Continuing Medical Education Article

Approach to the comatose patient

Robert D. Stevens, MD; Anish Bhardwaj, MD, FCCM

LEARNING OBJECTIVES

On completion of this article, the reader should be able to:

1. Describe changes in the level of consciousness.
2. Identify the indicators of prognosis in comatose patients.
3. Use this information in a clinical setting.
Dr. Stevens has disclosed that he is the recipient of direct grant/research funds from the National Institutes of Health, Public
Health Service; Dr. Bhardwaj has disclosed that he was the recipient of direct grant/research funds from the American Heart
Association and that he is/was the recipient of grant/research funds from the National Institutes of Health, Public Health
Service.
Wolters Kluwer Health has identified and resolved all faculty conflicts of interests regarding this educational activity.
Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information in obtaining continuing medical education
credit.

Background: Coma is a medical emergency and may constitute

a diagnostic and therapeutic challenge for the intensivist.
Objective: To review currently available data on the etiology,
diagnosis, and outcome of coma. To propose an evidence-based
approach for the clinical management of the comatose patient.
Data Source: Search of Medline and Cochrane databases;
manual review of bibliographies from selected articles and monographs.
Data Synthesis and Conclusions: Coma and other states of
impaired consciousness are signs of extensive dysfunction or
injury involving the brainstem, diencephalon, or cerebral cortex

oma and other states of impaired consciousness represent a severe derangement in

cerebral function that may be
structural or nonstructural (toxic-metabolic, pharmacologic, seizures) in origin.
Many of the underlying processes leading
to coma can be both life-threatening and

and are associated with a substantial risk of death and disability.

Management of impaired consciousness includes prompt stabilization of vital physiologic functions to prevent secondary neurologic injury, etiological diagnosis, and the institution of braindirected therapeutic or preventive measures. Neurologic
prognosis is determined by the underlying etiology and may be
predicted by the combination of clinical signs and electrophysiological tests. (Crit Care Med 2006; 34:3141)
KEY WORDS: coma; vegetative state; hypoxic-ischemic encephalopathy; traumatic brain injury; neurologic diagnosis; outcome
prediction

potentially reversible with the timely institution of medical or surgical therapy.

Physicians in the emergency and intensive care arena have a central role in
diagnosing and treating comatose patients, the principles of which are outlined in this review.

Disorders of Consciousness
Assistant Professor, Division of Neurosciences
Critical Care, Department of Anesthesiology/Critical
Care Medicine, Neurology and Neurosurgery (RDS),
Vice Chairman, Department of Neurology, Co-Director,
Division of Neurosciences Critical Care, Associate Professor of Neurology, Neurological Surgery, Anesthesiology/Critical Care Medicine (AB), The Johns Hopkins
University School of Medicine, Baltimore, MD.
Supported, in part, by grant NS 046379 from the
U.S. Public Health Service National Institutes of Health.
Copyright 2005 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000194534.42661.9F

Crit Care Med 2006 Vol. 34, No. 1

From a clinical perspective, consciousness may be schematized as the

product of two closely related cerebral
functions: wakefulness (i.e., arousal, vigilance, alertness), and awareness of self or
of the environment, often referred to as
the content of consciousness (1). The
content of consciousness encompasses,
in turn, several other overlapping brain
functions including attention, sensation
and perception, explicit memory, execu-

tive function, and motivation (2). The relationship between wakefulness and
awareness is hierarchical: Awareness cannot occur without wakefulness, but wakefulness may be observed in the absence of
awareness (e.g., the vegetative state; discussed subsequently).
Although many aspects of consciousness remain unexplained, its neuroanatomical underpinnings have been studied
extensively. Wakefulness is linked to the
ascending reticular activating system
(ARAS), a network of neurons originating
in the tegmentum of the pons and midbrain and projecting to diencephalic and
cortical structures (3, 4). Awareness is
dependent on the integrity of the cerebral
cortex and its subcortical connections
(5). Biochemical analysis of the ARAS reveals cholinergic and glutamatergic (pon31

Table 1. Global disorders of consciousness

Arousal

Awareness

Sleep/Wake
Pattern of
Cyclic
Arousal

Brain death

Absent

Absent

Absent

Absent

Absent

Coma

Absent

Absent

Absent

Nonpurposeful

Vegetative state

Present

Absent

Present

Nonpurposeful

Variable;
abnormal
patterns
Present

Minimally conscious
state
Akinetic mutism

Present

Partial

Present

Present

Present

Partial

Present

Intermittently
purposeful
Paucity of
movement

Delirium

Present

Partial

Present

Normal

Present

Locked-in syndrome

Present

Present

Present

Quadriplegia,
anarthria.
Vertical eye
movement and
blinking only

Present

Motor Function

Respiratory
Function

Present

EEG Activity
Electrographic
silence
Polymorphic
delta or theta
Polymorphic
delta or theta,
sometimes
slow alpha
Mixed theta and
alpha activity
Diffuse
nonspecific
slowing
Diffuse
nonspecific
slowing
Normal

