subarachnoid space to the venous sinuses If these granulations are blocked by inflammatory substances or disintegrated blood, nonob-structive hydrocephalus and increased ICP can result due to impaired CSF reabsorption Other meningeal components are the subdural and epidural spaces where bleeding may occur, requiring immediate atten-tion due to potential space-occupying lesions between these layers

(Fig 86-2).

PART 6: Neurologic Disorders

788

Duramater

Pia mater

SkullSkinSubdural

Brain

FIGURE 86-2 Meningeal layers The cerebrospinal fluid compartments located between the brain surface and inner skull are clinically described as subarachnoid, subdural, and (functionally

nonexisting) epidural spaces Arachnoid villi within the subarachnoid space have the important role of continuous CSF absorption and, if obstructed due to infection or disintegrated blood

prod-ucts, communicating hydrocephalus and eventually elevated intracranial pressure will occur The subdural and epidural spaces are important in that blood and fluid may track into and expand

these potential spaces in the setting of trauma or ruptured vascular malformations

The average volume within the cranium is 1500 mL, with ~88%

con-sisting of brain parenchyma, ~7.5% composed of intracranial blood,

and ~4.5% composed of CSF.1 The sum of the partial pressures and

volumes from these three main components is equal to the total ICP

Therefore, when one volume increases (eg, intraparenchymal brain

tumor), the other volumes compensate for the pressure change and

reduce their combined intracranial volumes to keep ICP constant

This is known as the Monro-Kellie doctrine Frequent mechanisms

responsible for maintaining a normal ICP (ie, <20 mm Hg) are a

compensatory increase in CSF absorption, drainage of blood from the

cerebral venous systems, and a shift of CSF from the cranial

subarach-noid space into the spinal (intraforaminal) compartment Because of

skull noncompliance, any uncompensated changes in the volume have

a significant impact on ICP and brain function If untreated, sustained

elevations in ICP may lead to compression of critical structures,

vascular compromise with impaired cerebral perfusion, irreversible

ischemia, and brain death

■ INTRACRANIAL PRESSURE

The first ICP measurements were performed by Guillaume and Janny

in 1951, but it was the seminal work of Nils Lundberg in 1960 who

established intraventricular ICP monitoring using bedside strain gauge

manometers to describe three ICP waveform patterns (A, B, C)

associ-ated with intracranial pathology Of particular importance, the A-wave

(or plateau wave) is observed with ICP increases between 25 and

75 mm Hg persisting for up to 20 to 25 minutes if left untreated The

rationale behind the study of ICP waveform and amplitude is that with

each heartbeat there is a pulsatile increase in cerebral blood volume, the

equivalent of a small intracranial volume injection, and the amplitude

of the ICP pulse waveform is the response of ICP to that increment of volume The properties of ICP wave should therefore be directly related

to the craniospinal elastance.2There is no level I evidence to support the use of a single ICP threshold to initiate therapy The recommended critical ICP elevation

in adults at which treatment should be initiated (Level II evidence) is

20 mm Hg sustained for more than 5 minutes.3 Failure of tory brain mechanisms to reduce ICP to normal values will result in intracranial hypertension and its clinical sequelae Common etiologies

compensa-for primary and secondary ICP elevations are listed in Table 86-1

Numerous studies have demonstrated that elevated ICP is ated with poor outcome and, therefore, that ICP control and pressure monitoring are among the key approaches to successful management of brain-injured patients.4-6 Too often, a general “cookbook” ICP manage-ment approach, without an understanding of the natural progression

associ-of the underlying injury and without real-time measurements associ-of ICP,

is applied leading to secondary brain injuries, which can exceed the magnitude of primary injury A primary focus of neurocritical care, therefore, is to minimize secondary injuries Examples of cases requir-ing continuous ICP monitoring are patients with large ischemic strokes and associated evolving edema; severe meningoencephalitis with gener-alized edema and hydrocephalus; and intracranial hematomas exerting local mass effect These patients may require prolonged ICP monitoring

in order to detect delayed cerebral edema or worsening primary injury

Another example of patients in need of invasive ICP monitoring are traumatic injuries, which may exhibit an otherwise undetected bimodal pattern of ICP elevations, or patients suffering from subarachnoid hemorrhage (SAH) who may develop ICP elevations due to unde-tected obstructive hydrocephalus or vasogenic edema secondary to vasospasm-induced ischemia

