Coma, Vegetative State, Brain Death, and Increased Intracranial Pressure

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16 Coma, Vegetative State, Brain Death, and Increased Intracranial Pressure


Clinical Vignette

A 76-year-old man was found unconscious in bed at home. His wife informed the emergency physician that he had a history of prostate cancer but no risk factors for vascular disease. She denied knowledge of any recent head injury. He was totally unresponsive to verbal and painful stimuli. Neurologic examination showed he was comatose with pinpoint pupils. Eye movements to doll’s-eyes maneuvers were full and conjugate, and cold caloric stimulation of the ear canals produced ipsilateral tonic deviation of the eyes without nystagmus. There were bilateral withdrawal responses of his extremities to noxious stimuli, and bilateral Babinski signs.

Intravenous administration of 0.4 mg naloxone produced dramatic change, with full awakening within a few minutes. Results of a subsequent brain computed tomography (CT) were normal, confirming that there was no evidence of intracerebral, subarachnoid, or subdural hemorrhage, cerebral infarction, or mass lesions. When asked about narcotic use, the patient stated that he was no longer able to tolerate the pain of metastatic prostate cancer; he had taken an overdose of an opioid analgesic.

The first vignette reflects a common scenario for anoxic–ischemic brain injury secondary to cardiac arrest. The degree of recovery usually depends on a number of factors that include age, extent, or duration of the ischemic insult and the initial presenting neurologic examination. A detailed history, review of in-field records, and serial examinations is an essential first step in guiding prognostic predications and determining the need for further workup. The second vignette illustrates the classic case of “toxic-metabolic” induced coma. Despite profound unresponsiveness and very miotic pupils, neurologic examination demonstrated retained brainstem reflexes and CT results were normal. Although pontine hemorrhage is often suspected in a comatose septuagenarian with pinpoint pupils, intact reflexive eye movement strongly indicated a metabolic cause. The prognosis in such cases, in the absence of secondary hypoperfusion or anoxia, is overwhelmingly favorable.

Consciousness is the state of awareness of internal and external stimuli and is manifested by the ability to react to these stimuli through thought or by directed physical movement. Coma is the loss of awareness of stimuli and the ability to react voluntarily to them. Full consciousness of one’s self and the surroundings can be disrupted partially without total loss of arousal or wakefulness and is sometimes referred to as a state of stupor. Varying degrees of consciousness can therefore be roughly delineated by the specificity or accuracy of the response to a particular stimulus, and terms such as confusion, obtundation, or stuporous are used to reflect this. However, the most useful tool in following patients with altered mentation remains the exact description of patient behavior and reactions to specific stimuli. For example, it is preferable to indicate that a patient stays alert without stimulation but is unable to give the exact date and location or follow two sequential commands than to only say that the patient is confused or clouded. Nevertheless, defining terms may provide uniformity in meaning when encountered in patient records. Obtundation describes a condition in which repeated stimuli are needed to draw the patients’ attention back to a task. Stupor is a state of extreme inattention in which wakefulness and minimal interaction with the examiner can be achieved only by repeated or constant stimulation. Delirium is an acute confusional state often involving sympathetic nervous system overactivity with attention marred by hyperexcitability. Tachycardia, perspiration, hypertension, and hallucinations may all be features of delirium.

Because the examining physician can only infer thought from patients’ actions (e.g., speech or movement), a reliable and reproducible physical examination is essential in evaluating the comatose or stuporous patient. The neurologist must make every effort to establish the presence or absence of a directed nonreflexive response and judge its quality. For example, in basilar occlusion when the lesion is restricted to the basis pontis a “locked-in” syndrome occurs with the patient seemingly having no directed response to stimuli, yet on close examination may blink in an exact fashion to instructions and indirectly answer questions appropriately. Partially preserved voluntary vertical eye movements may also be present. Similarly, in patients with severe acute polyneuropathies such as Guillain–Barré syndrome, consciousness is preserved but difficult to assess and quantify secondary to profound peripheral weakness.

The Glasgow Coma Scale assesses and quantifies the degree of consciousness across three measures: response to verbal commands, response of eye opening, and the nature of motor movements in response to verbal or physical stimuli. Those not responding to verbal commands or opening their eyes with a Glasgow Coma Scale score of 8 or less are defined as being in a coma (Fig. 16-1). The Glasgow Coma Scale is one of the primary predictors of long-term outcomes, especially in cases of head trauma.

Prevalence of the different etiologies of coma varies depending on the population surveyed. For example, head trauma and intoxicants are the major causes in registries based on densely populated high-crime areas. Stroke and cardiac events are the leading etiologies in suburban areas with retirement communities. Overall, trauma, stroke, diffuse anoxic–ischemic brain insult (secondary to cardiorespiratory arrest), and intoxicants are the leading mechanisms for coma. Infections, seizures, and metabolic–endocrine disorders account for the remaining cases (Fig. 16-2).

States that affect cognition and attention without affecting wakefulness such as the various degenerative dementias (characterized by progressive cognitive deterioration) and focal brain lesions (which cause restricted cortical dysfunction) do not fit the definition of coma. Sleep is a normal patterned physiologic disconnection of the cortex from external stimuli and is discussed elsewhere (Chapter 15).