Cerebral
Metabolism
(% Normal)a
0
50

4060

5060
4080

70100

90100

EEG, electroencephalograph.
As assessed by fluoro-deoxyglucose positron emission tomography.

tomesencephalic origin), adrenergic (locus ceruleus), serotonergic and

dopaminergic (brainstem), and histaminergic (hypothalamic) pathways (5). Many
of these neurons converge on the thalamus, which then sends projections to the
cerebral cortex. Additional neurons of the
ARAS project directly to the cerebral cortex or to other diencephalic structures
such as the hypothalamus.
Pathologic changes in consciousness
(Table 1) imply a significant alteration in
the awareness of self and of the environment, with variable degrees of wakefulness (6). Descriptive terms such as somnolence, stupor, obtundation, and
lethargy used to denote different levels of
wakefulness are best avoided, given the
lack of uniformity in the way these states
are defined in the literature (1, 6) and the
availability of objective measures such as
the Glasgow Coma Scale (Table 2) (1, 7,
8).
Brain Death. Consciousness disorders
must be distinguished from brain death,
which is the irreversible loss of all brain
and brainstem function, clinically diagnosed by demonstrating absence of consciousness, lack of motor response to
noxious stimulus, and the disappearance
of brainstem reflexes and respiratory
drive (9). Before this determination,
32

pharmacologic, physiologic, and metabolic causes of coma should be excluded.

Coma. Coma is characterized by the
total absence of arousal and of awareness.
As opposed to states of transient unconsciousness such as syncope or concussion, coma must last 1 hr (10). Comatose patients have no eye opening and do

Table 2. Glasgow Coma Scale

Motor response (M)
Follows commands
Localizes pain
Withdraws to pain
Flexion
Extension
None
Verbal response (V)
Oriented
Confused speech
Inappropriate words
Incomprehensible
None
Eye opening (E)
Spontaneous
To command
To pain
None

6
5
4
3
2
1
5
4
3
2
1
4
3
2
1

When assessing record best motor and response. Endotracheal tube or tracheostomy invalidates the verbal component. Coma defined as
M 4, V 2, E 2 (Glasgow Coma Scale 8).
Adapted from Teasdale and Jennett (8).

not speak or move spontaneously. They

do not follow commands, and when provoked by a noxious stimulus their eyes
remain closed, vocalization is limited or
absent, and motor activity is absent or
abnormal and reflexive rather than purposeful or defensive (1). Sleep-wake cycles are lacking. Coma is typically a transitional state, evolving toward recovery of
consciousness, the vegetative state, the
minimally conscious state, or brain death
(Fig. 1). Coma is associated with injury to
or functional disruption of bilateral cortical structures or of the ARAS. Lesions
involving the brainstem portion of the
ARAS frequently coexist with oculomotor
findings and pathologic breathing patterns.
Vegetative State. The vegetative state
(VS) is notable for preserved arousal
mechanisms associated with a complete
lack of self or environmental awareness
(10, 11). Patients in a VS open their eyes
spontaneously; however, there is no evidence of sustained visual pursuit (tracking) or visual fixation. They do not follow
commands and do not move in any meaningful or purposeful manner. They evolve
through temporal cycles of increased and
decreased arousal akin to a sleep-wake
pattern. Cardiovascular regulatory function, breathing patterns, and cranial
Crit Care Med 2006 Vol. 34, No. 1

Figure 1. Spectrum of consciousness disorders.

nerves are usually intact. Although some

patients who are in a VS regain partial or
complete consciousness, others remain
for extended periods without significant
changes in their neurologic state (Fig. 1),
prompting the term persistent vegetative state (PVS). The Multi-Society Task
Force, an interdisciplinary consensus
group, defined PVS as a VS present 1
month after an acute traumatic or nontraumatic injury (10). There has been debate regarding the significance of this
designation, and one expert panel suggested that the term PVS be abandoned
altogether (12). The VS is caused by widespread damage to bilateral cerebral hemispheres with sparing of the brainstem;
trauma and hypoxic-ischemic encephalopathy are the most common acute
causes of VS.
Minimally Conscious State. The minimally conscious state (MCS) describes a
subset of patients who do not meet the
criteria for coma or VS. Patients in MCS
have a severe alteration in consciousness
but demonstrate wakefulness and cyclic
arousal and intermittently demonstrate
self or environmental awareness, such as
following of commands, the ability to signal yes/no (regardless of accuracy), intelligible speech, or purposeful behavior
(13). Emergence from the MCS to higher
states of consciousness is signaled by the
ability to communicate reliably or use
objects functionally (13). Although data
are limited, it is believed that the MCS
represents a greater likelihood of recovery compared with the VS. As in the VS,
lesions or dysfunction associated with the
MCS involve the cerebral hemispheres,
with possibly greater sparing of corticocortical and cortico-thalamic connective
fibers (14, 15).
Crit Care Med 2006 Vol. 34, No. 1

