Coma
Shilpa Patel MBBS FRCA
Nicholas Hirsch FRCA FRCP FFICM
Key points
Consciousness is an active
process requiring intact
cerebral hemispheres and a
functioning ascending
reticular activating system
(ARAS).
Coma is a state of
unarousable
unresponsiveness, and it is
due to bilateral hemispheric
damage, brainstem
dysfunction that disrupts the
ARAS, or both.
The investigation of coma
requires careful and
structured general medical
and neurological
examination; the findings
dictate subsequent
management.
The prognosis of coma is
variable, ranging from full
recovery to minimally
responsive or vegetative
states. Prognostic features
include the aetiology,
duration, and depth of coma.
Shilpa Patel MBBS FRCA
Anaesthetic Specialty Trainee 7
The National Hospital for Neurology and
Neurosurgery
Queen Square
London WC1N 3BG
UK
Nicholas Hirsch FRCA FRCP FFICM
Consultant Neuroanaesthetist
The National Hospital for Neurology and
Neurosurgery
Queen Square
London WC1N 3BG
UK
Tel: þ44 0203 448 4711
Fax: þ44 0203 448 4734
E-mail: nicholas.hirsch@uclh.nhs.uk
(for correspondence)
220
The differential diagnosis of coma is wide, and
accurate and rapid diagnosis of the cause is es-
sential for optimal management. This article
outlines the physiological and pathological basis
of coma and details a structured approach to in-
vestigation and treatment.
Consciousness is defined as a state of aware-
ness of self and the environment, which allows
responsiveness to external stimulation and inner
need.1 – 3 In contrast, coma is defined as ‘unarou-
sable unresponsiveness’ or ‘the absence of any
psychologically understandable response to ex-
ternal stimulus or inner need’.4 Between full
consciousness and coma, there exists a spectrum
of altered consciousness and although terms
such as ‘obtundation’ and ‘delirium’ refer to
specific intermediate states, considerable overlap
exists (Table 1).
It is important to recognize that conditions
such as the Locked-in syndrome and Guillain–
Barré syndrome may mimic coma in that the
patient may be unable to move or communicate,
but their conscious level is not impaired
(Table 2).
Anatomical basis of
consciousness and coma
Consciousness depends on two fundamental
components: arousal (alertness) and content.
The latter consists of those higher cognitive
functions that allow awareness of self and the en-
vironment, and expression related to sensation,
emotion, memory, and thought. Arousal requires
a functioning reticular formation, a physiologic-
al structure that extends from the caudal medulla
to the rostral midbrain.3 Fibres from the reticular
formation ascend to the thalamus and project to
various non-specific thalamic nuclei. From these
nuclei, there is a diffuse distribution of connec-
tions to all parts of the cerebral cortex.1 The re-
ticular system and its interconnections are
known as the ascending reticular activating
system (ARAS; Fig. 1).
The cerebral cortex receives impulses from
the ARAS and modulates the incoming informa-
tion via corticofugal projections to the reticular
doi:10.1093/bjaceaccp/mkt061
Continuing Education in Anaesthesia, Critical Care & Pain | Volume 14 Number 5 2014
& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
All rights reserved. For Permissions, please email: journals.permissions@oup.com
Matrix reference 2A04,
2C01, 2F01, 2F03, 3F00
formation. Content, and therefore awareness of
self and environment and thus conscious behav-
iour, is dependent on the integrity of both cere-
bral hemispheres and their subcortical con-
nections. Any lesion which interferes with full
cognitive function diminishes the content of con-
sciousness and renders the patient less than fully
conscious.3
It therefore follows that coma is due to either
structural or metabolic damage of the brainstem
ARAS or bilateral cerebral cortical damage. In
general, unilateral hemispheric damage (e.g.
after a cerebrovascular accident) does not alter
consciousness.
Neuropharmacology
of consciousness
The acetylcholine and monoamine oxidase
systems are thought to mediate arousal, cogni-
tion, stupor, and coma.3 Cholinergic drugs such
as atropine, which cross the blood brain barrier,
produce behavioural arousal and electroencepha-
lographic (EEG) activation in coma. The central
monoamine oxidase system, involving serotonin
and norepinephrine neurotransmission, is also an
important component of the brainstem reticular
activating system.
