Catastrophic brain injury has widespread effects, among them coma. The assessment of comatose patients permeates the practice of all physicians. The causes of coma are many. Structural injury to the brain results in coma if it closely follows or directly affects the relay nuclei and connecting fibers that make up the ascending reticular activating system (ARAS). Its connections with the thalamus and both cortices make for a complex network (Box 8.1).
Elucidating the cause of coma cannot be compartmentalized into a simple algorithm, and novices may blanch and become unsure of themselves when a hastily ordered computed tomography (CT) scan and initial laboratory results are normal. The priorities in the evaluation of comatose patients have changed considerably with the arrival of magnetic resonance imaging (MRI). However, this may have encouraged a misconception that the cause of coma is easily established with neuroimaging. Relying solely on these tests can be counterproductive and potentially dangerous. Failure to recognize diabetic coma, thyroid storm, acute hypopituitarism, fulminant hepatic necrosis, nonconvulsive status epilepticus, or any type of poisoning while wasting time performing neuroimaging tests and waiting for cerebrospinal fluid (CSF) results may potentially lead to a rapidly developing neurologic fiasco.
The circumstances under which comatose patients are discovered can also be misleading. For example, a patient found next to an empty bottle of analgesic medication may have fulminant meningitis, traumatic head injury with skin lacerations may be a consequence of a fall from acute hemiplegia or brief loss of consciousness, and patients with massive intracerebral hematomas may be intoxicated. Comatose patients presenting with flexor posturing may have self-administered alkaloids as a recreational drug and, although suspected initially, may not have a primary structural lesion.1 Another dramatic situation occurs when a patient with diabetes consumes a little alcohol but fails to have dinner and is brought in comatose and smelling of alcohol but also is profoundly hypoglycemic. All of these eventualities have the potential for misjudgment.
Evaluation of comatose patients requires a systematic approach, exploring five major categories: (1) unilateral hemispheric mass lesions that compress or displace the diencephalon and brain stem; (2) bilateral hemispheric lesions that damage or compress the reticular formation in the thalamus, interrupting the projecting fibers of the thalamus-cortex circuitry; (3) lesions in the posterior fossa below the tentorium that damage or compress the reticular formation; (4) diffuse brain lesions affecting the physiologic processes of the brain; and (5) less commonly, psychiatric unresponsiveness, mimicking a comatose state (Table 8.1). Accidental and self-inflicted poisoning and illicit drug overdose are common in the emergency department and thus receive proportionally more attention in this chapter.
Three major issues in the clinical approach to comatose patients are discussed. First, this chapter merges a thorough physical examination with a neurologic examination. Second, it emphasizes stabilization of the patient in a threatening state. Many stabilizing measures are simple, require virtually no specific skills, are easily mastered, and should be applied by physicians without delay. Third, it consolidates the priorities of diagnostic tests and provides recommendations for management and triage in each of the major categories.
Box 8.1. Ascending Reticular Activating System
The role of the ARAS is to arouse and maintain alertness. Despite identifiable structures, its definition remains conceptual. Coma is understood as a dysfunction of this anatomic neural network, which spans a large part of the rostral upper pons, mesencephalon, and thalamus and projects to the cerebral cortex of both hemispheres. Populations of neurons situated in the tegmentum of the pons and mesencephalon, intralaminar nuclei of the thalamus, and posterior hypothalamus are linked to the basal fore-brain and associated cortex (Fig. 8.1). These networks communicate through neurotransmitters, such as acetylcholine, norepinephrine, serotonin, and dopamine and, through activation of the fore-brain, produce wakefulness.
Figure 8.1 Ascending reticular activating system. By permission of Mayo Foundation.
Table 8.1. Classification and Major Causes of Coma
Examination of the Comatose Patient
In assessing the nature of coma, an examination that sorts out representative localizing neurologic findings remains of great importance. Equally important is a reliable history. Relatives, bystanders, and police may all provide important information, including personal belongings and medical alerts.
The onset of coma may provide a clue. Acute onset in a previously healthy person points to aneurysmal subarachnoid hemorrhage, a generalized tonic-clonic seizure, traumatic brain injury, or self-induced drug poisoning. Gradual worsening of coma most often indicates an evolving intracranial mass, a diffuse infiltrative neoplasm, or a degenerative or inflammatory neurologic disorder.
A general physical examination is essential and may unpredictably provide a plausible explanation for altered awareness.
General Clinical Features
The general appearance of the patient may be deceptive, but extremely poor hygiene or anorexia may indicate alcohol or drug abuse. A foul breath in most instances means poor dental and periodontal hygiene or alcohol consumption. The classic types of foul breath should be recognized. These are “dirty restroom” (uremia), “fruity sweat” (ketoacidosis), “musty or fishy” (acute hepatic failure), “onion” (paraldehyde), and “garlic” (organophosphates, insecticides, thallium).
Fever and particularly hyperthermia (>40°C) in comatose patients may indicate an inflammatory cause, such as acute bacterial meningitis or encephalitis, but can occur in massive pontine hemorrhage, aneurysmal subarachnoid hemorrhage, and traumatic head injury. It may originate from direct compression, ischemia, or contusion of the hypothalamus. Hypothermia (<35°C) indicates exposure to a cold environmental temperature, a systemic illness, or intoxication. In patients with a devastating traumatic brain and spine injury, it may be a systemic sign of brain death or acute spinal cord transection.
Figure 8.4 Methods of pain stimuli in coma. A: Compression of temporomandibular joints. B: Compression of nailbed with handle of reflex hammer. C: Supraorbital nerve compression. By permission of Mayo Foundation.
Examination of the skin may provide important additional findings leading to the cause of coma. Bullae or excoriated blisters at compression points are nonspecific in most comatose patients but may indicate barbiturate overdose (see Color Fig. 8.2 in separate color insert). Carbon monoxide exposure, amitriptyline, theophylline, and diabetic ketoacidosis have also been linked to this curious skin manifestation.2,3,4 In a patient with a long bone fracture, rapidly developing pulmonary edema, and acute unresponsiveness, petechiae in the axilla strongly indicate fat emboli (see Color Fig. 8.3 in separate color insert). Intravenous illicit drug use should be considered when appropriate, and the skin should be carefully inspected for needle marks in multiple sites outside the cubital fossa. (However, scars in the cubital fossa alone often may indicate that the patient is a blood donor or receives regular blood transfusions.) Significant periorbital ecchymosis (“raccoon eyes”) and retroauricular ecchymosis (Battle's sign) indicate midface or skull base fractures; they should be carefully looked for but often become apparent much later. The skin should be touched at different areas to assess its texture; both dry skin and skin drenched in sweat may point to certain intoxications (Table 8.2). Dry skin in a comatose patient (particularly in moist locations such as the feet, groin, and axilla) points to overdose of anticholinergic agents (common tricyclic antidepressant). Characteristically, these intoxications are associated with tachycardia, fever, and cardiac arrhythmias. As discussed in a later section, because electrocardiographic abnormalities can be entirely absent in tricyclic antidepressant overdose, its recognition may thus be extremely difficult. Profuse sweating should always point to organophosphate pesticide poisoning or severe hypoglycemia.
Table 8.2. Important Skin Abnormalities That May Have Discriminatory Value in Assessment of Coma
Table 8.3. Common Changes in Vital Signs in Coma from Poisoning
Hypertension is a common clinical feature in coma associated with acute structural CNS lesions and therefore has little predictive value. It usually subsides after the sympathetic outburst associated with the initial insult wanes, but unexplained surges of hypertension indicate poisoning from certain drugs, such as amphetamines, cocaine, phenylpropanolamine, hallucinogens, and sympathomimetic agents. Conversely, hypertension should be considered a cause of diffuse encephalopathy only in patients with profound hypertension (diastolic values ≥:140 mm Hg), documented seizures, and papilledema, key signs that are often preceded by visual hallucinations.
Combinations of changes in vital signs may suggest certain poisonings. They are summarized in Table 8.3 and may be helpful in narrowing down the endless list of possible intoxications.
It should reflect the astuteness of a clinical neurologist to first evaluate whether the patient truly is comatose, in locked-in syndrome, or malingering. In locked-in syndrome, an acute structural lesion in the pons (which spares pathways to oculomotor nuclei of the mesencephalon and reticular formation) causes a nearly uncommunicative state. Before pain stimuli are applied, the patient should be asked to blink and look up and down. Grim accounts have been published of failure to appreciate this entity.5
The depth of coma should be documented, and many coma scales have been devised. Only the Glasgow Coma Scale (a combination of the best possible eye, motor, and verbal responses, as summarized in Table 8.4) has been tested for its reliability in daily clinical practice.6,7 This scale remains unsurpassed. (The need for the scale arose when researchers in Glasgow realized that a standard language had to be used rather than vague statements such as “He seems a bit brighter today.”8) The individual components of the Glasgow Coma Scale have been graded, at times summed to a score between 3 and 15. Grading coma by sum scores of the Glasgow Coma Scale alone is misleading because similar sum scores could represent different levels of decreased consciousness. A stimulus to elicit a response to pain, if needed, must be standardized: compression of the nailbed with the handle of the reflex hammer or pen, compression of the supraorbital nerve, or compression of the temporomandibular joint (Fig. 8.4).9Alternative stimuli are sternal and axillary rubs squeezing the trapezius muscle.
Table 8.4. Glasgow Coma Scale
Figure 8.5 Glasgow coma score. By permission of Mayo Foundation.
The components of the Glasgow Coma Scale (Fig. 8.5) are as follows:
1. Eye opening. By definition, patients in coma have their eyes closed. Spontaneous eye opening, however, does not portend awareness. Patients in a persistent vegetative state frequently have their eyes open, and they spontaneously blink. Eye opening can be produced by aural stimulus, such as a loud voice, or pain stimulus. Obviously, one should take care not to use both a loud voice and a pain or sternal rub stimulus at the same time. Eye opening is difficult to assess in patients with facial trauma or periorbital edema.
2. Motor response. By convention, the “best” motor response of the arm is noted, particularly when a different response between left and right exists. Responses in the legs are noted. They may vary from none to a triple-flexion response (flexion of hip, knee, and ankle) to following commands to wiggle the toes. In the fully alert patient, the legs can be crossed, mostly indicating a comfortable degree of relaxation (arguably this position is not seen in patients in acute distress).