Akinetic Mutism. Akinetic mutism

(AM) is a state of wakefulness with limited objective evidence of awareness (16,
17). Patients with this condition generally seem unable to move or speak and
have cyclic periods of increased arousal as
indicated by eye opening. Some authors
describe elements of visual pursuit and
an intent gaze suggesting an unfulfilled
promise of speech (18). Contrary to the
MCS, there is no motor responsiveness to
verbal, tactile, or noxious stimuli. A distinguishing feature from the VS is that
patients with AM do not have spasticity or
abnormal reflexes, suggesting relative
sparing of the corticospinal tract (19). AM
has been associated with bilateral medial
frontal lobe (e.g., cingulate gyrus) injury
or dysfunction, leading to a profound deficiency in motivation and an inability to
plan and initiate activity (executive dysfunction) (17).
Delirium. Delirium is synonymous
with the acute confusional state and with
acute encephalopathy (20, 21). Its is characterized by an acutely developing impairment in attention, associated with
changes in the level of consciousness,
disorganized thinking, and a fluctuating
course (22, 23). Additional features include perceptual disturbances, altered
sleep-wake cycle, increased or decreased
psychomotor activity, and memory impairment. Delirium is exceedingly common in hospitalized patients and particularly in the intensive care unit (24). It
may precede or may evolve from other
disorders of consciousness, namely coma
(Fig. 1) (25). Delirium should be distinguished from dementia. Both disorders
are characterized by memory impairment, but patients with dementia alone
are more commonly alert and do not have

the acute onset and fluctuating level of

consciousness that are characteristic of a
delirium (21). Delirium is frequently seen
in acute toxic, metabolic, or endocrine
derangements but may also result from
more focal injury to the frontal or right
parietal lobes (26). Nonconvulsive seizure
activity and the postictal state may also
mimic delirium.
Locked-In Syndrome. The locked-in
syndrome (LIS) consists of quadriplegia
and anarthria in the setting of preserved
awareness and arousal (1). It not a consciousness disorder per se but may be
clinically confused with one given the
limited expressive capability of these patients. It is associated with acute injury to
the ventral pons, just below the level of
the third nerve nuclei, thus classically
sparing vertical eye movements and
blinking and not interfering with the
more dorsally located ARAS. More rostral
lesions may induce a total LIS, in which
even eye and lid movement is lost, prohibiting all communication. Common
etiologies of the LIS are pontine infarction, hemorrhage, and trauma (27). An
analogous awake but de-efferented state
may occur in patients with severe Guillain-Barr syndrome, botulism, and critical illness neuropathy and those receiving neuromuscular blocking agents
without adequate sedation (28).
Other States of Impaired Consciousness. Several other states involve or suggest a global perturbation in consciousness. Hypersomnia or excessive daytime
somnolence is an increase in sleeping
time with preserved sleep-wake cycles,
most often seen in the setting of sleep
deprivation, sleep-related breathing disorders, narcolepsy, drug toxicity, metabolic encephalopathy, or damage to the
ARAS (29). When aroused, patients with
hypersomnia typically have a normal
neurologic examination. Catatonia is a
complication of psychiatric illnesses such
as severe depression, bipolar disorder, or
schizophrenia, in which patients have
open eyes but do not speak or move spontaneously and do not follow commands,
with an otherwise normal neurologic examination and an electroencephalogram
showing low voltage but no slowing (21,
30). General anesthesia and barbiturate
coma are pharmacologically induced
states of decreased arousal and awareness, associated with minimal or absent
responses to noxious (surgical) stimuli
and prominent brainstem dysfunction
and respiratory depression (31). Generalized convulsive or complex partial sei33

Table 3. Etiology of coma and altered consciousness

I. Primary cerebral disorders
Bilateral or diffuse hemispheric disorders
Traumatic brain injury (contusions, diffuse axonal injury)
Ischemic (watershed, cardioembolism, vasculitis, hypercoagulable disorder)
Hemorrhagic (subarachnoid hemorrhage, intraventricular hemorrhage)
Hypoxic-ischemic encephalopathy
Cerebral venous thrombosis
Malignancy
Meningitis; encephalitis
Generalized or complex partial seizures; status epilepticus (convulsive, nonconvulsive)
Hypertensive encephalopathy
Posterior reversible encephalopathy syndrome
Acute disseminated encephalomyelitis
Hydrocephalus
Unilateral hemispheric disorders (with displacement of midline structures)
Traumatic (contusions, subdural hematoma, epidural hematoma)
Large hemispheric ischemic stroke
Primary intracerebral hemorrhage
Cerebral abscess
Brain tumor
Brain stem disorders (pons, midbrain)
Hemorrhage, infarction, tumor, trauma
Central pontine myelinolysis
Compression from cerebellar infarct, hematoma, abscess, tumor
II. Systemic derangements causing coma
Toxic
Medication overdose/adverse effects (opioids, benzodiazepines, barbiturates, tricyclics, neuroleptics, aspirin, selective serotonin reuptake inhibitors,
acetaminophen, anticonvulsants)
Drugs of abuse (opioids, alcohol, methanol, ethylene glycol, amphetamines, cocaine)
Exposures (carbon monoxide, heavy metals)
Metabolic
Systemic inflammatory response syndrome-sepsis
Hypoxia; hypercapnia
Hypothermia
Hypoglycemia; hyperglycemic crises (diabetic ketoacidosis, nonketotic hyperosmolar hyperglycemic state)
Hyponatremia, hypernatremia
Hypercalcemia
Hepatic failure
Renal failure
Wernickes encephalopathy
Endocrine
Panhypopituitarism
Adrenal insufficiency
Hypothyroidism; hyperthyroidism

zures or a resulting postictal state may

also lead to altered consciousness.