Classification of coma
Coma may be caused by a large number of
neurological or general medical diseases, and a
simple scheme is helpful in determining the aeti-
ology. The most effective of these is to identify
the following features on initial examination of
the patient:
(i) the presence of lateralizing signs;
(ii) the presence of meningism;
(iii) the pattern of brainstem reflexes.
Having determined which of the features are
present, one can classify comatose patients into
one of the following four groups:
(i) Coma with intact brainstem function, no
meningism, and no lateralizing signs.
Advance Access publication 19 November, 2013

Table 1 Definitions of the spectrum of states of altered consciousness
Clouding of consciousness: a state of reduced wakefulness or awareness, characterized
by impaired attention and memory. The patient is easily distracted and sometimes
hyperexcitable, startled by stimuli2,3,5
Acute confusional state: impairment of consciousness in which stimuli are
intermittently misinterpreted. Patients are drowsy, disorientated in time and
occasionally place and person, and have poor short-term memory5
Delirium: acutely developing impairment of consciousness, attention, disordered
thinking—fear, disorientation, visual hallucinations, delusions, and misperception of
sensory stimuli. This can be interspersed with lucid intervals. It is commonly because
of metabolic, toxic, or endocrine derangements and is very common in hospitalized
patients. It follows a fluctuating course and rarely lasts for more than a week
Obtundation: mental blunting with apathy and inactivity. The patient is drowsy with
reduced alertness, has a decreased interest in the environment, and responds slowly to
stimulation2,3
Stupor: a condition similar to deep sleep or unresponsiveness, where the patient can be
aroused by episodes of repeated, vigorous stimuli. As the stimulation decreases, the
patient lapses back into a state of decreased responsiveness. Even when aroused,
communication is by monosyllabic sounds and simple behaviour5
Table 2 Disorders mimicking coma
Guillain –Barré syndrome: an acute peripheral neuropathy, which follows an acute
infective episode such as an upper respiratory tract infection or gastroenteritis. The
classical presentation is an ascending distal and proximal weakness accompanied by
sensory disturbance. Patients can experience rapidly declining forced vital capacity,
bulbar dysfunction, and autonomic instability6
Locked-in syndrome: these patients are awake and conscious with preserved cognition,
but have no means of producing limb, speech, or facial movements because of loss of
motor function. It is characterized by aphonia, quadriplegia, and vertical or lateral
eye movements or blinking of the upper eyelid. Patients are still able to breathe, but
they have limited ability to express themselves. It is associated with acute injury to
the ventral pons which occurs in basilar artery occlusion, just below the level of the
third nerve nuclei, disrupting corticospinal, corticobulbar, and corticopontine tracts.
Rostral lesions produce a total locked-in syndrome in which eye movements are lost,
prohibiting all communication—common causes of this are pontine infarcts,
haemorrhage, and trauma. Functional recovery is possible, and these patients require
an aggressive rehabilitation programme as early as possible
Botulism: a clinical syndrome caused by neurotoxins produced by the anaerobic
Gram-positive organism Clostridium botulinum. Clinical features include nausea,
vomiting, and abdominal pain with autonomic dysfunction followed by a descending
flaccid paralysis. Bulbar and respiratory failure may occur rapidly, often requiring
intubation and mechanical ventilation7
Fig 1 Ascending reticular formation pathways.
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
Coma
(ii) Coma with intact brainstem function and lateralizing signs.
(iii) Coma with meningism (with or without intact brainstem func-
tion and lateralizing signs).
(iv) Coma with signs of focal brainstem dysfunction.
Assigning the patient to one of these groups allows better definition
of the possible diagnosis (Table 3–6).