CHAPTER 86: Intracranial Pressure: Monitoring and Management 789

200

Simultaneous ECGArterial pressure

TABLE 86-2 Factors That Influence Cerebral Blood Flow and Intracranial Pressure

Factor Cerebral Blood Flow Intracranial Pressure Effect Clinical Commentary

Raised intracranial pressure Decrease NA – Cerebral injury occurs through ischemia and mechanical compression

Increased intrathoracic pressure Decrease Increase Cerebral venous outflow attenuation Valsalva maneuver

Volatile anesthetics Increase Increase Vasodilatation Additive ICP increases with head down positioning during anesthesiaSeizures Increase Increase Increased metabolism and Valsalva Maintain low threshold for prophylactic antiepileptic drugs in ICP

susceptible patientsPositive end- expiratory pressure (PEEP) Increase Increase Decrease in cerebral venous outflow Variable effect on intracranial pressure (Caution: PEEP of >12)

Common factors affecting cerebral blood flow and intracranial pressure

When ICP is monitored continuously, the tracing has a ballistic

waveform similar to systemic arterial pressure (Fig 86-3) The “pulse

pressure” of ICP, however, is much narrower and is expressed, by

con-vention, as a mean The normal mean ICP is generally below 15 mm Hg,

with an upper range at about 20 mm Hg, but its value will fluctuate in

normal individuals depending on many physiologic factors such as head

positioning, Valsalva maneuver, breathing pattern, etc (see Table 86-2).

■ INTRACRANIAL COMPLIANCE

A schematic diagram delineating the tight relationship between ICP

and intracranial volume is depicted in Figure 86-4 Intracranial

com-pliance is the association between changes in intracranial volume

TABLE 86-1 Causes of Elevated Intracranial Pressure

Primary (Intracranial) Secondary (Extracranial)

Nontraumatic

Intracranial hemorrhages (parenchymal,

subarachnoid, subdural, epidural)

Mass lesion (ie, epidural or subdural

hematomas, hemorrhagic contusions)

Hydrocephalus

Diffuse brain edema

Depressed skull fracture

Airway obstructionHypoventilationHypoxiaHypercarbiaHead position or postureVenous outflow obstructionHyperpyrexia

HyponatremiaAgitation, painDiabetic ketoacidosisEclampsia or hypertensive encephalopathyConvulsive or nonconvulsive seizureIncreased intrathoracic or intra-abdominal pressure (ie, Valsalva maneuvers, mechanical ventilation)

Fulminant hepatic encephalopathyHigh-altitude cerebral edemaDrugs (lead, tetracycline, doxycycline, retinoic acid)

Common etiologies that instigate elevated intracranial pressure are listed as primary and secondary causes above.

and expected changes in pressure, while the reciprocal is defined

as elastance—a change in pressure leading to a change in volume Intracranial compliance, although not measured directly in absolute numbers, is an important and frequently utilized clinical concept that can be readily estimated in an ICP-monitored patient Compliance describes the fact that a disease process that increases or displaces the volume of a component of the intracranial cavity will first be com-pensated for by a decrease in the least resistant compartment—the subarachnoid CSF spaces, which are contiguous over the convexities and within the cisterns and ventricles As a result, ICP may increase only minimally while a reserve for intracranial compliance exists dur-ing the early stages of the disease process The ICP waveform (but not its mean pressure) may already indicate a decline in brain compensa-

tory mechanisms, however (Fig 86-4B) Once CSF cannot be passively

displaced any further, the ICP rises more sharply as the reserve for

compliance decreases (Fig 86-4C) At this point, blood vessels begin

to provide an element of compliance, and will compensate for ICP

PART 6: Neurologic Disorders

ΔP = Elastance

= Compliance

ΔP

B C

ΔP ΔV

FIGURE 86-4 Intracranial compliance This curve represents the compliance function of

the brain With added volume, the intracranial compartment initially shows good

compen-satory reserve identified by normal ICP (A) Additional volume increases are still tolerated