Etiology and Pathogenesis

Common causes of coma are traumatic
brain injury (TBI), hypoxic-ischemic encephalopathy (HIE), drug overdose, ischemic stroke, intracranial hemorrhage, central nervous system infections, and brain
tumors. From a pathophysiologic standpoint, coma may be viewed as the expression of a) primary insults to the cerebral
cortex, diencephalic structures, midbrain
or rostral pons; and b) secondary cerebral
manifestations of systemic toxic, metabolic,
or endocrine derangements (Table 3) (1,
32).
To affect consciousness, lesions of the
cerebral cortex must involve both hemispheres or must be unilateral lesions large
34

enough to cause displacement of midline

structures (shift) (1). Brainstem and diencephalic lesions resulting in coma may be
comparatively small; however, they must
also involve bilateral structures (4). Compartmental shift of sufficient magnitude
will disrupt the structural integrity or function of contralateral reticulothalamic or
thalamocortical fibers, impairing the ARAS
and its projections. Shift may also cause
central or tentorial herniation with compression of the midbrain, compromising
more proximal elements of the ARAS (32).
The pathophysiology of toxic and metabolic coma is specific to the underlying
cause and in many instances incompletely understood (33). In a simplified
view, these conditions have been linked
to an interruption in the delivery or utilization of oxygen or substrate (hypoxia,
ischemia, hypoglycemia, carbon monox-

ide), alterations in neuronal excitability

and signaling (seizures, acidosis, drug
toxicity), or changes in brain volume (hypernatremia, hyponatremia). The degree
of neurologic impairment is related to
the time course of the underlying cerebral pathology. Thus, an acute hemispheric or brainstem hemorrhage with
mass effect will be associated with depressed consciousness, whereas a slowly
developing brain tumor of identical location and volume may be asymptomatic. A
similar observation can be made for metabolic changes, such as acute vs. progressive hyponatremia.

Approach to the Comatose

Patient
Disorders of consciousness such as
coma are potentially life threatening and
Crit Care Med 2006 Vol. 34, No. 1

Figure 2. Algorithm for initial emergent management of the comatose patient. GCS, Glasgow Coma
Scale; MAP, mean arterial pressure; ICP, intracranial pressure; IV, intravenous; CT, computed tomography; EEG, electroencephalograph; MRI, magnetic resonance imaging. Adapted from Reference 122.

warrant a rapid and structured approach.

A basic sequence of steps is outlined hereafter. These include stabilization of vital
physiologic functions, performing a focused neurologic examination, targeted
diagnostic tests, and when available the
institution of specific therapeutic measures (Fig. 2).
Initial Stabilization. As in any medical
or surgical emergency, initial steps
should be directed to ensuring adequacy
of airway, breathing, and circulatory
function. In patients who are comatose
from TBI, or in whom the trauma cannot
be ruled out as an etiological factor, the
neck should be immobilized until cervical spine instability has been ruled out by
clinical examination and appropriate imaging (34). Efforts should be made to
swiftly identify the causes of, and correct,
systemic derangements such as hypertension, hypotension, hypoxemia, anemia,
acidosis, hypothermia, hyperglycemia,
and hyperthermia.
Systemic Derangements. The relationship of acute neurologic disorders
with derangements in circulatory and respiratory function is complex, and it is
frequently not possible at the outset to
accurately determine whether the systemic derangement occurred secondary
to coma, was a cause of it, or was independent of it. Hypertension in the comaCrit Care Med 2006 Vol. 34, No. 1

tose patient suggests elevated intracranial

pressure,
drug
overdose
(amphetamines, cocaine), or hypertensive encephalopathy, but more frequently
hypertension is a nonspecific hyperadrenergic response to an acutely evolving intracranial or systemic process (35). Hypotension and shock in the comatose
patient usually reflect nonneurogenic
mechanisms of circulatory failure but
may also be a consequence of severe brain
damage (neurogenic stunned myocardium) (36). Acute respiratory failure in
the comatose patient may occur secondary to airway obstruction, pulmonary aspiration, acute lung injury, or lesions affecting the pontine and medullary
respiratory centers. Acute central nervous system insults have been linked to
neurogenic pulmonary edema, characterized by severe hypoxemia and proteinrich diffuse alveolar exudates (37). Coma
may also represent a consequence of hypercapnic or hypoxemic respiratory failure, suggesting a vicious cycle mutually
reinforcing brain and respiratory dysfunction.
The importance of appropriately treating systemic derangements is underscored by studies demonstrating that
neurologic outcomes are substantially
worse in patients with TBI who develop
hypotension and/or hypoxia (38 41).