Despite the myriad causes of coma, in most cases, there is an
obvious medical cause. In patients admitted to an Emergency
Department in coma of longer than 6 h duration, 40% will be caused
by drug ingestion with or without alcohol, 25% because of
hypoxic–ischaemic injury secondary to cardiac arrest, 20% because
of a cerebrovascular accident, and the remainder because of other
medical causes.5,6
Table 3 Classification of coma. Coma with intact brainstem function, no meningism,
and no lateralizing signs
Alcohol
Drugs and toxins: sedatives, anaesthetic agents, opioids, amphetamines, barbiturates,
salicylates, organophosphorus poisoning, carbon monoxide, methanol, lead, cyanide,
thallium
Seizure: convulsive and non-convulsive status epilepticus, post-ictal states
Hypoxic: ischaemic encephalopathy
Endocrine: hypo and hyperthyroidism, Addison’s disease, hypopituitarism, diabetic
ketoacidosis, hyperosmolar non-ketotic coma
Metabolic: hypo and hyperglycaemia, sepsis, electrolyte disturbance—hypo and
hypernatraemia, hypercalcaemia, hepatic failure, encephalopathy, renal failure
Respiratory: hypoxaemia, hypercarbia
Temperature disturbances: hypothermia, hyperthermia, malignant hyperpyrexia
Psychiatric: catatonia, non-epileptic seizures, malingering
Other: porphyria, Reye’s syndrome, mitochondrial disease, inborn errors of
metabolism. NMDA-receptor antibody encephalitis
Table 4 Classification of coma. Coma with intact brainstem function, no meningism,
and no lateralizing signs
Vascular: infarction (ischaemic, thromboembolic, or hypoperfusion), haemorrhage
(epidural, subdural, subarachnoid, and intracerebral), vasculitis, venous thrombosis,
hypertensive encephalopathy, eclampsia, endocarditis
Traumatic brain injury
Infection: brain abscess, subdural empyema, Creutzfeldt – Jakob disease, malaria, HIV
disease, endocarditis
Cerebral neoplasm
Table 5 Classification of coma. Coma with meningism (with or without intact
brainstem function and lateralizing signs)
Infection: meningitis, encephalitis, malaria, HIV disease
Vascular: subarachnoid haemorrhage
Coma with signs of focal brainstem dysfunction
Herniation syndromes
Intrinsic brainstem dysfunction
Vascular: vertebrobasilar occlusion, dissection, haemorrhage, arteriovenous
malformation
Mass lesions: posterior fossa tumours, abscesses, tuberculosis
Traumatic brain injury
Advanced metabolic/toxic encephalopathy
Others: central pontine myelinolysis, multiple sclerosis, brainstem encephalitis,
leukoencephalopathy
221
Coma

Table 6 Classification of coma. Coma with signs of focal brainstem Table 8 Medical examination
dysfunction
Breath: alcohol, ketones, hepatic, or renal fetor
Herniation syndromes Mucous membranes: cyanosis, anaemia, jaundice, carbon monoxide poisoning
Intrinsic brainstem dysfunction Skin: meningococcal rash, purpura/petechiae of coagulopathy, Battle’s sign or raccoon
Vascular: vertebrobasilar occlusion, dissection, haemorrhage, arteriovenous eyes of basal skull fracture, splinter haemorrhages of infective endocarditis, needle
malformation track marks of i.v. drug use, spider naevi of alcoholism, hyperpigmentation of
Mass lesions: posterior fossa tumours, abscesses, tuberculosis. Addison’s disease, or Kaposi sarcoma
Traumatic brain injury Temperature: hypo- or hyperthermia because of environmental, metabolic, endocrine or
Advanced metabolic/ toxic encephalopathy drugs, toxins, sepsis, malignant hyperpyrexia, neurogenic because of subarachnoid
Others: central pontine myelinolysis, multiple sclerosis, brainstem encephalitis, haemorrhage or hypothalamic lesions
leukoencephalopathy Cardiovascular system: dysrhythmias (bradycardia and hypertension may be a sign of
impending cerebral herniation), hypertension (subarachnoid haemorrhage,
hypertensive encephalopathy, increased intracranial pressure) and valvular disease
suggestive of endocarditis
Table 7 Immediate management and assessment of the comatose patient Fundoscopy: retinopathy (diabetes and hypertension), subhyaloid haemorrhage
(subarachnoid haemorrhage), papilloedema indicating raised intracranial pressure or
Resuscitation and emergency treatment including specific treatment (e.g. naloxone, hypercarbia
flumazenil) Meningism: meningitis or encephalitis
General medical history and examination
Assess level of consciousness
Glasgow Coma Score
FOUR score such as naloxone or flumazenil. If infection is suspected, blood cul-
Assess brainstem reflexes and activity tures should be taken and i.v. antibacterial or antiviral agents com-
Pupillary and eye movements
Corneal reflexes
menced.