The motor response is one of the most important elements in the neurologic examination of the comatose patient. Motor response is graded from “following commands or obeying” to “no response after a pain stimulus.” It additionally is useful to ask the patient to follow simple commands rather than to squeeze a hand alone because reflex grasping may be misinterpreted as obedience. An example of a simple command is to ask the patient to show a thumbs-up, fist, or victory sign.10 For localization of a pain response, the arms should either cross the midline toward a contralateral nail bed compression or reach above shoulder level toward a stimulus applied to the face. Withdrawal to pain is quick (snap-back response), usually involving only flexion and not arm or wrist flexion and adduction. Motor responses may include the so-called primitive responses. Both abnormal flexor responses (decorticate rigidity) and abnormal extensor responses (decerebrate rigidity) are nonlocalizing, indicating bilateral hemisphere diencephalic or brain stem lesions. Abnormal extensor responses imply a more severe lesion but not necessarily a worse prognosis. An abnormal flexion response in the arms (decorticate) is indicated by stereotyped, slow flexion of the elbow, wrist, and fingers, with adduction of the arms. An abnormal extensor response in the arms (decerebrate) consists of adduction and internal rotation of the shoulder and pronation of the hand with extension, internal rotation, and plantar flexion of the legs. Extreme extensor posturing may result in fist formation (thumb in palm) or wedging of the thumb between the index and middle fingers. Its presence is indicative of imminent demise (Fig. 8.6). 3.
3. Verbal response. A normal verbal response is speech that implies awareness of self, environment, and circumstances. The patient knows who he or she is, where he or she is, and why he or she is there. Confused conversation is conversational speech with disorientation in content. Inappropriate speech is intelligible but consists of isolated words only and may include profanity and yelling. The term incomprehensible speech refers to the production of fragments of words, moaning, or groans alone. Lack of speech may denote mutism or anarthria and speech is obviously absent in endotracheally intubated patients.
Meningeal irritation should be assessed (Fig. 8.7 and 8.8) but becomes less apparent in patients with deeper stages of coma (e.g., no eye opening to pain, abnormal motor responses, and moaning only). Both the classic Kernig sign (inability to extend the leg with flexion at the hip) and the Brudzinski sign (flexing the neck causes flexion of the hips and knees) may be useful, but the diagnostic value for meningitis has been questioned by some.11 Muscle tone can be flaccid (normal in coma but may indicate intoxication with benzodiazepine or tricyclic antidepressant poisoning) or rigid (e.g., neuroleptic agents, etomidate, strychnine, malignant catatonia, or malignant hyperthermia). Abnormal movements such as twitching in the eyelids (may indicate seizures), tremors, myoclonus (anoxic-ischemic encephalopathy, lithium intoxication, penicillin intoxication, pesticides), asterixis (acute renal, liver, or pulmonary failure), and shivering (sepsis, hypothermia) should be noted and integrated into the interpretation of the examination.
Neurologic examination proceeds with the cranial nerves. The size of the pupils and whether they are equal, round, oval, or irregular should be noted. It is important to understand the meaning of a unilateral dilated, fixed pupil (frequently designates uncal herniation); bilateral fixed, midposition pupils (frequently designate diencephalic herniation); brain death, or intoxication with scopolamine, atropine, glutethimide, or methyl alcohol); and pinpoint pupils (frequently designate narcotic overdose, acute pontine lesion, or syphilis [Argyll Robertson pupils]). The pupillary reactions to an intense beam from a flashlight are studied for both eyes. A magnifying glass may be needed to evaluate questionable “sluggish” pupillary responses, particularly in patients with small pupils. Pupillary abnormalities and their significance are shown in Figure 8.9.
Figure 8.6 Extreme form posturing, poor prognostic sign (fist and thumb in fingers).
Figure 8.7 Kernig's sign.
Funduscopy may reveal diagnostic findings in comatose patients. Subhyaloid hemorrhage (see Color Fig. 8.10A in separate color insert) is seldom seen in coma but when present implies aneurysmal subarachnoid hemorrhage (see Chapter 13) or shaken-baby syndrome (see Chapter 20). Papilledema (see Color Fig. 8.10B in separate color insert) indicates acutely increased intracranial pressure but also is present in some patients with acute asphyxia.
Absence of spontaneous eye movement should be documented, along with lateral deviation to either side or disconjugate gaze at rest. Forced gaze deviation indicates a large hemispheric lesion at the site looked at. Spontaneous eye movements—periodic alternating gaze, ocular dipping, and retractory nystagmus—may be seen in coma but have no localization value other than indicating diffuse brain injury. (However, ocular bobbing—rapid downward, slow return to baseline—is typical for acute pontine lesions.) The oculocephalic responses are evaluated in conjunction with passive, brisk horizontal head turning, and, if appropriate, the response to vertical head movements can be tested. (In patients with any suspicion of head or spine injury, the oculocephalic responses should not be tested because movement may luxate the cervical spine if fractured and immediately cause spinal cord trauma.) Oculovestibular responses are tested by irrigating each external auditory canal with 50 mL of ice water with the head 30 degrees above the horizontal plane (an intact tympanum needs to be confirmed). Comatose patients exhibit tonic responses with conjugate deviation toward the ear irrigated with cold water. Bilateral testing can be done by rapidly squirting 50 mL of ice water in each ear, resulting in a forced downward eye movement. Abduction of the eye only on the side being irrigated with adduction paralysis of the opposite eye implies a brain stem lesion (internuclear ophthalmoplegia) as a cause of coma (Fig. 8.11).
Figure 8.8 Brudzinski's sign.
Figure 8.9 Pupil abnormalities in altered consciousness and coma.
Finally, corneal responses are tested by drawing a cotton wisp fully across the cornea. Spontaneous coughing or coughing after tracheal suctioning is recorded (to-and-fro movement of the endotracheal tube is not an adequate stimulus). Absence of coughing may indicate either that the neurologic catastrophe has evolved into brain death or that sedative or anesthetic drugs or neuromuscular blocking agents for emergency intubation have markedly muted these responses.
The clinical diagnosis of brain death is strongly suspected when all brain stem reflexes are absent in a comatose patient, but the cause of the catastrophic event should be known and demonstrated to be irreversible.12,13,14 It often is suggested when patients with fixed pupils stop bucking the ventilator and blood pressure suddenly decreases to low systolic values around 80–90 mm Hg. Brain death can be diagnosed in the emergency department but remains a presumptive diagnosis, and organ donation should not proceed directly from this location.
Any physician assessing a patient with brain death should be very sensitive to the possibility that confounding causes may be present, particularly in patients admitted directly to the emergency department. Even when a catastrophic brain lesion is demonstrated on neuroimaging, the circumstances should be considered ambiguous until the history is complete and, if appropriate, a toxicologic study has ruled out drug ingestion.
Figure 8.11 Internuclear ophthalmoplegia associated with acute pontine lesion. Eye position with eyelid opening (A). Adduction paralysis (arrow) can be elicited by cold water irrigation of the right ear (B) or the left ear (C).
The accepted clinical criteria for brain death are shown in Figure 8.12. The technical procedure for the apnea test is shown in Table 8.5.
Assessment of Patients with Structural Causes of Coma
Structural lesions are often acute (hemorrhage, infarct, abscess) or may be a critical extension of an infiltrating tumor, abscess, or giant mass. The boundary in the vertical axis is the lower pons. Destructive lesions below this level may lead to acute dysfunction of autonomic nuclei, resulting in failure to drive respiration or vascular tone. Coma or impaired consciousness in localized medulla oblongata lesions therefore is only an indirect consequence of hypercapnia or hypotension-induced global hemispheric injury. These lesions do not involve the ARAS structures and thus by themselves do not produce coma or hypersomnia.15 These medullary structural lesions may involve hemorrhages (often arteriovenous malformation or cavernous hemangioma), metastasis, lateral or medially located medullary infarct, or an inflammatory lesion such as a bacterial or fungal abscess.
Tegmental pontine lesions interrupt the ARAS midway but result in impaired consciousness only with bilateral injury. The base of the pons does not participate in arousal; therefore, large lesions such as infarcts or central pontine myelinolysis do not impair consciousness but may interrupt all motor output except vertical eye movement and bunking initiated by centers in the mesencephalon. As alluded to earlier, this “locked-in syndrome” is often mistaken for coma until blinking and repeated up-and-down eye movements seem to coincide with questions posed to the patient. Cognition is intact, and patients may communicate through code systems.
Figure 8.12 Brain death diagnosis and guidelines for confirmatory testing. *Evidence preferably based on computed tomographic scan or cerebrospinal fluid exam. **Confirmatory test such as cerebral angiography, nuclear scan, or transcranial Doppler ultrasonography may obviate observation over time. ***Criteria vary worldwide. PaCO2, partial pressure of arterial CO2; EEG, electroencephalogram.
Mesencephalic damage usually is seldom seen in isolation and more commonly occurs from extension of a lesion in the thalamus (e.g., destructive intracranial hematoma) or as a result of occlusion of the tip of the basilar artery, producing simultaneous infarcts in both thalami and in the mesencephalic tegmentum.
Bilateral thalamic damage resulting in coma most often involves the paramedian nuclei, but damage to interlaminar, ventrolateral, or lateral posterior nuclei may impair consciousness by interrupting the thalamic cortex and thalamocortical projections. Infarcts in the distribution of the penetrating thalamogeniculate or anterior thalamic perforating arteries are the most common causes of bilateral thalamic damage, but an infiltrating thalamic tumor or infiltrative intraventricular masses in the third ventricle can produce sudden coma. Ganglionic hemorrhages may extend into the thalamus and compress the opposite thalamus.16 Bithalamic hematoma is more commonly seen as an extension of pontine hematoma (see Chapter 14). Combined thalamic and mesencephalic damage may result in so-called slow syndrome, characterized by immobility, voiceless-ness, flat emotions, and somnolence most of the day.15
Bihemispheric structural damage may involve the white matter or cortex or both, and a diversity of disorders may produce damage severe enough to reduce arousal. The most notable disorders are anoxic-ischemic encephalopathy from cardiac standstill destroying most of the cortical lamina, multiple brain metastatic lesions, multi-focal cerebral infarcts from isolated central nervous system (CNS) vasculitis, multiple emboli from a cardiac source, markedly reduced global cerebral blood flow from acute subarachnoid hemorrhage, cerebral edema, hydrocephalus, blunt head trauma causing extensive scattered lesions in white and gray matter structures, and encephalitis (see Table 8.1). Unusual structural causes for coma are bilateral internal carotid occlusions, very commonly leading to loss of all brain function from profound swelling within days.17
Table 8.5. The Apnea Test (Apneic Diffusion Method)
Assessment of Patients with Acute Unilateral Hemispheric or Cerebellar Mass
Two major clinical manifestations may be observed in patients with an acute hemispheric mass: first, direct destruction of brain tissue leading to clinical features related to the involved lobe and, second, remote effects from herniation and buckling of essentially normal tissue.
The differential diagnosis in unilateral brain masses is extensive (Table 8.6).
The quintessential patterns of brain herniation from mass effect are (1) cingulate herniation, (2) central syndrome of rostrocaudal deterioration (herniation of the diencephalon structures, such as the thalamus), (3) uncal herniation, and (4) upward or downward herniation of brain tissue of the posterior fossa (Box 8.2).
Cingulate herniation is often asymptomatic, and typically a diagnosis made by CT scanning or MRI. It most frequently is a prelude to central or uncal herniation, when masses shift brain tissue even more. The cingulate gyms is squeezed under the falx, but unless the anterior cerebral artery occludes (producing infarction and edema with frontal release signs and abulia), no major neurologic manifestation can be expected.