Similar observations have been made in

patients with ischemic stroke (42).
Neurologic Evaluation. The goal of
the neurologic examination is to recognize the type of consciousness disorder
and make inferences about its etiology.
Essential neuroanatomically localizing
information may be gleaned by a relatively rapid survey, which should include
the level of consciousness (wakefulness),
cranial nerve examination, motor examination, and respiratory pattern (1). Additional clues may be sought by examining
the head and neck (e.g., meningismus),
the optic fundi (e.g., subhyaloid hemorrhage in subarachnoid hemorrhage), and
the skin (e.g., purpuric lesions in meningococcal meningitis) (32, 43). An important early step is to differentiate patients
who have a structural cause of coma from
those with a metabolic one. Structural
causes are indicated by the presence of
lateralizing deficits and a rostrocaudal
progression of brainstem dysfunction
(Tables 4 and 5). The presence of involuntary movements (seizures, myoclonus,
asterixis), especially if generalized, suggests a metabolic etiology.
Level of Consciousness. The patient
should be inspected for spontaneous body
position, motor activity, eye opening, or
verbalization. Purposeful movements
(e.g., reaching for endotracheal tube) and
comfort postures (e.g., crossing the legs)
are signs of cortical integration. The response to stimuli of graded intensity
should then be observed, starting with
verbal commands, progressing to tactile
cues and finally to noxious provocation.
Noxious stimuli should be delivered without inducing tissue trauma and with regard to the possibility of conscious pain
perception; preferable sites are the nailbed and the notch of the supra-orbital
nerve.
The Glasgow Coma Scale (GCS) (Table
2) was initially devised for patients with
TBI (8) but has gained widespread acceptance as a bedside tool for evaluating the
level of consciousness in virtually all
acutely ill patients (44). It has good interobserver reliability (45) and is a powerful predictor of survival and neurologic
outcomes after head trauma (46 49),
nontraumatic coma (50), ischemic stroke
(51, 52), subarachnoid hemorrhage (53),
intracerebral hemorrhage (54, 55), and
meningitis (56). The GCS is also an independent predictor of survival in the general critically ill population (57) and has
been incorporated into a number of
widely used prognostic intensive care
35

scoring systems (58 64). Not withstanding, the GCS has several important limitations (44, 65, 66). Subtle alterations in
wakefulness and brainstem findings may
not be captured by the GCS. A full GCS
cannot be obtained in patients who are
endotracheally intubated, are sedated, or
have craniofacial trauma or in patients
with dominant hemisphere lesions and
aphasia. Midrange scores (6 12) may result in different combinations of the
three components yielding equivalent total scores that do not reflect the same
degree of unconsciousness (65, 67). Finally, differences in the higher GCS

range (1315) correlate poorly with outcome and neuroimaging findings (68,
69).
Cranial Nerve Examination. Examination of the eyes may yield valuable information about the level of brainstem
disease causing coma, given the proximity of centers governing eye movement,
pupillary function, and elements of the
ARAS. Completely normal pupillary function and eye movements suggest that the
lesion causing coma is rostral to the midbrain (70). Detection of brainstem injury
may also aid in prognostication (discussed subsequently).

Table 4. Signs of intracranial hypertension and associated herniation syndromes

Sign

Mechanism

Coma
Pupillary dilation
Miosis
Lateral gaze palsy
Hemiparesisa
Decerebrate posturing
Hypertension,
bradycardia
Abnormal breathing
patterns
Posterior cerebral artery
infarction
Anterior cerebral artery
infarction
a

Compression of midbrain tegmentum

Compression of ipsilateral third nerve
Compression of the midbrain
Stretching of the sixth nerves
Compression of contralateral cerebral
peduncle against tentorium
Compression of the midbrain
Compression of the medulla

Type of Herniation
Uncal, central
Uncal
Central
Central
Uncal

Vascular compression

Central, uncal
Central, uncal, cerebellar
(tonsillar)
Central, uncal, cerebellar
(tonsillar)
Uncal

Vascular compression

Subfalcine (cingulate)

Compression of the pons or medulla

Hemiparesis will occur ipsilateral to the hemispheric lesion (false-localizing sign).