Evaluation and Treatment of the Comatose Patient

The initial evaluation of a patient in coma must occur simultaneously with its management. Any delay in treatment while waiting to determine the exact cause is not acceptable. Clearing the airway and ensuring adequate ventilation and oxygenation with a bag mask or intubation, if needed, must be addressed immediately. Management of hypotension must be prompt, especially in suspected cases of increased intracranial pressure (ICP). Hemodynamic collapse should never be attributed to an intracranial process, and cardiac or circulatory causes need to be sought. These form the “ABCs of coma management”: airway, breathing, and circulation (Fig. 16-3). Immobilizing the neck until a cervical spine injury is excluded is also important in cases of suspected trauma.

Emergent evaluation of comatose patients requires the following blood studies: a full blood count, glucose level, serum chemistry, toxicology screen, liver profile, thyroid function tests, arterial blood gases, and cultures. Creatine kinase and troponin measurements, in conjunction with electrocardiography, are important for excluding myocardial infarction and transient cardiac arrest. Anticonvulsant drug levels and an electroencephalograph (EEG) can help identify patients with nonconvulsive status epilepticus.

The immediately treatable causes of coma are hypoglycemia and narcotic intoxication. These can be managed promptly, once oxygenation and hemodynamic status are stable. Infusion of 100 mg thiamine must precede the infusion of 50 mL of 50% dextrose in water as a precaution against Wernicke encephalopathy. This is postulated to be due to osmotic or metabolic damage to the mammillary bodies and the medial thalamus exerted by glucose, which, in the absence of thiamine, cannot be transported and metabolized in the tissue. When narcotics overdose is suspected, such as in comatose patients with miotic pupils, 0.4 mg intravenous (IV) naloxone, a central opioid antagonist, improves the level of consciousness within minutes. Repeated doses may be needed to maintain wakefulness and reverse respiratory depression. Caution should be exercised for known or suspected opioid dependency as abrupt or complete reversal of opioid effects by repeated doses may precipitate an acute withdrawal state. In such instances, only supportive care should be provided once the diagnosis is made. Administration of flumazenil, a pure benzodiazepine antagonist (0.2 mg IV), given three to four times, can improve the mental state and reverse respiratory depression in benzodiazepine overdose. As with naloxone, it should be used cautiously in those with a history of long-term benzodiazepine use or dependency as it can precipitate seizures. It should generally be avoided in patients with epilepsy and those at risk of seizures.

Urgent intravenous antibiotic coverage is indicated for febrile patients because time is crucial in treating meningitis and septicemia (Chapter 48). Lumbar puncture should be performed only after brain imaging has excluded mass lesions that could lead to herniation.

Assessment of the comatose patient should include examination of the skin. Rashes may indicate streptococcal or staphylococcal meningitis, bacterial endocarditis, or systemic lupus erythematosus. Purpura may indicate meningococcal meningitis, a bleeding diathesis, or aspirin intoxication. Skin dryness suggests anticholinergic or barbiturate overdose, whereas excessive perspiration indicates cholinergic poisoning, hypoglycemia, and other causes of sympathetic overactivity. Dark pigmentary changes in the axillary and genital areas suggest adrenal insufficiency, whereas doughy pale skin is typical of myxedema. Renal failure may present with urea salt crystal skin condensations or “urea frost.” Facial or basal skull fractures often cause ecchymosis around the eyes (raccoon eyes or panda bear sign) or in the mastoid area (Battle sign). Extremities must be examined for needle and track marks that indicate intravenous drug abuse.

The patient’s breath may be uremic, fruity as in ketoacidosis, or have the musty fishy odor of hepatic failure. Fever may indicate meningitis or encephalitis but also occurs with sympathomimetic or tricyclic (anticholinergic) overdose and drug or alcohol withdrawal. Occasionally a low-grade fever occurs with subarachnoid hemorrhage or brainstem lesions.

Focal neurologic signs on initial examination may implicate a structural lesion as the cause of coma and should be followed closely for signs of evolving herniation until brain imaging can be performed. Other causes of focal presentation are compensated old brain injuries clinically reemerging as a result of seizures, toxins, or metabolic derangements. However, metabolic disorders including nonketotic hyperosmolar hyperglycemia, hypoglycemia, and hepatic coma may cause focal seizures or lateralizing neurologic signs without focal brain lesions. Evolving signs of increased intracranial pressure or herniation must be treated promptly regardless of cause; there is no use in waiting for brain CT results or other tests.

Electroencephalography is often helpful in evaluating patients with altered consciousness or coma. An abnormal tracing makes psychogenic coma unlikely. EEG detects nonconvulsive or absence status, which can present de novo without a history of epilepsy. Although nonspecific, diffuse EEG background slowing correlates with metabolic derangements and focal slowing with localized structural brain disease. Hepatic and other metabolic encephalopathies may show triphasic waves. In herpes simplex encephalitis, periodic lateralized epileptiform temporal lobe discharges are often seen and support the clinical diagnosis. Finally, when a basis pontis lesion with the “locked-in syndrome” is suspected, a normal EEG shows that the patient is alert despite limited or no obvious response to stimuli.