Central or diencephalic herniation occurs when a mass located medially forces the thalamus-midbrain through the tentorial opening. During this downward shift, the brain stem caves in and becomes distorted, and the shearing off of penetrating branches from the basilar artery fixed to the circle of Willis results in irreversible brain stem damage.
Signs of central herniation have been recognized by the evolution of midposition or small bilateral pupils with sluggish light responses. At the same time, respiration becomes rapid, often with intermittent Cheyne-Stokes breathing. Patients barely localize pain stimuli and may fidget with bed linen or show a withdrawal response. Further progression results in extensor posturing and development of midposition pupils (diameter 5–6 mm) unresponsive to light, disappearance of oculocephalic reflexes, and irregular gasping. Central herniation may progress to a midbrain stage in a matter of hours but then halts or very slowly progresses further (Fig. 8.13). Central herniation may progress rapidly, but it is possible that the earlier signs of drowsiness, increased respiratory drive, and development of worsening motor responses are not appreciated by the physician or wrongly attributed to a new insult to the opposite hemisphere (e.g., in patients with a recent ischemic stroke).
Table 8.6. Diagnostic Considerations in Patients with Single Intracranial Mass
Box 8.2. Mechanisms of Herniation
Acute unilateral hemispheric masses may produce herniation syndromes from their volume or from surrounding edema. Whether displacement horizontally or vertically correlates with changes in consciousness and evolution of clinical signs remains a matter of some controversy. An alternative provocative but meritorious view is that horizontal shift measured by CT or MRI correlates better with early changes in consciousness in acute unilateral masses.18,19 The diencephalic structures are compressed and dislocated toward the opposite side of the mass lesion. Bilateral masses “pinch” the upper brain stem rather than push it down. In addition, direct destructive damage of the thalamus with compression of the opposite dorsal thalamus may produce in the process bilateral involvement of the ARAS and may cause coma despite an impressive shift in all directions (e.g., large, destructive putamen hematomas).19 The significance of vertical displacement thus may be vastly overrated, and early thalamus damage may be key. However, advances in neuroimaging studies have allowed us to identify the development of mesencephalon ischemia from progressive vertical shift or disappearance of the fourth ventricle from brain stem impaction, suggesting that rostrocaudal deterioration is key in the development of progressive stages of herniation,20 However, it is not certain whether these changes on MKI are the defining moment of irreversibility.
Uncal herniation denotes displacement of the uncal gyrus, which is part of the temporal lobe, into the incisura tentorii. Uncal herniation has a more apparent presentation, with sudden appearance of a wide pupil with loss of light response. Ptosis, adduction paralysis, and diminished elevation of the affected eye are seen. Level of consciousness is reduced further when the uncus forces itself through the tentorium, flattening the midbrain and shifting it to the opposite direction. Contralateral hemiparesis occurs when the brain stem truly is squeezed against the opposite tentorial edge, damaging the pyramidal long tracts (classically named after Kernohan, Kernohan's notch). The midbrain displaces horizontally and may rotate if the compression is off center. The process can progress only more vertically, or the brain stem buckles and is squashed (Fig. 8.14). Compression of the brain stem causes smaller pupils (often misinterpreted as “improvement of the blown pupil” after administration of mannitol). Damage to the pons may lead to a transient locked-in syndrome.21 Many of these features can be recognized on neuroimaging.
Acute cerebellar masses (e.g., hematoma) are manifested by vertigo, acute inability to walk, and excruciating headache. Vomiting is common, and many patients can only crawl to the bathroom. Approximately 60% of patients have a noticeable ataxia and nystagmus on examination before level of consciousness deteriorates from upward or tonsillar herniation.
Upward herniation occurs when the brain stem is lifted upward or when cerebellar tissue, particularly the vermis, is squeezed through the tentorial notch into the supracerebellar cisterns. The effects of brain stem compression and upward herniation are almost impossible to distinguish clinically. Patients deteriorate with progressive paralysis of upward gaze and further lapse into a deeper coma. Pupils become asymmetric and finally contract to pinpoint size when pontine compression advances. MRI can document these anatomic changes with accuracy (Fig. 8.15).22
Figure 8.13 Normal anatomy (A), sketch of central or diencephalic herniation (B), and corresponding magnetic resonance image (C). Note downward movement of the brain stem. The red nuclei (only visible using spin echo sequences), usually horizontally aligned, have tilted (arrows). Ischemic brain stem lesions are the result of tearing of the penetrating arteries. ACA, anterior cerebral artery; PCA, posterior cerebral artery; vent., ventricle; III, third cranial nerve.
Figure 8.14 Normal anatomy (A), sketch of uncal herniation (B), and corresponding magnetic resonance image (C,D). Note uncal herniation (C) (arrows) and disappearance of the oculomotor nerve due to compression (D) (arrow points to opposite oculomotor nerve). ACA, anterior cerebral artery; PCA, posterior cerebral artery; vent., ventricle; III, third cranial nerve.
Assessment of Patients with Poisoning or Drug Abuse Causing Coma
Intentional poisoning and drug abuse are common causes of coma in patients admitted to emergency departments (Box 8.3). The distribution of causes may reflect the geographic location of the hospital. The most common substances used for self inflicted death by poisoning are tricyclic antidepressants, salicylates (particularly children), and street drugs. In the elderly, suicide attempts and unintentional intoxication through misjudgment of dose remain leading circumstances.
This section reviews the most commonly encountered poisonings causing coma. It is hardly possible to discuss all drugs that may cause coma; in fact, many do when ingested in enormous quantities. Polydrug abuse or intentional intoxication often results in widely different clinical presentations. Many of the drug overdose cases are so complicated and difficult to diagnose that physicians are left with a dizzying array of possibilities. There is a potential flaw in presenting these intoxications in a simplistic fashion, but some clinical patterns are truly characteristic and should be recognize at first appearance.23
Figure 8.15 Normal anatomy (A), sketch of tonsillar herniation (B), and magnetic resonance images (C) (arrows point to orientation lines). The iter of the aqueduct, usually located on the horizontal line drawn from the anterior tuberculum sellae to the confluence of the straight sinus and great vein of Galen, is upwardly displaced. The cerebellar tonsils are herniated below the line of the foramen magnum. ACA, anterior cerebral artery; PCA, posterior cerebral artery; vent., ventricle; III, third cranial nerve.
Box 8.3. Mechanisms of Toxin-Induced Coma
Coma induced by poisoning may result from at least five mechanisms. First, a chief factor may be hypoglycemia. Because many toxins cause profound hypoglycemia, early intravenous administration of glucose in any comatose patient has been advocated. Common examples are salicylates, β-adrenergic blockers, and ethanol.
Second, in other toxins, hypoxia is the main mechanism underlying coma and is produced by interference of oxygen transport, tissue utilization of oxygen, or simply displacement of oxygen by another gas, such as an industrial gas. Hypoxia can also be produced by acute pulmonary edema (e.g., cocaine) or aspiration pneumonitis (e.g., after seizures).
Third, a major mechanism of coma is depression of neuronal function involving the γ-aminobutyric acid (GABA)-benzodiazepine chloride iodophor receptor complex. The mechanism of action through GABA, one of the major CNS neurotransmitters, is increased output of GABA, which also leads to reduction of the turnover of acetylcholine, dopamine, and serotonin, culminating in a marked hypnotic-depressant effect. Opioids, however, exert their depressant effects on the CNS through a different set of receptors.
Fourth, toxins may cause seizures, usually as a terminal manifestation, which may be followed by a postictal decreased level of consciousness or nonconvulsive status epilepticus.
Fifth, structural CNS lesions may be caused by the toxin itself or traumatic head injury. Coma in poisoning or drug abuse may be due to spontaneous intracranial hematoma (e.g., amphetamine or cocaine overdose) or hemorrhagic brain contusions associated with a fall.
Central Nervous System Depressants
CNS depressants first impair vestibular and cerebellar function. Therefore, nystagmus, ataxia, and dysarthria accompany or even precede the first signs of impaired consciousness.
Diagnosing an overdose of CNS depressant agents remains difficult, and one should appreciate the dangerous potential of some agents (e.g., tricyclic antidepressants).
Alcohol intoxication is a frequent cause of reduced arousal. Alcohol ingestion can be fatal, but for death to occur, extreme quantities of ethanol should have been consumed, and more often an alcoholic binge is combined with consumption of other depressant drugs, leading to respiratory arrest or respiratory airway obstruction from vomiting.24,25
The development of acute alcohol intoxication depends not only on the blood alcohol concentration but also on the rapidity of the increase in blood and on tolerance, which is significantly increased in heavy drinkers (typically, they are able to “drink someone under the table”). The clinical features of alcohol intoxication in relation to blood alcohol level are thus unreliable and apply only to naive drinkers. The clinical presentation of alcohol intoxication is well known and involves ataxia, dysarthria, loss of rapid reaction to sudden danger, and a feeling of high self-esteem that can lead to a series of misjudgments, including driving despite warnings from passengers. Aggression to well-intended restraint may lead to fist fights in susceptible persons and significant head injury or epidural hematoma due to acute skull fracture (see Chapter 20) overlying the middle meningeal artery.
Seizures are uncommon as a direct result of alcohol consumption but may be associated with severe hyponatremia (e.g., after consumption of large quantities at “beer fests”). Alcohol intoxication may mimic or coincide with many neurologic disorders, including hepatic encephalopathy, hypoglycemia, subdural hematoma, fulminant bacterial meningitis, and central pontine myelinolysis. Progressive confusion and combativeness in a previously alcoholic person, particularly if associated with tremors, marked (often initially unexplained) hypertension, and tachycardia, may indicate alcohol withdrawal and delirium. Recognition of profound alcohol withdrawal may become difficult, particularly if patients have passed well into a stage of agitation and decreased alertness.
The diagnosis of acute drunkenness seems straightforward, but laboratory confirmation and exclusion of confounding metabolic derangements are needed. Crucial laboratory tests should include measurement of serum alcohol level, arterial blood gases (to exclude hypoventilation), electrolytes, blood glucose (alcohol reduces gluconeogenesis and causes hypoglycemia in a predisposed patient), calcium and magnesium, and serum osmolality. A large osmolar gap is compatible with alcohol intoxication. Routine drug screens should be performed at all times to rule out other ingested drugs of abuse. When truly measured, the legal limit in many states is 80 mg alcohol/100 mL blood, but toxic levels are usually more than 200 mg alcohol/100 mL blood.
Management of patients in stupor or coma from alcohol intoxication consists of endotracheal intubation to protect the airway, thiamine intravenously, rewarming, liberal intravenous fluids, treatment of recurrent seizures, if any, and frequent assessment and management of potential hypoglycemia.
Barbiturates are hypnotic-sedative agents that should be considered a cause of coma in drug addicts rushed into emergency departments. It is not surprising to find that barbiturates have been taken with other street drugs, and they may considerably deepen the level of coma.