Unilateral pupillary dilation in the comatose patient is evidence of oculomotor

nerve compression from ipsilateral uncal
herniation until demonstrated otherwise.
This presentation may also occur in patients with posterior communicating artery aneurysmal rupture. Bilateral dilated
pupils that do not react to light are a sign
of extensive midbrain injury, central herniation, drug intoxication (tricyclic antidepressants, anticholinergic agents, amphetamines, carbamazepine), or brain
death. Unilateral miosis is suggestive of
Horners syndrome due to sympathetic
denervation. Bilateral miosis is seen with
lesions in the pontine tegmentum, opioid
overdose, and cholinergic toxicity (organophosphates and other cholinesterase
inhibitors).
Abnormalities of eye position and
movement may be informative. Conjugate lateral deviation of the eyes is a sign
either of an ipsilateral hemisphere lesion,
a contralateral hemisphere seizure focus,
or damage involving the contralateral
pontine horizontal gaze center (parapontine reticular formation). Lateral gaze
palsy may signal central herniation with
compression of bilateral sixth nerves.
Tonic downward deviation of gaze is suggestive of injury or compression involving the thalamus or dorsal midbrain such
as may occur with acute obstructive hydrocephalus or midline thalamic hemor-

Table 5. Brainstem reflexes in the comatose patient

Examination
Technique
Pupils

Response to
light

Oculocephalic

Turn head from

side to side

Vestibulooculocephalic

Irrigate external
auditory
canal with
cold water

Corneal reflex

Stimulation of
cornea
Stimulation of
carina

Cough reflex

Gag reflex

36

Stimulation of
soft palate

Normal
Response

Afferent Pathway

Brainstem

Efferent Pathway

Direct and
consensual
pupillary
constriction
Eyes move
conjugately
in direction
opposite to
head
Nystagmus with
fast
component
beating away
from
stimulus
Eyelid closure

Retina, optic
nerve, chiasm,
optic tract

Edinger-Westphal nucleus
(midbrain)

Semicircular
canals,
vestibular
nerve

Vestibular nucleus. Medial

longitudinal fasciculus.
Parapontine reticular
formation (pons)

Semicircular
canals,
vestibular
nerve

Vestibular nucleus. Medial

longitudinal fasciculus.
Parapontine reticular
formation (pons)

Oculomotor and
abducens
nerves

Trigeminal nerve

Facial nerve

Cough

Glossopharyngeal
and vagus
nerves
Glossopharyngeal
and vagus
nerves

Trigeminal and facial nuclei

(pons)
Medullary cough center

Symmetric
elevation of
soft palate

Medulla

Oculomotor
nerve,
sympathetic
fibers
Oculomotor and
abducens
nerves

Glossopharyngeal
and vagus
nerves
Glossopharyngeal
and vagus
nerves

Crit Care Med 2006 Vol. 34, No. 1

rhage. Tonic upward gaze has been associated with bilateral hemispheric
damage. Ocular bobbing, a rapid downward jerk followed by a slow return to
midposition, is indicative of pontine lesions. Rapid intermittent horizontal eye
movements suggest seizure activity.
Integrity of the brainstem may be further ascertained by eliciting specific reflexes (Table 4). Disappearance of brainstem reflexes may also aid in
prognostication (45) (discussed subsequently).
Motor Examination. Movements may
be classified as involuntary, reflexic, or
purposeful. Involuntary movements include seizures, myoclonus, or tremor
(e.g., toxic-metabolic encephalopathy).
Reflexes are stereotypical responses of the
extremities evoked in patients who lack
descending hemispheric modulation of
motor function. Purposeful movements
(e.g., localization) imply cortical processing of environmental variables.
Extensor (decerebrate) posturing is
characterized by adduction, extension,
and pronation of the upper extremities
and extension of the lower extremities; it
is indicative of injury to the caudal diencephalon, midbrain, or pons. Flexor
(decorticate) posturing involves flexion
and adduction of arms and wrists with
extension of lower extremities; it suggests hemispheric or thalamic damage,
with sparing of structures below the diencephalons (1).
Respiratory Pattern. Coma has been
associated with disordered breathing patterns, reflecting injury to brainstem respiratory centers or interference with suprabulbar regulation of these sites (1, 71).
Circulatory or respiratory failure, toxicmetabolic disorders, drugs used for sedation or analgesia, and mechanical ventilation may also contribute to abnormal
breathing, limiting the inferential value
of specific patterns. Cheyne-Stokes respiration denotes a cyclic pattern of alternating hyperpnea and apnea. It is seen in
patients with a bilateral hemispheric or
diencephalic insult but may also be
present in congestive heart failure,
chronic obstructive pulmonary disease,
and sleep apnea. Hyperventilation has
been linked to injury in the pontine or
midbrain tegmentum; however, it can
also result from respiratory failure, hemodynamic shock, fever, sepsis, metabolic disarray, and psychiatric disease.
Apneustic breathing is characterized by a
prolonged pause at the end of inspiration
and indicates lesions of the mid- and cauCrit Care Med 2006 Vol. 34, No. 1

