Coma

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Chapter 59 Coma

Ala Nozari, MD, PhD , Corey R. Fehnel, MD , Lee H. Schwamm, MD, FAHA

1 What is coma, and how is it different from persistent vegetative state (PVS), minimally conscious state (MCS), or locked-in syndrome?

Coma is a state of profound unresponsiveness caused by structural, metabolic, physiologic, or psychogenic brain dysfunction. The comatose patient is unaware of self and environment and cannot be roused to respond to vigorous stimulation.

In contrast to coma, patients with PVS are in a state of partial arousal and may briefly alert to sound or visual stimuli. They withdraw to noxious stimuli but are unable to interact or respond voluntarily or in any purposeful way to stimuli. PVS is a chronic condition and thus is typically not assigned unless a patient’s state of altered consciousness persists for more than 30 days.

Patients in MCS exhibit deliberate or cognitively mediated behavior, may intermittently follow commands, or have intelligible but inconsistent verbal output. Patients may evolve to MCS from coma or PVS.

Patients with locked-in syndrome have intact cognition but complete paralysis of voluntary muscles in all parts of the body. They traditionally have been able to communicate through code systems by blinking or repeated up-and-down eye movements; however, recent breakthrough technology has allowed some patients to communicate via a human-machine computer interface that allows patients to initiate computer commands with only their thoughts through the use of a surgically embedded microchip in the cerebral cortex.

2 Which are the major categories of disorders or injuries that cause coma?

Coma can be caused by structural brain injury involving the relay nuclei and connecting fibers of the ascending reticular activation system (ARAS), which extends from upper brainstem through synaptic relays in the rostral intralaminar and thalamic nuclei to the cerebral cortex. The base of pons does not participate in arousal, and lesions such as central pontine myelinolysis do not usually profoundly impair consciousness. Instead, these lesions can interrupt all motor output except vertical eye movements and blinking that are initiated by nuclei in the mesencephalon (locked-in syndrome).

Mesencephalic and thalamic injuries, for example, as a result of occlusion of the tip of the basilar artery, or bilateral thalamic injuries, may result in somnolence, immobility, and decreased verbal output characteristic for MCS.

Bihemispheric injuries involving the cortex, white matter, or both may also result in impaired arousal.

Similarly, an acute unilateral hemispheric or cerebellar mass can lead to coma through destruction of the brain tissue and displacement of the falx and brainstem.

Physiologic brain dysfunction as a result of generalized tonic-clonic seizures, hypothermia, and poisoning or acute metabolic and endocrine derangements can also lead to coma. Typically, metabolic coma may spare the pupillary light reflex as it causes selected dysfunction of the cortex, whereas brainstem centers that control the pupils are spared. Hypoglycemia or nonketotic hyperosmolar coma, dysnatremia, thyroid storm, myxedema, fulminant hepatic failure, and acute hypopituitarism are examples in this category and should always be considered in a comatose patient. Asterixis, tremor, myoclonus, and foul breath may predominate the examination before these patients become unresponsive.

Malignant catatonia and psychogenic unresponsiveness should also be considered in all unresponsive patients.

Acute muscle paralysis (e.g., botulism or other toxins) should also be ruled out, because these patients may be awake and cognitively intact but unable to demonstrate responsiveness.

3 Name common causes of structural brain injury in comatose patients

Structural brain injuries may be caused by the following:

Bilateral cortical or subcortical infarcts (e.g., as a consequence of cardiac embolization or occlusion of major cerebral vessels)

Bleeding (e.g., hemorrhagic contusions, epidural or subdural hematoma, subarachnoid hemorrhage)

Infections (e.g., meningitis, cerebral abscess, subdural empyema, and herpes encephalitis)

Neoplasm (primary tumors and metastases)

Vasculitis and leukoencephalopathy, or lateral (acute midline shift of the brain of >1 cm) or downward herniation from mass effect or increased intracranial pressure (ICP) (e.g., massive brain edema, obstructive hydrocephalus)

4 Describe the mechanisms of toxin-induced coma

Depression of neuronal function can be caused by a reduction in the turnover of major neurotransmitters such as acetylcholine, dopamine, and serotonin through the γ-aminobutyric acid–benzodiazepine chloride iodophor receptor complex. Moreover, toxins can result in hypoxia (e.g., through respiratory depression or aspiration) or hypoglycemia (e.g., ethanol, β-blockers, and salicylates) leading to coma. Seizures can also be induced by toxins, as are acute cerebral bleedings, for example, caused by hypertension (cocaine, amphetamine) or coagulation abnormalities. Insulin is a common factor among patients with insulin-dependent diabetes.

5 What are the initial steps in managing a patient with coma?

The immediate approach to the comatose patient includes measures to protect the brain by providing adequate cerebral blood flow and oxygenation, reversing metabolic derangements, and treating potential infections and anatomic or endocrine abnormalities.