Barbiturates significantly differ in duration of action (Table 8.7). They are very powerful stimulants of the inhibitory neurotransmitter GABA, resulting in early depression of respiratory drive. In the event of overdose, these differences often determine the time on the mechanical ventilator.
Depending on the degree of CNS depression, barbiturate overdose produces flaccid coma with initially small reactive pupils advancing to lightfixed, dilated pupils in near-fatal doses, often with associated profound hypotension from direct myocardial depression, clammy skin, and hypothermia. Bullous skin lesions (“coma blisters,” Fig. 8.2) can be seen at pressure points and are very uncommon at other sites, suggesting skin necrosis from ischemia rather than a specific cutaneous toxicity.
Table 8.7. Classification of Barbiturates
The depth of coma can be estimated by measurement of barbiturate levels and by an electroencephalogram, which in severe cases may show isoelectric tracing mimicking brain death, but more commonly displays a burst suppression pattern.
Management of barbiturate coma is supportive, with full mechanical ventilation until cough reflexes return. Vasopressors, such as dopamine, are needed to support blood pressure. Forced alkaline diuresis and hemodialysis with high blood flow rate should be considered.26
With the improvement in intensive care support and hemodialysis, outcome is difficult to predict on the basis of depth of coma. A landmark study by Reed et al.27 found that mortality was high in patients with respiratory failure, hypotension, and coma for more than 36 hours; but these data may not apply in modern times.
The prescription of antidepressant drugs for patients with severe depression may lead to use by the patient for a suicide attempt. This is possibly also related to the observation that it takes 2–3 weeks to achieve the antidepressant effect, and thus, patients with suicidal tendencies may take all of the medication at once. Tricyclic overdose is one of the principal causes of death in intensive care unit series of drug overdosing.28 By virtue of the profound cardiac toxicity of the drugs, death can be imminent in some patients on arrival in the emergency department.
Coma from tricyclic antidepressant toxicity may progress to a loss of all brain stem reflexes and apnea, mimicking brain death. However, coma with no response to painful stimuli occurred in only 13% of 225 patients with tricyclic overdose.29 Tricyclic overdose may be manifested by delirium from cholinergic blockade, and some patients have other manifestations, such as dry skin, hyperthermia, and dilated pupils.30 Seizures are common within hours of ingestion, often emerge at peak serum concentration, but seldom evolve into status epilepticus.31
A widened QRS interval on the electrocardiogram is a common manifestation, and at least initially cardiac arrhythmias may be absent. In a significant overdose, the management of cardiac arrhythmia determines care and can involve a temporary pacemaker. Sodium bicarbonate (50 mEq of NaHCO3, 1 mEq/mL) should be administered to produce alkalosis, which inhibits sodium channel blockade by tricyclic antidepressants, a mechanism thought to be responsible for cardiac arrhythmia. Seizures can be managed with intravenous administration of phenytoin or fosphenytoin, but because of its own risk of producing cardiac arrhythmias, this agent probably is indicated only if seizures recur.
Toxic manifestations of lithium are most often a result of incorrect dosage. Anticholinergic manifestations are common, including flushing of the face, dilated pupils, fever, and dry skin.32
With increasing blood levels, a rather slowly progressive clinical picture seems to emerge, characterized by myoclonus, hand tremor, and slurring of speech. This may further progress to delirium, acute mania, dystonic movements, oculogyric crises, facial grimacing, and, finally, stupor. Serum lithium levels are reasonably correlated with the severity of toxicity, which is serious when these levels reach or exceed 2.5 mEq/L.32
Restoration of sodium and water balance, which is disturbed by lithium-induced nephrogenic diabetes insipidus, is key in its management. Hemodialysis or peritoneal dialysis should be instituted immediately in most cases.
Patients with a benzodiazepine overdose (slang: downs, nerve pills, tranks) seldom are in need of a long hospital stay unless coingestions have occurred. Massive exposure to benzodiazepines results in coma, but with appropriate support, neurologic morbidity is rare. Coma can be profound, but most patients awaken within 2 days; recovery times are longer with increasing age.33
The clinical presentation of benzodiazepine poisoning is nonspecific, and coma with extreme flaccidity is common.34 Respiratory depression may not be evident, and hypoxic respiratory drive often becomes clear only when a pulse oximeter is connected to the patient on arrival in the emergency department. Not uncommonly, oxygen administration with high flow may then produce hypercarbia and hyperoxemia. Many patients may need to be intubated, but adjustment of the O2 source and rate-controlled, noninvasive ventilation may be effective in some instances.
The use of flumazenil is controversial because seizures from acute withdrawal have been reported. A more recent study in 110 patients contradicted these risks and demonstrated that flumazenil is safe.35
Abuse of Illicit Drugs
It is not possible to gather all illicit drugs under one umbrella and discuss them in a few paragraphs. This section discusses some of the most commonly encountered examples of drug overdose. For complex problems, readers should refer to major toxicology textbooks,36 available in most emergency departments, or a neurology text.37 Not infrequently, these unfortunate, poorly nourished, shelterless patients are found hypothermic or next to an empty syringe, bottle of liquor, or unlabeled pill vial.
Phencyclidine (slang, “angel dust”) is rising in popularity among illicit drug users and users in college students, and thus the prevalence of phencyclidine overdose is increasing in emergency departments. Phencyclidine is usually packed in tablets and sold as powder or mixed with marijuana (slang, “wacky weed”).36
Phencyclidine is a potent anesthetic agent, acting on both GABA and dopamine systems. Its clinical manifestations are highly unusual, with deep anesthesia and coma but a facial appearance of being fully awake.35 Typically, a strong pain stimulus is not registered by the patient, and this sign should immediately point to phencyclidine as a toxin. Commonly, phencyclidine produces hypertension, tachycardia, salivation, sweating, and bidirectional nystagmus. Many patients act violently, demonstrate bizarre behavior, and speak endlessly.38 Distortion of body image and vivid visual hallucinations may occur, and some patients are catatonic, which additionally may lead to rhabdomyolysis. When the patient's condition progresses to coma, cholinergic signs are obvious, with significant frothing, flushing, sweating (often with typical strings of large sweat droplets on the forehead), and miosis.38,39
Many patients recover fully with adequate ventilator support, but some may continue to manifest a schizophrenia-like picture of withdrawal, negativism, and delusions, which suggests chronic use of phencyclidine.
Cocaine (slang: blow, snow, toot, coke, rock) blocks the presynaptic uptake of norepinephrine and dopamine and causes excitation.40 Its recreational use is widespread, either by intranasal snorting or by smoking after dissolution in water and the addition of a strong base (so-called crack).
The clinical presentation after inhalation, smoking, or intravenous injection is characteristic. Patients have hypertension, widely dilated pupils, and tachypnea. Seizures often occur after the initial “rush.”41 In severely intoxicated patients, progression to generalized tonic-clonic epilepticus is not unusual.42,43
Coma from cocaine overdose may have other origins. These are cardiac arrest, producing a profound anoxic-ischemic encephalopathy; intracerebral or subarachnoid hemorrhage from brief malignant hypertension. Outcome is worse in aneurysmal subarachnoid hemorrhage associated with cocaine.44 Up to 50% of patients harbor a vascular malformation or aneurysm. Bilateral cerebral infarcts can be a result of diffuse vasoconstriction45,46 or long-standing occlusive disease of major cerebral arteries.47
General measures for cocaine overdose often include management of hyperthermia with cooling blankets or fans, α-adrenergic blockade or lidocaine to treat ventricular tachycardia, and careful monitoring for the possible development of acute myocardial infarction and recognition of status epilepticus.
Acute opiate overdose may be produced by heroin (diacetylmorphine [slang: “H,” speedball]) or deliberate use of massive doses of narcotic drugs used for pain control. Fentanyl dermal patches, particularly, have become popular for pain control, and the absorption of this very potent opioid is so erratic that rapidly progressive stupor may occur.48
The clinical manifestations of opiate overdose include miosis, hypoventilation, and flaccidity. Brain stem reflexes may become lost, and the preserved light reflex in patients with extremely small pupils may be impossible to discern. Severe hypoxia from hypoventilation or florid pulmonary edema may be a major contributory factor to coma. Seizures appear more commonly with meperidine and propoxyphene.
Management of opioid poisoning has been facilitated by the use of naloxone. This opiate antagonist is without major adverse effects, and dramatic reversal of coma is seen.
Arterial blood gas values are supportive in opioid overdose, demonstrating marked hypoxia and hypercapnia from hypoventilation. A point that cannot be emphasized strongly enough is that because serum drug screens do not identify opioids, urine samples are needed for detection. For other examples, see Appendix 8.1.
Naloxone is administered in doses of 0.4–2.0 mg repeated at 1- to 2-minute intervals. The effect is brief. An intravenous drip of naloxone is justified only in patients with a profound overdose resulting in hypotension and ventricular tachyarrhythmias.
Environmental and Industrial Toxins
Exposure to these toxins, whether intentional or accidental, frequently alters consciousness and produces prolonged coma long after the toxin has been eliminated, washed out, or neutralized. Important clues to environmental poisoning are dead pets and distinctive odors (from often-added sulfur-containing compounds) detected by neighbors.
The effect of these toxins on the CNS can be catastrophic, with a high probability of poor neurologic outcomes.
Carbon Monoxide Poisoning
Carbon monoxide remains one of the leading causes of death by poisoning. Exposure to this odorless gas is possible at the time of a fire, from poorly vented fireplaces, from furnaces, and in any closed space where internal combustion engines have been used without ventilation. In most instances, suicide can be implicated, but one-third of admitted patients are victims of accidental circumstances.
Carbon monoxide readily binds to hemoglobin, with a 200 times greater attraction than oxygen. The cerebral injury due to carbon monoxide poisoning, however, is an accumulation of factors. Early animal studies by Ginsberg49 clearly showed that the pathognomonic lesions can be produced only by carbon monoxide and hypotension and not by inhalation of carbon monoxide alone.
Carbon monoxide poisoning causes a shift of the hemoglobin dissociation curve to the left, which reduces oxygen unloading (Haldane effect). Through binding with myoglobin, carbon monoxide may trigger cardiac arrhythmias, hypotension, and hypoxemia from pulmonary edema, adding to the injury.50
The neuropathologic changes (selected from the most severe cases at autopsy) are predominant in the white matter, with demyelination and edema, and in the hippocampus, cerebellum, and globus pallidus. These lesions may be detected on CT scans;51 they predict a severely disabled state as the best possible outcome.52,53 MRI may more clearly delineate these abnormalities, which emerge even within hours of exposure, but only in patients with levels high enough to lead to coma (virtually always more than 50% carboxyhemoglobin levels).54
The symptoms preceding coma from carbon monoxide poisoning are nonspecific and vague, including headache, dizziness, and shortness of breath, all suggesting a developing viral illness. A cherry red appearance of the skin is very uncommon; it signals a near-fatal exposure.49 Other clinical findings are retinal hemorrhages, dark color of retinal arteries and veins, and pulmonary edema. Rhabdomyolysis may be related to pressure necrosis in patients immobilized for an unknown length of time.