(ie, high-normal ICP readings) but further reducing the compensatory reserve (B; worsening

compliance) At a critical point, compensation of intracranial compliance diminishes

exponentially (C; exhausted compensatory reserve), leading to abrupt ICP elevations

increases by extruding blood out of the intracranial space First, the less resistant cerebral venous system reduces its blood volume, and then the circulation within the arterial tree is reduced Lastly, brain parenchyma will follow by shifting along the ICP gradient within the cranial vault and away from the space-occupying lesion This is described as brain herniation Herniation syndromes can be distinguished clinically and radiographically depending on which vector the ICP gradient contin-ues to evolve, that is, from one to the opposite hemisphere or along the craniocaudal cerebrospinal axis

The important concepts of ICP-volume relationships and cranial compliance can be applied to the radiographic estimation of the likelihood of intracranial hypertension from a space-occupying intracranial process to determine the indication for invasive pres-

intra-sure monitoring For example, Figure 86-5A and B show a brain CT

scan identifying vasogenic edema from a right middle cerebral artery (MCA) territory infarction As there are still compressible spaces visible around the swollen brain (eg, basal cisterns, ipsilateral lateral ventricle, and ipsilateral cortical sulci), it is reasonable to expect that the ICP is not yet significantly or persistently elevated In contrast, the CT

in Figure 86-5C and D shows a more extensively swollen hemisphere than Figure 86-5A, with obliteration of all surrounding CSF spaces

The ICP is therefore predicted to be markedly elevated While ing the likelihood of intracranial hypertension by radiographic appear-ance is imperfect, it can provide some practically useful guidance in management decisions when the clinician is forced to initiate invasive

E

A-B20

torr

VolumeC-D

FIGURE 86-5 Neuroimaging and intracranial compliance Head imaging does not replace ICP monitoring; however, some estimates of intracranial compliance can be obtained The head CT

(A and B taken at 48 hours postevent) identifies right middle cerebral artery ischemic infarction with local mass effects; however, there are remaining compressible CSF spaces (ventricular system,

basal cisterns) visible indicating reduced but not exhausted intracranial compliance With further mass effects and tissue shift (C and D; CT taken at about 96 hours) almost complete compression

of neighboring CSF spaces and exhausted intracranial compliance is identified in addition to evolving herniation-induced (right to left subfalcine herniation) led to new right anterior cerebral

artery infarction (arrowhead in D) The estimated, relative intracranial compliance for the obtained head CT scans is delineated on the graph below (E).

CHAPTER 86: Intracranial Pressure: Monitoring and Management 791

ICP monitoring or to consider other therapeutic maneuvers such as

surgical decompression

■ CEREBRAL BLOOD FLOW AND CEREBRAL PERFUSION PRESSURE

To appreciate the progressive detriment of elevated ICP, it is essential

to understand the factors involved in determining and controlling

cerebral blood flow (CBF) Neglecting, for a moment, that cerebral

arteries are rather flexible conduits, CBF could be compared to

elec-tric current through a wire Ohm described that this current (I) is

proportional to the difference in the potential (ΔV) placed across

the ends of a wire and proportionally constant to the resistance (R) the

current faces while traveling through the wire That is, current =

potential difference/resistance (I = ΔV/R) or (ΔV = IR) Written

in flow dynamic terms, CBF depends on the perfusion pressure

(CPP) divided by the vascular resistance (CVR) or CBF = CPP/CVR

As CPP is calculated by the difference between the mean arterial

pressure (MAP) and the ICP, this equation can be rewritten as CBF =

MAP − ICP/CVR CVR is governed by precapillary, brain

penetrat-ing arterioles and is tightly regulated by pressure autoregulation in a

normal patient to provide a steady CBF with normal MAP

fluctua-tions Autoregulation is a function of vasoactive mediators between

neighboring vascular endothelial cells, adjacent smooth muscle, and

perivascular nerves.7,8 Dynamic increases in ICP can also be

esti-mated at the bedside by elevated blood flow velocities and pulsatility

indices as seen on transcranial Doppler (TCD) CVR changes can be

exhausted, however, leading to complete absence of flow if increased

ICP becomes intractable (Fig 86-6).