dal portions of the pons. Ataxic breathing

is irregular in both rate and tidal volume
and suggests damage to the medulla.
Diagnostic Tests. Patients with coma
should be placed on monitors including
pulse oximetry, blood pressure, and electrocardiogram, and blood should be immediately sent for glucose, electrolytes,
and arterial blood gas analysis. Routine
serum tests of liver, renal, thyroid, and
adrenal function and urine toxicology
screens should be obtained without delay.
Computed tomography (CT) of the
brain is warranted in virtually all patients
with an acute onset of unexplained coma.
CT will readily identify intracranial hemorrhage, hydrocephalus, brain edema,
and compartmental shift and may suggest stroke, abscess, or tumor. CT is unrevealing in most instances of hypoxicischemic or toxic-metabolic coma. Also,
the usefulness of CT in patients who become comatose during the course of a
critical illness is unclear. One study
found that CT was unlikely to reveal abnormalities in intensive care unit patients who did not have new neurologic
deficits or seizures (72). In each case, the
anticipated benefit of CT in terms of actionable information should be carefully
weighed against the risks of transporting
a critically ill patient outside the intensive care unit.
Magnetic resonance imaging (MRI)
should be sought in patients with unexplained coma and normal or equivocal CT
findings. MRI is highly sensitive to acute
ischemic stroke, intracerebral hemorrhage, cerebral venous sinus thrombosis,
brain edema, brain tumor, inflammatory
processes, and cerebral abscess. MRI is
more sensitive than CT to diffuse axonal
injury, a pattern of damage seen in TBI
patients (73, 74). Studies in encephalopathic or comatose patients with sepsis or
after cardiac surgery have found that MRI
may be highly sensitive for the detection
of lesions not suspected by clinical examination or CT (7578).
Lumbar puncture and cerebrospinal
fluid analysis should be considered in comatose patients with a suspected infectious or inflammatory central nervous
system condition (79). However, in immunologically competent critically ill patients being worked up for fever and encephalopathy who have not undergone a
recent neurosurgical procedure, the diagnostic yield of this test is low (80, 81).
Patients with alterations in consciousness should undergo CT of the head before lumbar puncture to identify occult

intracranial abnormalities that might

cause brain herniation after removal of
cerebrospinal fluid (82).
Electroencephalography (EEG) is frequently indicated in patients with unexplained coma as it may diagnose clinically
occult seizure activity and in particular
nonconvulsive status epilepticus. Recent
studies indicate that nonconvulsive status epilepticus is present in 8 19% of
patients who undergo EEG as part of the
workup for an unexplained decrease in
level of consciousness (83 85). The specificity of EEG for the etiological diagnosis
of nonepileptic causes of coma is low;
however, certain characteristic abnormalities have been described. In patients
with coma of metabolic origin, a generic
pattern of diffusely decreased frequency
and increased amplitude has been described, often in association with triphasic waves (86). Some comatose patients
have an EEG that superficially resembles
an awake (alpha) pattern. This alphacoma is most commonly seen in patients
with extensive damage or dysfunction involving the brainstem or cerebral cortex
and generally carries a poor prognosis
(87). Finally, herpesvirus encephalitis has
been associated with changes such as periodic sharp waves or epileptiform discharges (88, 89). Although the diagnostic
capabilities of EEG are disappointing, it
has emerged as a valuable tool in the
prognostication of comatose patients
(discussed subsequently).

Prognosis
Outcomes after coma include death,
VS, various degrees of functional impairment, and complete neurologic recovery.
Such categories have been formalized in
scoring systems such as the Glasgow Outcome Scale (GOS) (90) (Table 6) and extended GOS (91). There are many other
outcomes of coma including nonvegetative disorders of awareness (e.g., MCS,
AM) and gradations of cognitive dysfunction that are not captured by systems
such as the GOS (92). Nevertheless, the
GOS is widely used by clinical investigators in both traumatic and nontraumatic
coma.
The prediction of neurologic outcome
is a central concern in the management
of patients with coma. Surveys indicate
that many individuals would prefer death
to the prospect of living in a vegetative or
highly dependent state (93). Prognostic
information, when available, provides a
rational basis for decision making about
37

Table 6. Glasgow Outcome Scale

1
2
3

Death
Persistent vegetative state
Severe disability

Moderate disability

Good recovery

Patient exhibits no obvious cortical function.

(Conscious but disabled). Patient depends on others for
daily support due to mental or physical disability or
both.
(Disabled but independent). Patient is independent as far as
daily life is concerned. The disabilities found include
varying degrees of dysphasia, hemiparesis, or ataxia, as
well as intellectual and memory deficits and personality
changes
Resumption of normal activities even though there may be
minor neurological or psychological deficits.