The most important laboratory test is the determination of a carbon monoxide hemoglobin level, which may be “falsely low” if oxygen has been administered in the emergency room or if the time between exposure and blood testing is more than 6 hours, which is approximately the half-life of carboxyhemoglobin (a 5% level of hemoglobin carbon monoxide can be attributed to smoking). Other laboratory test results that are more or less supportive are metabolic acidosis, increased creatine kinase, and myocardial ischemia on electrocardiography.
Management of carbon monoxide poisoning is treatment with 100% oxygen with a sealed face mask. Hyperbaric oxygen increases the amount of dissolved oxygen 10 times and may significantly shorten the duration of coma.55 Hyperbaric oxygen is not routinely available, but there are hard data that prove a better outcome with this therapy. A recent clinical trial held three sessions within a 24-hour period consisting of 100% oxygen at 3 atmospheres followed by 2 atmospheres.56 Cognitive damage was almost halved, although number of treatments and time window are not exactly known. Benefit may still be possible 6–12 hours after exposure.56 Additional factors, such as hypotension, are equally important in carbon monoxide's damaging effect. Hyperbaric oxygen therapy is the preferred approach in nonintubated comatose patients and patients with significant myocardial ischemia despite initial breathing of 100% oxygen.
Cyanide poisoning should be entertained in any coma of undetermined cause, particularly in laboratory or industrial workers.57 A well-recognized intentional cause is the ingestion of nail polish removers.58 Prevalence of cyanide poisoning is low, but its effects can be reversed with antidotes.
Cyanide has an unusual mechanism of action.
By interacting with cytochrome oxidase (an essential enzyme in the mitochondrial electron transport chain), it greatly reduces production of adenosine triphosphate. Consequently, significant lactic acidosis results from a shift in anaerobic metabolism. Additionally, cyanide, like carbon monoxide, shifts the hemoglobin dissociation curve to the left and directly binds with the iron of hemoglobin, reducing the delivery of oxygen to the brain and other vital organs.59
Coma from cyanide poisoning is often accompanied by hypoventilation from central inhibition of the respiratory centers, severe lactic acidosis, bradycardia, hypotension, and rapidly developing pulmonary edema. A bitter almond or musty smell has been linked to cyanide poisoning, but recognition of its odor is impossible for many physicians.59
The supportive laboratory finding is metabolic acidosis, which may be combined with respiratory alkalosis from hyperventilation to overcome hypoxia or respiratory acidosis from hypoventilation. Plasma cyanide can be measured, but correlation with the degree of coma is poor, thus making testing impractical.
Cyanide poisoning has a good outcome when treated with the Lilly cyanide antidote kit. This contains amyl nitrite (by crushing of pellets and inhalation by patients), sodium nitrite, and sodium thiosulfate (intravenous, 50 mL of a 25% solution). The effect is based on conversion of hemoglobin into methemoglobin, which combines with cyanide but easily breaks down into free cyanide, which then combines with sodium thiosulfate and is eventually eliminated in the urine.
Reliable neurologic data on outcome are not available. Parkinsonism and dystonia have been reported, with associated lesions in the basal ganglia detected by CT scanning but with improvement in some instances.60,61
Methanol, ethylene glycol, and isopropyl alcohol are used in many commercial products, including antifreeze (ethylene glycol) and solvents (methanol). Isopropyl alcohol is best known as rubbing alcohol. The alcohols produce virtually similar laboratory effects, the most noticeable of which is a high anion gap metabolic acidosis.62
Methanol infrequently causes coma, but a fatal outcome is likely if it occurs. Methanol more commonly produces delirium and blurred vision. Careful examination reveals hyperemia of the optic disk, and blindness may follow as a result of the toxic effect of formaldehyde on retinal ganglion cells. Bilateral necrosis of the putamen is highly characteristic, frequently becoming apparent on neuroimaging studies in comatose patients only after several weeks.63However, the brains of patients dying of methanol poisoning may be normal or variably show congestion, edema, petechiae, and necrosis of the cerebellar white matter.
Several features of methanol poisoning are of interest. First, a latent period (up to 12 hours) is typical, making it very difficult for bystanders to understand the sudden occurrence of a lapse into coma, Second, prominent restlessness with vomiting and doubling over from abdominal cramps may be followed by seizures before a lapse into unresponsiveness. Treatment is focused on correction of the acidosis with bicarbonate, but in comatose patients extracorporeal hemodialysis is imperative. Although the outcome can be very satisfactory, permanent neurologic disability may occur.64
Ethylene glycol is most commonly known as a major component of antifreeze and many detergents.65 Suicide is the most common reason for ingestion, and then mortality is high. The metabolites produce toxicity, and the clinical features preceding coma are dramatic. Marked gait ataxia, nystagmus, paralysis of the extraocular muscles, and ocular bobbing are followed by generalized tonic-clonic seizures or profound myoclonus and, because of severe hypocalcemia, tetanic contractions. Lactic acidosis and an osmolar gap are characteristic laboratory features, but diagnosis is confirmed with the demonstration of calcium oxalate crystals in the urine.65 Ethylene glycol poisoning is often treated with hemodialysis and high doses of ethanol up to intoxication of the patient (plasma ethanol target is 1000 µg/mL). In a recent study, an inhibitor of alcohol dehydrogenase (fomepizole) was successful in preventing renal damage by inhibiting toxic metabolites such as oxalate. Fomepizole is an expensive alternative to ethanol but is without toxic effects. Intravenous loading of 15 mg/kg is followed by 10 mg/kg every 12 hours for 2 days, with a further increase to 15 mg/kg every 12 hours until the plasma ethylene glycol concentration is less than 20 mg/dL.66
Finally, isopropyl alcohol is rather potent, producing rapidly developing coma, always with severe hypotension from cardiomyopathy. The typical acetone breath should point to this toxin. The characteristic oxalate crystals in ethylene glycol are not found in isopropyl poisoning. Management involves gastric lavage; because the onset of coma is rapid, recovery of the substance from the stomach can still be substantial.
In this section, poisonings that are of great clinical importance and proportionally frequent or that produce striking clinical features are discussed.
As a result of safety packaging, the incidence of salicylate poisoning has substantially decreased, but it is still prevalent in children.
Salicylates may take some time to dissolve in the acidic stomach milieu but then are rapidly absorbed, and blood levels are maximal within 1 hour. After exposure to a massive dose, the pharmacokinetics are different, and through a complex mechanism the half-life of salicylates increases to 15–20 hours from a baseline level of 2–4 hours in therapeutic doses.67
Salicylates equilibrate rapidly with CSF, and the levels of salicylates in CSF appear to correlate better with outcome than do serum levels.65 Determination of salicylate levels in CSF, however, is cumbersome. Salicylates significantly interfere with platelet function and prolong pro-thrombin time and may preclude lumbar puncture.
The mechanism of action of salicylates is not entirely clear. It may involve (1) uncoupling of the oxidative phosphorylation and blocking of glycolysis, producing a metabolic acidosis; (2) direct stimulation of the brain stem respiratory centers, leading to respiratory alkalosis, independent of an already compensatory response to the induced acidosis; and (3) increased metabolic demand from increased glycolysis to compensate for the uncoupling in (1), which may result in profound hypoglycemia.67
Salicylate poisoning should always be considered in restless, hyperventilating patients. Hyperthermia and purpura due to platelet dysfunction in the eyelids and neck may occur, simulating fulminant acute meningococcal meningitis. Pulmonary edema may occur and may become rapidly life-threatening. Severe acidemia caused by increased lipid solubility of salicylates in an acidic environment facilitates the entry of salicylates into the brain.
The laboratory features of increased anion gap, metabolic acidosis, and respiratory alkalosis are well appreciated and should lead to measurement of serum salicylate levels or, more practically, ferric chloride testing of the urine. Purple discoloration of the urine is diagnostic, and the test has good predictive value. A plasma salicylate level of 6 mg/dL usually is correlated with seizures and coma.
Management of salicylate poisoning involves gastric lavage, activated charcoal, and forced alkaline diuresis. Alkalization is performed with sodium bicarbonate or, in less severe cases, acetazolamide.
Acetaminophen is a substance in many nonprescription drugs, and as a result, poisoning is common. Usually, however, extremely large doses (plasma level >800 µg/mL) are required to directly depress consciousness; more likely, the development of acute hepatic necrosis or hepatorenal syndrome causes coma.68
Overdose of acetaminophen proceeds in phases, but liver damage can occur within 24 hours after ingestion. The biochemical basis for acute liver necrosis has been elucidated and is the rationale for therapy with N-acetylcysteine. In normal situations, acetaminophen is metabolized in the liver through either sulfation or glucuronidation and only a small fraction through the P-450 oxidase system, which produces an active metabolite that has the potential for liver necrosis. Overloading of the glucuronidation system by large ingestion of acetaminophen increases the formation of toxic metabolites. Decreased glutathione stores, as in patients with long-term antiepileptic drug use or chronic alcoholism, may increase the probability of liver necrosis after acetaminophen intoxication.69,70
Clinical features of acetaminophen overdose are nausea, vomiting, diaphoresis, and abdominal pain in the right upper quadrant but no depression in consciousness unless hepatic failure develops. Hepatic encephalopathy, with its characteristic asterixis and myoclonus, develops approximately 4 days after ingestion. Brain edema may become a feature in fulminant hepatic failure when patients lapse into stupor.
Together with N-acetylcysteine loading, management is largely supportive. N-Acetylcysteine is metabolized to cysteine, which functions as a precursor for glutathione and restores the glutathione scavenging. Acetaminophen half-lives may vary from 4–120 hours depending on the severity of liver necrosis.71
Liver transplantation may be needed, and its consideration leads to an ethical quagmire in patients who used acetaminophen for a suicide attempt.
Overdose with antiepileptic drugs is most often intentional, but every now and then a prescription blunder or drug interaction that reduces metabolism can be implicated. Coma from antiepileptic drug overdose is not common, and most often nonspecific signs, such as dizziness, tremor, nystagmus, and profound ataxia, occur. Paradoxically, antiepileptic drug overdose may produce seizures, and the risk, at least in carbamazepine overdose, is increased in patients with a seizure disorder.72
Acute overdose of phenytoin (estimated serum levels >50 µg/mL) is characterized by rapid ataxia, dysarthria with combative behavior, and hallucinations, very seldom followed by generalized tonic-clonic seizures and progression to flaccid coma. Management is supportive, with mechanical ventilation, charcoal to minimize further absorption, and benzodiazepines (e.g., lorazepam) or barbiturates (e.g., phenobarbital) in the rare event that seizures occur.