Alterations in CBF and CVR can disturb autoregulation

homeo-stasis, leading to primary and secondary cerebral injury A graphical

Steep partmildly elevated

PI = ~0.9-1.19

Flat partnormal

PI = 0.5-0.9

Normal

Volume

Decreasing diastole Systolic peaks

Cerebral circulatory arrest

vascular bed, which eventually leads to circulatory arrest (right column) Characteristic TCD flow velocity waveform changes with increasing PI are represented above the graph TCD is a helpful

and readily available bedside technology to monitor intracranial compliance

depiction of CBF remaining constant over a wide range of arterial blood pressures, at least in the normotensive noninjured brain, is presented in

Fig 86-7 In chronically hypertensive individuals, the autoregulatory

threshold is shifted to the right Relative blood pressure lowering within the autoregulatory range will be compensated by cerebral vasodilation and a resultant increase in cerebral blood volume (CBV) Conversely, relative blood pressure elevations within an individual’s autoregulatory range leads to cerebral vasoconstriction and a subsequent decrease in cerebral blood volume The physiologic relationship between blood pressure, CBF, CPP, and CVR is unpredictable in damaged brain regions with impaired autoregulation Both ischemia (regionally due to arterial occlusion or globally as in ischemic encephalopathy following cardiac arrest) and CBV dysregulation (eg, hyperemia) are critical determinants

of ICP, especially in the noncompliant, autoregulatory-paralyzed brain already exposed to elevated ICPs from the primary injury This practical understanding of cerebral hemodynamics, and the concept that CBF in the injured brain is almost entirely dependent on MAP, is critical for the development of a rational therapeutic plan for patients with brain injury and intracranial hypertension

Regional CBF normally averages 50 to 60 mL/100 g/min, about 15% of the cardiac output (about 700 mL/min) Assuming normal cellular meta-bolic rate, increased oxygen extraction from the blood compensates for reduced CBF until CBF reaches 50% of its baseline value, when the first clinical and electroencephalographic (EEG) manifestations of hypoperfu-sion appear Impairment of cortical activity becomes more marked at 16

to 18 mL/100 g/min with loss of neurotransmission due to Na-K pump failure Cytotoxic edema then occurs at 10 to 12 mL/100 g/min At ranges

of 6 to 10 mL/100 g/min, progression to calcium and glutamate-dependent cell death is imminent Importantly, the ischemic threshold depends on both the regional CBF and duration of cellular hypoxia secondary to this

PART 6: Neurologic Disorders

4.0

FIGURE 86-7 Autoregulatory curve With intact cerebral autoregulation the cerebral blood flow is maintained constant over a wide range of cerebral perfusion pressures (50-150 mm Hg;

solid red line) Outside of this pressure range, cerebral arterioles collapse at very low CPP or at very high pressures abnormally (breakthrough) constricts Abnormal autoregulation, commonly

present in injured brain, is the complete dependence of cerebral perfusion on systemic arterial pressures, an abnormality that has important consequences on intracranial pressure