The clinician must ensure that the patient has a patent and protected airway and adequate breathing. Supplemental oxygen should be administered and airway secured by intubating the trachea, if needed.

Vascular access should be obtained and hypotension corrected with vasopressor agents or fluid administration as required.

Blood samples should be obtained to rule out infection and metabolic or endocrine abnormalities.

Generalized seizures should be treated and metabolic abnormalities corrected as soon as possible.

If the cause of coma is uncertain and hypoglycemia cannot be excluded, 50% dextrose should be administered. Empirical therapy for Wernicke encephalopathy or narcotic or sedative overdose should be considered and thiamine, naloxone, or flumazenil administered if appropriate. Thiamine must be given before dextrose to prevent worsening of Wernicke encephalopathy.

If increased ICP with mass effect is suspected, the patient should have hyperventilation, mannitol, or hypertonic saline solution administered, and specific surgical measures to evacuate possible mass or hematoma should be initiated.

If meningitis is suspected, antibiotic treatment should be initiated, and then a computed tomography (CT) scan of the head performed to rule out mass effect or herniation, in combination with laboratory evaluation for coagulopathy or thrombocytopenia before lumbar puncture.

6 Describe the diagnostic approach to the comatose patients

The history may be obtained from relatives, friends, police, or paramedics and may suggest an obvious cause such as drug or alcohol overdose, sepsis, or abnormalities of glucose metabolism. Acute onset of coma in a previously healthy person suggests intracranial hemorrhage, generalized seizure, poisoning, or traumatic brain injury. Gradual worsening, on the other hand, can indicate metabolic derangement, inflammatory neurologic disorders, cortical venous sinus thrombosis, or a gradually expanding intracranial mass. Physical examination should aim at identifying localizing neurologic deficits and possible triggering mechanisms. Blood sample and, if feasible, cerebrospinal fluid should be obtained to rule out infection, hypoglycemia, and other metabolic and electrolyte abnormalities. The depth of coma should be documented and graded on arrival and periodically thereafter to assess any change. Imaging studies such as a CT of the brain are often required to assess for structural causes of coma. Electroencephalography (EEG) can be helpful in diagnosing seizures or to identify EEG patterns suggestive of toxic metabolic abnormalities.

7 How can the respiratory pattern and brainstem reflexes help in the assessment of the comatose patient?

Respiratory pattern and rate are often helpful in identifying the cause of coma. Hyperventilation, as an example, may be a response to hypoxemia, metabolic acidosis, toxins, or dysfunction within the pons. Cheyne-Stokes breathing may indicate diencephalic lesions or bilateral cerebral hemisphere dysfunction, for example, increased ICP or metabolic abnormalities. Cluster breathing is associated with high medulla or lower pontine lesions. Brainstem reflexes should be examined and focal motor abnormalities, as well as reflex asymmetry, recorded. Equal and reactive pupils may indicate toxic or metabolic causes, whereas a unilateral fixed and dilated pupil usually indicates oculomotor palsy possibly as a result of uncal herniation. Bilateral pinpoint pupils with minute reaction suggest a pontine lesion, and bilateral fixed and dilated pupils may indicate medullary injury, global anoxia, or hypothermia. Ocular bobbing (a repetitive rapid vertical deviation downward and slow return to neutral position) indicates a pontine lesion often seen in basilar artery occlusion, whereas ping-pong or windshield-wiper eye movements usually indicate bilateral cerebral dysfunction. Eye movements can safely be elicited in the comatose patient without cervical spine injury by performing the oculocephalic maneuver (often called “doll’s eyes”), that is, by rapidly rotating the head from side to side. If the paramedian pontine reticular formation and the vestibular system are intact, the eyes should move smoothly in the direction opposite to that in which the head is rotated.

If cervical spine stability is in question, or no response to oculocephalic maneuvers occurs, the oculovestibular response (often called “cold calorics”) can be tested instead. One tympanic membrane is irrigated with 30 mL of ice-cold water and the response observed. When the underlying brainstem structures are intact, both eyes will deviate laterally toward the side where the cold water is instilled. If cortical structures and parts of the frontal lobe are intact, there will be nystagmus with the fast phase toward the nonirrigated ear. In metabolic or toxic coma the clinician usually sees intact gaze deviation toward the irrigated ear but absent or abnormal nystagmus indicating cortical dysfunction. In many comatose patients with structural brainstem injury, the oculovestibular system is impaired, and deviation of the eyes is absent or abnormal.

8 How do you manage a comatose patient after the initial work-up and stabilization?

After the initial assessment and treatment of the underlying cause of coma outlined in the answer to question 5, the comatose patient should be admitted to a specialized critical care unit for supportive care and to maximize the chance of recovery. Cardiorespiratory support should be maintained as appropriate with attention to maintenance of cerebral oxygenation. Care should be taken for prevention of ventilator-associated pneumonia. Electrolytes should be monitored closely and replaced as required. Early initiation of full enteral nutrition should be initiated whenever possible. Other essential steps in the care of the comatose patient include measures to reduce risk of infections, gastric ulcer prevention, thromboembolism prevention, physical therapy, splinting where appropriate, and skin care for pressure ulcer prevention. Early tracheostomy may be considered if prolonged mechanical ventilation is deemed necessary.