Carbamazepine is widely used in neurologic disorders. Its side effects are reminiscent of those of tricyclic antidepressants because of structural similarities, and neurologists, who are usually the primary healthcare providers, should appreciate this potential threat to life.73,75 Respiratory depression is common in carbamazepine overdose, and prospective studies have found a median duration of 18 hours. Coma occurs in 20%–50% of the reported series of carbamazepine overdose.73,74 Fatal outcome may reach 15% of patients, most often affecting those in coma, with seizures, and with resuscitation for cardiac arrest; ingestion often exceeds 100 tablets.73,76 Other manifestations of carbamazepine overdose are hypothermia, hypotension, tachycardia, and a diverse range of cardiac arrhythmias from its anticholinergic properties.73,76 Overdose with con-trolled-release carbamazepine may lead to peak toxicity 4 days postdigestion, and whole-bowel irrigation may be needed.77
Typically, management is focused on cardiac manifestations, and problems similar to those in tricyclic antidepressant overdose should be anticipated. Recovery from carbamazepine overdose can be protracted, with fluctuating levels of consciousness for many days.
Valproate toxicity is notable for its association with acute liver failure, but this devastating side effect has occurred only in young children and with concomitant use of other antiepileptic agents.78 Hyperammonemia may be a major mechanism for stupor.79 Massive ingestions (>200 mg/kg) produce coma with pinpoint pupils and hypertonia. As in acetaminophen poisoning, fulminant hepatic failure may produce many of the earlier manifestations of asterixis, myoclonus, and nystagmus. Valproate-associated hyperammonemia is treated with L-carnitine,80 which could mitigate its effect (50–100 mg/kg daily).81,82
Assessment of Acute Metabolic or Endocrine Causes of Coma
Acute metabolic derangements may produce reduced arousal and, when unrecognized, coma. Typical examples are hypoglycemia, hyponatremia, acute uremia, and acute liver failure. Overt hemiparesis, pupil abnormalities, and gaze preference are conspicuously absent on neurologic examination, but asterixis, tremor, and myoclonus predominate when deep coma sets in. Hyperglycemic nonketotic hyperosmolar coma is a notable exception, probably because of previous strokes in these patients with severe cerebrovascular risk factors. The mechanisms of these conditions causing hypometabolism in the brain are poorly understood, but many of these disorders cause diffuse cerebral edema (see Chapter 9); seizures intervene or cardiorespiratory resuscitation results in diffuse anoxic-ischemic damage (see Chapter 10). Endocrine crises, such as rarely encountered Hashimoto's thyroiditis (thyroid coma), Addison's disease, and panhypopituitarism, may be responsible for coma; and hormones of the hypothalamic pituitary axis should be measured in unexplained coma. The laboratory values compatible with marked impairment of consciousness are shown in Table 8.8. Coma should be attributed to other causes if the biochemical derangement is less severe.
Neuroimaging and Laboratory Tests
CT scanning of the brain is particularly useful when the neurologic examination reveals localizing symptoms. Acute lesions in the brain stem and cerebellum may not be visualized on CT. Patients with acute basilar artery occlusion or evolving cerebellar infarction often have normal CT findings on admission, and MRI is needed to resolve the cause of the coma (Fig. 8.16A). It may also demonstrate sparing of the ARAS in locked-in syndrome (Fig. 8.16B).
Table 8.8. Laboratory Values Compatible with Coma* in Patients with Acute Metabolic and Endocrine Derangements
CT findings in patients with altered consciousness, hemiparesis, or gaze preference are often abnormal. One should particularly evaluate whether basal cisterns are present on CT scans because they may be filled in early uncal herniation (Fig. 8.17).83Contralateral hydrocephalus may be present, usually caused by compression at the level of the foramen of Monro.83 The ambient cistern is usually effaced, and an enlargement of the temporal horn is seen.
Figure 8.16 A: Linear hyperintensity (arrows) on magnetic resonance imaging (T2-weighted) in a patient with basilar artery occlusion. B: Locked-in syndrome. Note sparing of tegmentum (arrows).
CT of the brain defines the existence of a mass, its remote effect, and edema and may hint at a cause. However, because of multiplanar views, MRI is more sensitive for recording the extension of the mass and may reveal necrosis, pigments (deoxyhemoglobin, melanin), or fat, which may suggest the underlying pathologic condition. MRI clearly identifies giant aneurysms that may mimic tumors on CT.
In the emergency department, the CT scan appearance of a mass is most often characteristic enough to determine an early plan of action. Solitary lesions in nonimmunosuppressed patients most commonly represent intra-axial brain tumors or abscess. On unenhanced images, low density may represent tumor with edema. The degree of edema may reflect the degree of malignancy; rapidly growing tumors, such as glioblastoma, produce much more surrounding edema. Edema is also comparatively common in metastasis.
Most intracranial masses are hypodense, but hyperdense masses may point to a meningioma, lymphoma, or hemorrhage into a tumor. Speckled calcification inside a mass, an important CT scan finding, is present in more than 50% of patients with an oligodendroglioma but may point to an inflammatory cause, particularly parasite infestation, such as cysticercosis, and less common disorders, such as paragonimiasis and echinococcosis.84,85 They are often seen in areas other than the cystic mass, indicating calcium deposits in necrotic brain tissue.
Intracranial mass of inflammatory origin has become a much more common presentation in the emergency department from the increase in transplantation surgery and the acquired immunodeficiency syndrome (AIDS) epidemic.
Brain abscesses, usually from toxoplasmosis, are very commonly associated with AIDS infection. Toxoplasmosis seldom appears as a single mass, although one large mass may predominate. Basal ganglia localization is typical, and hemorrhage may occur. Tuberculoma or aspergillosis should be considered as well.52MRI can be helpful because a dark (hypointense) T2 signal inside the mass is often found. The most common CT and MRI findings in comatose patients are summarized in Table 8.9.
Figure 8.17 Patterns of herniation on computed tomographic scans. A: Meningioma with massive edema causing distortion of the diencephalon (arrows) and cingulate herniation (arrows). B: Large intracranial hematoma in the temporal lobe causing shift of the temporal lobe (see tip of temporal horn, arrowhead) and brain stem distortion (arrows) typical of uncal herniation.
Table 8.9. Frequent Abnormalities on Neuroimaging Studies in Coma
Normal findings on neuroimaging, with no clinical evidence of an acute cerebellar infarction or acute basilar artery occlusion, should prompt immediate examination of the CSF to search for possible CNS infection. Failure to exclude a potentially treatable CNS infection may have devastating consequences. The evaluation of CSF findings in meningitis and encephalitis is further discussed in Chapters 7, 16, and 17.
Neuroimaging is an obligatory study in patients who may be brain dead. The results of neuroimaging studies or CSF examination should be generally compatible with the diagnosis of brain death. Thus, one should expect a large mass lesion producing brain tissue shift with herniation or an intracranial hemorrhage with enlarged ventricles. Other validating CT scan findings are multiple, large, acute cerebral infarcts, massive cerebral edema, multiple hemorrhagic contusions, and cerebellar-pontine lesions compressing or destroying the brain stem.
Normal brain images in brain death can be seen immediately after cardiac arrest, carbon monoxide poisoning, asphyxia, acute encephalitis, and cyanide or other fatal poisoning.
Abdominal radiographs can be helpful in establishing whether the patient has ingested any tablets or foreign objects. Examples of radiopaque pills are chloral hydrate, trifluoperazine, amitriptyline, and enteric-coated tablets; however, many tablets may have dissolved before the patient is admitted to the emergency department.
Electrocardiography can be useful, and results are nearly always abnormal if intoxication is due to phenothiazines, quinidine, procainamide, or tri-cyclic antidepressants. Tricyclic antidepressant overdose characteristically produces widening of the QRS complex and QT prolongation. Widening of the QRS complex considerably increases the risk of seizures associated with tricyclic antidepressant overdose.31 Electrocardiographic findings are also important in confirming hypothermia as a cause of coma (typically, the QRS complex widens and ST elevation occurs, also known as a “camel's hump”).
When poisoning is strongly considered as a cause of coma, laboratory tests are essential before time-consuming toxicologic screening is performed. However, most poisons and illicit drugs do not cause significant laboratory derangements. In fact, if abnormalities are found in a comatose patient, they may be more representative of poor nutrition, dehydration, or a rapidly developing febrile illness.
Acid-base abnormalities, however, may point to certain toxins.23 A high anion gap acidosis is most common. The most prevalent toxins are shown in Table 8.10. Often, a high anion gap acidosis indicates ethylene glycol or methanol ingestion. Increased lactate, particularly when venous lactate can entirely account for a decrease in serum bicarbonate, may point to previous, often undetected, seizures, shock, and early sepsis.
The anion gap is calculated from the serum electrolytes. Normally, more cations (sodium and potassium) than anions (chloride and bicarbonate) are present, causing an anion gap of 11–13 mEq/L. Generally, potassium is deleted from the equation because its extracellular contribution in the anion gap is minimal; therefore, the equation becomes as follows: anion gap = (Na+ - [Cl- + HCO3-]). Increases in the anion gap result from the additional presence of an anion. Most of the time, it is lactate that increases in serum and creates an anion gap, often originating from poor tissue perfusion.
Table 8.10. Blood Gas Abnormalities Due to Toxins
Salicylates usually produce a combined acid-base abnormality, and respiratory acidosis is often present.67 The partial pressure of CO2 (PaCO2) decrease in metabolic acidosis can be calculated (PaCO2 = [1.5 × (HGO3)] + 8 ± 2), and a lower PaCO2 should point to additional respiratory alkalosis.
Osmol gap is a useful test to determine accumulation of osmotically active solutes. The normal osmol gap is calculated with the equation 2 × Na + (glucose/18) + (blood urea nitrogen/2.8). This calculated osmolality is less than the measured osmolarity (the so-called osmol gap) and should be less than 10 mOsm/L. Alcohols of any land increase the osmol gap, and blood levels can be estimated by multiplying the osmol gap with the molecular weight of the alcohol (46 for ethanol) and dividing the result by a factor of 10.
Urine testing for salicylates is important and can be done with a 10% ferric chloride solution, which turns urine purple if salicylates are present. Urine should be tested for ketones. Ketones in combination with a marked anion gap immediately suggest salicylate poisoning, but this combination can also be observed in alcohol- or diabetes-induced ketoacidosis. The absence of ketones in a patient with anion gap metabolic acidosis suggests ingestion of methanol or ethylene glycol. Urinalysis is also important, specifically in looking for calcium oxalate crystals associated with ethylene glycol (antifreeze) ingestion. The use of Wood's lamp (if available) may be important because fluorescein is added to many antifreeze products.
Many hospitals have laboratories that can provide drug screens.86,87 Their value often lies in the demonstration of the toxin rather than quantification. The blood levels of many sedatives and alcohol correlate poorly with depth of coma, duration of mechanical ventilation, and time in the intensive care unit. This lack of correlation applies particularly to patients who attempt suicide with a medication they have taken long enough to cause tolerance.