Determining the prognosis of an individual comatose patient is a difficult task. Statistical numbers given to patients’ families as measures of outcome probabilities often are difficult to apply in relation to their loved one. The focus usually shifts to the chances of recovery, no matter how limited, rather than the likelihood of severe disability. A statistical grid or flow chart cannot be relied on to decide each individual case, and numerous factors, including cause of the coma, the evolution of the neurologic examination, age, comorbidities, and the religious or philosophical beliefs of the patient and the family must be considered.

Recovery from drug intoxication, barring ischemic brain injury from secondary hypoxemia or circulatory collapse, is usually good, with rare mortality or instances of severe disability. In hepatic and likely other metabolic comas, only brainstem dysfunction, with disruption of oculocephalic reflexes and loss of pupillary reactivity, increases the likelihood of poor prognosis or death. The duration of the coma and absent localizing motor responses do not exclude a good recovery and probably only reflect persistent metabolic derangement. Hepatic encephalopathy, to a large extent, is caused by the accumulation in the portal system of ammonia derived primarily from enzymatic activity of intestinal bacteria upon nitrogenous material and amino acids. Liver failure leads to shunting of portal vein ammonia into the systemic circulation and the brain not having proper detoxification. The effects of ammonia and other toxic elements on the brain include astrocyte swelling with cytotoxic brain edema, altered cerebral blood flow (CBF), and the accumulation of inhibitory neurosteroids and inflammatory cytokines. Numerous precipitants have been identified (anemia, constipation, dehydration, excessive dietary protein, gastrointestinal bleeding, metabolic alkalosis, hypoglycemia, hypothyroidism, hypoxia, infection, sedatives) and aggressive treatment is necessary to reverse the encephalopathy. Removal of intestinal ammonia with nonabsorbable disaccharides (lactulose) and antibiotics such as neomycin or metronidazole are commonly used and relatively effective. The mechanism of coma and brain edema in acute fulminate hepatic failure is less understood but likely involves some of the same pathophysiologic mechanism already described. However, a large proportion of these patients do not respond to treatment and have poor outcomes. Treatment consists of the above outlined measures and the preservation of cerebral perfusion pressure (CPP) by close monitoring and control of ICP. Liver transplantation, however, remains the most effective and immediate treatment to control brain edema and ICP and to reverse coma.

In most instances, coma from head trauma has a better outcome than that from nontraumatic mechanisms or cardiac arrest. Although severe head trauma has a mortality of approximately 50% within the first 48 hours, few surviving patients remain in a permanent vegetative state and most progress toward some degree of functional improvement. Those who remain vegetative usually succumb within 3–5 years. There are rare reports of patients who awaken after a prolonged vegetative period and show some return of functionality. None, however, return to their premorbid status or even an independent state. Signs that correlate with a poor prognosis after head trauma are age older than 60, bilateral pupillary abnormalities or absent oculocephalic reflexes at initial examination in a relatively stable patient. Large volumes of contused brain, large intra- or extra-axial hematomas, and lack of intracranial pressure response to conventional medical treatment (usually associated with compression of basal cisterns on CT) also betoken a poorer prognosis (Fig. 16-4).

Anoxic–ischemic causes of coma have a mortality rate of up to 60–70%, with generally only 10–15% of patients returning to a good functional status. The lack of bilateral pupillary responses for more than 6–12 hours correlates highly with poor functional outcome and death. Absent oculocephalic (vestibule–ocular or caloric) responses after 24 hours likely have the same prognostic value. In patients who do retain or regain pupillary reactivity, the absence of at least reflexive flexor motor movements on day 1, or some withdrawal movement on day 3, also holds a poor prognosis, with less than 10% chance of recovery to a state of even moderate disability. Lack of spontaneous eye opening or of localizing motor movements on day 7 holds the same grim prognostic significance. Myoclonus status epilepticus (generalized multifocal unrelenting myoclonus) correlates with severe ischemic damage to the cortex, brainstem, and spinal cord and is strongly associated with in-hospital mortality or a vegetative state.

Other laboratory findings have been shown to reliably predict a poor prognosis and can be used to assist in the evaluation. These include EEG tracings (without sedatives or metabolic abnormalities) showing patterns of complete suppression, burst suppression or periodic discharges upon a generalized flat background, absent N20 somatosensory evoked responses after 24 hours, and neuron-specific enolase >33 µg/L beyond the first day.

Vocalizations or any verbal response early within the first day of the causative event indicates a relatively good chance of functional improvement within a year.

These observations can guide families and staff toward the best course of action for each patient. Often the examination is changing or unclear. Consequently, further waiting and repeated evaluations, although stressful for the family, result in more certainty in the appropriateness of the eventual decisions taken. Those showing unfavorable prognostic signs on day 1 and who show no improvement or evolution in their neurologic examination are not likely to do well. However, for individuals who exhibit evolving neurologic function, the duration of observation needs to be extended and the final determination of outcome delayed, even if the initial examination shows no major interactive or directed function.