9 What is diffuse axonal injury (DAI), and how is it diagnosed and graded?

DAI is a term that arose in the pre–magnetic resonance imaging (MRI) era and is commonly cited as the cause of coma in patients with traumatic brain injury (TBI) in the absence of space-occupying lesions or apparent structural injuries. It can, nevertheless, also be present with subdural or epidural hematomas. DAI is a primary lesion of rotational acceleration-deceleration head injury. In its severe form, hemorrhagic foci occur in the corpus callosum and dorsolateral and rostral brainstem with microscopic evidence of diffuse injury to axons (axonal retraction balls, microglial stars, and a generation of white matter fiber tracts). It can be clinically diagnosed after TBI when coma lasts >6 hours in the absence of intracranial mass, increased ICP, or cerebral ischemia. MRI is more sensitive than CT for detecting characteristics of DAI, and newer studies such as diffusion tensor imaging can demonstrate the degree of white matter fiber tract injury.

DAI is graded as mild when coma lasts up to 24 hours and is followed by mild to moderate memory impairment and disabilities.

Coma lasts >24 hours in moderate DAI and is followed by confusion and long-lasting amnesia, with memory, behavioral, and cognitive deficits.

In severe DAI, coma lasts for months, and the patient has flexor and extensor posturing, dysautonomia, cognitive impairment, and memory, speech, and sensory motor deficits.

10 Describe the natural history and prognosis of coma, PVS, and MCS

The prognosis of coma is dependent on the underlying cause and other comorbidities. Metabolic and toxic disturbances can often be fully reversed and have, therefore, generally a better prognosis. Coma after TBI has also a better outcome than after anoxic brain injury. Coma often evolves into PVS within a few weeks, but patients may remain in coma, PVS, or MCS permanently. The chance of meaningful recovery is minimal if PVS lasts >12 months after TBI, or >3 months in other cases. Typically, life expectancy is 2 to 5 years, but patients with MCS, particularly those who had TBI, have a better survival rate and an improved chance of functional recovery.

EEG has not been validated as a prognostic tool, but recent advances in neuroimaging have improved the ability to predict outcome and may be helpful to guide decision making. As an example, injuries to the corpus callosum and dorsolateral brainstem on MRI are predictive of poor recovery. Of interest, functional MRI recently demonstrated that there are regions of preserved brain function and willful modulation of brain activity in a handful of patients with PVS and MCS. Thalamic deep brain stimulation is a promising approach to these patients and may improve responsiveness. Most patients undergo a trial of central nervous system stimulants to try to improve arousal.

11 Describe the pattern of injury and prognosis in patients with hypoxic coma

Hypoxemia (low arterial PO₂) and ischemia (e.g., after exsanguination or cardiac arrest) result in neuronal injury through a necrotic pathway or under certain circumstances through apoptosis or necrapoptotic cell death. Areas that are particularly vulnerable to this type of injury include cerebral gray matter, predominantly in the third cortical layer, hippocampus, and basal ganglia (selective vulnerability). Globus pallidus is often affected in hypoxemia, and caudate nucleus and putamen are usually affected after ischemia. Purkinje cells and dentate nuclei, as well as inferior olives, are also commonly affected. Patients with normal pupillary light reflex, Glasgow Coma Scale (GCS)–motor >1 and spontaneous extraocular movements within 6 hours of injury, or those with GCS-motor >3 and improved GCS-eye at 1 day have better chances of regaining independence. Absence of pupillary light reflexes, abnormal oculocephalic reflex, absent motor response to pain, and bilateral absence of early cortical somatosensory evoked potential are predictive of poor outcome. An EEG pattern of myoclonic status epilepticus after cerebral anoxia is also strongly predictive of poor outcome.

Key Points Coma

1. Coma can be caused by structural injury of the ARAS, metabolic and endocrine derangements, and psychogenic or physiologic brain dysfunction.

2. After adequate oxygenation and circulation are ensured, it is important to identify the cause of coma and employ measures to correct potentially reversible conditions.

3. If the cause of coma is unknown, dextrose and thiamine should be administered early, and reversal of opioids, benzodiazepines, and neurotoxins should be considered. Infections, metabolic derangements, and structural injuries should be ruled out.

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11 Ropper A.H. Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med. 1986;314:953–958.

12 Simeral J.D., Kim S.P., Black M.J., et al. Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array. J Neural Eng. 2011;8(2):025027.

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14 Zandbergen E.G. deHaan RJ, Stoutenbeek CP, et al: Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet. 1998;352:1808–1812.

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