Many smaller hospitals use thin-layer chromatography, which is less reliable, operator-dependent, and unable to quantitate the toxin.86 Most academic centers can measure with gas chromatography and mass spectrometry. This laboratory investigative tool is powerful and quantitates the toxin. The spectrum of drugs measured in serum is depicted in Appendix 8.1. Physicians assessing patients with poisoning and drug abuse should be well informed about the hospital laboratory practices available. Laboratory confirmation of the clinical diagnosis is often very desirable and may also serve a medicolegal purpose. Delay in the performance of these tests remains a major limitation, and often the information becomes available too late to be useful in guiding treatment in daily practice.
Blood tests that should be performed include a full hematologic screen and differential cell count, blood glucose, serum osmolality, liver function panel, electrolytes, and renal function tests (Table 8.11). Arterial blood gas measurements further assist in categorizing the major classes of acid-base imbalance, if present.
Initial Management of Vital Signs in Coma
One of the fundamental responsibilities of the physician faced with the care of a comatose patient is to maintain or correct the vital signs, such as oxygenation, gas exchange, blood pressure, pulse rate, cardiac rhythm, and temperature.
Table 8.11. Laboratory Tests in the Evaluation of Coma
Airway Assessment and Gas Exchange
The basic principles of airway management apply and have been discussed in Chapter 1. The need for intubation remains difficult to judge in comatose patients, but tachypnea, desaturation on pulse oximetry (<95%), or emerging pulmonary abnormalities on examination or chest X-ray are clear indications. Seizures do not warrant intubation, but status epilepticus does if second-line drugs are contemplated. Vomiting could be a reason for intubation to protect the airway, certainly if the patient has poor reflexive cough. In patients with minor intoxications that seem to be resolving, noninvasive ventilation with rate control may be useful to bridge the period of elimination of the drug. Early intubation in severe traumatic head injury is probably justified and allows better control of the airway and oxygenation. Early tracheostomy may be needed when the face and neck are severely injured, increasing the risk of loss of airway (in facial fractures of LeFort type, posterior displacement may seriously obstruct the airway).88
Assessment of Circulation and Blood Pressure
Dehydration resulting in reduced intravascular volume is often a cause of hypotension. Hypotension should be corrected by placing the patient in the Trendelenburg position and infusing isotonic saline or blood when indicated in traumatized patients. If blood pressure is not reversed with these measures, hypotension may indicate that the patient has (1) toxic effects from ingestion of a drug that produces vasodilation or myocardial depression, (2) major abdominal trauma, or (3) a life-threatening illness, such as myocardial infarction, pulmonary embolus, or sepsis. It is a misconception to attribute hypotension to catastrophic damage to the brain, which occurs only in patients who are brain dead or who have severe spinal cord injury. Vasoparalysis in brain death results in marked hypotension and may be noted acutely in a rapidly progressing catastrophe. Hypertension, however, is very common in a patient with an acute structural lesion in the CNS. Usually, hypertension is caused by a sympathoadrenal discharge or is part of the Cushing response, particularly when the brain stem is distorted. Acute severe hypertension (MAP >140 mm Hg) may also have its origin in poisoning caused by such agents as amphetamines, cocaine, phencyclidine, and cyclic antidepressants. Often, hypertension in these types of intoxication is associated with significant tachycardia.
The management of acute hypertension in comatose patients is complex. At least theoretically, untreated hypertension may exacerbate cerebral edema in injured areas from increased cerebral blood flow. Too rapid correction of blood pressure may introduce ischemic areas surrounding acute mass lesions from reduction of cerebral perfusion pressure. In patients with longstanding hypertension, the autoregulation curve has shifted to the right, and this further increases the risk of decreased cerebral blood flow, with a decrease in blood pressure at this juncture. One should probably avoid extremes, and persistent surges of blood pressure (MAP >120 mm Hg) can be treated with a short-acting α- or β-adrenergic blocking drug, such as labetalol (40 mg at 10-minute intervals).
Patients with hypothermia (defined as core temperature <34°C) should be gradually warmed. Physicians should be aware that noxious stimuli applied to patients with moderate hypothermia to assess responsiveness can potentially trigger ventricular fibrillation. Virtually all brain stem reflexes are lost when the core temperature reaches 27°C, and they can entirely return after rewarming.
Patients with a core temperature of 32°C-35°C need to be warmed with blankets, those with a core temperature of 30°C-32°C are warmed with IV infusions, and those with a core temperature <30°C may need peritoneal lavage with heated dialysate.
In patients comatose after cardiac resuscitation, induced hypothermia could be beneficial and subnormal temperatures should be tolerated.89 The effect of superficial cooling in patients with devastating anoxic-ischemic injury to the brain appears promising, but much larger clinical trials are needed to prove its effect.89 It remains unclear what its effect could be in traumatic brain injury. Some more recent studies continue to suggest 35°-35.5°C reduces intracranial pressure while maintaining cerebral perfusion pressure90 despite lack of effect in the National Brain Injury Hypothermic Study (see Chapter 19).
All patients in coma for whom the diagnosis is very unclear should receive concentrated dextrose (50% dextrose, 50 mL, 25 g IV). The well-known adrenergic symptoms from the counterregulating hormone epinephrine, such as sweating, tremor, and tachycardia, may not be present when hypoglycemia has developed more or less gradually. However, its use in patients in whom the proximate cause of coma is known is ill-advised.
Wernicke's encephalopathy is a rare cause of coma.91 However, if chronic alcohol abuse or malnourishment is suspected during the physical examination, a “routine” glucose infusion may precipitate acute Wernicke's encephalopathy. To prevent this, 100 mg of thiamine should be administered IV (slowly over 5 minutes) or intramuscularly. Indiscriminate use of thiamine in comatose patients is potentially dangerous because of acute anaphylactic reactions and acute pulmonary edema.
Cardiac arrhythmias often define the severity of the intoxication in patients with an overdose of a cyclic antidepressant drug. Sodium bicarbonate, 1–2 mEq/kg IV, is advised when the QRS interval narrows. In patients with sympathomimetic agent intoxication resulting in tachycardia, esmolol can be used: 500 µg/kg over 1 minute, followed by an infusion of 50 µg/kg per minute for 4 minutes; maximum maintenance dose is 200 µg/kg per minute. If tachycardia is caused by an anti-cholinergic overdose, physostigmine, 0.01–0.03 mg/ kg IV, is used.92 Patients with ventricular fibrillation or ventricular tachycardia associated with amphetamines or overdose should be treated with lidocaine, 1–3 mg/kg IV up to 300 mg in a 1-hour period.
Management in Specific Causes of Coma
Supratentorial Mass Lesions
Patients with a mass lesion that causes shift of brain structures need immediate management of increased intracranial pressure. If available, an intracranial pressure monitoring device should be inserted to measure increases in intracranial pressure and possible development of plateau waves that indicate imminent decompensation of brain compliance. Transfer to a neurologic or neurosurgical intensive care unit is imperative.
The most successful method of decreasing intracranial pressure is the brief use of hyperventilation (aiming at a partial pressure of arterial CO2 [PaCO2] of 30 mm Hg) and equally effective use of osmotic diuretics, such as mannitol (aiming at an increase in plasma osmolality of 310 mOsm/L). Hyperventilation results in profound vasoconstriction from hypocapnia and reduces cerebral blood flow, thus contributing to reduction of the intracranial volume. One may expect cerebral blood flow to decrease 40% in 30 minutes if the PaCO2 is reduced by 15–20 mm Hg.93 However, the physiologic effects of hyperventilation are less significant after several hours because efficient buffering systems rapidly correct changes in CSF pH. Its effect is short, probably hours.94
Hyperventilation can be easily instituted by changing the respiratory rate on the mechanical ventilator. The respiratory rate should be increased to approximately 20 breaths/minute while a normal tidal volume is maintained. Increasing minute ventilation by changing both components is ill-advised because it may lead to high airway pressures and increases the risk of barotrauma.
In addition, hyperosmolar agents, preferably mannitol, should be administered, starting with a 20% solution at a dose of 1 g/kg.95 The effect on intracranial pressure is rapid and may last for at least 4 hours. Mannitol essentially decreases brain volume by extracting water from brain tissue.96 This influx to the intravascular compartment is generated by an osmotic gradient. Mannitol, therefore, expands the blood volume just before its diuretic action, hence the name “osmotic diuretic.” First, a bolus of 1 g/kg of body weight is given. If no effect is seen after 15 minutes, a double dose is administered. The effect of mannitol is at least twofold. First, infusion of mannitol produces an osmotic gradient between the intravascular component and the brain. Second, a more complex mechanism of mannitol is a possible rheologic effect.97 Mannitol reduces hematocrit and blood viscosity, thereby increasing cerebral blood flow. Vasoconstriction becomes a compensatory reflex and reduces cerebral blood volume. This mechanism rather than diuresis, which usually is seen at a later stage, may be the prime means by which mannitol causes a rapid response. Mannitol may cause significant changes in electrolytes, particularly increase in serum potassium and acute renal failure from altered glomerular hemodynamics. Mannitol, when extravasated, could produce a compartmental syndrome.98
Failure of the patient to improve with hyperventilation and mannitol indicates that surgical evacuation of the mass should be considered. When swelling of one hemisphere is prominent, decompressive craniotomy with duraplasty can be considered. Preliminary studies in patients with encephalitis and a large hemispheric infarction have shown promise.
Corticosteroids should be considered in patients who have edema surrounding a cerebral metastatic lesion or primary brain tumor. There is no proof that corticosteroids improve outcome in patients with other mass lesions, such as intracranial hematoma, closed head injury, infarction, and cerebral abscess.99,100Corticosteroid therapy is usually initiated with a single 100-mg dose of dexamethasone given IV, and this is followed by a 16-mg daily dose.
The management of acute supratentorial mass lesions is summarized in Table 8.12.
Acute posterior fossa lesions that evolve into coma from a compressive brain stem lesion need immediate neurosurgical evacuation. Only occasionally does decreased level of consciousness result from an evolving hydrocephalus, and then ventriculostomy improves the degree of responsiveness. A cerebellar hematoma or cerebellar infarct is a neurosurgical emergency, and craniotomy is necessary to remove the hematoma or necrotic tissue.
An intrinsic lesion of the brain stem is usually best initially treated medically with endotracheal intubation and mechanical ventilation. Patients with acute basilar artery occlusion should be placed in a flat body position to augment blood pressure, and intra-arterial thrombolysis, if available, should be considered. We have been able to reverse a virtually locked-in syndrome in acute basilar occlusion by using intra-arterial thrombolysis with urokinase but not when pontomesencephalic reflexes have been lost. Criteria for intra-arterial thrombolysis in the posterior circulation are further discussed in Chapter 15. Specific management in subtentorial lesions is summarized in Table 8.13.
Table 8.12. Management of Acute Supratentorial Mass with Brain Shift
Comatose patients with infectious disease have fever and meningeal irritation at presentation. If focal neurologic signs are present, the three steps to take are (1) an immediate IV infusion with antibiotics and dexamethasone (bacterial meningitis), (2) a CT scan to exclude an abscess, and (3) a lumbar puncture for final culture of the offending organism.