Bulbar function
Respiratory patterns
Motor function General medical history and examination
Limb movements
Posturing (e.g. decerebrate/decorticate) After resuscitation, a full collateral history should be taken regarding
Muscle tone
Tendon reflexes and plantar responses length and history of current illnesses, including history of cerebral
neoplasm, sepsis, trauma, potential precipitating factors such as
illicit drug and alcohol use, psychiatric history, and possibility of
overdose of any medication. Drug history, family history, and past
Immediate management and assessment
medical history of epilepsy, endocrine disorders such as diabetes
of the patient with impaired consciousness
and thyroid dysfunction or metabolic disorders, or unusual behav-
This is outlined in Table 7. iour before illness indicating meningitis, encephalitis, or brain
abscess should be ascertained. In the case of cardiac arrest, history
of events leading up to the event, bystander cardiopulmonary resus-
Resuscitation and immediate management citation, and estimated downtime should be established if possible.
A detailed medical examination follows, looking especially for
Although early diagnosis of the underlying cause of coma is essen-
clinical signs pointing to a cause of the coma (Table 8).
tial, it is vital to perform rapid and effective resuscitation to prevent
secondary cerebral damage. Tracheal intubation should be carried
out if the level of consciousness is low [Glasgow Coma Scale (GCS) Assess level of consciousness
,8], oxygenation is inadequate, or airway protection is poor. If
trauma is suspected, the cervical spine should be immobilized The level of consciousness should be carefully assessed using the
during intubation. After intubation, arterial oxygen and carbon GCS, which has proved to be a valuable and reproducible scale.
dioxide tensions should be kept within normal levels. Arterial blood However, full assessment cannot be carried out when the patient is
pressure should be maintained at appropriate levels to ensure normal intubated and for this reason, the FOUR (Full Outline of
cerebral perfusion pressure using i.v. fluids and vasopressors/ino- Responsiveness) score, which replaces the verbal scoring of the
tropes as necessary. GCS with observation of brainstem reflexes, is becoming more com-
During resuscitation, estimation of serum electrolytes and monly used (Table 9).
glucose, full blood count, and liver and thyroid function should be
performed. Urine should be sent for toxicology screening. If hypo-
Assess brainstem reflexes and activity
glycaemia is present, 25 ml of 50% glucose should be given imme-
diately together with thiamine if alcoholism is suspected. The latter Careful assessment of pupillary, corneal, oculovestibular, cough,
will prevent the precipitation of Wernicke’s encephalopathy. and gag reflexes, together with resting eye position, spontaneous eye
If drug overdose is suspected, the appropriate management movements, and respiratory patterns, provides detailed information
should be carried out, including administration of specific antidotes about the function of the various component areas of the brainstem.

222 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014

Table 9 The FOUR score
Eye response 4 Eyelids open, tracking, or blinking to command
3 Eyelids open but not tracking
2 Eyelids closed but open to a loud voice
1 Eyelids remain closed with pain
Motor response 4 Thumbs-up, fist, or peace sign
3 Localizing to pain
2 Flexion response to pain
1 No response to pain or myoclonic status
Brainstem reflexes 4 Pupil and corneal reflexes present
3 One pupil wide and fixed
2 Pupil or corneal reflexes absent
1 Absent pupil, corneal, and cough reflex
Respiration 4 Not intubated, regular breathing pattern
3 Not intubation, Cheyne – Stokes respiration
2 Not intubated, irregular breathing pattern
1 Breaths above ventilator rate
0 Breaths at ventilator rate or apnoea
Similarly, body postures, limb movement and tone, and tendon
reflexes will allow further localization of pathology.
Subsequent management
After the pathway set out in Table 7, it should now be possible to
assign the patient to one of the groups detailed in Tables 3–6, and
this will direct the most appropriate investigations and subsequent
treatment. However, the majority of patients in coma will require
urgent computerized tomography (CT), which will detect most
lesions associated with acute-onset coma. Magnetic resonance
imaging is superior in detecting early ischaemic stroke and cerebral
venous sinus thrombosis, but is difficult to perform in medically un-
stable patients. If central nervous system infection is suspected, a
lumbar puncture ( preceded by CT scanning) is the investigation of
choice. EEG examination is indicated if the coma is thought to be
the result of epilepsy.