decreased blood flow For example, a CBF of 18 to 23 mL/100 g/min can

be tolerated for 2 weeks, as opposed to 10 to 12 mL/100 g/min for 3 hours

and 8 mL/100 g/min for only 1 hour before neuronal death ensues

In addition to autoregulatory cerebral vascular failure, the injured

brain also suffers from uncoupling of cerebral metabolism In normal

brain, cerebral metabolic demand and regional blood flow fluctuate in a

proportional manner Neural activation leads to increased cerebral

met-abolic activity, which increases the demand for glucose and oxygen and

is met by local increases in CBF This phenomenon is called metabolic

autoregulation, with the interaction between metabolic fluctuation and

alterations in ICP intimately intertwined at the precapillary level The

close coupling between metabolic supply and demand can be monitored

and clinically applied to managing brain-injured patients by correlating

cerebral metabolic rate of oxygen consumption (CMRO2) and the

arte-riovenous difference in oxygen saturation (AVDO2) as expressed by the

Fick equation: CMRO2 = CBF × AVDO2 or AVDO2 = CMRO2/CBF In

healthy brain parenchyma, AVDO2 is constant, and changes in demand

are met by changes in CBF by adjusting local CVR In the traumatized

brain, however, mismatch of supply and demand in the face of

preexist-ing abnormal pressure autoregulation can lead to AVDO2 that may be

either higher or lower than necessary

Under physiologic conditions, a MAP of 80 to 100 mm Hg and an ICP

of 5 to 10 mm Hg can lead to a CPP of 70 to 85 mm Hg.9 However, the

true regional CPP may vary by as much as 27 mm Hg from

measure-ments utilizing global MAP and ICP values.8 Obtaining accurate MAP

measurements for CPP determination requires the placement of an

arte-rial pressure catheter, with its transducer at the level of the foramen of

Monro, which approximates to the level of external auditory meatus (see

Fig 86-8) The ICP should be measured in units of mm Hg to accurately

calculate CPP In the normal brain, CBF is constant as long as the MAP

is maintained between 50 and 150 mm Hg The local regulation of

arte-rial vascular resistance is affected by CO2, O2, pH/lactate levels,

adenos-ine, nitric oxide, and other components Neurogenic regulation of the

cerebral arterial tone is also regulated by sympathetic input leading to mild tonic vasoconstriction and allowing for higher limits to be reached

on the regulation curve.7Clinically important factors that influence CBF and ICP are pre-

sented in Table 86-2 Control of these factors constitutes the basis for

much of the medical management of raised ICP in brain injury For example, CVR changes linearly within a PaCO2 range between 20 and

80 mm Hg As a result, PaCO2 and its manipulation have a dramatic effect on CBF and ICP even when CPP is held constant by alterations

in MAP As an example, inhalation of low CO2 concentrations 7%) can double CBF through changes in extracellular pH that lead to vasodilation of cerebral vasculature and a resultant increase in ICP To the contrary, low CO2 created by hyperventilation results in vasocon-striction and lowered ICP and can ultimately result in brain ischemia due to prolonged vasoconstriction Changes in PaO2 also affect CBF when values fall to less than ~50 mm Hg, which is demonstrated

below 40, autoregulation fails and blood vessels collapse (Fig 86-7),

lowering both intracranial blood volume and CBF Conversely, CPP sustained above 110 mm Hg overcomes mechanisms of autoregulation and hyperperfuses the brain due to passive, irreversible dilation of arte-rioles with resultant elevation in brain swelling and ICP Maintenance

CHAPTER 86: Intracranial Pressure: Monitoring and Management 793

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EAMForamen of Monro

Drain pressure

Drainage portDrainage tube clamp

Pressure scalesCollection bagOne-way stopcockDrip chamberZero reference

PART 6: Neurologic Disorders

794

of CPP within a targeted range of 50 to 70 mm Hg can therefore be an

important therapeutic strategy in providing a margin of “reserve” with

which the brain can compensate for challenges of normal perfusion via

fluctuations in ICP or MAP

As pressure autoregulation and microcirculatory homeostasis may

be severely disrupted in the brain-injured patient, ischemia can result

even in the presence of adequate ICP and CPP Adjusting the target CPP

in a particular patient based on the clinical situation, the underlying

etiology of brain injury and the vasoreactive state is therefore necessary

Some studies support the concept of CPP targeting based on cerebral

vasoreactivity monitoring.11,12 In addition, improved tools for ICP

mea-surements (ie, via minimal invasive intraparenchymal devices) with

continuous CPP determinations and the ability to correlate additional

brain monitoring parameters such as cerebral blood flow, oxygenation,

and chemical profiling allow multimodal, real-time pathophysiologic

analysis of brain injury at the bedside

■ PLATEAU WAVES

One of the most feared complications of intracranial hypertension and

poor intracranial compliance is the development of plateau waves (PW)