Table 8.13. Management of Acute Subtentorial Mass or Brain Stem Lesion
Patients with acute viral encephalitis may be in a coma at presentation without any other localizing neurologic signs. The history obtained from family members may reveal fluctuating aphasia, seizures, or significant confusion before the lapse into unresponsiveness. It is important to immediately start an infusion of acyclovir. In herpes simplex encephalitis, outcome is largely determined by early treatment; however, the prospects for full recovery remain small in patients in stupor or coma.
With the emergence of immunosuppression (particularly in the human immunodeficiency virus population), toxoplasma encephalitis should be considered. Initial treatment remains empiric and includes pyrimethamine and sulfadiazine, particularly in patients with multiple abscesses. In endemic areas, patients in coma may have cysticercosis associated with Taenia solium infestation, and immediate treatment with praziquantel is required. It is important to start these treatments early, after consulting an infectious disease specialist. The initial management in these acute inflammatory conditions of the CNS is summarized in Table 8.14.
Acute Metabolic Derangements and Poisoning
No harm is done if patients with a high likelihood of hypoglycemia are given 50 mL of a 50% glucose solution. Immediate awakening during infusion is highly indicative of severe hypoglycemia.
Failure to awaken after hypoglycemia, however, may indicate that hypoglycemia has been lengthy and has caused significant brain damage leading to prolonged or no recovery.
Table 8.14. Empirical Antibiotic and Antiviral Therapy in Patients in Coma Associated with Inflammatory Conditions
Management of severe hyponatremia involves hypertonic saline and furosemide (3% hypertonic saline, 0.5 mL/kg hourly) with frequent serum sodium surveillance. Overcorrection (≥ 140 µg/L) and rapid correction (within 12 hours) have been linked to the development of central pontine myelinolysis.
Hypercalcemia is adequately corrected by saline rehydration infusion (3–4 L) followed by the parenteral bisphosphonate pamidronate (infused at 60 mg over 24 hours).
The use of a “coma cocktail” in assessing and managing coma of undetermined cause must be questioned.101 Usually, this cocktail consists of a combination of hypertonic dextrose, thiamine hydrochloride, naloxone hydrochloride, and, recently, flumazenil.102 Its use must be discouraged simply because of the possible side effects of naloxone and flumazenil. Naloxone has great efficacy but also potentially serious side effects, such as aspiration from rapid arousal and development of a florid withdrawal syndrome103 characterized by agitation, diaphoresis, hypertension, dysrhythmias, and pulmonary edema.103,104 In addition, after 30 minutes, the patient may again lapse into coma, which if unwitnessed may cause significant respiratory depression and respiratory arrest. A more prudent approach is to prophylactically intubate the patient and to gradually reverse the overdose of opiates by use of naloxone, 0.4–2 mg every 3 minutes by incremental doubling.105 At the first sign of relapse, 0.4–4 mg of naloxone can be given IV106 or an infusion of 0.8 mg/kg hourly started. Failure to reverse coma from alleged opiate overdose has many causes, and they are summarized in Table 8.15.
Flumazenil reverses the effect of any benzodiazepine but has the same major disadvantages as naloxone: rapid arousal and risk of life-threatening aspiration pneumonitis. In addition, when high doses of flumazenil are administered, seizures may occur.106,107 Therefore, flumazenil is contraindicated in patients with a seizure disorder and in patients in whom concomitant tricyclic antidepressant intoxication is suspected.13,106 When flumazenil is administered, cardiac arrhythmias may occur, and status epilepticus has been reported in patients who had an overdose of tricyclic antidepressants and received treatment with flumazenil.106 The recommended dose of flumazenil, by slow IV administration, is 0.2 mg/minute up to a total dose of 1 mg.35 We seldom use flumazenil to reverse coma. Benzodiazepine overdose, in general, is not life-threatening and can be managed by supportive care only.
Table 8.15. Differential Diagnosis in Failure to Reverse Coma from Alleged Opiate Overdose
Inducing emesis in a patient who is stuporous from poisoning may be a mistake because of the significant danger of aspiration. Gastric lavage, which is possible if a comatose patient is protected by endotracheal intubation, should be done if the suspicion of a massive overdose is great. Also, activated charcoal (60–100 g) can be delivered through the gastric tube. Placement of the tube in the stomach before administration of charcoal should be confirmed by radiography because charcoal deposition in the lung is often fatal. The technique of gastric lavage includes placement of the patient in the left lateral decubitus position after intubation of the trachea with a cuffed endotracheal tube. This position greatly facilitates drainage. The largest possible gastric tube should be inserted through the nose or mouth into the stomach and checked often with air insufflation while the physician listens over the stomach. The stomach aspirate should be investigated for possible toxins, and activated charcoal should be administered before lavage is started. Charcoal absorbs material that cannot be removed by active suctioning and that may enter the intestine. Lukewarm tap water or saline in 200 mL aliquots up to a total of 2 L is infused and aspirated until no pills or toxic material is observed.
Elimination of the toxin can also be enhanced by hemodialysis and hemoperfusion, and many drugs and toxins can be cleared (the most common are acetaminophen, amitriptyline, lithium, and salicylates).
Coma of Unknown Origin
In some patients it may seem very difficult to pinpoint the exact grounds of coma. The management of coma of undetermined cause is full intensive care support and observation over time while a more detailed history and laboratory test results are awaited. When no cause of decreased arousal or coma is found and results of laboratory tests including CT scan or MRI and CSF examination are negative, unidentified toxin exposure, plant or berry ingestion or other type (such as tetrodotoxin from puffer fish),108 should be considered. However, toxin exposure may have resulted in significant hypoxemic-ischemic damage, which may cause persistent coma.109 Electroencephalography may be helpful to exclude nonconvulsive status epilepticus or prolonged postictal state despite no documentation of a seizure.
Basilar artery migraine may produce drowsiness, confusion, and prolonged amnesia and may progress to coma.110 Typically, a strong family history of common migraine exists. Of the patients originally reported by Bickerstaff,110 about 80% had a positive family history. Basilar artery migraine is more prevalent in children but may persist through adulthood, often converting later into common migraine. The clinical presentation is impressive. Visual hallucinations, bilateral zigzag forms or photopsia, and even sudden blindness or grayouts may occur as a result of hypoperfusion of the occipital lobes. Most of the time, patients present with vertigo, ataxia, diplopia, dysarthria, and tinnitus from ischemia to the brain stem. Bilateral throbbing headache may last for hours, commonly with vomiting, after resolution of the neurologic deficits. Coma remains uncommon in basilar migraine. More commonly, patients with migraine become drowsy or stuporous from over-medication, particularly with narcotics. A retrospective review in a large series of patients noted stupor or coma in 24% of 49 patients and more often “somnolence.”110 Bickerstaff's original descriptions110 highlight gradual onset of a dreamlike state. Seizures may occur and can be documented on electroencephalograms at the time of a full-blown attack. The precise nature of the disorder is unresolved. Unfortunately, brain stem infarcts may occur, with a fatal outcome.111
A recently reported disorder characterized by spells of sudden coma has been linked to increased endogenous production of benzodiazepines (endozepine stupor, idiopathic recurrent stupor). Patients may awaken immediately after administration of flumazenil. The prevalence of this disorder is unknown.112
Psychogenic unresponsiveness should always be considered after all laboratory test results are negative. Unfortunately, many of these patients have already received a battery of laboratory tests even though the discrepancies with detailed clinical examination are very obvious. Most often, psychogenic unresponsiveness lasts for only 1 or 2 days, with characteristic sudden unexpected “awakening” and often complete amnesia for the episode and for events during many months preceding hospital admission.
Malignant neuroleptic syndrome and catatonia may produce decreased responsiveness and are fatal if untreated. Profound rigidity and continuous autonomic storm with impressive tachycardia, hypertension, and profuse sweating may result in cardiac arrest (from subendocardial and myocardial hemorrhages) or renal failure (due to severe acidosis from massive rhabdomyolysis). Therapy is discussed in Chapter 5.
Hereditary metabolic disorders may be manifested by impaired consciousness during adolescence. These disorders are exceptionally uncommon but should be excluded when the cause of coma is unknown. These disorders are acute porphyria (psychosis rather than coma and seizures in some), mitochondria! encephalopathy, and necrotizing encephalopathy of Leigh. Acute porphyria often has resulted in earlier visits to the emergency department because of “abdominal colic” or a chronic pain syndrome. It can be diagnosed by demonstrating increased δ-aminolevulinic acid and porphobilinogen in the urine.
It is highly unusual when a patient presents comatose with markedly elevated venous ammonia, respiratory alkalosis, and normal anion gap. In the vast majority of cases, these patients can be eventually diagnosed with a heterozygotic form of ornithine transcarbamylase deficiency. (This X-linked disorder in homozygotes is commonly fatal.) Twenty percent of female carriers may become symptomatic. Known triggers are delivery, gastrointestinal bleed, infection, surgical procedure, and antiepileptic medication (e.g., valproate). In these instances, the liver is overwhelmed by excess nitrogen load. Hyperammonemia may lead to cytotoxic brain edema and death if untreated (Box 8.4).79,113,114,115
Box 8.4. Hyperammonemic Coma
Deficiencies of urea cycle enzymes increase serum ammonia. The most common, albeit rare in adults, is X-linked ornithine transcarbamylase (OTC) deficiency, the second enzyme in the urea cycle located in the liver mitochondria matrix (Fig. 8.18). Multiple pathologic mutations of the OTC gene are known. Prior early symptoms could have been present (seizures, migraine, vomiting episodes). Ironically, antiepileptic agents for seizures are known triggers (e.g., valproate). Presentation may be typical in the teenage years, but patients 50–60 years old have been reported.
The diagnosis is confirmed by increased urine levels of orotic acid, particularly after loading with allopurinol treatment in hemodialysis, IV sodium benzoate, and occasionally liver transplantation. An inefficient carnitine reserve may be present in valproate-associated hepatotoxicity, and L-carnitine should be supplied.
The mitochondrial encephalopathies include ME LAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Kearns-Sayre syndrome, and Leigh's disease. Lactic acidosis with increased lactate and pyruvate as well as typical MRI abnormalities (MELAS, cortical T2-weighted hyperintensities in both cerebral hemispheres, with a predilection for the posterior regions and the cerebellum; Leigh, bilateral putaminal lesions) should suggest the diagnosis. Evaluation is very complex and outside the scope of this book. Most recently, confusion and coma have been described as an unusual presentation of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL). Prior migraine and family history of stroke or dementia in combination with profound confluent white matter lesions could suggest the diagnosis. Most reported cases have resolved slowly.116,117All of these causes for coma are exceptional and rarely observed. In many elderly patients, transient stupor or coma remains unexplained.
Figure 8.18 Biochemical interactions causing hyperammonemia.
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