Prognosis
Most of the patients who survive the initial insult recover from coma
within 2–4 weeks,3 although the extent of the recovery is variable,
ranging from full recovery to a minimally conscious or vegetative
state (Table 10). The extent of recovery is multifactorial and deter-
mined by the aetiology, depth of coma at presentation, duration of
coma, and other factors. The prognosis of coma is largely determined
by its underlying aetiology. Toxic/metabolic causes carry a better
prognosis than coma of structural origin. The prognosis of traumatic
coma is better than that of non-traumatic coma. Coma caused by
structural cerebral disease carries the worst prognosis with only 7% of
patients achieving moderate or good recovery.3,6 The depth of coma
at presentation also affects prognosis; those who have a higher GCS at
presentation, maintain normal brainstem reflexes throughout resusci-
tation, and who have early recovery of speech have the best outcome.
Survival after cardiopulmonary resuscitation is strongly correlated
with the duration of coma. There is also a correlation between age at
cardiac arrest and outcome—the younger doing better and the older,
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
Coma
Table 10 Spectrum of states of recovery
Minimally aware/conscious state: a state of severely altered consciousness where
patients demonstrate wakefulness and cyclic arousal, and intermittently demonstrate
evidence of self or the environment. This must be reproducible by evidence of
following simple commands, gestural, or verbal yes/no responses or intelligible
verbalization or purposeful behaviour. Such patients are, therefore, by definition, not
in a coma, and may eventually recover some ability to communicate reliably or use
objects functionally6
Vegetative state: patients are awake (preserved arousal) but unaware of themselves or
the environment, and thus, show a lack of cognitive function. Patients open their eyes
spontaneously to verbal stimuli, but there is no evidence of visual pursuit, and do not
move in a meaningful or purposeful manner. There are no reproducible purposeful or
behavioural responses to visual, tactile, auditory, or noxious stimuli. Cardiovascular
regulatory function, breathing patterns, and nerves are usually intact. The sleep –
wake cycle, hypothalamic, and brainstem autonomic responses are all intact. There is
bladder and bowel incontinence, but cranial nerve, spinal, and primitive reflexes are
intact. The vegetative state is because of widespread diffuse lesions on the grey and
white matter, resulting in damage to bilateral cerebral hemispheres with sparing of
the brainstem5
Persistent vegetative state: vegetative state persisting over 1 month after the initial
cerebral insult. It does not imply irreversibility
often with multiple co-morbidities faring worse. Myoclonic status
epilepticus after resuscitation carries a very poor prognosis.
Secondary insults, such as increased intracranial pressure and
low cerebral perfusion pressure, are associated with an increase in
severe disability and higher mortality. In non-traumatic coma,
absent brainstem reflexes and motor responses at 24 h indicate a
poor prognosis, but the combination of GCS at 48 h, presence or
absence of somatosensory evoked potentials, and EEG findings
permits a more reliable prediction of outcome.3,6
Declaration of interest
None declared.
References
1. Young GB. Coma. Ann NY Acad Sci 2009; 1157: 32– 47
2. Howard R, Hirsch N, Kitchen N, Kullman D, Walker M. Disorders of con-
sciousness, intensive care neurology and sleep. In: Clarke C, Howard R,
Rossor M, Shorvon S, eds. Neurology, a Queen Square Text Book. Oxford:
Wiley-Blackwell, 2009; 723– 53
3. Posner JB, Saper CB, Schiff N, Plum F. Plum and Posner’s Diagnosis of Stupor
and Coma. New York: Oxford University Press, 2007
4. Medical Research Council; Brain Injuries Committee. A Glossary of
Psychological Terms Commonly Used in Cases of Head Injury. MRC War
Memorandum No. 4. London: His Majesty’s Stationery Office, 1941
5. Howard RS, Hirsch NP. Coma, vegetative state and locked in syndrome. In:
Miller DH, Raps E, eds. Critical Care Neurology. Boston: Butterworth
Heinemann, 1999; 91–120
6. Hirsch N, Howard R. Assessment and management of coma. In: Matta BF,
Menon DK, Smith M, eds. Core Topics in Neuroanaesthesia and Neurointensive
Care. Cambridge: Cambridge University Press, 2011; 488–97
7. Stevens RD, Bhardwaj A. Approach to the comatose patient. Crit Care Med
2006; 34: 31– 41
Please see multiple choice questions 17–20.
223