Adapted from Jennett and Bond (90).

therapeutic intensity, withdrawal of life

support, and rehabilitation (94). Prognostication of comatose patients is based on
a consideration of etiology, clinical signs,
electrophysiology, neuroimaging, and
biochemical data (95).
Etiology. The prognosis of coma is
determined in large part by the underlying etiology. It is widely believed that
toxic/metabolic coma carries a better
prognosis than coma of structural origin;
however, direct evidence demonstrating
this is limited. On the other hand, the
better prognosis of traumatic vs. anoxic
coma is supported in a number of studies
and two recent systematic reviews (96,
97). In adults with PVS secondary to TBI
who were reevaluated at 1 yr, the proportion with a good recovery was 7%, moderate disability 17%, severe disability
28%, PVS 15%, and dead 33% (96). In
patients with nontraumatic PVS (principally HIE), these outcomes were significantly worse (respectively 1%, 3%, 11%,
32%, and 53%) (96). Younger age and
better general health of TBI patients may
account for some of this difference.
Clinical Signs. Clinical signs that correlate with poor prognosis after coma include the motor component of the GCS
(46, 47, 50, 51, 53, 55, 56), the length of
time a patient remains in coma (97, 98),
and signs of brainstem damage. In two
separate systematic reviews of postanoxic
coma, absent motor responses (GCS motor score 1) on day 3 were highly predictive of poor outcome (death or VS) (45,
99). Absent pupillary responses on day 1
(45) or 3 (99) and absent corneal reflexes
on day 1 (45) were also strongly correlated with poor outcome. Clinical signs
appeared to be less accurate in the prediction of outcome after TBI (100).
Electrophysiologic Tests. Electrophysiologic tests that have been used for
predicting coma outcome include EEG,
38

somatosensory evoked potentials (SSEP),

transcranial motor evoked potentials,
brainstem auditory evoked potentials
(BAEP), and event-related potentials (86,
101). In patients with postanoxic coma,
meta-analysis revealed that EEG with an
isoelectric or burst-suppression pattern
was independently associated with poor
outcome (99). A recent systematic review
implied that in patients with an alphacoma after HIE or TBI, mortality rate was
6190%, whereas mortality rate was 27%
when alpha-coma was metabolic in origin
(87). Although it remains a dependable
tool for epilepsy assessment, EEG is limited by its high sensitivity to the electrical
environmental noise, its alteration by
sedative drugs, and its inability to test the
brainstem.
Data from SSEP are strongly predictive of outcome. A systematic review revealed that among comatose patients
with bilaterally absent cortical SSEP, the
incidence of death or VS was 100% after
HIE, 99% after intracranial hemorrhage,
95% after TBI, and 93% in children and
adolescents 18 yrs old with coma of
diverse etiologies (102). These results
were consistent with the meta-analysis
that concluded from a review of 33 studies that bilateral absence of cortical SSEP
within the first week after anoxic coma
was 100% specific in identifying patients
with poor outcome (99). Most studies of
BAEP to assess prognosis after coma were
conducted with patients with TBI (101). A
pooled analysis demonstrated that of 107
patients with absence of peak V (generated in the upper pons and in the midbrain) on BAEP recorded 159 days after
TBI, 106 were dead or vegetative at 312
months follow-up (100). At our institution, BAEP and SSEP are obtained in
selected comatose patients in whom
prognosis is not readily predictable from
clinical parameters alone.

Neuroimaging. Neuroimaging is essential to coma diagnosis and may have

prognostic value. In patients with traumatic coma, patterns on CT that have
been associated with worse neurologic
outcome include lesions in the brainstem, encroachment of the basal cisterns,
and diffuse axonal injury (103108). CT
findings are also predictive of outcome in
comatose patients with intracerebral
hemorrhage (55) and subarachnoid hemorrhage (109). However, when compared
with electrophysiologic and clinical variables, the predictive value of CT is reported to be low (110). MRI in comatose
patients may disclose pathologic changes
of prognostic importance (73, 74, 111). In
a study of patients with posttraumatic
PVS, Kampfl et al. (112) assessed the relationship between MRI findings and outcome at 12 months. They noted that lesions in the corpus callosum and
dorsolateral brainstem were highly predictive of nonrecovery, whereas initial
GCS and pupillary findings were not
(112). A relationship between MRI abnormalities and outcome is also suggested in
comatose patients following ischemic
stroke (113) and hypoxic-ischemic injury
(114).
Biochemical Markers. The presence of
brain-specific molecules in the blood or
cerebrospinal fluid has been postulated to
reflect the severity of brain damage. Molecules that have been studied in the prognostic evaluation of coma include neuron
specific enolase (115118), s100 beta
(118), glial fibrillary acidic protein (117,
119), and the BB isoform of creatine kinase (120). Although sensitive to brain
injury, the specificity and predictive value
of these tests have been insufficient when
compared with clinical variables and
studies such as SSEP (101, 121, 122).

CONCLUSIONS
The goal of acute care of patients with
coma is to maximize the likelihood of
neurologic recovery. Initial resuscitative
steps should be as in any other medical
emergency. Subsequent therapeutic intervention is dependent on the underlying etiology, and the clinician must rapidly integrate clinical examination,
laboratory, and imaging data in the formulation of a presumptive diagnosis. Prediction of outcome may be accomplished
by clinical examination and electrophysiological tests.
Crit Care Med 2006 Vol. 34, No. 1

anagement of
impaired consciousness in-

cludes prompt stabilization

of vital physiologic functions
to prevent secondary neurologic injury, etiological diagnosis, and the institution of
brain-directed therapeutic or
preventive measures.

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