(Fig 86-4) These waves are associated with acute elevations in ICP

ranging from 50 to 100 mm Hg They typically occur in patients with

reduced intracranial compliance discussed later Plateau waves can last

from several minutes to more extended durations in severe cases and

are rapid in onset and offset While there are many causes of PW, one

important and common mechanism is generalized cerebral vasodilation

from an uncontrolled autoregulatory response to a decrease in systemic

blood pressure.13 Other causes include processes that increase CBF and

CBV (Table 86-2) Since compromised CPP can play an important role

in the occurrence of the most severe PW, relative CPP drops should be

avoided and/or rapidly treated Similarly, during a PW, maneuvers that

aim to correct CPP toward the target range, such as swift blood pressure

augmentation, will potentially abort the PW in many circumstances

Even if blood pressure augmentation does not abort the process, it will

likely reduce cerebral ischemia until other treatment modalities can

suc-cessfully lower the uncontrolled ICP

CEREBRAL EDEMA, MASS EFFECT, BRAIN HERNIATION

■ CEREBRAL EDEMA AND MASS EFFECT

Cerebral edema is an increase in tissue water content within and or

around brain cells Patients with acute brain injuries invariably present

with different degrees of edema as a result of different mechanisms of

intra-and extraaxial injury The consequences of uncontrolled edema

range from cerebral ischemia to mechanical compression of brain

tissue Initially, edema affects a regional area and can progress to

compartmental parenchymal shifts in response to trajectories of ing pressure differentials The end result of untreated, progressive brain edema is herniation and ultimately brain death Despite the obvious clinical importance of cerebral edema, the precise mechanisms of water transport and accumulation of excess water within the brain remain unclear A series of recent studies on cerebral edema focused on the glial water protein channel aquaporin-4 (AQP4), among others, such as AQP1 and AQP9, that have been shown to facilitate astrocyte swelling (“cytotoxic edema”) and also to be responsible for the reabsorption

increas-of extracellular edema fluid (“vasogenic edema”) Therefore, AQP4 modulation via pharmacologic interventions has become an interesting potential therapeutic approach.14-16 AQP4 knock-out, or disruption of its polarized expression pattern, mitigates brain water accumulation and therefore decreases associated ischemia, water intoxication, and hypona-tremia in animal models.17

The most common types of cerebral edema are cytotoxic edema from cellular injury and swelling, and vasogenic edema from breakdown

of the blood-brain barrier and interstitial fluid extravasation Other types, such as hydrocephalic edema, ischemic edema (a combination

of cytotoxic and vasogenic edema), osmotic edema, and hydrostatic

or interstitial edema have also been characterized as distinct entities based on their underlying mechanisms and the predominant location

of fluid.18-20 Table 86-3 lists the categories of cerebral edema along with

their distinguishing characteristics Clinically, vasogenic and cytotoxic edema are most frequently encountered Disruption of the blood-brain barrier results in plasma-derived, protein-rich exudate accumulating in the extracellular white matter, constituting vasogenic edema Despite the commonly encountered severity of vasogenic edema, CBF is often unaffected and cellular mechanisms remain intact Among the disease entities with predominant but variable degrees of vasogenic edema are

brain tumors (Fig 86-10), abscesses, traumatic brain injury, and

menin-gitis Corticosteroids play a primary role in reducing this type of edema, and their effect is most profound when vasogenicity is the primary etiology, as with brain tumors, and to a lesser degree with abscesses.21

In comparison, osmotic agents have little beneficial effect on vasogenic edema.18 Cytotoxic edema, in contrast, is characterized by intracellular swelling of neurons, glia, and endothelial cells with an accompanying reduction in the extracellular space It occurs without disruption of the blood-brain barrier, and is primarily due to cellular energy depletion, which results in failure of the ATP-dependent sodium pump and accu-mulation of sodium and water within cells.18 Cytotoxic edema can occur

in both gray and white matter Hypoperfusion (ischemic) injuries are most classically associated with cytotoxic edema While edema in TBI was thought to be vasogenic in origin, clinical and experimental studies indicate that cytotoxic edema predominates following TBI.22-24 This may explain why drugs that attenuate vasogenic brain edema (eg, corticoste-roids) are only beneficial in certain conditions (eg, tumors) but not in

TABLE 86-3 Classification of Cerebral Edema

Vasogenic Cytotoxic Ischemic Hydrostatic Hydrocephalic (Interstitial) Osmotic

Pathophysiologic

mechanism Increased vascular permeability Cellular failure Anoxia/hypoxia Increased blood pressure Impaired CSF outflow or absorption Relative plasma hypoosmolarity

extracellular

extracellular

periventricular white matter)

White and gray

Disorders (examples) Primary or metastatic brain

tumor, Inflammation

Cerebrovascular disorders, fulminant hepatic failure, disequilibrium syndrome

Hypoxic-anoxic encephalopathy

Dysautoregulatory responsePosterior reversibleedema syndrome (PRES)

Obstructive hydrocephalus Myelinolysis

BBB, blood-brain barrier; CSF, cerebrospinal fluid; gray, gray matter; white, white matter

Common categories of cerebral edema divided into cytotoxic and vasogenic edema as well as other, anatomically defined edema forms